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© Validation in Partnership Ltd.

2007

GUIDANCE DOCUMENT
REFERENCE VERSION

HVAC SYSTEMS AND ENVIRONMENT CONTROL/MONITORING

Document Reference:
Date of Issue: Page:

SGD-110-ENV Rev. 08
14 May 2007 1 of 185

Author: Title: Regulatory Consultant Company: Validation in Partnership Ltd.

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Guidance Document HVAC Systems & Environment Control/Monitoring

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DOCUMENT HISTORY Revision No. 01 02 03 04 05 06 07 08 Date: April 2000 March 2001 May 2002 January 2003 May 2004 August 2005 August 2006 May 2007

ABOUT THE AUTHOR Since 1995, Validation in Partnership has been an entirely independent organisation specialising in the successful management and support of validation and CGMP compliance projects for the life science industries supplying the European and American markets. With our proven in-house project staff and extensive network of vetted quality contract personnel, we pride ourselves on a pragmatic approach that focuses effort on process critical areas to ensure the optimum business solution to any compliance challenge. Supported by the most extensive regulatory database in existence, courtesy of which this guidance document has been compiled, our team and clients are secure in the knowledge they have instant access to up-to-the-minute regulatory fact, and our state of the art automated document generation system ensures the rapid delivery and consistent quality of your protocols and reports. Whatever your requirement, ...
• • • • • • • Managed Validation/Compliance Projects CGMP Compliance Reviews/Audits Complete Site Validation Packages Validation Plans and Master Plans Computer Systems Validation Cleaning Validation SOPs • • • • • • • Skilled and Vetted Contract Personnel Gap Analysis and Remedial Action Plans Validation Policies DQ, IQ, OQ, PQ Process Validation CGMP Compliance Training Complete CGMP Compliance Assistance

… and whatever your industry sector …
• • • • Finished Pharmaceuticals Active Pharmaceutical Ingredients Medical Devices Equipment Manufacture • • • • Biotechnology Veterinary Products Cosmetics Engineering Design and Construction

… ViP is your perfect compliance partner.

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TABLE OF CONTENTS DOCUMENT HISTORY.................................................................................................................................................2 ABOUT THE AUTHOR..................................................................................................................................................2 1. 2. 3. 4. 5. 6. 7. AUTHOR’S NOTE .................................................................................................................................................4 PURPOSE..............................................................................................................................................................4 SCOPE ...................................................................................................................................................................4 INTRODUCTION ...................................................................................................................................................4 DESIGN GUIDANCE.............................................................................................................................................5 GLOSSARY ...........................................................................................................................................................5 ENVIRONMENT CONTROL REGULATORY GUIDANCE.............................................................................. 10
7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 HVAC System Design Considerations ......................................................................................................................10 Air Cleanliness Specification......................................................................................................................................62 Drawings .....................................................................................................................................................................79 Filtration ......................................................................................................................................................................81 Air Flow .......................................................................................................................................................................92 Air Velocity ................................................................................................................................................................101 Pressure Difference..................................................................................................................................................103 Temperature and Humidity.......................................................................................................................................110 Training .....................................................................................................................................................................111 Calibration and Maintenance ...................................................................................................................................114 Change Control ........................................................................................................................................................119

8.

ENVIRONMENT MONITORING REGULATORY GUIDANCE...................................................................... 121
8.1 8.2 8.3 General .....................................................................................................................................................................121 Physical.....................................................................................................................................................................144 Microbiological ..........................................................................................................................................................152

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VIP CONTACT DETAILS ................................................................................................................................. 185

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1.

AUTHOR’S NOTE This guidance document is one in a series produced by Validation in Partnership Limited to assist personnel in the life science industries in obtaining the regulatory perspective surrounding specific aspects of their work. We have long recognised that one of the issues in our industry is not that we do not possess sufficient regulatory guidance on specific topics, but that we possess too much, albeit in the wrong format to support its efficient use. Mountains of guidance documents, directives, warning letters and establishment inspection reports cover a multitude of topics in a multitude of formats. In creating this guidance document, we have used our regulatory database, the most extensive and searchable in existence, to extract individual statements from over 900 regulatory documents and compile them under logical headings to present them in a more usable form. The end product is not intended to steer the reader through the process of developing HVAC (Heating, Ventilation, Air Conditioning) and Environmental Monitoring procedures or validation packages, but simply to highlight the regulatory points he or she will need to consider along the way. Indeed, there are certain points, FDA 483 inspectional observations and warning letter extracts within the guide, with which the author does not concur. However, since each one has been derived from a regulatory information source, they have been included for consideration. It is for this reason that each regulatory point has been provided with sufficient source reference to enable the reader to further investigate any point of contention in the context, in which the statement was made. We hope you find it useful.

2.

PURPOSE To provide the regulatory perspective on the development of HVAC and Environmental Monitoring procedures and validation packages to meet the requirements of both the American (references shown in blue) and European (references shown in red) regulatory bodies.

3.

SCOPE This guidance is applicable to the HVAC and environment control and monitoring systems serving facilities used in the manufacture of healthcare products for the US and European markets. Please note: This guidance document does not include references associated with the monitoring of storage or distribution environmental conditions, unless they specifically refer to HVAC systems. Storage and distribution environmental condition references are included in our ‘Storage and Distribution Environment Validation’ guidance document, which also includes regulatory considerations for Cold Chain.

4.

INTRODUCTION HVAC systems play a key role in the manufacture of healthcare products, by providing specific process environmental conditions or simply maintaining operator comfort. Demonstration of compliance with a registered process may require the monitoring and recording of the environment provided by the HVAC systems, and environment validation provides the necessary documented evidence that the HVAC system is consistently capable of providing the design conditions. This eighth revision of the guidance document has been compiled from a detailed review of: • over 900 regulatory texts • over 20,000 regulatory records

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• over 4,200 warning letter extracts • over 3,100 FDA 483 observations The end product comprises nearly 850 points for consideration when developing procedures and protocols associated with environment validation. For ease of reference, the points are collated under logical headings and sub-headings, although it is appreciated that the grouping of the points is subjective. The term "points for consideration" should be emphasised, as the document is intended to form a series of regulatory prompts rather than a definitive list of word for word requirements. Each paragraph within the guide is supported by one or more regulatory references. American references are shown in blue, European references are shown in red and references applicable to both regulatory bodies are shown in green. There are also some references shown in purple, which are from Health Canada. Although this guide incorporates the latest annexes to the EU Guide to Good Manufacturing Practice, Eudralex Volume 4, the author has chosen to include a number of extracts from selected superseded documents (marked SUPERSEDED!) alongside those from the latest versions. The author believes that the earlier texts contain a number of useful prompts that have been omitted from the latest documents. Notes: • The references compiled under each of the headings in sections 7 and 8 are not intended to be a definitive listing of all regulatory points relevant to the topic. There may well be additional references scattered throughout this document which are also deemed to be relevant. • In the interest of brevity, references covering more than one topic are not repeated under each relevant topic, although there are exceptions, for the purpose of emphasis. • References containing information relating to both physical and microbiological elements of environmental monitoring are located under the ‘General’ heading in the ‘Environmental Monitoring’ section. • Where text is followed or preceded by three dots ( … ), this indicates that there is additional text in the original document, which has been omitted from this guide because it has no relevance to the subject matter.

5.

DESIGN GUIDANCE Detailed guidance on the design of HVAC systems is presented in Volumes 2 and 3 of the ISPE Baseline Guides for Oral Solid Dosage Forms (First edition, February 1998) and Sterile Manufacturing Facilities (First edition, January 1999) respectively. The scope of the Baseline Guides is restricted to the design, construction and operation of HVAC systems, and is intended primarily for regulatory compliance for the domestic United States (US) market. The baseline guides have been organised to assist in a logical decision process to determine the type of system required and the system design needed to provide it.

6.

GLOSSARY The following are definitions/explanations of some of the terms used in this document, together with their sources (they may have different meanings in other contexts): 1. Air lock - An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g. of differing class of cleanliness, for the purpose of controlling the air-flow between those rooms when they need to be entered.

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide. They may have different meanings in other contexts. Air lock [VIP ID: 187200] “An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g. of differing class of cleanliness, for the purpose of controlling the air-flow between those rooms when they need to be entered. An air-lock is designed for and used by either people or goods.”

2.

Action Level - An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Action Level [VIP ID: 112320] “Action Level - An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.”

3.

Alert Level - An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Alert Level [VIP ID: 112310] “Alert Level - An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem. Alert levels are always lower than action levels.”

4.

Alert Limits - Established microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 3. DEFINITIONS Alert limits (environmental monitoring): [VIP ID: 188808] “Alert limits (environmental monitoring): Established microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.”

5.

Aseptic techniques and manipulations - The manipulation of sterile materials in such a way as to minimise the risk of microbiological contamination from the environment.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5. DEFINITIONS/GLOSSARY 5.4. Aseptic techniques and manipulations [VIP ID: 190436] “Aseptic techniques and manipulations: The manipulation of sterile materials in such a way as to minimize the risk of microbiological contamination from the environment. These techniques usually involve eliminating surface to surface contacts (except between sterile surfaces) minimizing the area exposed and the duration of exposure.”

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide. : SGD-110-ENV Rev. the existence of airlocks and/or sterilises for the exit of materials and secure operating procedures.Doc. constructed and used in such a way as to reduce the introduction. Note: The different degrees of environmental control are defined in the Supplementary Guidelines for the Manufacture of sterile medicinal products.An area with defined environmental control of particulate and microbial contamination. constructed and used in such a way as to reduce the introduction.” © Validation in Partnership Ltd 2007 . Containment [VIP ID: 187226] “The action of confining a biological agent or other entity within a defined space. Containment: The action of confining a biological agent or other entity within a defined space. Clean Area .” 7. Clean area [VIP ID: 187222] “An area with defined environmental control of particulate and microbial contamination. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 7 of 185 : 14 May 2007 6. It involves the use of rooms with specially designed air handling. In many cases it may add to the effectiveness of primary containment. … Secondary containment: A system of containment which prevents the escape of a biological agent into the external environment or into other working areas. Ref. generation and retention of contaminants within the area. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 3. 08 Author : Validation in Partnership Ltd. They may have different meanings in other contexts. In many cases it may add to the effectiveness of primary containment. It involves the use of rooms with specially designed air handling. They may have different meanings in other contexts. DEFINITIONS Environmental monitoring programme: [VIP ID: 188818] “Environmental monitoring programme: Defined documented programme which describes the routine particulate and microbiological monitoring of processing and manufacturing areas. … Secondary containment: A system of containment which prevents the escape of a biological agent into the external environment or into other working areas.Defined documented programme which describes the routine particulate and microbiological monitoring of processing and manufacturing areas. and includes a corrective action plan when action levels are exceeded. and includes a corrective action plan when action levels are exceeded. the existence of airlocks and/or sterilises for the exit of materials and secure operating procedures. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide.” 8. generation and retention of contaminants within the area. Environmental Monitoring Programme .

PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide.g.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY HEPA filter [VIP ID: 112540] “HEPA filter . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 8 of 185 : 14 May 2007 9. HEPA Filter . 08 Author : Validation in Partnership Ltd. containers.High efficiency particulate air filter. Buildings and Facilities A.A critical area is one in which the sterilised drug product.5. product components or product contact surfaces are exposed to the environment.” 10. Ref.97 percent. containers.Doc.3 µm particle retaining efficiency of 99.High efficiency particulate air filter with minimum 0. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Controlled Area . Critical Area . Critical zone [VIP ID: 190438] “Critical zone: Zone within the Aseptic Processing Area where sterile product. Controlled area [VIP ID: 187230] “An area constructed and operated in such a manner that some attempt is made to control the introduction of potential contamination (an air supply approximating to grade D may be appropriate).42(c)(10)). They may have different meanings in other contexts.” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 3. the area should be maintained at a pressure negative to the immediate external environment and allow for the efficient removal of small quantities of airborne contaminants. DEFINITIONS/GLOSSARY 5. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . and closures are exposed to environmental conditions that must be designed to maintain product sterility (§ 211.An area constructed and operated in such a manner that some attempt is made to control the introduction of potential contamination and the consequences of accidental release of living organisms. Critical Zone . and the consequences of accidental release of living organisms. DEFINITIONS High efficiency particulate air (HEPA) filter: [VIP ID: 188822] “High efficiency particulate air (HEPA) filter: Retentive matrix designed to remove a defined percentage of particulate matter of a defined size. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5.” 11. : SGD-110-ENV Rev. and closures are exposed to environmental conditions that must be designed to maintain product sterility. sterile ingredient additions) of sterile materials prior to and during filling and closing operations. aseptic connections.Class 100 (ISO5) (para 1) [VIP ID: 110180] “A critical area is one in which the sterilized drug product. Critical Area ..Zone within the Aseptic Processing Area where sterile product.” 12. The level of control exercised should reflect the nature of the organism employed in the process.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. product components or product contact surfaces are exposed to the environment.” © Validation in Partnership Ltd 2007 . At a minimum. Activities conducted in such areas include manipulations (e.

sterilization processes.2. HVAC .Heating. ventilation. the following definitions apply: 5. ventilation. or environmental monitoring.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Laminar flow [VIP ID: 112580] “Laminar flow . sporicidal processes (usually by gassing) and prevention of recontamination from the external environment.” 14. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 5. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 9 of 185 : 14 May 2007 13. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .3 [VIP ID: 190224] “negative controls: Refers to the sterility test controls that may be used to identify a "false positive" test result.For the purposes of this document. and air conditioning. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5.An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector. Growth in the media sterility test.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY HVAC [VIP ID: 112550] “HVAC .Doc.” © Validation in Partnership Ltd 2007 . Laminar Flow . or negative product controls may contribute to the verification of a "false positive" test finding and an invalid test result. DEFINITIONS . DEFINITIONS/GLOSSARY 5. Control is achieved by the use of microbiologically retentive filters. air conditioning. Negative Controls . Industrial isolators used for aseptic processing [VIP ID: 190432] “Industrial isolators used for aseptic processing: Industrial isolators used for aseptic processing are isolators in which the internal space and exposed surfaces are microbiologically controlled. : SGD-110-ENV Rev. Industrial isolators used for aseptic processing .” 16.” 15.Refers to the sterility test controls that may be used to identify a "false positive" test result. 08 Author : Validation in Partnership Ltd. Ref.Industrial isolators used for aseptic processing are isolators in which the internal space and exposed surfaces are microbiologically controlled.An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector.Heating.

Ultra-low penetration air filter with minimum 0. the use of open versus closed equipment and clean rooms versus isolator technologies. ENVIRONMENT CONTROL REGULATORY GUIDANCE 7.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Unidirectional flow [VIP ID: 112650] “Unidirectional flow . Unidirectional Flow . : SGD-110-ENV Rev.3 µm particle retaining efficiency of 99. and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area. in a robust and uniform manner. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .” 19. © Validation in Partnership Ltd 2007 . in a robust and uniform manner.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY ULPA filter [VIP ID: 112670] “ULPA filter .An isolator is an arrangement of physical barriers that are integrated to the extent that the isolator can be sealed in order to carry out a routine leak test based on pressure to meet specified limits. which is separated from the surrounding environment. the minimisation of contamination. Equipment and Utilities Design of facility/equipment [VIP ID: 191166] “To determine appropriate zones when designing buildings and facilities. Manipulations can be carried out within the space from the outside without compromising its integrity.” 7.” 18. Factors to be considered in the design of a facility should include the flow of material and personnel.Doc. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 10 of 185 : 14 May 2007 17. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5. Pharmaceutical Isolator .Ultra-low penetration air filter with minimum 0. ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9 (November 2005) Annex II: Potential Applications for Quality Risk Management II.4 Quality Risk Management for Facilities..g.1.An airflow moving in a single direction. ULPA Filter .1 HVAC System Design Considerations 7. Pharmaceutical Isolator [VIP ID: 190430] “Pharmaceutical Isolator: An isolator is an arrangement of physical barriers that are integrated to the extent that the isolator can be sealed in order to carry out a routine leak test based on pressure to meet specified limits. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Manipulations can be carried out within the space from the outside without compromising its integrity. Internally it provides a workspace.999 percent. Internally it provides a workspace.1 General 1.999 percent. flow of material and personnel. Ref. which is separated from the surrounding environment.An airflow moving in a single direction. the necessity for dedicated or segregated facilities or equipment and the need for utilities such as HVAC systems.3 µm particle retaining efficiency of 99. and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area. DEFINITIONS/GLOSSARY 5.1. e. 08 Author : Validation in Partnership Ltd.

. clean rooms versus isolator technologies. dedicated or segregated facilities/equipment. dedicated or segregated facilities/equipment. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 11 of 185 : 14 May 2007 - minimize contamination. Finally. Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 1 [VIP ID: 194656] “Failure to establish defined areas or such other control systems to prevent contamination or mix-ups for handling and/or manufacturing potent compounds. … To determine appropriate utilities (e. particularly in areas where product is exposed. your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potent compounds (e.g. The ventilation system shall be arranged so as to prevent the dissemination of microorganisms from one manufacturing area to another and to avoid other conditions unfavorable to the safety of the product. and care. formulation of batches in open equipment. Precautions shall be taken to exclude extraneous infectious agents from manufacturing areas. … heating. Facilities should be designed to provide the necessary segregation and protection. Furthermore. operators de-gowned after handling potent compounds in an unclassified corridor between the manufacturing area and the packaging area. sterile operations are conducted. Your firm lacked documentation to determine sources of potential airborne transfer.BIOLOGICAL PRODUCTS: GENERAL (April 2006) Subpart B--Establishment Standards Sec. Work rooms shall be well lighted and ventilated. Due to the above factors. Precautions shall be taken to avoid clogging and back-siphonage of drainage systems. prevention of mix-ups. © Validation in Partnership Ltd 2007 .42(c)] For example.000) where operators move throughout the parenteral manufacturing areas. Specifically. to minimise the risk of contamination and cross-contamination and to ensure the appropriate air quality is maintained. 08 Author : Validation in Partnership Ltd.4 Quality Risk Management for Facilities. shall be adequate to meet manufacturing needs and such rooms shall be constructed and equipped to permit thorough cleaning and to keep air-borne contaminants at a minimum. and other rooms where open. open versus closed equipment. [21 CFR § 211. cytotoxic and hormone products. dust.. potent active pharmaceutical ingredients (APIs) were introduced into the manufacturing environment during sampling of APIs.Doc. clean rooms versus isolator technologies. (a) [VIP ID: 1850] “Work areas.” 21 CFR PART 600 .11 Physical establishment. vermin and objects not required for manufacturing. and lyophilization of solutions into partially stoppered vials. physical and environmental. : SGD-110-ENV Rev. …” 2. Filling rooms. and free of dirt. … open versus closed equipment. Controls necessary to prevent cross-contamination of products were not adequately defined. both physically and microbiologically. All rooms and work areas where products are manufactured or stored shall be kept orderly. possible migration of levels of potent compounds may have occurred at your manufacturing facility.. Ref. mechanical transfer.g. 600.000) exhausted directly into the entry room (Class 100. including the aseptic filling room. aseptic filling of solutions into open vials. Equipment and Utilities Design of facility/equipment [VIP ID: 191166] “To determine appropriate zones when designing buildings and facilities. animals.g. as well as other products of high pharmacologic activity) at your facility. for the operations being performed. …). pest control measures. Your firm utilized a single air pathway for manufacturing different potent compounds. ventilation and air conditioning (HVAC). flow of material and personnel. and/or mix-up in the manufacturing and handling of these potent compounds. e. equipment. your firm's potent compound formulation room (Class 10..” ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9 (November 2005) Annex II: Potential Applications for Quality Risk Management II. minimize contamination.. clean.

FACILITIES AND EQUIPMENT B.15 [VIP ID: 24835] “Appropriate equipment and environmental controls should be used to minimize the risk of contamination.. Ref.Doc. filter and vial) for sterile filtration of the PET drug product. : SGD-110-ENV Rev. selection of stainless steel grade. power source.” GUIDANCE PET DRUG PRODUCTS . and the prevention of contamination of equipment or product by substances. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open.” GUIDANCE PET DRUG PRODUCTS . These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure. water).” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18.1 General 18.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4.g. or environmental conditions.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. where appropriate. ventilation and air conditioning (HVAC). FACILITIES AND EQUIPMENT A. personnel. needle.g. heating. or contained systems).21 [VIP ID: 24540] “Adequate ventilation. closed. dust. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 12 of 185 : 14 May 2007 To determine appropriate product contact materials for equipment and containers (e. Items within a laminar airflow aseptic workstation are kept to a minimum and not interrupt the airflow.g. To determine appropriate utilities (e. compressed air. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.2 Utilities 4.g. the prevention of mix-ups. and temperature. and sterility testing of the finished PET drug product. steam. humidity. Aseptic Processing Area para 1 [VIP ID: 187390] “An aseptic work area should be suitable for the assembly of the aseptic components required for the preparation of a sterile PET drug product. a LAFW or barrier isolator). inventory of necessary spare parts). as appropriate to the stage of manufacture.. …” © Validation in Partnership Ltd 2007 . gaskets. We recommend that the following precautions be taken to help maintain the appropriate air quality of the aseptic workstation: The aseptic workstation is sanitized before each operation.. Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation (e. lubricants). Facilities 2..30(a) would require that a PET production facility have adequate facilities to ensure the orderly handling of materials and equipment. We recommend that air quality in the aseptic processing area be controlled to limit the presence of microorganisms and particulate matter. Examples of such activities include the aseptic assembly of sterile components (syringe. 08 Author : Validation in Partnership Ltd. To determine appropriate preventive maintenance for associated equipment (e. BUILDINGS AND FACILITIES 4. Particular attention should be given to areas where APIs are exposed to the environment. air filtration and exhaust systems should be provided. microorganisms (if appropriate).CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. gases. Regulatory Requirements para 1 [VIP ID: 187374] “Proposed 21 CFR 212.

our inspection revealed that the HVAC system is not designed to maintain a "Class 100" or ISO "Class 5" environment within the manufacturing area used for ophthalmic drug products.70(c). In addition. A review of Filling Room temperature records revealed several instances where the temperature range limits (on the form) were exceeded. and products exposed." ….” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Ref.” FDA Warning Letter SJN-05-02 (December 2004) Extracted from FDA warning letter SJN-05-02 Puerto Rico 20/12/2004 [VIP ID: 133500] “… You stated during the inspection of your firm that the aseptic area was classified as a Class 100 (ISO Class 5) clean room. the air supplied to the manufacturing area has not been filtered through highefficiency particulate air (HEPA) filters.42(c)(10)]. …” FDA Warning Letter SEA 05-16 (March 2005) Extracted from FDA warning letter SEA 05-16 USA 17/03/2005 [VIP ID: 135300] “3. You have also not established any written procedures for environmental monitoring that specifically address issues such as sample location. interpretation of results. 08 Author : Validation in Partnership Ltd. and there is no control of room pressurization to ensure that the manufacturing area will maintain significant positive pressure relative to the adjacent rooms within your facility. humidity. The areas immediately adjacent to the aseptic processing area. …You have failed to establish formal parameters for temperature. Also. components. and pressure. separate or defined areas of operation in an aseptic processing facility should be appropriately controlled to attain different degrees of air quality depending on the nature of the operation. "Additionally. For example: d. our inspection disclosed that you perform environmental monitoring only on a semi-annual basis. sample frequency. The investigator noted that the room adjacent to the aseptic area is an unclassified area utilized by ungowned personnel performing 'prescription data entry. as required by 21 CFR 820. Appropriate procedures were not followed for controlling environmental conditions. Further. as well as the operational activities conducted in the area. and corrective actions in the event of failures. Specifically. as required by 21 CFR 820. your firm did not have an established procedure to control environmental conditions of the white area during power outages. at a minimum. Failure to establish and maintain procedures to adequately control environmental conditions. Design of a given area involves satisfying microbiological and particle criteria as defined by the equipment. sample size. there is no control of room pressurization to ensure that the aseptic area will maintain significant positive pressure relative to the unclassified area when employees enter/exit the aseptic area. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 13 of 185 : 14 May 2007 Extracted from FDA Warning Letter 05-ATL-21 (August 2005) USA 11/08/2005 [VIP ID: 171010] “2.70(c) [FDA 483. should meet Class 10. analytical techniques. The 'drop ceiling' in the unclassified area extends over the partition into the aseptic area. Your firm failed to establish and maintain procedures to adequately control environmental conditions which could reasonably be expected to have an adverse effect on product quality. your firm did not monitor the partial pressure differential and/or airflow between the 'white area' and the uncontrolled areas as described in procedure [redacted]. the wall separating the two areas is only a drywall partition that does not extend to the structural ceiling of the room.” FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 134980] “1. Finally.000 (ISO 7) standards under dynamic conditions.' The only entrance into the aseptic area is through a door in the unclassified room.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV Buildings and Facilities (para 1) [VIP ID: 110130] “As provided for in the regulations. Item 4]. During the power outage. sampling technique. our Investigator observed loss of power to the 'white area' during the establishment inspection.” © Validation in Partnership Ltd 2007 . Thus.Doc. : SGD-110-ENV Rev. Failure to have control systems for your firm's operations necessary to prevent contamination of drug product during aseptic processing [21 CFR 211.

004 2.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.02. Regarding the latter. and designing equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5) clean area are essential to achieving high assurance of sterility (Ref. : SGD-110-ENV Rev. or single pass air. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 14 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . 4). utensils) as it transfers from lesser to higher classified clean areas to prevent the influx of contaminants.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Airlocks and interlocking doors will facilitate better control of air balance throughout the aseptic processing facility. Use of a double-door or integrated sterilizer helps ensure direct product flow. The layout of equipment should provide for ergonomics that optimize comfort and movement of operators. often from a lower to a higher classified area. should be minimized.” CPGM-DB CHAPTER 56 . Design (para 2) [VIP ID: 110440] “Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation.” HEALTH CANADA . or an isolator. in-process supplies..1 PREMISES . The number of personnel in an aseptic processing room should be minimized. container-closures. Inspection 9. movement adjacent to the critical area should be appropriately restricted. Buildings .C. should be used in post-viral inactivation areas and the aseptic core. Buildings and Facilities E.1 [VIP ID: 65590] “ARE FIRMS REQUIRED TO USE HEPA FILTERS IN THE MANUFACTURE OF NON-STERILE DOSAGE FORMS? The GMP regulations do not specifically require manufacturing facilities for non-sterile drugs to maintain highefficiency particulate air (HEPA) filtered air. Buildings and Facilities E. Positive pressures should be maintained in downstream processing areas and the aseptic core. The flow of personnel should be designed to limit the frequency with which entries and exits are made to and from an aseptic processing room and. its critical area.1. GMP b. optimizing process flow.GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2. In this regard. providing the highest possible environmental control.iv.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. © Validation in Partnership Ltd 2007 . or the surrounding environment. materials should be disinfected according to appropriate procedures or. it is essential to carefully define and control the dynamic interactions permitted between cleanrooms.Inspectional B. For example. Negative pressures may be maintained during upstream processing to provide containment.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III . Other interfaces such as personnel transitions or material staging areas are appropriate locations for air locks. rendered sterile by a suitable method. the number of transfers into the critical area of a traditional cleanroom. To prevent changes in air currents that introduce lower quality air.g.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2. Ref. 08 Author : Validation in Partnership Ltd. Separate air handling units. equipment. when used in critical areas. Design (para 3) [VIP ID: 110450] “Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product. written procedures should address how materials are to be introduced into the aseptic processing room to ensure that room conditions remain uncompromised. Design (para 7) [VIP ID: 110490] “Due to the interdependence of the various rooms that make up an aseptic processing facility. HVAC systems (para 1) [VIP ID: 77680] “The HVAC system should be designed to provide containment or product protection when and where necessary. most significant.DRUG QUALITY ASSURANCE 7356. Buildings and Facilities E.Doc. It is critical to adequately control material (e. Airlocks should be installed between the aseptic manufacturing area entrance and the adjoining unclassified area. Limiting the duration of exposure of sterile product elements.

where appropriate. : SGD-110-ENV Rev. humidity and temperature. …” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. even in small quantities. as required by 21 CFR 211. microorganisms (if appropriate).46 describes ventilation control procedures in more detail. as appropriate. micro-organisms. Particular attention should be given to areas where APIs are exposed to the environment. or such other control systems as are necessary to prevent contamination during the course of aseptic processing operations.2 Utilities 4. In areas where air contamination occurs during production. dust.Doc.21 [VIP ID: 153720] “Adequate ventilation. humidity. 211. Examples of 21 CFR. Example 7: 606. and the key phrase is "when appropriate".” FDA Warning Letter 2002-DT-21 (January 2002) Extracted from FDA warning letter 2002-DT-21 USA 30/01/2002 4 [VIP ID: 48290] “4) Failure to have separate or defined areas. shall be used when appropriate on air supplies to production areas. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 15 of 185 : 14 May 2007 The Regulations do require the use of equipment for adequate control over air pressure. These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure. this section calls for use of air filtration systems. 08 Author : Validation in Partnership Ltd.46 (b) Equipment for adequate control over air pressure. and temperature. If air is recirculated to production areas. dust. could pose a significant health hazard when carried over into other products. microorganisms. packing. or holding of a drug product. BUILDINGS AND FACILITIES 4. Parts 210 through 211 and Parts 600 through 680 Supplementing Each Other. processing.42(c)(10). These provisions speak of measures to prevent cross contamination. as appropriate to the stage of manufacture.40(b) describes requirements for adequate ventilation. Despite the lack of an explicit GMP requirement. In addition. (c) Air filtration systems. dust. measures shall be taken to control recirculation of dust from production. CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICAL (INCLUDES BLOOD AND BLOOD COMPONENTS) 211. some firms may elect to use HEPA filtered air systems as part of their dust control procedures. when appropriate. there shall be adequate exhaust systems or other systems adequate to control contaminants. The aseptic manufacturing area interfaces directly with an unclassified packaging area at the exit end for the filled. For example: a. including prefilters and particulate matter air filters on air supplies to production areas. humidity and temperature shall be provided when appropriate for the manufacture. Ref.” GUIDELINE FOR QUALITY ASSURANCE IN BLOOD ESTABLISHMENTS (July 1995) APPENDICES Appendix A. including prefilters and particulate matter air filters. air filtration and exhaust systems should be provided. For example. capped vials. firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that.40(b) [VIP ID: 184080] “[The guidance document displays the following information in tabular form] CURRENT GOOD MANUFACTURING PRACTICE SPECIFIC FOR BLOOD AND BLOOD COMPONENTS 606. …” © Validation in Partnership Ltd 2007 .

” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . As far as possible. For example.PREMISES AND EQUIPMENT Premises . Design (para 11) [VIP ID: 110530] “Equipment should be appropriately designed (§ 211. reduce. GMP b. Cleanrooms and cleanroon equipment should be designed and constructed to ensure ease of cleaning and sanitisation. and ceilings should be constructed of smooth.Doc. for maintenance purposes.10. fixtures. Cleanrooms also should not contain unnecessary equipment. It is also important to ensure ease of installation to facilitate aseptic setup. [VIP ID: 368] “Pipework.Are appropriately constructed to prevent. As far as possible. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES . they should be accessible from outside the manufacturing areas. for maintenance purposes. Equipment should not obstruct airflow and. Ceilings and associated HEPA filter banks should be designed to protect sterile materials from contamination. walls. Buildings (para 5) [VIP ID: 77570] “Make certain that buildings: .Production Area 3. or materials. Floors.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. they should be accessible from outside the manufacturing areas. The effect of equipment design on the cleanroom environment should be addressed. The materials of construction of cleanrooms ensure ease of cleaning and sanitizing.Inspectional B. light fittings. ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean.10 [VIP ID: 185572] “Pipe work.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Horizontal surfaces or ledges that accumulate particles should be avoided. areas where particles can collect should be avoided.” CPGM-DB CHAPTER 56 . hard surfaces that can be easily cleaned. Inspection 9.DRUG QUALITY ASSURANCE 7356.Production Area 3. : SGD-110-ENV Rev. and control potential contaminants and support the environmental control program …” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 .63) to facilitate ease of sterilization. Ref. Examples of adequate design features include seamless and rounded floor to wall junctions as well as readily accessible corners. Buildings and Facilities E.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III . its design should not disturb unidirectional airflow. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 16 of 185 : 14 May 2007 3.” © Validation in Partnership Ltd 2007 . Design (para 9) [VIP ID: 110510] “Cleanrooms are normally designed as functional units with specific purposes. light fittings. Buildings and Facilities E. in critical areas. 08 Author : Validation in Partnership Ltd.

General 3.16 [VIP ID: 185060] “When assessing the suitability of a mobile site.3. humidity and ventilation should be appropriate and such that they do not adversely affect.” PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. directly or indirectly. either the medicinal products during their manufacture and storage. Lighting. Ref. consideration should be given to areas such as ventilation. the starting material (incl. softgoods) or the accurate functioning of equipment (GMP 3. humidity and ventilation should be appropriate and such that they do not adversely affect. humidity and ventilation should be appropriate and such that they do not adversely affect. Storage areas should be clean. or the accurate functioning of equipment. : SGD-110-ENV Rev. either the medicinal products during their manufacture and storage. Gas cylinders should be stored under cover and not be subjected to extremes of temperature. [VIP ID: 361] “Lighting.General 3. PREMISES Mobile sites 7. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 6 .2 [VIP ID: 186558] “Gas cylinders should be stored under cover and not be subjected to extremes of temperature.” PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7.Doc. dry. directly or indirectly. hand-washing facilities. well ventilated and free of combustible materials to ensure that cylinders remain clean up to the time of use. directly or indirectly. either the product. humidity and ventilation should be appropriate and such that they do not adversely affect. directly or indirectly.PREMISES AND EQUIPMENT Premises . PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES .” 5. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 17 of 185 : 14 May 2007 4. temperature.).3 [VIP ID: 185558] “Lighting. temperature. STORAGE AND RELEASE 7.2 PREMISES AND HYGIENE Principle: [VIP ID: 189254] “… Lighting. dry. donor interview facilities and blood storage. lighting. reliable communication to the central site. either the medicinal products during their manufacture and storage. or the accurate functioning of equipment.MANUFACTURE OF MEDICINAL GASES 7.” © Validation in Partnership Ltd 2007 .3. Storage areas should be clean. or the accurate functioning of equipment. 08 Author : Validation in Partnership Ltd. temperature. electrical supply. …” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 . well ventilated and free of combustible materials to ensure that cylinders remain clean up to the time of use. temperature.

7 [ViP ID: 185042] “Premises for the preparation of blood components should be situated. EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 .” 7.. well ventilated and free of combustible materials to ensure that cylinders remain clean up to the time of use. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .. .. equipped and ventilated in a suitable way and used entirely for this purpose. Premises for the preparation of blood components should be situated. Storage areas should be clean. PREMISES Production areas 7. the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level.2. and minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air.. the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level. [VIP ID: 23310] “Gas cylinders should be stored under cover and not be subjected to extremes of temperature. Cross-contamination should be avoided by appropriate technical or organisational measures. Ref. Storage and release 7.” 8. After sterilisation.PRODUCTION Prevention of cross-contamination in production 5. such as appropriate air locks and air extraction. [VIP ID: 63770] “After sterilisation.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Sterilization with ethylene oxide 81.Doc. for example: … (b) providing appropriate air-locks and air extraction.MANUFACTURE OF STERILE MEDICINAL PRODUCTS STERILISATION WITH ETHYLENE OXIDE 81 [VIP ID: 186160] “After sterilisation. equipped and ventilated in a suitable way and used entirely for this purpose. .MANUFACTURE OF STERILE MEDICINAL PRODUCTS STERILISATION WITH ETHYLENE OXIDE 81 [VIP ID: 186160] “After sterilisation.MANUFACTURE OF MEDICINAL GASES (September 2001) 7.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . This process should be validated. a load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level. the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level.” PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. [VIP ID: 529] “Cross-contamination should be avoided by appropriate technical or organisational measures. : SGD-110-ENV Rev.19. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . (c) minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air: …” © Validation in Partnership Ltd 2007 . 08 Author : Validation in Partnership Ltd.” 6. dry. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 18 of 185 : 14 May 2007 EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 06 .

it is a common practice to recycle a portion of the exhaust air back into the same area. especially if several products are processed simultaneously. the extent of filtration of the supply air (combined fresh make-up air and recycled air) is not a problem (although other regulatory agencies or company policy may impose restrictions) except when the closed system must be opened (charging). Equipment passes should normally be ventilated in the same way. The final stage of the changing room should.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . In multi-use areas where several products are completely confined in closed vessels and piping systems.MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 28 [VIP ID: 186054] “Both airlock doors should not be opened simultaneously. For dedicated areas processing the same BPC. Changing rooms should be supplied with air filtered to the same standard as that for the work area. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. 08 Author : Validation in Partnership Ltd. : SGD-110-ENV Rev. Ref. The final stage of the changing room should. the firm should be able to demonstrate adequacy of their air handling system with data and (in case of doubt) the investigator should consider collection of product samples for analysis for cross-contamination. and extracts to produce an adequate air circulation independent of that of the work area. filter efficiencies on the supply air system as low as 85% may be perfectly adequate. in the "at rest" state.Doc.” 9. In general hand washing facilities should be provided only in the first stage of the changing rooms. For economic reasons. In those areas wherein one or more of the products is being processed in a dry form. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . may be acceptable. Changing rooms should be designed as air locks. or those equipped with supply air only. in the ‘at rest’ state. be the same grade as the area into which it leads. even total filtration of the entire supply air flow with HEPA filters may not be adequate. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time. They should be flushed effectively with filtered air. be the same grade as the area into which it leads. They should be flushed effectively with filtered air. this is not objectionable. but unventilated passes.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . In those areas where the BPCs are in a damp or moistened form (such as filter or centrifuge cake) and may be exposed to the room air environment. In all cases.SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Buildings and Facilities (a) Contamination/Cross Contamination (para 5) [VIP ID: 3421] “Air handling systems for BPC plants should be designed to prevent cross-contamination.” © Validation in Partnership Ltd 2007 . which should not be opened simultaneously and used to provide physical separation of the different stages of changing to minimise microbial and particulate contamination of protective clothing.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 12 [VIP ID: 186352] “Equipment passes and changing rooms should have an interlock mechanism or other appropriate system to prevent the opening of more than one door at a time. The adequacy of such a system of operation for multi-use areas.MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 27 [VIP ID: 186052] “Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. should be carefully analyzed. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 19 of 185 : 14 May 2007 GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II .

MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 12. Air being supplied to product exposure areas where sterile drugs are processed and handled should be HEPA filtered under positive pressure.Doc. open processing should be performed in areas that are separate from other processing activities and have separate air handling units.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 28 [VIP ID: 63200] “Both airlock doors should not be opened simultaneously. or those equipped with supply air only.CGMPR'S (October 1993) 1. but unventilated passes. Air being supplied to product exposure areas where sterile drugs are processed and handled should be high efficiency particulate air (HEPA) filtered under positive pressure.5 Viral Removal/Inactivation steps 18. Ref. may be acceptable.” 10. and equipped with air extraction facilities to produce an adequate air circulation independent of that of the work area. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 20 of 185 : 14 May 2007 EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS . Therefore. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time. Air (para 1) [VIP ID: 2666] “Air supplied to the non-sterile preparation or formulation area for manufacturing solutions prior to sterilization should be filtered as necessary to control particulates.52 [VIP ID: 24859] “Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .” © Validation in Partnership Ltd 2007 .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . Air supplied to non sterile preparation or formulation areas for manufacturing solutions prior to sterilisation should be filtered as necessary to control particulates. Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. be the same grade as the area into which it leads. [VIP ID: 1598] “Equipment passes and changing rooms should have an interlock mechanism or other appropriate system to prevent the opening of more than one door at a time. The final stage of the changing room should.” 11. open processing should be performed in areas that are separate from other processing activities and have separate air handling units. : SGD-110-ENV Rev. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18. Therefore. Equipment passes should normally be ventilated in the same way.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 27 (para 1) [VIP ID: 63180] “Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. in the at-rest state. 08 Author : Validation in Partnership Ltd. They should be flushed effectively with filtered air. Changing rooms should be supplied with air filtered to the same standard as that for the work area. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18.

drying and/or tableting operation should be segregated in enclosed areas with its own air handling system. If air is recirculated to production areas. Lack of temperature and humidity controls can affect the quality of the tablet.Doc.5 Viral Removal/Inactivation steps 18. cleaning. Some manufacturers recirculate air without adequate filtration. To prevent cross-contamination. Ref. PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 21 of 185 : 14 May 2007 ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18.11 [VIP ID: 185050] “The preparation of blood components should be carried out in an appropriately controlled environment. : SGD-110-ENV Rev. FACILITIES (para 3) [VIP ID: 3208] “The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage particularly where potent or highly sensitizing drugs are processed. To prevent cross-contamination in the tableting department. humidity. investigate the problem and collect in-line samples (INV) and official samples of the suspect product.” 13.. drying and/or tableting operations should be segregated in enclosed areas with their own air handling system..46 Ventilation. Where air is recirculated.52 [VIP ID: 156640] “Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. and location of equipment.CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -.” 14. Determine what precautions are taken to prevent cross-contamination. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18. 21 CFR PART 211 . 08 Author : Validation in Partnership Ltd. separated from activities. measures shall be taken to control recirculation of dust from production. mixing. and the storage of granulations and tablets. which are not compatible. review the firm's data which demonstrates the efficiency of air filtration such should include surface and/or air sampling.” GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994) II. Air should only be recirculated to production areas if there is adequate filtration installed and data available. to demonstrate the efficiency of the air filtration. including prefilters and particulate matter air filters.CGMPR'S (October 1993) Tablet and Capsule Products (para 3) [VIP ID: 2657] “Tablets and capsules are susceptible to airborne contamination because of the manipulation of large quantities of dry ingredients. granulation. In areas where air contamination occurs during production. GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS . Determine what temperature. and dust collecting controls are used by the firm in manufacturing operations. Therefore. air heating and cooling (c) [ViP ID: 41] “Air filtration systems. separated from activities which are not compatible. shall be used when appropriate on air supplies to production areas. including surface and/or air sampling. air filtration.” 12. PREMISES Environmental Control 7. The preparation of blood components should be carried out in an appropriately controlled environment. open processing should be performed in areas that are separate from other processing activities and have separate air handling units. To prevent cross-contamination.Buildings and Facilities Sec. pay close attention to the maintenance. When cross-contamination is suspect. there shall be adequate exhaust systems or other systems adequate to control contaminants. the mixing. 211. .” © Validation in Partnership Ltd 2007 . granulation.

are categorized as beta-lactam drugs and present a health hazard to consumers with sensitivities to these compounds. doorways.” 16. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 22 of 185 : 14 May 2007 15. Selected FDA 483 Observations (March 2007) Packaging & Labelling [VIP ID: 194406] “Air-handling systems for the packing of penicillin should be completely separate from those for other drug products for human use.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 .” Extracted from FDA warning letter CIN-07-30670-09 (January 2007) Extracted from FDA warning letter CIN-07-30670-09 USA 11-Jan-07 1) [VIP ID: 194702] “Separate or defined areas or other control systems to prevent contamination or mixup are inadequate. and continuous monitoring if necessary.MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (January 1993) Premises and Equipment 14. penicillin drug products must also be separate from other drug products. which repacks human drugs. air handling systems. certain hazardous or toxic drugs. : SGD-110-ENV Rev. Cephalosporin products. the processing of non-penicillin beta-lactam drugs (e. and operations relating to the repacking of penicillin are not performed in facilities separate from those used for nonpenicillin drug products for human use. Consequently. your firm. Air handling units should be specific to the processing area concerned and recirculation of air should not occur from areas handling live pathogenic organisms. cephalosporin) into non-beta-lactam areas. cephalosporin) should be separate from other drug products. personnel.. an overhead door near the maintenance room. Your facility shares a common dock area. There must be separate facilities and completely separate air handling systems for the production of penicillin. 08 Author : Validation in Partnership Ltd. pesticides. Adequate separation should include physical barriers. In addition..Doc. Ref. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 2 . alkaloids. shares a building with a pharmacy that packs beta-lactam antibiotics. do not carry residue from penicillin into non-penicillin areas or non-penicillin beta-lactams (e. The separation should be verified by testing. Pursuant to 21 CFR 211. including penicillins and cephalosporins. in moving about the plant. We recommend a system-based approach that involves a complete separation of every aspect of the repackaging operation. The pharmacy uses the common area to receive beta-lactams.g.g. under 21 CFR 211. and/or starting materials. cephalosporins. like penicillin products. [21 CFR § 211.42(c). chemicals. and equipment with well established written procedures and controls. containment procedures have not been established to assure that employees.42(d).MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE PREMISES AND EQUIPMENT 14 [VIP ID: 186216] “Air handling units should be specific to the processing area concerned and recirculation of air should not occur from areas handling live pathogenic organisms. auditing. either with penicillin drug products or with each other.42(c) and (d)] Specifically. Sufficient controls have not been established to prevent the exposure of cephalosporin drug products and non-beta-lactam drug products to cross-contamination.” © Validation in Partnership Ltd 2007 . cleaning equipment. including non-penicillin beta-lactams. common receiving area. [ViP ID: 1527] “Air filtration units should be specific to the processing area concerned and recirculation of air should not occur from areas handling live pathogenic organisms. and personnel with the pharmacy.

176] Specifically. common receiving area. cleaning equipment. This entails a complete separation of every aspect of the manufacturing operation. 08 Author : Validation in Partnership Ltd. are categorized as beta-lactam drugs and present a health hazard to consumers with sensitivities to these compounds. Adequate separation should include physical barriers. personnel.” 21 CFR PART 211 . air heating and cooling (d) [ViP ID: 42] “Air-handling systems for the manufacture.42(c) and (d). auditing. air handling systems. penicillin and non-penicillin beta-lactam drugs must also be separate from each other. [21 CFR § 211. and an air handling system with a pharmacy that packs beta-lactam antibiotics. and packaging of beta-lactam drugs (e. processing.46(d)] The pharmacy and the repacking operations share a common air handling system.CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -.g.Buildings and Facilities Sec. nor separation between the beta-lactam and non-beta-lactam products. and packing of penicillin shall be completely separate from those for other drug products for human use. Pursuant to 21 CFR 211. like penicillin products. an overhead door near the maintenance room. [21 CFR § 211. and equipment with well established written procedures and controls.42(c) and (d)]. Consequently. and continuous monitoring if necessary.” © Validation in Partnership Ltd 2007 . and packing of penicillin and cephalosporin performed in facilities separate from those used for other drug products for human use [21 CFR 211. under 21 CFR 211. processing. personnel. vents. penicillin products (amoxicillin and penicillin VK) and a cephalosporin product (cephalexin) were repacked using the same equipment and/or in the same production area of your facility as other non-penicillin products. when a reasonable possibility existed that a non-penicillin drug product had been exposed to cross-contamination with penicillin. Your firm shares the building.” FDA Warning Letter FEI:1122528 VL#05200161 (March 2005) Extracted from FDA warning letter FEI:1122528 VL#05200161 USA 15/03/2005 [VIP ID: 135230] “1. including common air returns. The agency has taken the position that all three of those drug products should be separated from each other.Doc..46 Ventilation. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 23 of 185 : 14 May 2007 Extracted from FDA warning letter CIN-07-30670-09 (January 2007) Extracted from FDA warning letter CIN-07-30670-09 USA 11-Jan-07 2) [VIP ID: 194704] “Air-handling systems for the packing of penicillin are not completely separate from those for other drug products for human use. 211. processing. ibuprofen). : SGD-110-ENV Rev. and air sources. a system-based approach towards separation should be taken.. air filtration. doorways.” Extracted from FDA warning letter CIN-07-30670-09 (January 2007) Extracted from FDA warning letter CIN-07-30670-09 USA 11-Jan-07 9) [VIP ID: 194718] “Non-penicillin drug products were not tested for the presence of penicillin. the Agency requires that the manufacture. This air handling system uses nearly 100% recirculated air. In order to reach the goal of no cross contamination. As pointed out in items 1) and 2) above. including penicillins and cephalosporins. your firm has not tested any of the human drug products that have been repacked by your firm for the presence of penicillin. penicillin and cephalosporin) be separate from non-beta-lactam drugs (e. a common dock area. In this case. Failure to have operations performed within specifically defined areas of adequate size as necessary to prevent contamination and to have operations relating to the manufacture.g. your firm does not have separate facilities nor do you have separate air handling systems for handling penicillin products. there is neither separation of the cephalosporin and penicillin drug products repackaging processes. Ref.42(d). For example. The separation should be verified by testing. Cephalosporin products.

such as penicillins or cephalosporins.gov” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. the firm could not verify through blueprints or diagrams that the air handling system for the repackaging of penicillins is separate from the air handling system used for repackaging non-penicillin drug products that is required by 21 CFR 211. Your firm has not established minimal personnel. VOLUME 09. Although CGMPs require separate facilities for the production of penicillin and non-penicillin products.4 Containment 4. HFD-322. [21 CFR 211. In addition. Ref. The purpose of the referenced CGMP regulations is to avoid penicillin cross-contamination of non-penicillin products.Doc. NUMBER 01 (First Quarter. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 24 of 185 : 14 May 2007 FDA Warning Letter FEI:1122528 VL#05200161 (March 2005) Extracted from FDA warning letter FEI:1122528 VL#05200161 USA 15/03/2005 [VIP ID: 135240] “2. 211. In addition. Ibuprofen. dust observed on ducts) through the HVAC air handling system. BUILDINGS AND FACILITIES 4. air filtration. For example. should be employed in the production of highly sensitizing materials. and packing of penicillin from those for other drug products for human use and to have an adequate air filtration system [21 CFR 211. 08 Author : Validation in Partnership Ltd. air-heating cooling.176 Penicillin contamination. and other control systems to prevent crosscontamination.46(d). equipment. they do not require separate laboratories for the testing of penicillin and non-penicillin products.46(d)] The same air handling system is used for the repackaging of penicillin and cephalosporins in violation of 21 CFR 211.42(c) and 211. a single HVAC air handling system fitted with one [redacted] filter at the air intake unit located on the roof top is used to process the air supplied to the area of your facility where penicillin products (amoxicillin and penicillin VK). CGMPs require that there be adequate controls to prevent penicillin cross-contamination of non-penicillin drugs in production areas of the firm. The CGMP regulations also require that the air handling system in such a shared laboratory be separate (not connected) to non-penicillin production areas of the facility.fda. the inspection disclosed that you have not established measures to control recirculation of contaminants (i. (301) 594-2454 e-mail: melendeze@cder. processing. minimal containment controls. However. and non-penicillin products (including but not limited to Methocarbomol. Levaquin. Macrobid) are repacked.46(c) and (d)]. … Contact for further information: Edwin Melendez. : SGD-110-ENV Rev. A shared laboratory can be located within a non-penicillin production facility.42(d) Design and construction features. air handling equipment and/or process equipment.” © Validation in Partnership Ltd 2007 . Hasselbalch QUESTIONS AND ANSWERS: [Question 1] [VIP ID: 71900] “Do the CGMPs allow for locating in a non-penicillin production facility a shared laboratory for testing penicillin and non-penicillin products? References: 21 CFR Sections: 211.e. 2001) (March 2001) Brian J. and material movement controls.” HUMAN DRUG CGMP NOTES. Failure to separate completely the air handling systems for the packing of penicillin products and non-penicillin beta-lactam drug products from non-penicillin drug products. 211.40 [VIP ID: 153810] “Dedicated production areas.” FDA Warning Letter [Reference Obliterated] (February 2004) Extracted from FDA warning letter USA 27/02/2004 [VIP ID: 126210] “2. These controls must also be applied to the re-packing of non-penicillin beta-lactam drug products (cephalosporin).46(d) Ventilation.42(c) and (d). which can include facilities. a cephalosporin product (cephalexin). Failure to have a completely separate air-handling system for the manufacture. Yes.

e.e. In one penicillin cross-contamination case reviewed it was demonstrated how a non-penicillin facility was contaminated by a separate penicillin facility located in the same manufacturing campus.43. air filtration.. or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed? References: 21 CFR 211.. 9/29/78 (Vol.176 requires non-penicillin products to be tested for traces of penicillin where the possibility of exposure exists.Doc. The separation should be audited. These should operate with well established written procedures and controls. 08 Author : Validation in Partnership Ltd. In another case.42(d) and 211. the non-penicillin products must be tested (21 CFR 211. air heating and cooling.. For a discussion on this issue. 21 CFR 211. Even with separation. However. CDER concurred with a district recommendation to withhold approval on a sensitizing beta-lactam manufacturing facility that was adjacent to another drug processing building. and not marketed if detectable levels of penicillin are found. An example of possible contamination could be inadequate controls over movement of equipment or personnel.can be achieved by sealing off. the non-penicillin products must be tested (21 CFR 211. Cross contamination issues have been a concern for a number of years." ". air filtration.does not necessarily mean. However.can be achieved by sealing off.190.46(d) Ventilation. meaning every aspect of the operations must be separate.. please review the article "Is it acceptable under section 211. VOLUME 08. if any possibility of contamination exists..." ". Issue 2.176 Penicillin contamination Federal Register.isolation of penicillin production operations. or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed? References: 21 CFR 211. 21 CFR 211. with adequate cleaning validation procedures in place? © Validation in Partnership Ltd 2007 .the two operations.42(d) and 211.separate buildings.46(d)] require separation of penicillins from non-penicillins during processing.. An example of possible contamination could be inadequate controls over movement of equipment or personnel. Section 211.separate buildings. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 25 of 185 : 14 May 2007 HUMAN DRUG CGMP NOTES. procedures validated.. 21 CFR 211. NUMBER 01 (March 2000) RUSS'S RAMBLINGS: PENICILLIN ISSUES: Question 2 [VIP ID: 8430] “Is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i. and where necessary monitored. Personnel and equipment from the penicillin facility should not enter the non-penicillin facility... The discussion of the comments in the preamble to the regulations note that ".190.. No. Adequate separation should include physical barriers and separate air handling systems.176). NUMBER 01 (March 2000) RUSS'S RAMBLINGS: PENICILLIN ISSUES: Question 1 [VIP ID: 8420] “What do the CGMPs mean by separate facilities? Must the buildings be totally separated. June 1998).43. due to the lack of containment controls which ensured against cross contamination of the other drugs. These should operate with well established written procedures and controls. : SGD-110-ENV Rev. procedures validated.” HUMAN DRUG CGMP NOTES..42(d) Design. Even with separation.. While this section prohibits marketing of products found to be contaminated with penicillin.46(d)] require separation of penicillins from non-penicillins during processing. Adequate separation should include physical barriers and separate air handling systems.176 to release products to market as long as the products are tested and no penicillin is found?" published in "Human Drug CGMP Notes" (Volume 6. there must be total separation of operations. air heating and cooling." Thus. The separation should be audited. .176)... the conversion of production facilities to a different product line on a routine basis) basis. Ref.. two buildings are not required. 21 CFR 211.. and not marketed if detectable levels of penicillin are found. two buildings are not required. there can be a "building within a building".the two operations. Other CGMP requirements must still be met. NUMBER 01 (March 2000) RUSS'S RAMBLINGS: PENICILLIN ISSUES: Question 1 [VIP ID: 8420] “What do the CGMPs mean by separate facilities? Must the buildings be totally separated.176 Penicillin contamination Federal Register. Section 211. No.. and continue to be problematic.176 requires non-penicillin products to be tested for traces of penicillin where the possibility of exposure exists. This occurred due to lack of controls regarding movements of personnel.” HUMAN DRUG CGMP NOTES.46(d) Ventilation. there can be a "building within a building".. it does not sanction marketing of non-penicillin products based only on test results that show no detectable levels of such contamination...isolation of penicillin production operations. meaning every aspect of the operations must be separate.i..does not necessarily mean. if any possibility of contamination exists. there must be total separation of operations.42(d) Design." Thus. VOLUME 08. equipment and materials. VOLUME 08.e. and construction features.. 9/29/78 (Vol. and construction features. Book 2) Preamble to the CGMPs at comment 142 CGMP regulations [21 CFR 211. Personnel and equipment from the penicillin facility should not enter the non-penicillin facility. and where necessary monitored. The discussion of the comments in the preamble to the regulations note that ". Book 2) Preamble to the CGMPs at comment 142 CGMP regulations [21 CFR 211.i.

CURRENT GOOD MANUFACTURING PRACTICE: AMENDMENT OF CERTAIN REQUIREMENTS FOR FINISHED PHARMACEUTICALS: PROPOSED RULE (May 1996) PROPOSED MODIFICATIONS (211 New Subpart M . and 211.42(d) and ..176 Penicillin contamination.it is important to make clear in these regulations that completely separate air-handling facilities for penicillin and non-penicillin production are required.46(d) Ventilation. 211.” HUMAN DRUG CGMP NOTES. and equipment. must it still maintain separate facilities and equipment for packaging penicillin products? Reference: 21 CFR Sections 211. A separate area dedicated to penicillin products within a larger facility may be acceptable if penicillin containment can be established and validated. air heating and cooling. A facility contaminated with penicillin could not begin non-penicillin production until extensive decontamination and clean-up of the facility is accomplished in accordance with the established procedures. e-mail: rothmanb@cder. This is important because campaign production has the potential for recontamination of the air handling systems and facilities. This would be difficult because the air handling system throughout its length has uneven areas and crevices that create the possibility of penicillin residue build-up. 21 CFR 211." Campaign production of penicillin and any non-penicillin product in the same facility and with the same equipment violates the CGMP regulations [211.46(d)]. which may include facilities. Thus penicillin contamination would not be uniformly distributed in the air handling system. in that sampling is extended to include the environment.190.46(d). The discussion of the comments in the preamble to the regulations state that ".43. and construction features. The regulations also require separate air-handling systems in facilities used for penicillin products. Federal Register. and "representative" samples (retain. 08 Author : Validation in Partnership Ltd.. NUMBER 02 (June 1998) Motise's Notebook: POLICY QUESTIONS: Question 3 [VIP ID: 5901] “If a firm's only operation is performing finished packaging operations for bulk tablet and capsule drug products. : SGD-110-ENV Rev. Ref. air handling equipment. CGMPs require that the non-penicillin drug be tested for the presence of penicillin. 9/29/78 (Vol. processing and packaging of penicillin be performed in facilities that are separate from those facilities used for other drugs.240 Control of chemical and physical contaminants. and can lead to cross contamination of nonpenicillin products with penicillin. No. with slough-off at undetermined periods during the non-penicillin production period.. air filtration. and representative environmental samples demonstrate that the facility conforms with its decontamination protocol/specifications.Doc. . as well as surfaces of the facility and equipment that are to be decontaminated. The CGMP regulations explicitly require that operations relating to the manufacture. shall be employed where contaminants. it is not acceptable. 301-594-0098.. This means that representative samples from all batches of non-penicillin products produced in each campaign must be tested with an acceptable method and found non-detectable for the penicillin product produced prior to the start-up of the non-penicillin campaign. facilities. Contact for further info: Barry Rothman. Ventilation. Book 2) Preamble to the CGMPs at comment 148 No. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 26 of 185 : 14 May 2007 References: 21 CFR 211..(d). Penicillin contamination Yes. 21 CFR 211. air heating and cooling.” © Validation in Partnership Ltd 2007 . The concept of decontamination is broader than a typical cleaning procedure validation.the Commissioner finds it necessary to state that any such interconnection would be unacceptable.fda.gov” FR FDA 05/03/96 PR 61 FR 20103 . One case we reviewed demonstrated a positive environmental surface sample from the fan blade of an exhaust hood in the repack room for beta-lactam residue. HFD-325.". Current technology makes decontamination of air handling systems difficult. non-penicillin products must be tested for traces of penicillin and not marketed if detectable levels are found.Contamination) 211. (b) [VIP ID: 5439] “Dedicated production. It should be noted that the requirement for separate facilities does not necessarily mean that operations relating to penicillin products must be conducted in separate buildings from other drugs. if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin. This is because the decontamination/cleaning procedures would necessitate sampling and residual testing of other parts of the air handling system.. such as penicillin. A concern is that the cleaning validation process does not include the air handling system throughout the facility. 21 CFR 211. And ". pose a special danger to human or animal health or if there are no reasonable methods for the cleaning and removal of drug substances and/or component residues from buildings.because it is possible for air-handling systems between penicillin and non-penicillin production areas to be interconnected. air filtration. VOLUME 06. and/or process equipment.176. to include the ductwork. surface and/or air) may not be an accurate portrayal of the level of contamination.176 indicates that where the possibility of exposure exists.42.42(d) Design. Furthermore. Design and construction features [Buildings and Facilities]. The CGMPs make no exceptions from the foregoing for operations that are limited to repackaging solid oral dosage forms. even though the most recent beta-lactam repackaging operation had been performed more than six months prior to sampling.

we are reviewing the need to extend the penicillin separation provisions to other drugs that might pose unique health hazards.SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Buildings and Facilities (a) Contamination/Cross Contamination (para 3) [VIP ID: 3419] “Even though penicillin production may take place in the same building as non-penicillin production.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 17 [VIP ID: 186362] “Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . Temperature and humidity controls may also be smooth operation of the equipment. pesticides. all connections being also heat sterilised after making and before breaking. per se to be as important as what those particles are.” 17. VOLUME 02. 301-594-1089. Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilised equipment. used for manufacturing multiple drugs. even simultaneously. and/or starting materials. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids. chemicals. certain hazardous or toxic drugs. air heating and cooling.SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Buildings and Facilities (a) Contamination/Cross Contamination (para 1) [VIP ID: 3417] “Cross contamination is not permitted under any circumstances. : SGD-110-ENV Rev. alkaloids. along with separation of personnel. the fact that a BPC plant is.Doc. provided that there is no risk of accidental cross-contamination. This includes fermentation procedures. air handling systems must at all times be completely separate. The key is to identify the most significant potential problem Particulates and microbial counts. within the same area. It may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. of course. Design and construction. This is the only means by which cross-contamination can be prevented through air facilities.” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II . Ventilation. need control in a "clean room" environment where sterility must be preserved. however. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 27 of 185 : 14 May 2007 HUMAN DRUG CGMP NOTES. but the concept is under review. or can be. and design an environment and containment provisions that would avoid putting other products at risk. However. cephalosporins. is not in itself objectionable with only a few exceptions. Nothing has been firmed up yet. and 211. and the danger they may present if they found their way into other products. HFD-323. There must be separate facilities and completely separate air handling systems for the production of penicillin as the CGMP regulations require for dosage form drug products. we would advise the firm to evaluate the potential cross contamination problem. all connections being also heat sterilized after making and before breaking. it may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. would be the matter of dust removal and containment to prevent cross contamination. more important than air quality itself. Different products may be placed in different biogenerators. © Validation in Partnership Ltd 2007 . However. air filtration. in terms of particulates and microbial content. We've had similar inquires before and. Motise. Ref. Division Contact for Further Info: Paul J.46. unfortunately. there is no set answer. such as we encounter in penicillin production would warrant separation of facilities. The sterilization parameters used before breaking the connections must be validated for the organisms being used. As part of future CGMP revisions.” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II . Until the regulations are modified. We would not expect particle counts. NUMBER 04 (December 1994) Motise's Notebook POLICY QUESTIONS: 4) [VIP ID: 3854] “What quality standard should be set for air around a capsule repacking machine where the capsules contain alpha blocker drugs? References: 21 CFR 211. In the case described. 08 Author : Validation in Partnership Ltd. dedicated equipment and air handling systems.42. A severe cross contamination problem.

MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Equipment 23. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 28 of 185 : 14 May 2007 organisms generally subject to special requirements for containment should be in areas dedicated to such products." will depend on the purported quality characteristics of the material under sample and the warehouse environment. Containers. (para 3) [VIP ID: 1615] “The introduction or removal of material should take place using a sterilizable closed system. For container/closures purporting to be sterile or depyrogenated.e. sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 211.. any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i. if they are to be examined for microbial contamination. Ref. or possibly in an appropriate laminar air flow. At a minimum. all connections being also heat sterilized after making and before breaking. This is to preserve the fitness for use of the remaining container/closures as well as ensure sample integrity. and packaging materials be sampled for receipt examination in the warehouse? Yes. GOOD GUIDANCE PRACTICES. …” © Validation in Partnership Ltd 2007 . Well-written and followed procedures are the critical elements. and sealed in a manner designed to prevent contamination of their contents. But whether the act of collecting a sample in the warehouse violates the CGMPs requirement that containers "be opened. sampled.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 17. closures. we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container/closure or affect the integrity of the sample results.. wiping outside surfaces. It may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. BIOTECHNOLOGY INSPECTION GUIDE (November 1991) ASCITES PRODUCTION B. However. 08 Author : Validation in Partnership Ltd.Doc. provided that there is no risk of accidental cross-contamination. and properly resealing original package). LEVEL 2 GUIDANCE CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES (August 2004) 2 [VIP ID: 190902] “Can containers. …” 19.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . Different products may be placed in different biogenerators. Once a supplier's reliability has been established by validation of their test results.94 and 211.113(b)). closures.” 18. Note that the CGMPs at 211.. limiting time that the original package is open. Manufacturing Processes 2. and packaging materials can be sampled for receipt examination in the warehouse. QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES. within the same area. organisms generally subject to special requirements for containment should be in areas dedicated to such products. a manufacturer could perform the visual examination entirely in the warehouse. [VIP ID: 1603] “Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment. : SGD-110-ENV Rev. if the environment is appropriate. Tapping Procedure [VIP ID: 1058] “Injection of mice and removal of ascites fluid should be done in a clean environment such as under a unidirectional hood or at a station that will protect the mice from infectious agents. The sterilization parameters used before breaking the connections must be validated for the organisms being used. Injection of mice and removal of ascites fluid should be done in a clean environment such as under a unidirectional hood or at a station that will protect the mice from infectious agents.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 .84 permit a manufacturer to release for use a shipment of containers/closures based on the supplier's certificate of analysis and a visual identification of the containers/closures. Generally.

Consideration should be given to having a timing device on the door interlock to allow sufficient time for the decontamination process to be effective.31 [VIP ID: 24844] “Where the quality of the API can be affected by microbial contamination.Doc.. recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs. and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). FACILITIES AND EQUIPMENT B. © Validation in Partnership Ltd 2007 . manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment. Facilities 1.31 [VIP ID: 156490] “Where the quality of the API can be affected by microbial contamination. and that from production areas not recirculated. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. Air should be extracted through HEPA filters and not be recirculated except to the same area.3 Cell Culture/Fermentation 18. • an air lock system for the passage of equipment. • a ventilation with air at negative pressure. which is constructed so that there is no flow of contaminated air between the work area and the external environment or risk of contamination of equipment within the lock.3 Cell Culture/Fermentation 18. : SGD-110-ENV Rev. Containment premises should be easily disinfected and should have the following characteristics: • the absence of direct venting to the outside. and equipped with washing and showering facilities if appropriate. manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment. the first of which is continuously monitored for integrity. The air lock should be of a size which enables the effective surface decontamination of materials being passed through it. Air pressure differentials should be such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area.” GUIDANCE PET DRUG PRODUCTS . in a laminar airflow workbench (LAFW). and there are adequate measures for safe venting of exhaust air should this filter fail.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. However. General para 2 [VIP ID: 187380] “Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimize the possibility of such contamination (e. • air from manufacturing areas used for the handling of exotic organisms should be vented through two sets of HEPA filters in series.” 21. Where the quality of the API can be affected by microbial contamination. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 29 of 185 : 14 May 2007 20. or barrier isolator system). 08 Author : Validation in Partnership Ltd. … • changing rooms designed and used as air locks.g. Ref. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18. manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.

… (e) changing rooms designed and used as air locks. and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). the first of which is continuously monitored for integrity. (c) air from manufacturing areas used for the handling of exotic organisms should be vented through 2 sets of HEPA filters in series. Ref. c) air from manufacturing areas used for the handling of exotic organisms should be vented through 2 sets of HEPA filters in series. temperature. : SGD-110-ENV Rev. and that from production areas not recirculated. if applicable. Consideration should be given to having a timing device on the door interlock to allow sufficient time for the decontamination process to be effective. The air lock should be of a size which enables the effective surface decontamination of materials being passed through it.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 20 [VIP ID: 186368] “Documentation relating to the premises should be readily available in a plant master file. [VIP ID: 1597] “Containment premises should be easily disinfected and should have the following characteristics: (a) the absence of direct venting to the outside. as should the type. and that from production areas not recirculated. if applicable. 08 Author : Validation in Partnership Ltd. which is constructed so that there is no flow of contaminated air between the work area and the external environment or risk of contamination of equipment within the lock. Air pressure differentials should be such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area. The air lock should be of a size which enables the effective surface decontamination of materials being passed through it. recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 11 [VIP ID: 186350] “Containment premises should be easily disinfected and should have the following characteristics: a) The absence of direct venting to the outside. and there are adequate measures for safe venting of exhaust air should this filter fail. exhaust and recirculated air should be indicated. supply air quality. and should also include room classifications. efficiency and change limit of installed filters. Consideration should be given to having a timing device on the door interlock to allow sufficient time for the decontamination process to be effective. The proportions of supply. and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). pressure differentials. Air should be extracted through HEPA filters and not be re circulated except to the same area. which is constructed so that there is no flow of contaminated air between the work area and the external environment or risk of contamination of equipment within the lock. … e) changing rooms designed and used as air locks. © Validation in Partnership Ltd 2007 . However. Air pressure differentials should be such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area. b) a ventilation with air at negative pressure. However. and equipped with washing and showering facilities if appropriate. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . (b) a ventilation with air at negative pressure. and there are adequate measures for safe venting of exhaust air should this filter fail. f) an air lock system for the passage of equipment. air change rates and alarms. (f) an air lock system for the passage of equipment. and equipped with washing and showering facilities if appropriate. …” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . …” 22. the first of which is continuously monitored for integrity. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 30 of 185 : 14 May 2007 PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . humidity. A Site Master File should contain a brief description of the ventilation systems.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 11.Doc. Air should be extracted through HEPA filters and not be recirculated except to the same area. It should include schematic drawing(s) of the system(s) indicating filter challenge aerosol introduction points. recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs.

The flow of people and product should also be clearly marked.Bag 99% eff. the point must be shown.3. 08 Author : Validation in Partnership Ltd. They should indicate which pressure gradients are monitored by pressure indicator.g. 7.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI.3. Facilities 1.3. (500 words/two A4 pages) … Note 2: To reduce the narrative. FACILITIES AND EQUIPMENT B.1 Design criteria e.3. C.3 [VIP ID: 185434] “REQUIREMENT C.g. and pressure gradients. filters and their specifications. Details of any alarms on the ventilation system should be given. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 31 of 185 : 14 May 2007 The manufacturing site and buildings should be described in sufficient detail (by means of plans and written explanations) so that the designation and conditions of use of all the rooms are correctly identified as well as the biological agents which are handled in them.g.1. Plans of contained and/or clean area premises. in a laminar air flow workbench (LAFW).3.Doc. . : SGD-110-ENV Rev.3 Brief description of ventilation systems. Classification of the rooms used for the manufacture of sterile products should be mentioned. schematic drawings should be used.. General para 2 [VIP ID: 187380] “Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimize the possibility of such contamination (e.3.. e.2 Filter design and efficiency e.3 The limits for changing the filters should be given.” © Validation in Partnership Ltd 2007 . The following data should be given: C. More details should be given for critical areas with potential risks of airborne contamination (schematic drawings of the systems are desirable). .4 If DOP (dioctyl-phthalate) is introduced. should describe the ventilation system indicating inlets and outlets.2 Laminar Flow Units 1.g.3 Brief Description of Ventilation Systems etc.3.” PE 008-2 1 ANNEX EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE (July 2004) REQUIREMENT C. C.3.3.Hepa 99. in a laminar airflow workbench (LAFW). The animal species accommodated in the animal houses or otherwise on the site should be identified. GUIDANCE C. Ref.3. the number of air changes per hour. Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimise the possibility of such contamination. Specification of the air supply Temperature Humidity Pressure differentials and air change rate Simple pass or recirculation (%) C.997% eff. GUIDANCE PET DRUG PRODUCTS . The activities carried out in the vicinity of the site should also be indicated.3. or barrier isolator system).3 PREMISES AND EQUIPMENT Premises REQUIREMENT C.

. under laminar flow conditions in an air classification of Class 100. Disinfecting gloves or changing them frequently when working in the laminar flow hood. laminar flow hoods) to aid in preventing contamination and cross-contamination of product. . The environment required. and sanitized at appropriate intervals following written procedures” 3.. Sterile Products/Aseptically Processed Products [VIP ID: 183918] “We recommend that special precautions be taken for investigational new drugs intended to be sterile. Thorough consideration should be given to controls for aseptic processing. consideration should be given to conducting aseptic manipulations in an aseptic workstation. Any facility. before aseptic manipulation. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 . used for production of investigational drugs for use in phase 1 studies should have adequate work areas and equipment for the intended task: Sufficient space. while ensuring that the laminar air flow is not interrupted. RECOMMENDATIONS FOR COMPLYING WITH THE STATUTE C.” © Validation in Partnership Ltd 2007 . The following examples are recommendations that should be considered: Conducting aseptic manipulation in an aseptic workstation under laminar flow conditions (e.g. biosafety cabinets. ventilation. or between different operations during the same day). Ensuring that items within a laminar airflow aseptic workstation not interrupt the airflow. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. Some examples of workstations include a laminar air flow workbench.g. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 32 of 185 : 14 May 2007 2.APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. GUIDANCE FOR INDUSTRY INDS . such as a laminar air flow workbench. additive. and heating … Appropriate air handling systems (e. calibrated.Doc. Performing manipulations of drug or components subsequent to a sterilizing step under appropriate conditions.g. SPECIAL PRODUCTION SITUATIONS D. Disinfecting the entire aseptic workstation as appropriate (e.. Total containment work stations may provide these requirements. Facility and Equipment para 1 [VIP ID: 183856] “Any facility. and the overwrap for sterile syringes and filters) with sterile disinfectant solution before placing them in the laminar flow hood.g. GUIDANCE FOR INDUSTRY INDS . may be achieved by the provision within the work station of a laminar flow of HEPA filtered air and by fitting air locks to entry ports.. test tube rack. including a laboratory. : SGD-110-ENV Rev.g. or absorptive with the product and that is properly maintained. clean environment.APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) V. appropriate construction Appropriate lighting. including a laboratory.MANUFACTURE OF RADIOPHARMACEUTICALS PREMISES AND EQUIPMENT 4 [VIP ID: 186286] “For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. used for production of investigational drugs for use in phase 1 studies should have appropriate air handling systems (e... Ref. For investigational new drugs intended to be sterile. laminar flow hoods) to aid in preventing contamination and crosscontamination of product Appropriate equipment that will not contaminate the product or otherwise be reactive. cleaned.” - 4. They should be in an environment conforming to at least grade D. or barrier isolator system. 08 Author : Validation in Partnership Ltd. an air classification of Class 100). where sterile radiopharmaceutical products or containers are exposed. Disinfecting the surface of nonsterile items (e.

MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Premises and equipment 4. The sterilization parameters used before breaking the connections must be validated for the organisms being used. : SGD-110-ENV Rev.” 5. They should be in an environment conforming to at least grade D. organisms generally subject to special requirements for containment should be in areas dedicated to such products. [VIP ID: 1562] “For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. all connections being also heat sterilized after making and before breaking.” 6. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . it may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. it may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. Different products may be placed in different biogenerators.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . within the same area. Ref. It may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. However. Open circuit operations involving immunological veterinary medicinal products or components not subsequently sterilised should be carried out within a laminar air flow work station (grade A) in a grade B area.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 9.” © Validation in Partnership Ltd 2007 .Doc. all connections being also heat sterilized after making and before breaking. provided that there is no risk of accidental cross-contamination. Total containment work stations may provide these requirements.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 9 [VIP ID: 186346] “Open circuit operations involving products or components not subsequently sterilized should be carried out within a laminar air flow work station (grade A) in a grade B area. In the production of biological agents. organisms generally subject to special requirements for containment should be in areas dedicated to such products.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . The sterilization parameters used before breaking the connections must be validated for the organisms being used.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 17. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 33 of 185 : 14 May 2007 EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 . provided that there is no risk of accidental cross-contamination. However.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 17 [VIP ID: 186362] “Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment. within the same area. [VIP ID: 1595] “Open circuit operations involving products or components not subsequently sterilised should be carried out within a laminar air flow work station (grade A) in a grade B area. 08 Author : Validation in Partnership Ltd. Different products may be placed in different biogenerators. [VIP ID: 1603] “Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports.

chemical disinfection of ports and laminar air flow protection of connections may be acceptable.” © Validation in Partnership Ltd 2007 . chemical disinfection of ports and laminar air flow protection of connections may be acceptable. the introduction or removal of material may take place in an appropriate laminar air flow. and again before disconnection) should be sterilised with steam. before the flow of product. (para 3) [VIP ID: 1615] “The introduction or removal of material should take place using a sterilizable closed system.” 8. cultures or product. and connectors (after connection. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 34 of 185 : 14 May 2007 7.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS EQUIPMENT 23 [VIP ID: 186374] “… The introduction or removal of material should take place using a sterilizable closed system. Ref. for instance when two or more fermentors are within a single area. : SGD-110-ENV Rev.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Equipment 23. In other circumstances.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . before the flow of product. transfer operations must be protected by laminar air flow workstations.” 9. before the flow of product. Where this is not possible. and connectors (after connection. chemical disinfection of ports and laminar air flow protection of connections may be acceptable. should be carried out in presterilised closed systems. sampling and addition ports. wherever possible. cultures or product should be carried out in pre-sterilized closed systems wherever possible. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 .Doc. and again before disconnection) should be sterilized with steam. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . or possibly in an appropriate laminar air flow. [VIP ID: 1649] “Where necessary.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Operating principles 50. such as sterile media. transfer operations must be protected by laminar airflow work stations. 08 Author : Validation in Partnership Ltd. for instance when two or more fermentors are within a single area. or possibly in an appropriate laminar air flow.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 .MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS STARTING MATERIALS Operating principles 50 [VIP ID: 186426] “When necessary. Operations involving the transfer of materials. In other circumstances. sampling and addition ports. for instance when two or more fermentors are within a single area.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Operating principles 48. Where necessary. In other circumstances. and again before disconnection) should be sterilized with steam. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 . Where this is not possible. sampling and addition ports. [VIP ID: 1647] “Operations involving the transfer of materials such as sterile media. For immunological veterinary medicinal products. and connectors (after connection.

Items within a laminar airflow aseptic workstation are kept to a minimum and not interrupt the airflow.. Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation (e. Filled and partially stoppered vials should be transported and loaded into a lyophiliser under a primary barrier such as a laminar flow hood. a LAFW. It is recommended that microbiological testing for Sterile PET drugs is conducted in a controlled area such as a laminar airflow workbench (LAFW) with clean room apparel. needle. Aseptic Processing Area para 1 [VIP ID: 187390] “An aseptic work area should be suitable for the assembly of the aseptic components required for the preparation of a sterile PET drug product. GUIDANCE PET DRUG PRODUCTS . that expose the PET drug product or the sterile surface of the container/closure system to the environment. Validation of this handling should also include the use media fills. and it is recommended that items within a LAFW are kept to a minimum and do not interrupt the air flow. GUIDANCE PET DRUG PRODUCTS . One manufacturer as a means of correction developed a laminar flow cart to transport the vials from the filling line to the lyophilizer.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) XI. since they are not sealed. Critical activities in the production and testing of a PET drug product.Doc. vials are transported and loaded into the lyophilizer. the failure to provide laminar flow coverage or a primary barrier for the transport and loading areas of a lyophilizer has been regarded as an objectionable condition. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 5) [VIP ID: 2757] “Once filled and partially stoppered. FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA C. and sterility testing of the finished PET drug product. such as loading of the lyophilizer.. filter and vial) for sterile filtration of the PET drug product. such as the laminar flow hoods under which the vials were filled. Other manufacturers building new facilities have located the filling line close to the lyophilizer and have provided a primary barrier extending from the filling line to the lyophilizer.. The transfer and handling. During inspections and in the review of new facilities. We recommend that the following precautions be taken to help maintain the appropriate air quality of the aseptic workstation: . : SGD-110-ENV Rev. a LAFW or barrier isolator). should be conducted within an aseptic workstation.” 12.g. FACILITIES AND EQUIPMENT B. Ref. Examples of such activities include the aseptic assembly of sterile components (syringe. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 35 of 185 : 14 May 2007 10. Microbiological Tests for Sterile PET Drugs para 2 [VIP ID: 187558] “We recommend that testing be conducted in a controlled area such as a laminar airflow workbench (LAFW) with clean-room apparel. should take place under primary barriers. e.The aseptic workstation is sanitized before each operation. 08 Author : Validation in Partnership Ltd. . …” 11.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI.g. . Facilities 2.” GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 9) [VIP ID: 2762] “In the transport of vials to the lyophilizer. We recommend that air quality in the aseptic processing area be controlled to limit the presence of microorganisms and particulate matter. there is concern for the potential for contamination.” © Validation in Partnership Ltd 2007 .

000.g. and gowning rooms should be included. Isolators or barrier systems should be identified.. autoclaves. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 36 of 185 : 14 May 2007 13. A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas. In addition. and filling heads.” 14. Information to be included in drug applications for aseptic fill manufacturing processes should include a brief description of the building and facilities indicating the placement of critical equipment such as laminar flow hoods. Cartons and boxes should not be stored or opened in the production area to minimize ingress of dust and particulate into the aseptic work area.. 2. filtering and filling areas.000).SUPERSEDED! (January 1993) II. gowning rooms. filtering and filling areas. The placement of all critical equipment such as laminar flow hoods. [VIP ID: 3030] “Provide a brief description of the building and facilities. and ceilings in the aseptic work areas should be easily cleaned. Class 10. autoclaves. Ref. filling heads. Cleaning should be performed frequently to ensure consistent control of the environmental quality. Class 100.g. but not limited to. : SGD-110-ENV Rev. should be identified.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. LAFW) should be situated in the section of the room with the lowest traffic and lowest activity. 2. lyophilizers. GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. FACILITIES AND EQUIPMENT B. including. Facilities 2. the room should not be carpeted nor have overhanging pipes or hanging light fixtures. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. etc. All areas of the production and processing room should be easily accessible for cleaning. should be identified. This should include the following types of information: 1. Buildings and Facilities [VIP ID: 17240] “A brief description of the manufacturing building and facilities should be provided. Equipment within barrier or isolation systems should be noted. Floor Plan A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas. For example. Class 100. The air cleanliness class of each area should be identified (e.” © Validation in Partnership Ltd 2007 . A laminar air flow workstation for aseptic manipulations should be situated in the section of the room with the lowest traffic and lowest activity. laminar flow hoods. Surfaces of the walls.000. etc. A. Class 100. The following information should be included: 1. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. The air cleanliness class of each area should be identified (e. the aseptic processing area (e. Aseptic Processing Area para 2 [VIP ID: 187392] “We recommend that conditions in the room where aseptic manipulations are conducted not present a challenge to the operating capability of the aseptic workstation.). lyophilizers. Location of Equipment The placement of all critical equipment. 08 Author : Validation in Partnership Ltd.. A.g.Doc. Class 100. GUIDANCE PET DRUG PRODUCTS . etc. floors.” STERILIZATION PROCESS VALIDATION .000.Class 10.

” 16. e. filling zone. The maintenance of laminarity should be demonstrated and validated.54 m/s (guidance value) at the working position in open clean room applications. stopper bowls.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade A: [VIP ID: 62370] “The local zone for high risk operations. There should be documented performance specifications and action or alert limits to prompt investigation or corrective action for laminar air flow hoods within aseptic filling rooms. open ampoules and vials.Doc. Laminar air flow systems should provide a homogeneous air speed in a range of 0. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .” © Validation in Partnership Ltd 2007 .g. filling zone. : SGD-110-ENV Rev. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. e.54 m/s (guidance value) at the working position and have a Grade B background environment. which should provide a homogenous air speed of 0. Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.36 . Normally such conditions are provided by a laminar air flow work station.36 . The local clean area for high risk operations in the manufacture of sterile medicinal products.MANUFACTURE OF STERILE MEDICINAL PRODUCTS .SUPERSEDED! (July 1996) General 3.54 m/s (guidance value) at the working position in open clean room applications. this is the background environment for grade A zone. filling zone. Laminar air flow systems should provide an homogenous air speed of 0. A unidirectional air flow and lower velocities may be used in closed isolators and glove boxes. Grade A: The local zone for high risk operations. open ampoules and vials. Grade B: For aseptic preparation and filling.0.45 m/s +/. open ampoules and vials. making aseptic connections.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . making aseptic connections should be Grade A. stopper bowls. stopper bowls.g. making aseptic connections. 08 Author : Validation in Partnership Ltd. For the manufacture of sterile medicinal products 4 grades can be distinguished.0. Normally such conditions are provided by a laminar air flow work station. Normally this environment is provided by a laminar air flow workstation. Laminar air flow systems should provide a homogeneous air speed in a range of 0. The maintenance of laminarity should be demonstrated and validated. e. stopper bowls. this is the background environment for grade A zone.0.20% (guidance value) at the working position. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 37 of 185 : 14 May 2007 15. Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 2472] “There should be documented performance specifications and action or alert limits to prompt investigation or corrective action for laminar air flow hoods within aseptic filling rooms. open ampoules and vials.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . Grade A: The local zone for high risk operations. Grade B: For aseptic preparation and filling. Ref. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.36 . [ViP ID: 185986] “The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. filling zone. Normally such conditions are provided by a laminar air flow work station.g. making aseptic connections. paras 3 to 7 inc.g. (para 3) [VIP ID: 1369] “For the manufacture of sterile medicinal products there are normally 4 grades of clean areas. e.

: SGD-110-ENV Rev.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. Equipment 1. Aseptic Workstation para 2 [VIP ID: 187412] “We recommend that a qualified operator change the prefilters in the aseptic workstation periodically in accordance with written procedures and preventive maintenance schedules. Equipment 1. We recommend that an integrity test be conducted at installation (including after each change of the high-efficiency particulate air (HEPA) filter) to ensure proper performance. FDA Warning Letter 320-01-11 (September 2001) Extracted from FDA warning letter 320-01-11 USA 05/09/2001 [VIP ID: 43210] “The laminar flow hood in the micro lab and **** filters in the Class 100. We recommend that certification (integrity testing of the HEPA filter) of the aseptic workstation be performed when the unit is initially installed and at least every 6 months thereafter to ensure the desired air quality.” 18. For laminar flow hoods equipped with easily readable static pressure gauges to indicate when the pressure builds up behind the filter because of the clogging of the filter. Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year. Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27740] “Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year. Production Equipment para 6 b.” © Validation in Partnership Ltd 2007 . it is recommended that the filter be changed when clogging is detected.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. GUIDANCE PET DRUG PRODUCTS . FACILITIES AND EQUIPMENT C. There should be certification for laminar flow hoods in micro labs and filters in Class 100.000 areas. Examples of workstations include a laminar air flow workbench (LAFW) or barrier isolator system. Production Equipment para 6 b. Ref. More frequent testing may be appropriate if air quality is found to be unacceptable. GUIDANCE PET DRUG PRODUCTS . More frequent testing may be appropriate if air quality is found to be unacceptable. We recommend that the filter be changed when clogging is detected. or if leakage or decrease in optimal airflow is found.” • For a laminar air flow workbench for aseptic procedures. as part of an investigation into a finding of sterility failure in a PET drug. It is recommended that a qualified operator change the prefilters in an aseptic workstation periodically in accordance with written procedures and preventive maintenance schedules. for example. 08 Author : Validation in Partnership Ltd.” 19.Doc.000 production area had not been certified. it is recommended that integrity testing of the HEPA filter be performed when the unit is initially installed and at least every 6 months thereafter (and after each change of the HEPA filter) to ensure the desired air quality. Some laminar flow hoods are equipped with easily readable static pressure gauges that indicate when the pressure builds up behind the filter because of the clogging of the filter. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 38 of 185 : 14 May 2007 17. Aseptic Workstation para 1 [VIP ID: 187410] “The aseptic workstation should provide an appropriate environment for aseptic procedures.

Examples from the FDA-483 are: … i. Schneider] 22.194(d) k. as required by your firm’s procedure (EM 5). equipment has not been maintained or replaced as per SOP entitled "---" For example: … iii. 08 Author : Validation in Partnership Ltd. FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28420] “3. item 24. Your firm failed to have in place written procedures for many of the operations performed by your laboratory. maintain.194 Laboratory Controls-Laboratory Records The laboratory records fail to consistently and accurately include complete data derived from all tests necessary to assure compliance with specifications and standards.194(a)(8) … [FDA Investigators: Renee L.160(b)(1) … [FDA Investigators: Renee L. Laminar air flow hood replacement frequency should be documented. Item 25. Some examples from the FDA483 are: … f. incubator. There is no documentation to support that the procedures for cleaning the laboratory benches and laminar flow hood are effective from microbiological contamination. Rice and Miah I. to establish or maintain written procedures for cleaning and maintenance of equipment.Doc. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 39 of 185 : 14 May 2007 FDA Warning Letter CBER-98-024 (August 1998) Extracted from FDA warning letter CBER-98-024 USA 14/08/1998 [VIP ID: 12170] “Failure to clean. and sanitize equipment. FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28430] “4.67 and 600. 211. Schneider] © Validation in Partnership Ltd 2007 .” 21. strength quality or purity of the drug product. identity. utensils. and to maintain records [21 CFR 211. 211. thermometers). These procedures should include scientifically sound specifications and test procedures. Cleaning of the Laminar flow hood the day after samples are processed in the hood. : SGD-110-ENV Rev. LFH. 211.12]. the laminar air flow hood pre-filters have not been replaced.” 20. and supplies at appropriate intervals to prevent malfunctions or contamination that would alter the safety.g. Item 21. There is no documentation that equipment calibration was performed when scheduled as stated in your firm’s procedures (e. in that: a. 211. that were drafted by an appropriate organizational unit and reviewed and approved by a quality control unit. There should be documentation to support that procedures for cleaning a laminar flow hood are effective from microbiological contamination. Ref. Selected FDA 483 Observations (February 1998) Sterile Product Manufacture [VIP ID: 6324] “Laminar air flow hood replacement frequency should be documented.160 Laboratory Controls-General Requirements. Rice and Miah I. balances. is not always documented. There should be documentation that laminar flow hood calibration is performed when scheduled and that cleaning is documented as required by procedures. 211.

Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 40 of 185 : 14 May 2007 23.2 Non-viable monitoring 7.2 [VIP ID: 190296] “Environmental monitoring should be performed under operational (dynamic) conditions either within the isolator or in the laminar airflow and associated background areas. [VIP ID: 2180] “Is the air flow in critical areas laminar when delivered to the point of use? At what velocity? Is velocity determined at the critical area or at the filter face?” • The location of an environmental monitoring sample device should not compromise the laminarity of the air flow in the critical zone. and that microbiological monitoring (e. using settle plate) in the LAFW be conducted during sterility testing and critical aseptic manipulation.” • The air flow in critical areas should be laminar when delivered to the point of use. We recommend that operators be trained on the importance of minimizing objects and equipment within the critical area so laminar airflow is not disrupted. Aseptic Workstation para 3 [VIP ID: 187414] “We recommend laminar airflow velocities be monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area. ENVIRONMENTAL AND PERSONNEL MONITORING 7. Environmental monitoring should be performed under operational (dynamic) conditions in the laminar air flow and associated background areas.1 [VIP ID: 188974] “The location chosen for monitoring should be checked to ensure that the positions reflect the worst case.” 24.DRUG QUALITY ASSURANCE 7356.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. For the filling environment the counts should be performed adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas. Equipment 1. GUIDANCE PET DRUG PRODUCTS .2. the counts should be performed in locations where there is most operator activity. We recommend that microbiological monitoring (e. : SGD-110-ENV Rev. ENVIRONMENTAL MONITORING 10. CPGM-DB CHAPTER 56 .g.Doc. For room monitoring. It is recommended that aseptic workstation laminar air flow velocities are monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area.” © Validation in Partnership Ltd 2007 . FACILITIES AND EQUIPMENT C. Monitoring with sampling probes located in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones should be avoided. Initial validation should be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed during process simulation tests. 08 Author : Validation in Partnership Ltd. However the location of the sample device should not compromise the laminarity of the air flow in the critical zone. that operators are trained in the importance of minimising objects and equipment within the critical area so laminar air flow is not disrupted. Production Equipment para 6 b. Ref.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 28.g. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. using settle plate) in the LAFW be conducted during sterility testing and critical aseptic manipulation..

A sterility test environment. 211.2 [VIP ID: 190252] “The test environment. as required by 21 CFR 211. and material should be placed in such a way that it does not disrupt the laminar air flow. which includes the laminar airflow cabinet or isolator. Failure to have a quality control unit adequate to perform its functions and responsibilities. 08 Author : Validation in Partnership Ltd.1 CLEAN ROOM DESIGN 8.Doc. Some examples from the FDA-483 are: … c. or in an isolator that need not be located within a controlled environment. Ref. if available.DRUG QUALITY ASSURANCE 7356. The laminar flow hood failed a sterility test.22(b) … [FDA Investigators: Renee L. [VIP ID: 2437] “What air quality is specified for sterility testing areas? Is laminar air flow provided?” 25.1. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8.1. until acceptable sterility test results were obtained **** days later.” CPGM-DB CHAPTER 56 . should be certified at least annually by a competent person for compliance with the specified standard conditions.1. which includes a laminar air flow cabinet. but was used for subsequent testing after an invalidated cleaning procedure was performed.22 Responsibility of the quality control unit. STERILITY TEST FACILITIES 8. Rice and Miah I.1 CLEAN ROOM DESIGN 8.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) LABORATORY Environment 285.” 26. Your failure to have an adequate quality control unit is demonstrated by the number and types of inspectional observations made during this inspection. 211. If a laminar flow hood fails a sterility test. FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28400] “1. Item 15. Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow.1 Classification 8. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. should be certified at least annually by a competent person for compliance with the specified standard conditions. STERILITY TEST FACILITIES 8.1 [VIP ID: 190250] “The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room.1.1. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 41 of 185 : 14 May 2007 • A sterility test may be conducted within a class A laminar air flow cabinet located within a class B clean room. : SGD-110-ENV Rev.1. cleaning it until acceptable sterility test results are obtained is not good practice. Schneider] © Validation in Partnership Ltd 2007 .22. The test may also be performed within a class A clean room.1 Classification 8.

It was speculated that new air currents resulted in rebound contamination off the floor. They are normally found as carefully placed flexible plastic curtains or rigid shields (e. VOLUME 09. There are some further key differences in operation and design of aseptic processing lines contained in an isolator versus one that utilizes barriers. which is supplied with HEPA or ULPAfiltered air.” 7." but this term does not connote a single technology. and that which surrounds the isolator.g. Barriers are also frequently helpful in fulfilling this CGMP requirement. A barrier provides partial separation of the manufacturing and surrounding environments.1. One major distinction lies in the need for an isolator to employ an air pressure differential that provides uncompromised. surface-sterilized) with a sporicidal agent. the lyophilization process includes the stoppering of vials in the chamber. Aseptic processing operations utilizing isolators designed and operated in accord with CGMP's (e. Some have used the tandem term "barrier-isolator. which are full enclosures. the interior of isolators. firms have essentially enclosed parts of the processing line with the latter rigid walls. Fortunately. Initially.113. is a physical partition that affords aseptic manufacturing zone protection by partially separating it from the surrounding area (which is. barriers provide a partial barricade. high velocities with inadequate return caused a contamination problem in a media fill. but does not provide for isolation of the aseptic line from the surrounding environment. This design represents an extensive barrier. : SGD-110-ENV Rev. 08 Author : Validation in Partnership Ltd. and instead very broadly refers to both.g.63. on the other hand.g. the enclosed environment in which a product is processed and the environment surrounding the isolator. Ref.” • Isolators could be seen as a more encompassing development of the barriers used in conventional clean rooms.65) can be quite effective in diminishing such microbiological contamination risks to the product. 211. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 10) [VIP ID: 2763] “In order to correct this type of problem. HUMAN DRUG CGMP NOTES.. In addition. is also regularly biodecontaminated (i.3 Isolators 1. The clean room barriers evolved from plastic flexible curtains through to rigid barriers with glove ports. 2001) (June 2001) Brian J. of lower air cleanliness) and activities occurring near the processing line. which requires that procedures be designed to prevent microbiological contamination of drug products purporting to be sterile. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 42 of 185 : 14 May 2007 27. Media fills and smoke studies can provide enough meaningful information to correct a problem with air currents resulting in rebound contamination off the floor into a vertical laminar flow hood. Isolators and barriers are used by aseptic processors in order to help satisfy 21 CFR 211. © Validation in Partnership Ltd 2007 . with few exceptions. Knowledge of the definitions of the separate terms is becoming increasingly important as these two technologies evolve and gain in popularity. NUMBER 02 (Second Quarter. continuous isolation of its interior from the external environment (e. A barrier.. 21 CFR 211. another manufacturer installed a vertical laminar flow hood between the filling line and lyophilizer.. Plexiglas). media fills and smoke studies provided enough meaningful information that the problem could be corrected prior to the manufacture of product. An isolator provides full separation of two environments.Doc.42. Hasselbalch QUESTIONS AND ANSWERS: [Question 4] [VIP ID: 72060] “What is an aseptic processing isolator? What is the difference between an isolator and a barrier? An aseptic processing isolator ("isolator") can be fundamentally defined as a unit that provides full separation of two environments: an enclosed environment in which a product is processed or manipulated. In some cases. In contrast with isolators. Typically.e. but the resulting box-like structure is not designed to employ a separative pressure differential and operators routinely access the line by opening panel doors found throughout the line to monitor and control the aseptic tilling process.. surrounding room air and personnel). and 211.

it is important to demonstrate that the air overpressure remains acceptable during use of gloves and half-suits. includes an exit portal for product egress. Pharm. 34. while both open and closed isolators normally interface with the surrounding environment through aseptic transfer ports and air filters (e.. air filtration. An appropriately qualified minimum positive air pressure differential specification should be established and followed to ensure the continuous isolation of environments. Furthermore. An "open" isolator. 08 Author : Validation in Partnership Ltd. References: 21 CFR 211. When the degree of containment is nearly complete. and are also known as positivepressure isolators because they operate under air pressures greater than the external environment. HUMAN DRUG CGMP NOTES. HEPA.113: Control of microbiological contamination a Guideline on Sterile Drug Products Produced by Aseptic Processing.g. While we have described the use of positive pressure isolators as protection to the exposed sterile product and container-closures throughout operations. ULPA. An "open" isolator. the sporicidal procedures used for many years in other applications could be applied without harming the operators.Doc. Their use is limited by the quantity of filled units that can be stored in or transferred out of the isolator during operation. : SGD-110-ENV Rev. negative pressure isolators also exist. personnel gowning would reflect that used in a traditional aseptic processing operation. such as clinical-scale aseptic filling operations..63: Equipment design. air heating and cooling 21 CFR 211. or microbial-retentive filters). Sci. The objectives of barriers are to increasingly separate the surrounding clean room including the operator from the critical zone where aseptic operations are carried out and sterile materials are exposed. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 43 of 185 : 14 May 2007 PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. and location 21 CFR 211. it is necessary for firms to include special design provisions to assure protection of the exposed sterile product. common industry practice is to place these units in a Class 10. Supplement. isolators have been categorized as either "open" or "closed": A "closed" isolator is a unit that does not include any portals (or "mouseholes. 55. However. Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products. popular for high speed/output lines.000. PDA J.4 [VIP ID: 190416] “Isolators could be seen as a more encompassing development of the barriers used in conventional clean rooms. NUMBER 02 (Second Quarter. An important part of qualifying an open isolator is demonstrating that its design and the positive pressure differential used achieve full physical separation from the external environment at the product exit portal. These isolators have been used for various non-sterile applications and. the open isolator also includes an exit portal in its design.” • A "closed" isolator is a unit that does not include any portals that directly communicate air with the surrounding. Both normally interface with the surrounding environment through aseptic transfer ports and air filters (e. Since negative pressure isolators have significant potential to exchange air with the surrounding environment. The clean room barriers evolved from plastic flexible curtains through to rigid barriers with glove ports.46: Ventilation. For example. popular for high speed/output lines. Technol. or when needed. Closed isolators are most commonly used in sterility testing laboratories and for smaller batch applications. PDA Technical Report No. Hasselbalch QUESTIONS AND ANSWERS: [Question 5] [VIP ID: 72070] “What is the difference between an open and closed isolator system? What is a positive pressure isolator? It is helpful to become acquainted with some of the terms used to characterize the different types of isolators. INTRODUCTION 2. Both are also known as positive-pressure isolators because they operate under air pressures greater than the external environment. such as opening and closing cleanroom doors. ULPA. No. VOLUME 09. sterile operations. size. includes an exit portal for product egress. For example. a cleanroom environment of higher air cleanliness. 1987.65: Equipment construction 21 CFR 211.42: Design and construction features 21 CFR 211. when used for aseptic processing applications. the objective of a negative pressure isolator is to protect workers by providing containment of a potent or toxic drug. and is unaffected by activities in the external environment. 2001) (June 2001) Brian J. HEPA." as they are commonly called) that directly communicate air with the surrounding environment. or microbial-retentive filters). When used for aseptic operations. Ref.g. Thus. in some cases. 5 (2001) Contact for further information: © Validation in Partnership Ltd 2007 .

1 [VIP ID: 190410] “The term ‘Isolator’ as used in the Pharmaceutical Industry covers a variety of pieces of equipment.” • One type of isolator has the main objective of providing containment for the handling of dangerous materials either aseptically or not. A well-designed positive pressure isolator. However.Doc. and control. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. In general the area inside the isolator is the local zone for high risk manipulations. and control. monitoring. One group has the main objective of providing containment for the handling of dangerous materials either aseptically or not. Design 1.MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] “The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. supported by adequate procedures for its maintenance. Ref.fda. offers tangible advantages over traditional aseptic processing. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms. INTRODUCTION 2. Open isolators have openings to the surrounding environment that are carefully engineered to segregate the inner isolator environment from the surrounding room via overpressure. supported by adequate procedures for its maintenance.” • A well designed positive pressure isolator. users should remain vigilant to potential sources of operational risk. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Airflow (para 1) [VIP ID: 111930] “There are two types of aseptic processing isolators: open and closed. Another group has the main objective of providing a microbiologically controlled environment within which aseptic operations can be carried out. Another has the main objective of providing a microbiologically controlled environment within which aseptic operations can be carried out.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. HFD-325301-827-7284 Friedmanr@cder. although it is recognised that laminar air flow may not exist in the working zone of all such devices. monitoring. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . 08 Author : Validation in Partnership Ltd. : SGD-110-ENV Rev. Manufacturers should also be aware of the need to establish new procedures addressing issues unique to isolators. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 44 of 185 : 14 May 2007 Richard L. It should be controlled and for aseptic processing be at least grade D. Friedman. © Validation in Partnership Ltd 2007 .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators (para 1) [VIP ID: 111890] “Aseptic processing using isolation systems separates the external cleanroom environment from the aseptic processing line and minimizes its exposure to personnel. The air classification required for the background environment depends on the design of the isolator and its application. Closed isolators employ connections with auxiliary equipment for material transfer. offers tangible advantages over traditional aseptic processing. Isolators are constructed of various materials more or less prone to puncture and leakage. including fewer opportunities for microbial contamination during processing.gov” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . There are many possible designs of isolators and transfer devices.

General para 2 [VIP ID: 187380] “Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimize the possibility of such contamination (e. often called a mousehole. 6.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 6. anaerobic conditions. can be used to aid microbiological control.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 6.g.” 2. There are many possible designs of isolators and transfer devices. or barrier isolator system). The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimise the possibility of such contamination (e. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms. in a barrier isolator system).” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . PRINCIPLES RELATED TO THE SELECTION AND USE OF ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.g. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 45 of 185 : 14 May 2007 Containment isolators often employ negative internal air pressure and most isolators used for aseptic processing employ positive pressure. and reducing the risk of microbiological and other contamination of the product from the environment. 9. to permit continuous removal of sealed product. 6.Doc.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 7 (para 1) [VIP ID: 62850] “The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. PRINCIPLES RELATED TO THE SELECTION AND USE OF ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. 08 Author : Validation in Partnership Ltd.1 Principles related to the selection and use of isolators subjected to a sporicidal process. : SGD-110-ENV Rev. GUIDANCE PET DRUG PRODUCTS . A sporicidal process. Some large scale isolators provide an opening. 9.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. usually delivered by gassing. in a laminar airflow workbench (LAFW). Ref.” © Validation in Partnership Ltd 2007 . Isolators are constructed of various materials more or less prone to puncture and leakage.2 [VIP ID: 190510] “This Recommendation focuses on the aspect of reducing the risk of microbiological contamination arising from the environment.3 [VIP ID: 190444] “This Recommendation focuses on the aspect of reducing the risk of microbiological contamination arising from the environment.2 [VIP ID: 190442] “The reasons for selecting an isolator include containment.. Facilities 1. The capability for the isolator to be sealed allows operations to be carried out in controlled gaseous environments e.g. to protect the operator and environment. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.1. Other isolators remain sealed throughout production operations. FACILITIES AND EQUIPMENT B.

We recommend that the following precautions be taken to help maintain the appropriate air quality of the aseptic workstation: The aseptic workstation is sanitized before each operation. a LAFW or barrier isolator). should be filtered using microbiologically retentive filters or sterilized prior to entry. HEPA filtration of the exhaust system is a standard precaution against backflow. 7. All gases.5. or that may gain access. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 46 of 185 : 14 May 2007 • Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation such as a barrier isolator.1 [VIP ID: 190582] “All gases. FACILITIES AND EQUIPMENT B. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. Items within a laminar airflow aseptic workstation are kept to a minimum and not interrupt the airflow. and sterility testing of the finished PET drug product. Consideration should be given to providing a HEPA prefilter for the air inlet system mainly to provide redundancy in the event of failure of one of the filters.5 The prevention of recontamination 7. : SGD-110-ENV Rev. …” 3. GUIDANCE PET DRUG PRODUCTS . Facilities 2.1 [VIP ID: 190490] “All gases. needle. should be filtered using microbiologically retentive filters or sterilised prior to entry. 9. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. The main intention is to provide redundant filtration because if only single filtration is used in the isolator a filter failure could increase the risk of contamination significantly. filter and vial) for sterile filtration of the PET drug product. Any vacuum points should be guarded by filters.5. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. Examples of such activities include the aseptic assembly of sterile components (syringe.e. Aseptic Processing Area para 1 [VIP ID: 187390] “An aseptic work area should be suitable for the assembly of the aseptic components required for the preparation of a sterile PET drug product.Doc. and sterility testing of the finished PET drug product. The duty to exclude penetration by microorganisms in the incoming air is probably higher than for conventional clean rooms as discussed in 9. We recommend that air quality in the aseptic processing area be controlled to limit the presence of microorganisms and particulate matter. once into the room and again into the Grade A zone. Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation (e. Ref. needle. HEPA filtration is not absolute and a rare penetration is to be expected. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. The air that is supplied to the critical zone of a conventional clean room is generally double HEPA filtered i. All gases and fluids passing into the isolator should be filtered using microbiologically retentive filters or sterilized prior to entry through the envelope so that any escape inside the isolator will be of uncontaminated material.g. fluids and air supplied to the isolator. fluids and air supplied to the isolator or that may gain access.5 The prevention of recontamination 9. Examples of such activities include the aseptic assembly of sterile components (syringe.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI.1. filter and vial) for sterile filtration of the PET drug product. fluids and air supplied to the isolator or that may gain access.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. should be filtered using microbiologically retentive filters or sterilized prior to entry.. 08 Author : Validation in Partnership Ltd.” © Validation in Partnership Ltd 2007 .

1 Classification 8. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 47 of 185 : 14 May 2007 4.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 7 (para 3) [VIP ID: 62870] “The air classification required for the background environment depends on the design of the isolator and its application. : SGD-110-ENV Rev. It should be controlled and for aseptic processing be at least grade D. A sterility test may be conducted within an isolator that need not be located within a controlled environment. if available.1. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . allow access only to trained staff.1. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. of Grade B. The air classification required for an aseptic processing isolator background environment should be at least grade D. containing workstations.MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] “… The air classification required for the background environment depends on the design of the isolator and its application. transfer ports).” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. STERILITY TEST FACILITIES 8. Design 4. but not necessarily classified. of Grade D or better containing equipment called isolators providing a Grade A environment. A smaller number of controlled environments are provided by clean rooms. or in an isolator that need not be located within a controlled environment. A Class 100.000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations.Doc.. 08 Author : Validation in Partnership Ltd.” © Validation in Partnership Ltd 2007 .1 CLEAN ROOM DESIGN 8.” 5. An aseptic processing isolator should not be located in an unclassified room. It should be controlled and for aseptic processing it should be at least grade D. of Grade A complying with the PIC/S and EC guide to GMP. Clean Area Classifications [VIP ID: 111980] “The interior of the isolator should meet Class 100 (ISO 5) standards. Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow. The classification of the environment surrounding the isolator should be based on the design of its interfaces (e. as well as the number of transfers into and out of the isolator. INTRODUCTION 2.g.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .1.3 [VIP ID: 190414] “Controlled environments for aseptic operations are currently mainly provided by conventional clean rooms. Ref.1 [VIP ID: 190250] “The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room.g.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. The environment should be controlled e. When isolators are used for sterility testing there is no formal requirement for them to be placed in a Grade D environment. The test may also be performed within a class A clean room.

9. Any air supplied by the generator e.3 [VIP ID: 190518] “The materials that should be sterilized i. All inlet and outlet filters associated with the isolator should be exposed to gas or sterilized. the possibility of the filter becoming unseated should be investigated. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. Dispersed oil droplets used for integrity testing HEPA filters may break down the gas. When the sporicidal process cannot be assured the use of presterilized filters may be necessary. Whether it is possible to maintain these surfaces in a satisfactory condition by a sporicidal process for some sequence of batches is unresolved. If this is not possible arrangements should be made to assure that all terminal inlet and exhaust filters are exposed to gas. then sterilization is necessary before reuse. The delivery of gas to the isolator should be via defined ducts with no possibility of loss or contamination. treated using a validated sterilization process as specified in the Pharmacopoeia. All of the gas should ideally enter by all of the air inlet filters and leave by all of the exhaust filters.g. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 48 of 185 : 14 May 2007 6. gloves etc are exposed to a sporicidal process. should be filtered though microbiologically retentive filters that have been sterilised or subjected to a sporicidal process. : SGD-110-ENV Rev. The rationale used should be documented. If part of the process involves a reversal of the flow through a filter. should be identified. during a purge stage. Non product contact surfaces including machine surfaces. The isolator should be designed to enable access to all surfaces for cleaning without major dismantling. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. The surfaces of packaged materials and all other items to be exposed to the sporicidal process within the isolator should be clean. the list should be a controlled document and consistent with that used in validation. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. 9. Ref. during a purge stage. Particular attention should be paid to microbiologically retentive filters used to treat services to and from the isolator. the use of presterilised filters may be necessary. the possibility of the filter becoming unseated should be investigated. If this is not possible arrangements should be made to assure that all terminal inlet and exhaust filters are exposed to gas. 9.4.g.8 [VIP ID: 190534] “The isolator should be cleaned prior to the sporicidal process.” • Any air supplied by the generator.Doc. Inlet and exhaust air pathways should be designed with this in mind. Particular attention should be paid to microbiologically retentive filters used to treat services to and from an isolator.” 7. If the indirect product contact surfaces are exposed to the environment surrounding the isolator by being removed or due to loss of integrity of the isolator. There is a hierarchy of risk leading to direct product contact parts being subject to a conventional sterilization process e. e. When a sporicidal process cannot be assured. All of the gas should ideally enter by all of the air inlet filters and leave by all of the exhaust filters.g. © Validation in Partnership Ltd 2007 . filling needles.4 9. should be filtered though microbiologically retentive filters that have been sterilized or subjected to a sporicidal process. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. This should be examined during validation and it may be necessary to consider the first gassing after testing as a neutralising operation.4 9. If part of the process involves a reversal of the flow through a filter.e. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.4. and those that should be subjected to a sporicidal process.6 [VIP ID: 190530] “The delivery of gas from the generator into the isolator should assure that only the gas generated is supplied. stoppers etc. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. The indirect product contact surfaces such as stopper hoppers and delivery chutes should ideally be sterilized into the isolator to prepare for the start of each batch of product. 08 Author : Validation in Partnership Ltd.

Doc. The principles necessary to assure a microbiologically controlled environment for production. in most cases. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 49 of 185 : 14 May 2007 All the surfaces inside the isolator should be clean prior to exposure to the sporicidal process.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. The isolator should be designed to enable access to all surfaces for cleaning without major dismantling. 08 Author : Validation in Partnership Ltd. are also appropriate.” 8.” 11. This Recommendation deals mainly with the provision of a microbiologically controlled environment for aseptic processing for producing medicinal products labelled as sterile. for isolators used for sterility testing.1. ENVIRONMENTAL MONITORING 10.1. are also appropriate. which includes the isolator. STERILITY TEST FACILITIES 8.” 9. which includes the laminar airflow cabinet or isolator. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8.” 10.2 [VIP ID: 190412] “Aseptic operations can include sterility testing or aseptic processing to produce medicinal products. INTRODUCTION 2.1. Pressure Differential (para 1) [VIP ID: 111960] “Isolators that include an open portal should be designed to ensure complete physical separation from the external environment. should be certified at least annually by a competent person for compliance with the specified standard conditions. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2.2 [VIP ID: 190252] “The test environment. If clean in place systems are used. A positive air pressure differential adequate to achieve this separation should be employed and © Validation in Partnership Ltd 2007 . If requirements for operator safety drive the need to use a negative pressure critical zone.2 [VIP ID: 190296] “Environmental monitoring should be performed under operational (dynamic) conditions either within the isolator or in the laminar airflow and associated background areas. The maintenance of positive pressure should be monitored and fitted with an alarm. the presence of deposits may enable microorganisms to survive the process by physical shielding or neutralization of the process of inactivation.1 Classification 8. : SGD-110-ENV Rev. Design 3. consideration should be given to enclosing it in a positive pressure envelope. The test environment. The principles necessary to assure a microbiologically controlled environment for production. Ref.1 CLEAN ROOM DESIGN 8. any risks that may arise from the presence of spray balls. for isolators used for sterility testing. Inlet and exhaust air pathways should be designed with this in mind. drains and retained fluids should be identified and eliminated. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Environmental monitoring should be performed under operational (dynamic) conditions within an isolator. Whichever cleaning method is used it should result in a visibly clean dry surface free from risk of residues. A suitable positive differential air pressure should be maintained between the isolator and the surrounding room to protect against unforeseen circumstances. Apart from removing chemical residues that may contaminate subsequent production. should be certified at least annually by a competent person for compliance with the specified standard conditions. in most cases. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10.

” 12. Positive air pressure differentials from the isolator to the surrounding environment have largely ranged from approximately 17. Local Class 100 (ISO 5) protection at an opening is an example of a design provision that can provide a further barrier to the external environment. If requirements for operator safety drive the need to use a negative pressure critical zone. when applicable. tracer gas penetration etc. 9. There should be a program to reduce the risk of leaks due to accident and means of detecting them which have known sensitivity e. Induction can result from local turbulent flow causing air swirls or pressure waves that might push extraneous particles into the isolator. should be assured as far as possible. but this should be due to essential engineering tolerances as opposed to poor design. the use of laminar. 7. Ref. The risk posed by undetected leaks and unanticipated deterioration can be reduced by operating the isolator at positive pressure with respect to lower grade connecting and surrounding areas. The appropriate minimum pressure differential established by a firm will depend on the system’s design and. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 50 of 185 : 14 May 2007 supported by qualification studies. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.5. 7. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.2 [VIP ID: 190584] “The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary. Pressure Differential (para 2) [VIP ID: 111970] “The positive pressure differential should be coupled with an appropriately designed opening to the external environment to prevent potential ingress of surrounding room air by induction. the application of aseptic technique and risk of error due to human fallibility. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. its exit port. [22] 0. It is recognized that there will be some leakage. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7.5. The maintenance of positive pressure should be monitored and fitted with an alarm. As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect against unforeseen circumstances. pressure hold tests.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.2 [VIP ID: 190492] “The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary. should be assured as far as possible. The maintenance of positive pressure should be monitored and fitted with an alarm.20" water gauge. construction and maintenance. A pressure sufficient to maintain a differential of at least 10Pa under all operating conditions is suggested. consideration should be given to enclosing it in a positive pressure envelope. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .g.5 The prevention of recontamination 9.5 The prevention of recontamination 7. As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect against unforeseen circumstances. 08 Author : Validation in Partnership Ltd. The rationale for the decisions taken should be documented. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. An isolator opening to the external environment should be appropriately designed to prevent potential ingress of surrounding room air by induction.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B.07" to 0.5 to 50 Pascals [22].Doc. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. unidirectional or turbulent air flow. The isolator should be designed to be free from leaks that are a microbiological risk and maintained in that state. Air balance between the isolator and other direct interfaces (e. The design of the isolator system should include consideration of air change rate. dry heat tunnel) should also be qualified. Design 3.. : SGD-110-ENV Rev.” 13.5 The prevention of recontamination © Validation in Partnership Ltd 2007 .g.

” © Validation in Partnership Ltd 2007 . aseptic technique. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .1 Principles related to the selection and use of isolators subjected to a sporicidal process.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. Air quality should be monitored periodically during each shift.6 Monitoring and testing 7. : SGD-110-ENV Rev.3 [VIP ID: 190512] “This position leads to an apparent paradox as to whether an isolator that has been subjected to a sporicidal process that demonstrates a classical clean room pattern of the occasional detection of microorganisms. swabs and the presence of sampling points for active air samplers or particle counters during microbiological monitoring may add risk to an isolator subjected to a sporicidal process. e. Air quality should be monitored periodically during each shift. surfaces.5.6 Air change.g. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.” 14.2 [VIP ID: 190504] “Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7.Doc. within the isolator. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 9. the application of aseptic technique and risk of error due to human fallibility. Media used for environmental monitoring should not be exposed to decontamination cycle residues. 9. unidirectional or turbulent airflow. surfaces. Ref.6. as recovery of microorganisms would be inhibited. in an exhaust. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. and ergonomics 7. The rationale for the decisions taken should be documented. within the isolator.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators F. laminar/turbulent. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. The use of settle plates. (See below). we recommend monitoring the exit port for particles to detect any unusual results. and gloves (or half-suits) as well as particle levels. these may include the following: Reduced frequency of autoclaving of indirect product contact parts.1 [VIP ID: 190500] “The design of the isolator system should include consideration of air change rate. 7. Some of the ways this may be addressed include sampling at the end of production and sampling at potentially worst case positions. the presence of microorganisms implies that the validated condition probably no longer prevails and the fault should be identified and corrected. An environmental monitoring programme should be established that routinely ensures acceptable microbiological quality of air. Environmental Monitoring [VIP ID: 112070] “An environmental monitoring program should be established that routinely ensures acceptable microbiological quality of air.6. Extend the allowable period of exposure of sterile surfaces and materials.1. contact plates. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 51 of 185 : 14 May 2007 7. The choice of an isolator that has been subjected to a sporicidal process inevitably drives up the standard. Another factor to take into account is the method of use of the isolator. 08 Author : Validation in Partnership Ltd. the use of laminar. For example. Nutrient media should be cleaned off of surfaces following a contact plate sample. The lower risk of contamination may be used to justify different practices than used in clean rooms. Reduce the need to discard open containers surrounding an intervention via the glove ports. is acceptable for aseptic processing. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. It is difficult to conceive of an isolator that has been subjected to a sporicidal process being designed and validated to assure and demonstrate clean room performance if it is working correctly.” 15.5. and gloves (or half-suits) as well as particle levels.

5. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 52 of 185 : 14 May 2007 PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.” - - PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) © Validation in Partnership Ltd 2007 . contact plates.7 Monitoring and testing 9.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.5 The prevention of recontamination 9. 9.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.2. Quantitative results are not as relevant as in conventional clean rooms because the detection of any contamination probably indicates something has failed. : SGD-110-ENV Rev. in an exhaust.g. Ref.7. may reduce the risk of introducing contamination into the system. Built in sampling systems should be gassed or otherwise assured to be free from contamination and not compromise operations.7.3 [VIP ID: 190616] “The use of settle plates. Conventional sampling may be replaced by ‘in house’ devices known to be sterile. swabs and the presence of sampling points for active air samplers or particle counters may add risk to the system subjected to a sporicidal process. Another risk to the interpretation of results is the presence of a colony that developed prior to irradiation.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. such as settling pots full of media or transport fluid.7. Sampling at potentially worst case positions e. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.7 Monitoring and testing 9. 9.5.Doc.1 [VIP ID: 190612] “Media fills and sterility testing should be carried out as normal for aseptic processing. Some of the ways that this may be addressed include the following: Sampling at the end of production. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.2. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. special arrangements of filters and/or valves may be used.5.5. The fertility of irradiated media should be given special attention. 9.5. by subsequent handling.5.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations.2 [VIP ID: 190614] “Environmental monitoring within the isolator should not interfere with zone protection.7.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations.7.7 Monitoring and testing 9. A significant risk to the interpretation of results is the accidental infection of plates etc. 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. Testing the supplier’s formula at extremes of the irradiation treatment using local isolates as well as standard cultures should be considered. The effect of exposure of wrapped plates etc. but there have been instances when the supplier has made changes or mistakes and compromised processes.7. Large areas of the gloves and isolator surfaces may be swabbed and the swab incubated in sterile broth.5. to the sporicidal process should be examined in case of loss of fertility due to penetration of the agent. 9.5.5 The prevention of recontamination 9. 9.2. 08 Author : Validation in Partnership Ltd.5 The prevention of recontamination 9. and in process controls should not carry any risk for production.5. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. so incubation in sealed sterile pass out bags may be necessary. Using multiple wrapped irradiated plates and swabs etc.

These may include: Gas detection in the isolator/exhaust Gas concentration in the isolator/exhaust Air flow in Air flow out Gas inlet temperature Isolator pressure Pressure drop across filters Airborne particles Condensation detection Temperature of the external surface of the isolator Temperature of internal points in the isolator Humidity in the isolator Absence of alarm conditions Correct operation and position of gas drivers such as fans. 9.” - - 16.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. 9. Loss of integrity of gloves.5. Physical testing of an isolator should be organised to monitor the parameters considered to be critical.5. but the whole sterility assurance system including components.9. mistakes in transfer of materials into the system. . If a clear cause is found. : SGD-110-ENV Rev.1.5.7.7. and intensive monitoring shows no further contamination.5 The prevention of recontamination 9. pumps and evacuation Displacement to expose occluded surfaces Gas concentration during ventilation Process step times.7. failure or aging that could compromise operations. together with their alarm systems.5. formulated drug sterilization. and contaminated settle plates have been implicated as causes based on past experience. A positive media fill unit or positive sterility test unit is a more serious event and the effects on product in the field may have to be considered as there is some evidence of non-sterile product being produced and supplied. 9. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system.1 [VIP ID: 190608] © Validation in Partnership Ltd 2007 . product integrity etc. together with the probability of contamination of product.Doc. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. Ref. 08 Author : Validation in Partnership Ltd.5.7.1 Physical monitoring and testing should be based on a systematic failure mode analysis or a suitable alternative and assure the detection of change.2.7 Monitoring and testing 9. Consideration should be given to the wisdom of releasing product still in house and the continued use of the isolator may not be appropriate. It is only when the cause is found that appropriate action can be taken. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.7 Monitoring and testing 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. In this case the investigation would not only involve possible failure of the isolator to control the environment. and as long as they do not reoccur they may have to be accepted. this may be a case when the slight imperfections of the system are revealed. the implications on existing product could be evaluated based on the likely level and type of environmental contamination. If no clear cause is found after a genuinely searching investigation. on site and any off site sterilization processes.5 The prevention of recontamination 9.4 [VIP ID: 190618] “Evaluation of results The detection of any microorganisms from environmental monitoring inside the isolator should be considered as requiring a full scale investigation.5. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 53 of 185 : 14 May 2007 9.

but the particular risk of chemical contamination of the exhaust filters and potential for blowback into the adjacent critical zone should be considered.4 9. These may include the following: Gas detection in the isolator/exhaust. Temperature of the external surface of the isolator. The testing should be organized to monitor the parameters considered to be critical together with their alarm systems.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. When powders are handled the sampling program should select times and positions to provide relevant information. operational qualification and process qualification are appropriate with the additional provision for periods of development work particularly for the sporicidal process. Gas concentration in the isolator/exhaust. Gas inlet temperature. Isolator pressure.g. The following should be considered. 08 Author : Validation in Partnership Ltd. 9. therefore. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 54 of 185 : 14 May 2007 “The main thrust of control of this type of isolator is physical. : SGD-110-ENV Rev. Temperature/Humidity-depends on process.” © Validation in Partnership Ltd 2007 . Sampling near the point of fill. installation qualification. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. These are general principles of GMP.” 17. Flow rate in exhaust. Airflow in. An isolator subjected to a sporicidal process should undergo a standard qualification approach with the additional provision for periods of development work particularly for the sporicidal process. Pressure drop across filters. Other aspects that should be considered are the principles of dedication to avoid cross contamination and mix up. The delivery of the validated process will involve monitoring parameters and events in addition to those from the gas generator. in the recirculation ducts or exhaust ducts may be more informative. Alarms should be latched so that the occurrence of the alarm is still evident even though the deviation leading to the alarm being triggered has corrected itself. This is valuable when the isolator is left unattended e. Condensation detection. physical monitoring and testing is preeminent. validation and use should arise from the objectives employed to make the decision to use an isolator subjected to a sporicidal process and the consequent user requirements specifications. Isolator pressure. 9. Pressure change across filters. at night. Ref. Standard approaches to design qualification. If it is positioned just to sample a limited output of the air inlet filter it is unlikely to provide useful information. the position of the sampling probe for continuous monitoring should be carefully considered.12 [VIP ID: 190542] “The range of parameters and events that should be monitored to assure the delivery of the validated process should be defined. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.1 Principles related to the selection and use of isolators subjected to a sporicidal process. Absence of alarm conditions. Temperature of internal points in the isolator. Airflow out. 9. Correct operation and position of gas drivers such as fans.Doc.4. It is recognized that the considerations may include operator protection and financial optimization as well as reduced risk of microbiological contamination of the product from the environment. Process step times.1. pumps and evacuation. Airborne particles. Displacement to expose occluded surfaces. Gas concentration during ventilation.1 [VIP ID: 190508] “The principles of design.

9. The design should ensure that the opening should be able to be sealed during gassing or when left unattended. 08 Author : Validation in Partnership Ltd. but the recovery system may not be able to allow organisms exposed to the gassing agent to outgrow. Gas may have absorbed into the material of the BI carrier and into the isolator and load. Transfer of material into or out of the isolator should not compromise the critical zone. calibration and culture of the biological indicator and definition of the final protocols. When transfer out involves transition to another aseptic stage such as a lyophilizer connected to the isolator system.4. The cultural conditions may not be optimized in terms of media.5.5. Details of the handling and culture of biological indicators should be fully investigated and defined for validation of a sporicidal process involving gassing. 9. Ref.5 The prevention of recontamination 9. directional airflow. transition chambers or tunnels and distance from the critical zone. Materials to be transferred into the isolator should comply with 6. or supplier of sterile components.” 19. or use of heat or light sporicidal processes coupled with no direct or indirect product contact.4 Transfer of material out [VIP ID: 190594] “Transfer of material out of the isolator should not compromise the critical zone. When it is impossible (as opposed to inconvenient) to provide a continuous gassed/sterilized/ physical barrier. All these factors combine together to produce the potential for residual lethality which may be outside the controlled lethality delivered by the gassing cycle.5 Transfer of material in [VIP ID: 190596] “Transfer of material into the isolator should not compromise the critical zone. Product and waste should ideally be removed from the isolator without loss of integrity.1 to avoid them carrying contamination into the isolator once it is in its gassed state. 9. This may include manual surface sanitisation. © Validation in Partnership Ltd 2007 . When the BI is eventually placed into the tube of broth or carrier medium prior to culture. development and validation of a sporicidal process involving gassing should include at least the following steps. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. k) The details of handling and culture of the BIs should be fully investigated and defined. isolator. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 55 of 185 : 14 May 2007 18. The design.5 The prevention of recontamination 9. Alternating gassed accumulation airlocks or heat sealed sterile plastic film tube may be applicable depending on the scale of production. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. Transfer to the isolator should be minimized and secure to prevent penetration of contaminants during the transfer process[1].4. the opening should be properly designed. The fertility of the particular batch of media used may have varied. Any small area of the gasket that has been exposed to the external environment and is then exposed to the inside of the isolator should be managed (this includes the 'ring of concern' of rapid transfer ports). the gas absorbed in the BI may not be inactivated and could prevent the outgrowth of survivors. All these possibilities should be studied and taken into account in the design of the testing systems. the design should provide robust methods of preventing penetration by the use of. the transfer should assure the integrity of the isolator as well as the safety of the product. Examples of transfer in scenarios are as follows: Secure transfer ports from a separate autoclave. temperature and time for the outgrowth of survivors. development and validation of the sporicidal process should encompass all relevant aspects from methods of gas distribution to quantification of target lethality. At the end of the gassing phase there will be a lag as the ventilation reduces the gas concentration.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. for example. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. selection.4 9.13 k) [VIP ID: 190564] “The design. : SGD-110-ENV Rev.Doc. formulated drug powder etc. The desorption of this gas may be difficult to predict. During use. The BI organism may be viable after exposure to the gas.

The rationale for the decisions taken should be documented. Design 1. [1] The special problem of the cooling zone in a sterilizing tunnel has been discussed above. Other aseptic processing isolators employ unidirectional airflow that sweeps over and away from exposed sterile materials. The rationale for the decisions taken should be documented. The layout of equipment should provide for ergonomics that optimize comfort and movement of operators. The flow of personnel should be designed to limit the frequency with which entries and exits are made to and from an aseptic processing room and.” 20. To prevent changes in air currents that introduce lower quality air. the use of laminar. autoclaves. The interfaces should be carefully designed to withstand the stresses of extreme temperatures.5 The prevention of recontamination 9. its critical area. avoiding any turbulence or stagnant airflow in the area of exposed sterilized materials. the use of laminar. When intervening doors are opened. To prevent changes in air currents that introduce lower quality air. The number of personnel in an aseptic processing room should be minimized. sterilizing tunnels etc. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. expansion and contraction and retain the integrity of the isolator system. 9. The air handling system should be capable of maintaining the requisite environmental conditions within the isolator. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Buildings and Facilities E. or the surrounding environment. In most sound designs. 08 Author : Validation in Partnership Ltd. or an isolator. unidirectional or turbulent air flow. Ingress of steam and condensate from an autoclave should be prevented. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. the number of transfers into the critical area of a traditional cleanroom. aseptic technique.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. should be minimized.5 The prevention of recontamination 9. the application of aseptic technique and the risk of error due to human fallibility. Ref.5. Regarding the latter. should be minimised. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 56 of 185 : 14 May 2007 - Direct connection between the isolator and other isolators. movement adjacent to the critical area should be appropriately restricted. hot air ovens. unidirectional or turbulent airflow. and container closures. The design of the isolator system should include consideration of air change rate. most significant. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design (para 3) [VIP ID: 110450] “Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product. Airflow (para 2) [VIP ID: 111940] “Turbulent flow can be acceptable within closed isolators.” • The number of transfers into an isolator.6. 9.5. laminar/turbulent.2 [VIP ID: 190602] © Validation in Partnership Ltd 2007 . and ergonomics [VIP ID: 190598] “The design of the isolator system should include consideration of air change rate. there should not be any exposure of non-sterile or non-gassed surfaces or ingress of unfiltered air. container-closures. the application of aseptic technique and the risk of error due to human fallibility. product. air showers over the critical area once and then is systematically exhausted from the enclosure. : SGD-110-ENV Rev.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. which are normally compact in size and do not house processing lines.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.6 Air change. movement adjacent to the critical area should be appropriately restricted.Doc.

it would seem sensible to also gain another increment of sterility assurance and arrange airflows and production operations accordingly. the piston effect of arms entering the sleeves and occlusion. In general the area inside the isolator is the local zone for high risk manipulations. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.” © Validation in Partnership Ltd 2007 .. Ref. to the extent possible in isolators. In general the area inside the isolator is the local zone for high risk manipulations.” • It is recognised that laminar air flow may not exist in the working zone of all isolators.5 The prevention of recontamination 9.5.3. although it is recognised that laminar air flow may not exist in the working zone of all such devices. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . to the extent possible in isolators.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.” • The use of aseptic techniques. The lower air velocity generated by the laminar or unidirectional option may reduce risks of venturi effects and impacts on production operations. During the design of isolators it may be as convenient to arrange for incoming air to be delivered to form a laminar or unidirectional flow or as a turbulent flow.Doc.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 7 (para 2) [VIP ID: 62860] “The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. They may not be protected by positive pressure due to localized sealing effects. although it is recognised that laminar air flow may not exist in the working zone of all such devices.5. In these cases.5. 08 Author : Validation in Partnership Ltd.3 9.” 21. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 57 of 185 : 14 May 2007 “As the absence of microorganisms is expected the questions of laminar flow versus turbulent flow and the rigour of implementation of aseptic procedure may be irrelevant.3. . Glove ports and full or half-suits present particular risks due to the air and surfaces exposed by a leak possibly being microbiologically contaminated due to the proximity of the operator’s body.5 The prevention of recontamination 9.1 [VIP ID: 190588] “Glove ports and full or half suits present particular risks for the following reasons: They are more prone to damage. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.5. The air and surfaces exposed by the leak may be microbiologically contaminated due to the proximity of the operator’s body. 9.. 9. provides additional reduction in the risk to product arising from loss of integrity of sleeves and gloves. : SGD-110-ENV Rev.3 9.MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] “… The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. They may be very close to exposed sterile materials.3 [VIP ID: 190592] “The use of aseptic techniques. provides additional reduction in the risk to product arising from loss of integrity of sleeves and gloves.

There should also be an all encompassing preventative maintenance programme that includes specification of examination and pre-emptive replacements. gaskets. Frequent leak testing. vigilance and the absence of sharp edges. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. and seams should receive daily attention and be addressed by a comprehensive preventative maintenance programme. Ref.MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 9 [VIP ID: 186002] “Monitoring should be carried out routinely and include frequent leak testing of the isolator and glove/sleeve system. 7. There should also be an all encompassing preventative maintenance program that includes specification of examination and preemptive replacements. Preventative maintenance program that includes specification of examination and preemptive replacement” • The integrity of isolator gloves. This should include operator practices.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.5.5 The prevention of recontamination 9.5. vigilance and the absence of sharp edges.” © Validation in Partnership Ltd 2007 . Inner or outer sterile gloves. Sterile inner sleeves or garments. This should include operator practices. Operator training to avoid damage and vigilance to examine for damage. sleeves and suits should be present.3 9. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS.5.3 [VIP ID: 190586] “A program to minimize the risk of loss of integrity of gloves. 08 Author : Validation in Partnership Ltd. 9.5. There should be routine integrity testing and replacement frequencies should be established in written procedures that ensure parts will be changed before they breakdown or degrade.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9.Doc. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . sleeves and suits should be present.3. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 58 of 185 : 14 May 2007 • A programme to minimise the risk of loss of integrity of gloves. There should also be an all encompassing preventative maintenance program that includes specification of examination and preemptive replacements. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. Use of double skinned sleeves where puncture of one or both of the skins causes separation of the two layers and is easily detected by the operator. half-suits.5 The prevention of recontamination 9.2 [VIP ID: 190590] “The analysis of these risks should be documented and preventative actions such as the following should be considered: Selection of robust materials. and seals. vigilance and the absence of sharp edges. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7.3 [VIP ID: 190494] “A program to minimize the risk of loss of integrity of gloves. : SGD-110-ENV Rev. This should include operator practices. as should other parts including transfer systems. 9.5 The prevention of recontamination 7. sleeves and suits should be present.

Maintenance 1. If an isolator transfer port design has the potential to compromise isolation by allowing ingress of air from the surrounding room. gloves should be visually evaluated for any macroscopic physical defect. ultraviolet) or a design that has the potential to compromise isolation by allowing ingress of air from the surrounding room.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators C. Transfer of Materials/Supplies (para 2) [VIP ID: 112000] “Multiple material transfers are generally made during the processing of a batch. transfers are performed via direct interface with manufacturing equipment. Frequently. A breach in glove integrity can be of serious consequence. half-suits.g.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators A. : SGD-110-ENV Rev. The monitoring and maintenance program should identify and eliminate any glove lacking integrity and minimize the possibility of placing a sterile product at risk. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Maintenance 2.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 9. The integrity of gloves. a leak in certain components of the system can constitute a significant breach of integrity.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Properly maintained and operated rapid transfer ports (RTPs) are an effective transfer mechanism for aseptic transfer of materials into and out of isolators. A preventative maintenance program should be established. However. Transfer systems. Maintenance 2. With every use.” 22.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . localised HEPA filtered unidirectional air flow cover should be provided in the area of the port. gaskets.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators A. and seals are among the other parts that should be covered by the maintenance program. we recommend affording attention to the sanitary quality of the inner surface of the installed glove and to integrating the use of a second pair of thin gloves.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators A. are key aspects of good manufacturing practice to be addressed.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . and seams should receive daily attention and be addressed by a comprehensive preventative maintenance program. [VIP ID: 62890] “Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system. Some transfer ports might have significant limitations. coupled with a well-justified replacement frequency. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 59 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Physical integrity tests should also be performed routinely. Replacement frequencies should be established in written procedures that ensure parts will be changed before they breakdown or degrade. Although no isolator forms an absolute seal. very high integrity can be achieved in a welldesigned unit. In the latter © Validation in Partnership Ltd 2007 . Glove Integrity (para 2) [VIP ID: 111920] “Due to the potential for microbial migration through microscopic holes in gloves and the lack of a highly sensitive glove integrity test.. non-isolated aseptic processing operations.Doc. 08 Author : Validation in Partnership Ltd. The choice of durable glove materials. including marginal decontaminating capability (e. General [VIP ID: 111900] “Maintenance of isolator systems differs in some significant respects from the traditional. Ref. Glove Integrity (para 1) [VIP ID: 111910] “A faulty glove or sleeve (gauntlet) assembly represents a route of contamination and a critical breach of isolator integrity.

minimize contamination. ventilation and air conditioning (HVAC). This frequency. opening the isolator to the outside environment. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 60 of 185 : 14 May 2007 case. water). blow/fill/seal equipment used for aseptic production. e.” 23. established during validation studies. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . localized HEPA-filtered unidirectional airflow cover in the area of such a port should be implemented.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators D.4 Quality Risk Management for Facilities. inventory of necessary spare parts). 08 Author : Validation in Partnership Ltd. To determine appropriate product contact materials for equipment and containers (e. gaskets. To determine appropriate utilities (e. compressed air. The frequency adopted between decontamination cycles of an isolator should be established during validation studies and should be re-evaluated and increased.4 Blow/Fill/Seal Technology 1. provided that grade A/B clothing is used.g. Isolators often include a mousehole or other exit port through which product is discharged. flow of material and personnel. steam.MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. power source. open versus closed equipment.Doc. selection of stainless steel grade. heating. if production data indicate deterioration of the microbiological quality of the isolator environment. the frequency adopted should be justified. pest control measures. Equipment and Utilities Design of facility/equipment [VIP ID: 191166] “To determine appropriate zones when designing buildings and facilities.g. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . When an isolator is used for multiple days between decontamination cycles.. Sufficient overpressure should be supplied and monitored on a continuous basis at this location to ensure that isolation is maintained. which is fitted with an effective grade A air shower. Potential uses of quality risk management tools and principles include the options for clean rooms versus isolator technologies. clean rooms versus isolator technologies. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation.1. lubricants). should be reevaluated and increased if production data indicate deterioration of the microbiological quality of the isolator environment. : SGD-110-ENV Rev. Ref. gases.. Decontamination 3. Frequency (para 1) [VIP ID: 112040] “The design of the interior and content of an isolator should provide for its frequent decontamination.” 24.g.. Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment. ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9 (November 2005) Annex II: Potential Applications for Quality Risk Management II. prevention of mix-ups. To determine appropriate preventive maintenance for associated equipment (e. dedicated or segregated facilities/equipment.g.. may be installed in at least a grade C environment.” 7. para 1 © Validation in Partnership Ltd 2007 . To satisfy the European regulatory agencies.

all by the one automatic machine. should enter the classified environment surrounding the BFS machinery.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment. Particular attention should be paid to the background clean room environment in which the equipment is located. 08 Author : Validation in Partnership Ltd. who have been qualified and appropriately gowned. or better.g. container molding or filling steps). parison formation. or better. validation and reproducibility of cleaning-in-place and sterilisation-in-place. Blow/fill/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment. in one continuous operation.” 3. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology A. operator training and clothing. background clean room environment in which the equipment is located. and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .Doc. HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e. Refer to Section V of this document for guidance on personnel training. The environment should comply with the viable and nonviable limits "at rest" and the viable limit only when in operation. depending on the design of the BFS machinery and the surrounding room. containers are formed from a thermoplastic granulate. parison formation. qualification. filled and then sealed. standards. and monitoring. standards. in one continuous operation. provided that grade A/B clothing is used. qualification. Ref. filled and then sealed. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. containers are formed from a thermoplastic granulate.” 2. Equipment Design and Air Quality (para 4) [VIP ID: 112130] “The classified environment surrounding BFS machinery should generally meet Class 100. Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment. container molding or filling steps).. HEPA filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e.000 (ISO 8).MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Blow/fill/seal technology 10 © Validation in Partnership Ltd 2007 . : SGD-110-ENV Rev. A well designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . (para 1) [VIP ID: 62900] “Blow/fill/seal units are purpose built machines in which. all by the one automatic machine. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 61 of 185 : 14 May 2007 [VIP ID: 186004] “Blow/fill/seal units are purpose built machines in which. depending on the design of the BFS machinery and the surrounding room. Refer to Section V of this document for guidance on personnel training. provided that grade A/B clothing is used. and monitoring. Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. Only personnel. Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. To satisfy the FDA. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. para 2 [VIP ID: 186006] “Because of this special technology particular attention should be paid to at least the following: equipment design and qualification. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment.g.MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Blow/fill/seal technology 10. the classified environment surrounding BFS machinery should generally meet Class 100.000 (ISO 8).

leakers. Samples should be taken according to a comprehensive sampling plan that provides data representative of the entire filling operation.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology C. [VIP ID: 2183] “Is room classification system based upon Federal Standard 209d or other?” © Validation in Partnership Ltd 2007 . pressure vacuums. background cleanroom environment in which the equipment is located. It is essential to monitor the microbial air quality. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 62 of 185 : 14 May 2007 (para 2) [VIP ID: 62910] “Because of this special technology particular attention should be paid to.2 Air Cleanliness Specification Note: This section should be read in conjunction with the Cleanroom Classification Table. equipment designs that separate the filling zone from the surrounding environment provide additional product protection.” 4.. there have been various standards used for the classification of clean room environments. Over the years. at least the following: equipment design and qualification.1. CPGM-DB CHAPTER 56 . fill weight. Smoke studies and multi-location particle data can provide valuable information when performing qualification studies to assess whether proper particle control dynamics have been achieved throughout the critical area.Doc. Barriers. which can be freely downloaded from the ‘Downloads’ section of our web site. while preventing any ingress from the adjacent environment. the design considerations 1. Furthermore. microenvironments. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. particles) is critical for sterile drug product manufacture. there may well be additional relevant references in section 7. Equipment Design and Air Quality (para 5) [VIP ID: 112140] “BFS equipment design typically calls for use of specialized measures to reduce particle levels that can contaminate the exposed product. Particles generated during the plastic extrusion.” 5. Provisions for carefully controlled airflow can protect the product by forcing generated particles outward while preventing any ingress from the adjacent environment. : SGD-110-ENV Rev. In contrast to nonpharmaceutical applications using BFS machinery.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 31. Ref. Continuous monitoring of particles can provide valuable data relative to the control of a blow-fill-seal operation. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .” 7. operator training and clothing. Provisions for carefully controlled air flow can protect the product by forcing generated particles outward. It is essential to monitor the microbial air quality. 08 Author : Validation in Partnership Ltd.g. Batch Monitoring and Control (para 1) [VIP ID: 112190] “Various in-process control parameters (e.. air pressure) provide information to monitor and facilitate ongoing process control.DRUG QUALITY ASSURANCE 7356. validation and reproducibility of cleaning-in-place and sterilisation-in-place. As well as the references listed here. and appropriately directed high velocities of sterile air have been found useful in preventing contamination (Ref.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology A. container weight variation. cutting. control of air quality (i. 15). and sealing processes should be controlled.e.

Metric units are preferred.000 as their class limit. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled. at least with respect to people "shopping around" within the Class Limits Chart. 9/11/92).Doc. developing a sampling plan for the number of sampling locations based upon one system using "sloppy" conversion factors. collecting sample volumes based upon another system again with "sloppy" conversion factors. (301-594-0095)” HUMAN DRUG CGMP NOTES.” © Validation in Partnership Ltd 2007 . qualified or validated at a class in the English system need not re-qualify the facility in Metric terms to remain in compliance. The was intended to be the "thrust" of the last editions article. 3 of the Human Drug CGMP Notes Sept 1993). The document serves as a transition from English to Metric units. 08 Author : Validation in Partnership Ltd. We would not object to use of a particle counter designed to sample one cubic foot of air and convert this precisely into the equivalent number of liters. NUMBER 03 (September 1993) Motise's Notebook POLICY EMERGING: 5) [VIP ID: 3656] “Item: Metrification of Federal Standard 209E (Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones. this concern has been largely mitigated in this country. VOLUME 01. In Vol 1. Clean areas. however. Ref. an insufficient number of sampling points could be used. There were two original purposes for this statement. we said it is not acceptable to qualify a clean room in Metric units by performing a mathematical conversion of the English values. First. mathematical conversion of the old English system data into metric units until a sufficient data base has been established to use "pure" metric data. than converting that number using "sloppy" conversion factors into a number to be read against a limit to determine compliance with a specific Class. then using some rounded off conversion factor and suddenly obtaining passing results. [VIP NOTE: The FDA stepped back from this statement in Vol 1. No.MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. Division Contact: Robert Sorensen CSO. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . are classified according to the required characteristics of the environment. HFD-322. 2 of the Human Drug CGMP Notes. (301-295-8095)” 2. Clarification. proposed using 4. In theory. As the finally issued version of FS-209E uses a fairly accurate conversion factor of 3. The degree of cleanliness in the English system would remain acceptable. was to prevent people from playing "mathematical games". para 1 [VIP ID: 185982] “Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Revised Federal Standard 209(e) includes metrification of units of measurement. However. No.530 particles per cubic meter for Class 100. Division Contact: Robert Sorensen. Our position is that a facility that has been properly certified. so both types are presented. The switch from English to Metric as a means of expressing particulate air quality entails some precision of conversation and sampling point differences such that it is not acceptable to qualifying a clean room in Metric units by performing a mathematical conversion of the English values. CSO. VOLUME 01. The second reason was to assure that the number of sampling locations used was properly based upon the system used. obtaining a failing result in the English system. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 63 of 185 : 14 May 2007 HUMAN DRUG CGMP NOTES. NUMBER 02 (May 1993) Motise's Notebook POLICY EMERGING: 1) [VIP ID: 3606] “Item: Metrification of Federal Standard 209E (Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones. The French. we would accept for trending purposes only. We would object to "juggling" the numbers. HFD-322. for the manufacture of sterile products. based upon how "sloppy" a conversion factor was used. so there could be some problem in portions of Europe. : SGD-110-ENV Rev. Requalification in the Metric system may be delayed until it would otherwise have been scheduled or required. 9/11/92).

Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 64 of 185 : 14 May 2007 PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . stopper bowls.20% (guidance value) at the working position.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade B: [VIP ID: 62380] “For aseptic preparation and filling.45 m/s +/. e. For the manufacture of sterile medicinal products 4 grades can be distinguished. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0. Normally such conditions are provided by a laminar air flow work station.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .” © Validation in Partnership Ltd 2007 .g. filling zone. The maintenance of laminarity should be demonstrated and validated. making aseptic connections.Doc. filling zone.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade A: [VIP ID: 62370] “The local zone for high risk operations.36 . open ampoules and vials. Ref. Grade A: The local zone for high risk operations.SUPERSEDED! (July 1996) General 3.36 .MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade C and D: [VIP ID: 62390] “Clean areas for carrying out less critical stages in the manufacture of sterile products. stopper bowls. filling zone.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . 08 Author : Validation in Partnership Ltd.0. Grade A: The local zone for high risk operations.54 m/s (guidance value) at the working position in open clean room applications. e. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. this is the background environment for the grade A zone. : SGD-110-ENV Rev. [ViP ID: 185986] “The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms. making aseptic connections. this is the background environment for grade A zone. Normally such conditions are provided by a laminar air flow work station. A unidirectional air flow and lower velocities may be used in closed isolators and glove boxes. paras 3 to 7 inc. (para 3) [VIP ID: 1369] “For the manufacture of sterile medicinal products there are normally 4 grades of clean areas.MANUFACTURE OF STERILE MEDICINAL PRODUCTS .g.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .g.54 m/s (guidance value) at the working position in open clean room applications. making aseptic connections. stopper bowls. Laminar air flow systems should provide an homogenous air speed of 0. Laminar air flow systems should provide a homogeneous air speed in a range of 0.0. e. Grade B: For aseptic preparation and filling. open ampoules and vials. The maintenance of laminarity should be demonstrated and validated. open ampoules and vials.

500 350. in-process materials. para 8 [VIP ID: 185988] “The airborne particulate classification for these grades is given in the following table.000 3 in operation (b) maximum permitted number of particles/m equal to or above (a) 5 µm 1 (e) 1 (e) 2.000 not defined (f) © Validation in Partnership Ltd 2007 . (b) The particulate conditions given in the table for the "at rest" state should be achieved after a short "clean up" period of 15-20 minutes (guidance value) in an unmanned state after completion of operations. Supporting clean areas can have various classifications and functions.500. and is recommended for the surrounding grade B areas. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone. filling area c.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 65 of 185 : 14 May 2007 3.500. : SGD-110-ENV Rev. Supporting Clean Areas (para 1) [VIP ID: 110260] “Supporting clean areas can have various classifications and functions. and container/closures are prepared. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress.MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. due to the generation of particles or droplets from the product itself. [VIP ID: 2182] “What are the firm's air quality classifications for: a.” CPGM-DB CHAPTER 56 . 3.000 20.000 3. Ref.5 µm (d) A B (c) C (c) D (c) Notes: (a) Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. equipment. formulated products. at rest (b) Grade 0. or transferred.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 30.000 0.500 350. Many support areas function as zones in which nonsterile components.Doc. These environments are soundly designed when they minimize the level of particle contaminants in the final product and control the microbiological content (bioburden) of articles and components that are subsequently sterilized.000 not defined (f) 5 µm 1 (e) 2. exposed product areas b.000 20. surrounding plant areas” 4. held.DRUG QUALITY ASSURANCE 7356.500 3.5 µm (d) 3.000 3. The following references explain the physical and/or microbiological properties of the various air classifications: PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas. Buildings and Facilities B. The particulate conditions for grade A "in operation" given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. 08 Author : Validation in Partnership Ltd.

Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants. B and C. : SGD-110-ENV Rev. the limits are set to 1 particle/m3.000 1 (e) 7 10 100 1 (e) 3 5 50 All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity. (f) The requirements and limits will depend on the nature of the operations carried out.5 µm particles/ft3) Microbiological Active Air Action Levels (c) (cfu/m3) Microbiological Settling Plates Action Levels (c. with a range of plus or minus 20 percent around the setpoint.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV Buildings and Facilities TABLE 1. (d) The guidance given for the maximum permitted number of particles in the "at rest" and "in operation" conditions correspond approximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . The air system should be provided with appropriate terminal filters such as HEPA for grades A.” © Validation in Partnership Ltd 2007 .000 100.000 10. During the clean room qualification it should be shown that the areas can be maintained within the defined limits.45 meters/second (90 feet per minute) has generally been established.000 3. The additional use of settling plates is optional. C and D air grades. cfu/4 hours) ISO Designation (b) > 0.520. the number of air changes should be related to the size of the room and the equipment and personnel present in the room. Critical Area .520 35. As it is impossible to demonstrate the absence of particles with any statistical significance. Ref. Values represent recommended levels of environmental quality. 08 Author : Validation in Partnership Ltd.5 µm particles/m3 100 1.000 a b c d e 5 6 7 8 3. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A.Air Classifications (a) [VIP ID: 110160] Clean Area Classification (0.5 µm.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .200 352.Class 100 (ISO5) (para 6) [VIP ID: 110230] “HEPA-filtered [4] air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 66 of 185 : 14 May 2007 (c) In order to reach the B. ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. 3) [5] [4] High Efficiency Particulate Air filter [5] A velocity of 0. Higher velocities may be appropriate in operations generating high levels of particulates.d) (diam. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref.Doc. (e) These areas are expected to be completely free from particles of size greater than 5 µm. 90mm.

due to the generation of particles or droplets from the product itself. Ref. The air system should be provided with appropriate terminal filters such as HEPA for grades A. (b) The particulate conditions given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations. As it is impossible to demonstrate the absence of particles with any statistical significance the limits are set to 1 particle/ m3. B and C.5 µm (d) A B (c) C (c) D (c) 3. In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.5 µm.000 20. Buildings and Facilities A.000 20.g.500 350. Once relevant parameters are established.Doc.500 3. It is important to note that even successfully qualified systems can be compromised by poor operational.500.500. interventions) and equipment design. : SGD-110-ENV Rev.000 3 in operation (b) maximum permitted number of particles/m equal to or above (a) 5 µm 1 (e) 1 (e) 2. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress.500 350.000 3.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . (c) In order to reach the B.000 not defined (f) (a) Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. or personnel practices. from an adjoining lower classified area). (e) These areas are expected to be completely free from particles of size greater than or equal to 5 µm.. The particulate conditions for grade A “in operation” given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment.. it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. C and D air grades.g. (d) The guidance given for the maximum permitted number of particles in the “at rest” and “in operation” conditions correspond approximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0. and is recommended for the surrounding grade B areas. and include evaluation of the impact of aseptic manipulations (e.000 not defined (f) 5 µm 1 (e) 2.000 0. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 [Table and Notes] [VIP ID: 62400] at rest (b) Grade 0. (f) The requirements and limits will depend on the nature of the operations carried out.5 µm (d) 3. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 67 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Critical Area . maintenance.000 3. the number of air changes should be related to the size of the room and the equipment and personnel present in the room.” © Validation in Partnership Ltd 2007 . 08 Author : Validation in Partnership Ltd.Class 100 (ISO5) (para 7) [VIP ID: 110240] “Proper design and control prevents turbulence and stagnant air in the critical area. The studies should be well documented with written conclusions. During the clean room qualification it should be shown that the areas can be maintained within the defined limits.

GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .06 inches of water gauge. A smaller number of controlled environments are provided by clean rooms.” © Validation in Partnership Ltd 2007 .Doc. Buildings and Facilities C. Maintaining a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide beneficial separation. There are various options for controlled environments for aseptic operations. of Grade A complying with the PIC/S and EC guide to GMP. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. outward airflow should be sufficient to minimize ingress of contamination. When doors are open. If this pressure differential drops below the minimum limit. equipment cleaning).g.3 [VIP ID: 190414] “Controlled environments for aseptic operations are currently mainly provided by conventional clean rooms. Buildings and Facilities C. it is important to achieve a proper air flow from areas of higher cleanliness to adjacent less clean areas. at a minimum.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. When isolators are used for sterility testing there is no formal requirement for them to be placed in a Grade D environment. Manufacturers can also classify this area as Class 1. : SGD-110-ENV Rev. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 68 of 185 : 14 May 2007 5.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. Buildings and Facilities B.g. it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. FDA recommends that the area immediately adjacent to the aseptic processing line meet. allow access only to trained staff. In any facility designed with an unclassified room adjacent to the aseptic processing room. For example. it is important that the environmental quality of the aseptic processing room be restored and confirmed. 08 Author : Validation in Partnership Ltd. Clean Area Separation (para 1) [VIP ID: 110280] “An essential part of contamination prevention is the adequate separation of areas of operation. Class 10. 4).CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. of Grade B. of Grade D or better containing equipment called isolators providing a Grade A environment.000 (ISO 7) standards (see Table 1) under dynamic conditions. Ref.04-0. at least 12. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination. Supporting Clean Areas (para 2) [VIP ID: 110270] “The nature of the activities conducted in a supporting clean area determines its classification. The environment should be controlled e.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .000 (ISO 6) or maintain the entire aseptic filling room at Class 100 (ISO 5). containing workstations. INTRODUCTION 2. but not necessarily classified.. To maintain air quality.” 6. a positive pressure differential of at least 10-15 Pascals (Pa) [6] should be maintained between adjacent rooms of differing classification (with doors closed). An area classified at a Class 100. Clean Area Separation (para 2) [VIP ID: 110290] “In some cases. [6] Equal to 0. a substantial overpressure (e. and it is critical that the time a door can remain ajar be strictly controlled (Ref.g. To maintain air quality. the aseptic processing room and adjacent cleanrooms have the same classification.000 (ISO 8) air cleanliness level is appropriate for less critical activities (e..

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The following operations need to be performed in at least a Grade A (Class 100) environment:
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. para 3 [VIP ID: 186012] “Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. ...” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 1 [VIP ID: 186014] “... Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 2 [VIP ID: 186016] “… if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 3 [VIP ID: 186018] “Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 4 [VIP ID: 186020] “Transfer of partially closed containers, as used in freeze drying, should, prior to the completion of stoppering, be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 5 [VIP ID: 186022] “Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.”

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 9 [VIP ID: 186346] “Open circuit operations involving products or components not subsequently sterilized should be carried out within a laminar air flow work station (grade A) in a grade B area.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 2) [VIP ID: 110190] “This area is critical because an exposed product is vulnerable to contamination and will not be subsequently sterilized in its immediate container. To maintain product sterility, it is essential that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be controlled and maintained at an appropriate quality. One aspect of environmental quality is the particle content of the air. Particles are significant because they can enter a product as an extraneous contaminant, and can also contaminate it biologically by acting as a vehicle for microorganisms (Ref. 2). Appropriately designed air handling systems minimize particle content of a critical area.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 3) [VIP ID: 110200] “Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations would be of appropriate particle quality when it has a per-cubic-meter particle count of no more than 3520 in a size range of 0.5 µm and larger when counted at representative locations normally not more than 1 foot away from the work site, within the airflow, and during filling/closing operations. This level of air cleanliness is also known as Class 100 (ISO 5).” PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 11. COMPONENT PREPARATION Preparation of Components 11.7 [VIP ID: 185164] “The premises used for the production of blood components in an "open process" should preferably be a grade A environment with a grade B background, as defined in the current European Guide to Good Manufacturing Practice, Annex 1. A less stringent environment may be acceptable if in combination with additional safety measures such as preparing the blood component just in time for transfusion or immediately after preparation applying storage conditions which are unfavourable to microbial growth. Personnel performing open processing should wear appropriate clothing and should receive regular training in aseptic manipulations. Aseptic processing must be validated. ('Open' processing involves a breach of the integrity of the 'closed system', and as a consequence, a risk of microbial contamination).” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.1 [VIP ID: 190250] “The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room, or in an isolator that need not be located within a controlled environment. The test may also be performed within a class A clean room, if available. Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow.”

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Terminally sterilised products 11. (para 3) [VIP ID: 1419] “Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. …” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 1) [VIP ID: 1420] “... Handling of sterile starting materials and components, unless subjected to sterilization or filtration through a microorganism-retaining filter later in the process, should be done in a grade A environment with grade B background.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 2) [VIP ID: 1421] “… if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 3) [VIP ID: 1422] “Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 4) [VIP ID: 1423] “Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying, should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 5) [VIP ID: 1424] “Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 9. [VIP ID: 1595] “Open circuit operations involving products or components not subsequently sterilised should be carried out within a laminar air flow work station (grade A) in a grade B area.”

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para 2 [VIP ID: 186010] “Filling of products for terminal sterilisation should be done in at least a grade C environment.MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10.02.. filled and then sealed.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . para 2 [VIP ID: 186016] “Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment. The following operations need to be performed in at least a Grade C environment: PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .13 STERILE PRODUCTS .. preparation should be done in a grade C environment. creams. The environment should comply with the viable and nonviable limits "at rest" and the viable limit only when in operation. .MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12..4 [VIP ID: 66540] “WHAT ARE THE ROOM CLASSIFICATION REQUIREMENTS FOR THE CAPPING (CRIMPING) OPERATION OF ASEPTICALLY FILLED VIALS (WITHOUT TERMINAL STERILIZATION)? © Validation in Partnership Ltd 2007 .13.Doc. Ref. containers are formed from a thermoplastic granulate. Where there is unusual risk to the product because of microbial contamination.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. for example. all by the one automatic machine.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . suspensions and emulsions should generally be done in a grade C environment before terminal sterilisation.. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 72 of 185 : 14 May 2007 Selected FDA 483 Observations (July 2000) Sterile Product Manufacture [VIP ID: 16080] “Local Class 100 LAF units used to provide localized protection for performing aseptic connections in a class 10. Preparation and filling of ointments.” 8. : SGD-110-ENV Rev. para 3 [VIP ID: 186012] “. because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels.MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. provided that grade A/B clothing is used.000 area should be validated to include environmental monitoring during use. para 1 [VIP ID: 186004] “Blow/fill/seal units are purpose built machines in which. para 1 [VIP ID: 186008] “.. .” HEALTH CANADA .GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment. in one continuous operation.C.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.. 08 Author : Validation in Partnership Ltd..” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .029 2..

SUPERSEDED! (July 1996) Aseptic preparation 12. .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 ... For aseptically filled vials. The conveyor belts for aseptically filled products must not re-enter Grade A or B from an area of lower cleanliness unless they are continuously sterilized (as per Interpretation 5 in the equipment sub-section of C. Preparation and filling of ointments. When this filling/stoppering is finished. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 73 of 185 : 14 May 2007 It is important to distinguish between filling/stoppering and crimping which are 2 different operations requiring different environmental conditions. be segregated and disposed off in accordance with SOP.. (para 1) [VIP ID: 1417] “.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . Equipment utilization logs should indicate line stoppages and time lapses. the filling/stoppering must be performed under Grade A conditions with a Grade B background.. - Another important point to consider is the validation of the entire aseptic process including periodic verifications by media-fills.SUPERSEDED! (July 1996) Terminally sterilised products 11.SUPERSEDED! (July 1996) Terminally sterilised products 11. The distance between the exit of the Grade A/B to the actual point of crimping in the lower environment should be kept as short as possible. it is considered that a Grade C environment. for example.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . Where there is unusual risk to the product because of microbial contamination. Ref.02. when in operation.. Procedures are in place to ensure that the stoppers are properly seated prior to the crimping operation. the product is usually taken to a lower grade environment by means of a conveyor belt where the crimping is performed. The following must also be considered: The crimping should be done as soon as possible after the stoppering.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . (para 2) [VIP ID: 1421] “Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment..029). (para 2) [VIP ID: 1418] “Filling of products for terminal sterilization should be done in at least a grade C environment. creams.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . 08 Author : Validation in Partnership Ltd. : SGD-110-ENV Rev. Stoppered vials which do not get crimped within the established time lapse. suspensions and emulsions should generally be done in a grade C environment before terminal sterilization. (para 3) [VIP ID: 1419] “. because the product actively supports microbial growth or must be held for a long period before sterilization or is necessarily processed not mainly in closed vessels. is the minimal grade to be used for the crimping operation.Doc.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . preparation should be done in a grade C environment.” © Validation in Partnership Ltd 2007 .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .SUPERSEDED! (July 1996) Terminally sterilised products 11. Because complete integrity may not yet be achieved at this point.

Isolators are constructed of various materials more or less prone to puncture and leakage.MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] “The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. : SGD-110-ENV Rev. para 1 [VIP ID: 186004] “… Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment. although it is recognised that laminar air flow may not exist in the working zone of all such devices.” © Validation in Partnership Ltd 2007 . The air classification required for the background environment depends on the design of the isolator and its application. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . Total containment work stations may provide these requirements. In general the area inside the isolator is the local zone for high risk manipulations.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. They should be in an environment conforming to at least grade D.Doc.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . para 1 [VIP ID: 186008] “Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination. It should be controlled and for aseptic processing be at least grade D. .MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. Ref.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 .. There are many possible designs of isolators and transfer devices. The following operations need to be performed in at least a Grade D environment: PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 74 of 185 : 14 May 2007 9.MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12.. 08 Author : Validation in Partnership Ltd. suitable for filtration and sterilisation.. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms. . The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. para 1 [VIP ID: 186014] “Components after washing should be handled in at least a grade D environment.MANUFACTURE OF RADIOPHARMACEUTICALS PREMISES AND EQUIPMENT 4 [VIP ID: 186286] “For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products.MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11.

or better.” HEALTH CANADA . qualification. it is not mandatory to use containers and packaging materials that are sterile but those that are in direct contact with the product should be free of pyrogen. Methods used for opening bags.6 [VIP ID: 66560] “WHAT ARE THE ROOM CLASSIFICATION REQUIREMENTS FOR THE PREPARATION OF CONTAINERS AND OTHER PACKAGING MATERIALS TO BE USED IN THE FABRICATION OF STERILE PRODUCTS? The preparation (cleaning. depending on the design of the BFS machinery and the surrounding room. dry heat oven).g.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 14 .02.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 10 PREMISES AND EQUIPMENT 3 [VIP ID: 186668] “Where products or clean components are exposed.g. etc. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery. : SGD-110-ENV Rev. Refer to Section V of this document for guidance on personnel training. container molding or filling steps).CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology A. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels.C. After these operations.13 STERILE PRODUCTS . and monitoring.MANUFACTURE OF PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA PRODUCTION AND QUALITY CONTROL 22 [VIP ID: 187022] “In order to minimise the microbiological contamination of plasma for fractionation or the introduction of foreign material. The cleanroom requirements for all other open manipulations should conform to the requirements of Annex 1 of the PIC/S guide to GMP. wearing the appropriate clothing and in addition face masks and gloves should be worn. © Validation in Partnership Ltd 2007 . pooling and thawing should be regularly monitored.GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.13. the containers and materials used for drugs sterilized by filtration (and not further subjected to terminal sterilization in their final containers) must be depyrogenated and sterilized before being introduced in the aseptic rooms by the use of double-ended sterilizers or any other validated method. HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e. For products submitted to terminal sterilization. Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. 08 Author : Validation in Partnership Ltd.000 (ISO 8).Doc. the area should be fed with filtered air. standards.) of containers and packaging materials is normally performed in a "clean" room (grade C or D). parison formation. washing.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2. the thawing and pooling should be performed at least in a grade D clean area. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 75 of 185 : 14 May 2007 PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 4 .MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICALS STERILE VETERINARY MEDICINAL PRODUCTS 10 [VIP ID: 186320] “Where this has been accepted by the competent authorities. e. but at least in a grade D environment.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . should comply with the requirements of at least a Grade D environment and should be entered through airlocks. The depyrogenation step can be done using pyrogen-free WFI for the last rinse prior sterilization or by performing the depyrogenation and sterilization in one operation using a dry heat oven.029 2.. by testing for bioburden. Ref. Filling of these products normally takes place in a class A with a B background. terminally sterilized veterinary medicinal products may be manufactured in a clean area of a lower grade than the grade required in the annex on "Sterile preparations". This is usually achieved by using pyrogen-free WFI for the last rinse of these materials unless they are subsequently depyrogenated by another method (ex. Equipment Design and Air Quality (para 4) [VIP ID: 112130] “The classified environment surrounding BFS machinery should generally meet Class 100.

MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Premises and equipment 4.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 . (para 1) [VIP ID: 1417] “Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination. background clean room environment in which the equipment is located.. [VIP ID: 1562] “For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. ..” © Validation in Partnership Ltd 2007 .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 04 .MANUFACTURE OF STERILE MEDICINAL PRODUCTS .” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .MANUFACTURE OF STERILE MEDICINAL PRODUCTS .MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Sterile veterinary medicinal products 10. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 76 of 185 : 14 May 2007 In addition. : SGD-110-ENV Rev. the initial bioburden of these materials should meet pre-established limits (that are based on sound science) and the risk of contamination during their introduction in the filling areas should be kept to a minimum.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . operator training and clothing.SUPERSEDED! (July 1996) Terminally sterilised products 11. . [VIP ID: 1580] “Where this has been accepted by the competent authorities. (para 2) [VIP ID: 1412] “… The air classification required for the background environment depends on the design of the isolator and its application.SUPERSEDED! (July 1996) Isolator technology 7.. terminally sterilized veterinary medicinal products may be manufactured in a clean area of a lower grade than the grade required in the annex on "Sterile preparations". para 2 [VIP ID: 186006] “Because of this special technology particular attention should be paid to at least the following: equipment design and qualification. Total containment work stations may provide these requirements.Doc. They should be in an environment conforming to at least grade D.MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. but at least in a grade D environment. Ref. It should be controlled and for aseptic processing be at least grade D. and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . suitable for filtration and sterilisation. validation and reproducibility of cleaning-in-place and sterilisation-in-place. (para 1) [VIP ID: 1420] “Components after washing should be handled in at least a grade D environment.MANUFACTURE OF STERILE MEDICINAL PRODUCTS .. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports.SUPERSEDED! (July 1996) Aseptic preparation 12. 08 Author : Validation in Partnership Ltd.

The final stage of the changing room should. Nothing has been firmed up yet. Although we believe it is necessary to monitor and validate the environmental quality of the rooms housing such chambers. VOLUME 02. be the same grade as the area into which it leads. dedicated equipment and air handling systems. there is no set answer. Design and construction. They should be flushed effectively with filtered air. Motise. in the "at rest" state. In general hand washing facilities should be provided only in the first stage of the changing rooms. Division Contact for Further Info: Terry Munson. 08 Author : Validation in Partnership Ltd. and. be the same grade as the area into which it leads. we consider this level of air cleanliness to be prudent and acceptable. We would not expect particle counts. of course. NUMBER 01 (March 1994) Motise's Notebook POLICY QUESTIONS: 4) [ViP ID: 3766] “What clean room classification is required for environments which house aseptic processing isolation chambers? Reference: 21 CFR § 211. Guideline on Sterile Drug Products Produced by Aseptic Processing. though not strictly a CGMP requirement. per se to be as important as what those particles are. NUMBER 04 (December 1994) Motise's Notebook POLICY QUESTIONS: 4) [VIP ID: 3854] “What quality standard should be set for air around a capsule repacking machine where the capsules contain alpha blocker drugs? References: 21 CFR 211.Doc. in terms of particulates and microbial content. HFD-323. HFD-322. As part of future CGMP revisions.” © Validation in Partnership Ltd 2007 . Integrity breeches would permit entry of contaminants from the unit's surrounding environment. Temperature and humidity controls may also be smooth operation of the equipment. (301-594-0095). 301-594-1089. however. air filtration.” 11. Design and construction features. such as we encounter in penicillin production would warrant separation of facilities. and design an environment and containment provisions that would avoid putting other products at risk. new drug application reviewers have been calling for controlled environments that meet class 10. Until the regulations are modified. In the case described. unfortunately. The final stage of a changing room should. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. and 211. we are reviewing the need to extend the penicillin separation provisions to other drugs that might pose unique health hazards. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 77 of 185 : 14 May 2007 10. would be the matter of dust removal and containment to prevent cross contamination. air heating and cooling. but the concept is under review. more important than air quality itself. we would advise the firm to evaluate the potential cross contamination problem. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . high quality environments in which humans are not a potential source of contaminants. need control in a "clean room" environment where sterility must be preserved.42.42(10). HUMAN DRUG CGMP NOTES. Isolation chambers are used to aseptically assemble drug products within highly contained.” HUMAN DRUG CGMP NOTES. and the danger they may present if they found their way into other products.000 conditions for the rooms.MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 27 [VIP ID: 186052] “Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. along with separation of personnel. : SGD-110-ENV Rev.46. Until more formal policy is established. A severe cross contamination problem. For some operations there is no specified environment. We've had similar inquires before and. in the ‘at rest’ state. Ref. The need to maintain the integrity of the environments within such chambers is obviously critical. VOLUME 02. However. Division Contact for Further Info: Paul J. FDA has published no formal FDA policy on air quality for the rooms housing isolation chambers. The key is to identify the most significant potential problem Particulates and microbial counts. We encourage use of isolation chambers. Ventilation.

Label areas and annotate plan with names.. Ref. STERILITY TEST FACILITIES 8. They should be flushed effectively with filtered air.1 Simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required). which includes the laminar airflow cabinet or isolator. Plans could be on A3 sheets of paper if considered necessary. within a sterility test facility.2 [VIP ID: 190252] “The test environment. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 78 of 185 : 14 May 2007 EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . 08 Author : Validation in Partnership Ltd.” 14.g. or barrier isolator system. SPECIAL PRODUCTION SITUATIONS D.” 12.3.1. C.g. Some examples of workstations include a laminar air flow workbench. which includes the laminar air flow cabinet or isolator.1 Classification 8. : SGD-110-ENV Rev. C. The final stage of the changing room should. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 27 (para 1) [VIP ID: 63180] “Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing.1 CLEAN ROOM DESIGN 8.1.1.3.1 Provide a site plan highlighting production areas.1. an air classification of Class 100). GUIDANCE C.1.3. PE 008-2 1 ANNEX EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE (July 2004) REQUIREMENT C. a Site Master File should include details of room and area classification and pressure differentials between adjoining areas of different classifications. in the at-rest state. The test environment.1 [VIP ID: 185430] “REQUIREMENT C.APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI.Doc. For sterile product areas.2 Provide a simple plan of each production area with indication of scale. should be certified at least annually by a competent person for compliance with the specified standard conditions.1 C. …” 13. The following examples are recommendations that should be considered: Conducting aseptic manipulation in an aseptic workstation under laminar flow conditions (e. Sterile Products/Aseptically Processed Products [VIP ID: 183918] “We recommend that special precautions be taken for investigational new drugs intended to be sterile.3 Plans should be legible and on A4 sheets of paper.3.3 PREMISES AND EQUIPMENT Premises REQUIREMENT C.4 For sterile product areas indicate room and area classification and pressure differentials between adjoining areas of different classifications.3. Thorough consideration should be given to controls for aseptic processing. be the same grade as the area into which it leads. biosafety cabinets. should be certified at least annually by a competent person for compliance with the specified standard conditions. Consideration should be given to conducting aseptic manipulations in an aseptic workstation under laminar flow conditions (e.” © Validation in Partnership Ltd 2007 . GUIDANCE FOR INDUSTRY INDS .1.3. C.1. with an air classification of Class 100).3.

The air cleanliness class of each area should be identified (e. A.000. Equipment within barrier or isolation systems should be noted.. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 79 of 185 : 14 May 2007 7.” © Validation in Partnership Ltd 2007 . The air cleanliness class of each area should be identified (e. Class 10.” STERILIZATION PROCESS VALIDATION . but not limited to. filling heads. The placement of all critical equipment such as laminar flow hoods. You disagreed with the investigator’s observation in that HEPA-filtered air is not necessary for each of the **** clean rooms (Class **** because the aseptic processing is being performed under the biological hoods that are equipped with HEPA filters.g..000).SUPERSEDED! (January 1993) II. 2. should be identified. gowning rooms.Doc. laminar flow hoods. Class 100.” 2. A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas. lyophilizers. GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. your firm was cited for not providing HEPA-filtered air into the **** clean rooms as required by 21 CFR 211. etc. 2. Class 100. Ref. Air Heating and Cooling [FDA-483 Item 3].000. should be identified.).3 Drawings 1. (3) the specific ratings of each of the successive filters found in the HVAC system that serve the Class **** clean room. [VIP ID: 3030] “Provide a brief description of the building and facilities. FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42760] “With regard to the air filtration system. filtering and filling areas.46(c) Ventilation. The following information should be included: 1. and (4) diagrams/ charts of the HVAC system. autoclaves. filtering and filling areas. Isolators or barrier systems should be identified. Class 100. (2) data from a routine environmental monitoring program. : SGD-110-ENV Rev. This should include the following types of information: 1. Floor Plan A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas. Buildings and Facilities [VIP ID: 17240] “A brief description of the manufacturing building and facilities should be provided. The information to be provided in Drug Applications for Aseptic Fill Manufacturing Processes should include a floor plan of the areas holding the aseptic filling facilities showing the air cleanliness class of each area and the placement of all critical equipment such as laminar flow hoods. A.000. Diagrams should be available for HVAC systems serving clean rooms. Air Filtration. Location of Equipment The placement of all critical equipment. autoclaves. Class 100.g. including. etc. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. etc. and filling heads. lyophilizers. and gowning rooms should be included. Your justification is not adequate because you have not provided supporting documentation of (1) air cleanliness qualification data. 08 Author : Validation in Partnership Ltd.Class 10.

3. Ref.3. For sterile product areas a summary of the results of the most recent qualification/requalification should be given Note 2: To reduce the narrative.3.3 The limits for changing the filters should be given. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 .3.3 [VIP ID: 185434] “REQUIREMENT C. Specification of the air supply Temperature Humidity Pressure differentials and air change rate Simple pass or recirculation (%) C. Classification of the rooms used for the manufacture of sterile products should be mentioned.g.3 PREMISES AND EQUIPMENT Premises REQUIREMENT C. : SGD-110-ENV Rev.3. Plans of contained and/or clean area premises.3. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 80 of 185 : 14 May 2007 3. The following data should be given: C.g. C.” 4. Air (para 3) [VIP ID: 2668] “Review the compressed air system and determine if it is filtered at the point of use to control particulates.1 Design criteria e.” © Validation in Partnership Ltd 2007 . They should indicate which pressure gradients are monitored by pressure indicator. C. Diagrams of HEPA filtered air systems should be reviewed and evaluated.4 If DOP (dioctyl-phthalate) is introduced.3.3 Brief description of ventilation systems. Details of any alarms on the ventilation system should be given. (para 5) [VIP ID: 1610] “Plans of contained and/or clean area premises. (500 words/two A4 pages) Note 1: More details should be given for critical areas with potential risks of airborne contamination. filters and their specifications. should describe the ventilation system indicating inlets and outlets. the number of air changes per hour.Doc.5 Give the frequency of revalidation of the system. C. filters and their specifications.Hepa 99.3. the number of air changes per hour.3. They should indicate which pressure gradients are monitored by pressure indicator.CGMPR'S (October 1993) 1. Diagrams of the HEPA filtered and compressed air systems should be reviewed and evaluated. PE 008-2 1 ANNEX EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE (July 2004) REQUIREMENT C. and pressure gradients. should describe the ventilation system indicating inlets and outlets.Bag 99% eff. Schematic drawings of ventilation systems are desirable in a Site Master File. GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS .3.3. the point must be shown.3 Brief Description of Ventilation Systems etc. and pressure gradients.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 20.2 Filter design and efficiency e. GUIDANCE C. schematic drawings should be used. . granulation and tabletting.3.3.997% eff. This will include sterile product areas as well as areas for processing powders. . More details should be given for critical areas with potential risks of airborne contamination (schematic drawings of the systems are desirable). 08 Author : Validation in Partnership Ltd.” 5.

Air Heating and Cooling [FDA-483 Item 3]. : SGD-110-ENV Rev. FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42760] “With regard to the air filtration system.” 7.46(d). In addition. equipment. There should be blueprints or diagrams available showing that an air handling system serving an area where penicillin drug products are processed is separate from an air handling system used for non penicillin drug products.46(c) Ventilation. Your firm has not established minimal personnel.4 Filtration 1. Selected FDA 483 Observations (February 2004) Sterile Product Manufacture [VIP ID: 71060] “The Quality Unit should review and approve engineering drawings/diagrams provided by engineering firms performing Environmental Control/HVAC System modifications. minimal containment controls. the firm could not verify through blueprints or diagrams that the air handling system for the repackaging of penicillins is separate from the air handling system used for repackaging non-penicillin drug products that is required by 21 CFR 211. © Validation in Partnership Ltd 2007 . The Quality Unit should review and approve engineering drawings/diagrams provided by engineering firms performing Environmental Control/HVAC System modifications. There should be specifications for the ratings of all HEPA filters installed in HVAC systems serving clean areas. FDA Warning Letter [Reference Obliterated] (February 2004) Extracted from FDA warning letter USA 27/02/2004 [VIP ID: 126210] “2. Failure to separate completely the air handling systems for the packing of penicillin products and non-penicillin beta-lactam drug products from non-penicillin drug products.42(c) and (d). your firm was cited for not providing HEPA-filtered air into the **** clean rooms as required by 21 CFR 211. (3) the specific ratings of each of the successive filters found in the HVAC system that serve the Class **** clean room. Ref. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 81 of 185 : 14 May 2007 6.” 2.42(c) and 211. You disagreed with the investigator’s observation in that HEPA-filtered air is not necessary for each of the **** clean rooms (Class **** because the aseptic processing is being performed under the biological hoods that are equipped with HEPA filters. Your justification is not adequate because you have not provided supporting documentation of (1) air cleanliness qualification data. and material movement controls. HEPA filter integrity testing should include: • laminar flow velocity measurements within 12" of the work surface • confirmation of uniform velocities between HEPAs related to common plenums • acceptance criteria defining leakage as a percentage of the challenge agent • measurement of the distance between smoke entry and exit planes during laminar air flow (smoke) studies to ensure the flow is laminar • more than just a narrative report to fully and accurately assess air flow patterns. and (4) diagrams / charts of the HVAC system.” 7. These controls must also be applied to the re-packing of non-penicillin beta-lactam drug products (cephalosporin). [21 CFR 211. (2) data from a routine environmental monitoring program. Air Filtration. 08 Author : Validation in Partnership Ltd.46(d)] The same air handling system is used for the repackaging of penicillin and cephalosporins in violation of 21 CFR 211.Doc. and other control systems to prevent crosscontamination.

” Selected FDA 483 Observations (December 1999) Sterile Product Manufacture [VIP ID: 8730] “There should be a specification for the maximum surface area of HEPA filter that can be repaired prior to replacement. (4) how the percentage of patching will be tracked throughout the life of the HEPA filter. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 82 of 185 : 14 May 2007 Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 19420] “HEPA filter integrity testing should include: a) LAF velocity measurements within 12" of the work surface b) confirmation of uniform velocities between HEPAs related to common plenums c) acceptance criteria defining leakage as a percentage of the challenge agent d) the measurement of the distance between smoke entry and exit planes during laminar airflow (smoke) studies to ensure the flow is laminar e) more than just a narrative report to fully and accurately assess airflow patterns” 3. HEPA filter procedures should address: • the maximum allowable size of any leak.Doc. VOLUME 04.” Selected FDA 483 Observations (April 1998) Sterile Product Manufacture [VIP ID: 6378] “Procedures for the performance testing/monitoring of HEPA filters should specify: a. NUMBER 04 Motise's Notebook POLICY QUESTIONS: Question 4 [ViP ID: 2954] Selected FDA 483 Observations (July 2001) Sterile Product Manufacture [VIP ID: 40260] “HEPA filter procedures should address the following: (1) the maximum allowable size of any leak which can be patched (2) the minimum cure time or set time between patching of the HEPA and turning the air handling unit back on. Ref. The maximum air velocity above which the HEPA filter must be replaced. (3) the distance from the filter face that velocity measurements shall be taken from. A specification pertinent to HEPA filter to HEPA filter variation in the Aseptic core particularly above the filling and stoppering line. b. which can be patched or sealed • the minimum cure time or set time between patching of the HEPA and turning the air handling unit back on • the distance from the filter face that velocity measurements shall be taken from • how the percentage of patching will be tracked throughout the life of the HEPA filter • a specification pertinent to HEPA filter to HEPA filter variation • the maximum air velocity above which the HEPA filter must be replaced.” © Validation in Partnership Ltd 2007 . HUMAN DRUG CGMP NOTES. : SGD-110-ENV Rev. The specification for the maximum limit on the size of any individual HEPA leak that may be patched or sealed. 08 Author : Validation in Partnership Ltd. c.

the first of which is continuously monitored for integrity. (f) require HEPA leak testing of all filters supplying air to the sterile suite. 08 Author : Validation in Partnership Ltd.” 6. (d) require the review/approval of data and describe the remedial actions if specifications are not met. [VIP ID: 1597] “Containment premises should be easily disinfected and should have the following characteristics: … (c) air from manufacturing areas used for the handling of exotic organisms should be vented through 2 sets of HEPA filters in series. [VIP ID: 1597] “Containment premises should be easily disinfected and should have the following characteristics: … (b) a ventilation with air at negative pressure. Standard Operating Procedures for HEPA certification should: • indicate the frequency of certification • indicate the frequencies of each individual test • include the specification for velocity checks • require the review/approval of data • describe the remedial actions if specifications are not met • describe and require all tests done under the programme • require HEPA leak testing of all filters supplying air to a sterile suite. recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs. Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27740] “Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 83 of 185 : 14 May 2007 4. Air should be extracted through HEPA filters and not be re circulated except to the same area. and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). (c) include a specification for velocity checks.Doc. Air from containment premises should only be recirculated to other areas if it passes through two exhaust HEPA filters. Selected FDA 483 Observations (June 2002) Sterile Product Manufacture [VIP ID: 47190] “Standard Operating Procedures (SOPs) for HEPA certification should: (a) indicate the frequency of certification. Ref.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 11. (e) describe and require all tests done under the program. and there are adequate measures for safe venting of exhaust air should this filter fail. Air from manufacturing areas used for the handling of exotic organisms should be vented through two sets of HEPA filters in series and not recirculated.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 11. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 . Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year. (b) indicate the frequencies of each individual test. and that from production areas not recirculated. : SGD-110-ENV Rev. …” © Validation in Partnership Ltd 2007 . EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 .” 7. However.” 5.

2. which should be fitted with audible and/or visual alarms to indicate any sustained. out of specification pressure differentials across the HEPA filters.1. regardless of whether flow is laminar or nonlaminar. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. humidity and temperature. out of specification pressure differentials across the HEPA filters. Leaks requiring patching or replacement were found in 75% to 100% of the HEPA filters in Fill Rooms 1. For example.Doc. a) The testing of HEPA filters in the Aseptic Core during the Winter 2006 (January 2006) shutdown. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 84 of 185 : 14 May 2007 8.2 Air Supply 8. including prefilters and particulate matter air filters on air supplies to production areas. microorganism. Air supplied to aseptic processing areas should be filtered through HEPA filters. which includes as appropriate: … (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure. STERILITY TEST FACILITIES 8. found widespread HEPA filters failures in the Class 100 areas. and also equipment for adequate control over air pressure. [VIP ID: 2181] “How is the air filtered that is supplied to controlled areas (where unsterilized product.42(c)(10)(iii).2. regardless of whether flow is laminar or non-laminar as required by 21 CFR 211. VOLUME 05. but they are required. Ref. Firms are not required to use HEPA filters in the manufacture of tablets and capsules. to use air filtration systems. which should be fitted with audible and/or visual alarms to indicate any sustained. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: … (10) Aseptic processing. 08 Author : Validation in Partnership Ltd.1. when appropriate. [VIP ID: 194578] “Failure to establish an adequate air supply that is filtered through high-efficiency particulate air filter under positive pressure. : SGD-110-ENV Rev. …” CPGM-DB CHAPTER 56 .” 9. HUMAN DRUG CGMP NOTES. 4 and 5.CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 29. NUMBER 03 (September 1997) Motise's Notebook Policy Questions: 5) [VIP ID: 4025] © Validation in Partnership Ltd 2007 .Buildings and Facilities Sec. …” 21 CFR PART 211 . in-process materials.1 CLEAN ROOM DESIGN 8. 211. Extracted from FDA warning letter CHI-3-07 (December 2007) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 3) a. and container/closures are prepared)?” 10.1 [VIP ID: 190254] “Air supplied to the environment should be provided through terminal HEPA filters.DRUG QUALITY ASSURANCE 7356.42 Design and construction features (c) [VIP ID: 20] “Operations shall be performed within specifically defined areas of adequate size. Air supplied to the clean room environment should be provided through terminal HEPA filters. dust.

leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. HFD-325.3 micron sized particles and assesses filter media. 301-594-1089. or as part of an investigation into a media fill or drug product sterility failure. tablet and capsule production rooms seldom need the same level of air filtration. air filtration. In addition. even in small quantities. . 211. Air Filtration 2.. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 85 of 185 : 14 May 2007 “Are firms required to use HEPA filters in the manufacture of tablets and capsules? References: 21 CFR 211. through the frames. fda.46. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Buildings and Facilities D.” CPGM-DB CHAPTER 56 . dust. air heating and cooling. For example. © Validation in Partnership Ltd 2007 . [8] An intact HEPA filter should be capable of retaining at least 99. firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that. do require use of equipment for adequate control over air pressure.DRUG QUALITY ASSURANCE 7356. microorganism. could pose a significant health hazard when carried over into other products. Ref. For example. such testing should be performed twice a year for the aseptic processing room. HEPA filters should be efficiency tested using an appropriate aerosol challenge to determine the rating of the filter. HEPA filters should be integrity tested using an appropriate aerosol challenge to identify leak paths in the filter or its housing. this section calls for use of air filtration systems. Additional testing may be appropriate when air quality is found to be unacceptable. as appropriate. Ventilation. Buildings and Facilities D. 08 Author : Validation in Partnership Ltd. Do not confuse the 211. some firms may elect to use HEPA filtered air systems as part of their dust control procedures. Whereas such filtration is the norm for aseptic areas. Gov” 11. : SGD-110-ENV Rev. High-Efficiency Particulate Air (HEPA) \7\ (para 3) [VIP ID: 110380] “There is a major difference between filter leak testing and efficiency testing. The regulations. and the key phrase is "as appropriate".CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. including prefilters and particulate matter air filters on air supplies to production areas. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.Doc. [8] The efficiency test uses a monodispersed aerosol of 0. with an air supply filtered through HEPA filters.3 µm in diameter. Air Filtration 2. Design and construction features No. or through various points on the filter media. Efficiency tests are not intended to test for filter leaks. High-Efficiency Particulate Air (HEPA) \7\ (para 1) [VIP ID: 110360] “HEPA filter integrity should be maintained to ensure aseptic conditions.42.42(c)(10)(iii) which calls for aseptic processing areas to be equipped. e-mail: motise@cder. [VIP ID: 2184] “Are HEPA filters efficiency tested?” 12. Despite the lack of an explicit CGMP requirement. at 211. Motise. Contact for further info: Paul J. facility renovations might be the cause of disturbances to ceiling or wall structures. The CGMP regulations do not specifically require tablet and capsule manufacturing facilities to maintain highefficiency particulate air (HEPA) filtered air. These provisions speak to measures to prevent cross contamination. humidity and temperature when appropriate.46. An efficiency test is a general test used to determine the rating of the filter.97 percent of particulates greater than 0. Leak testing should be performed at installation to detect integrity breaches around the sealing gaskets. Thereafter.46 provisions with 211..002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 32. as appropriate. Downstream readings represent an average over the entire filter surface.

is to detect leaks from the filter media. on the other hand. Ref. Some aerosols are problematic because they pose the risk of microbial contamination of the environment being tested.DRUG QUALITY ASSURANCE 7356. The downstream leakage measured by the probe should then be calculated as a percent of the upstream challenge. at a sampling rate of at least one cubic foot per minute. Buildings and Facilities D. Buildings and Facilities D. 08 Author : Validation in Partnership Ltd. Buildings and Facilities D. Dioctylphthalate (DOP) and poly-alpha-olefin (PAO) are examples of appropriate leak testing aerosols. Emery 3004 (POA) is an acceptable substitute for Dioctyl phthalate (DOP) for integrity testing HEPA filters. Performing a leak test without introducing a sufficient upstream challenge of particles of known size upstream of the filter is ineffective for detecting leaks. repair in a limited area. it is greater than 0. the evaluation of any alternative aerosol involves ensuring it does not promote microbial growth. when appropriate.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.01 percent of the upstream challenge would be considered as indicative of a significant leak and calls for replacement of the HEPA filter or. Air Filtration 2.3 µm.Doc. A subsequent confirmatory retest should be performed in the area of any repair. [9] including a sufficient number of particles at approximately 0.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 33. High-Efficiency Particulate Air (HEPA) \7\ (para 4) [VIP ID: 110390] “The purpose of performing regularly scheduled leak tests. and the filter face scanned on the downstream side with an appropriate photometer probe.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . [VIP ID: 2185] “How often are HEPA filters integrity tested? What test method is used?” 13.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . The challenge involves use of a polydispersed aerosol usually composed of particles with a light-scattering mean droplet diameter in the submicron size range.” CPGM-DB CHAPTER 56 . Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 2) [VIP ID: 110370] “Any aerosol used for challenging a HEPA filter should meet specifications for critical physicochemical attributes such as viscosity. Accordingly.” © Validation in Partnership Ltd 2007 . This comprehensive scanning of HEPA filters should be fully documented. An appropriate scan should be conducted on the entire filter face and frame. Air Filtration 2. filter frame. or seal. : SGD-110-ENV Rev. High-Efficiency Particulate Air (HEPA) \7\ (para 5) [VIP ID: 110400] “A single probe reading equivalent to 0.3µm. The leak test should be done in place.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . It is important to introduce an aerosol upstream of the filter in a concentration that is appropriate for the accuracy of the aerosol photometer. [9] Although the mean is normally less than one micron. at a position about one to two inches from the face of the filter. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 86 of 185 : 14 May 2007 [7] The same broad principles can be applied to ULPA filters.

and electrical/hydraulic fluids.gov” HUMAN DRUG CGMP NOTES. di-sec octyl phthalate.” HUMAN DRUG CGMP NOTES. Army testing with assistance from various private companies was a Henkel Corporation (Emery Group) product called Emery 3004 PAO.1. concerns about the potential health risks attendant to exposure to DOP has precipitated a search for acceptable alternatives. used primarily as a lubricant base stock for oils. DOP. VOLUME 02. have long been used to test the integrity of high efficiency particulate air (HEPA) filters.2 [VIP ID: 65600] “IS THERE AN ACCEPTABLE SUBSTITUTE FOR DIOCTYL PHTHALATE (DOP) TO INTEGRITY TESTING OF HEPA FILTERS? Yes.Doc. However. Discussions with the Army and the companies involved in the original studies indicate the product remains the same from the new site of manufacturing. The original manufacturing site which produced the Emery 3004 (POA) for the data submitted has changed since the study and Emery 3004 (POA) is now manufactured at a different site. e-mail: verdim@cder. © Validation in Partnership Ltd 2007 . Dioctyl phthalate aerosols also called Di (2-ethylexyl) phthalate. This product is a polyalphaolefin (POA) in the 4 centistoke (4 cSt) viscosity grade. 08 Author : Validation in Partnership Ltd. Yes.GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2. have long been used to test the integrity of high efficiency particulate air (HEPA) filters but concern about the potential health effects to people working with DOP test aerosols has led to a search for a safer equivalent replacement.1 PREMISES . : SGD-110-ENV Rev. and electrical/hydraulic fluids. air heating and cooling. 301-594-0095. HFD-322.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.004 2. lubricants. Dioctylphthalate (DOP) aerosols have long been used to test the integrity of high efficiency particulate air (HEPA) filters. Ventilation. and 211.67 Equipment cleaning and maintenance. DOP. or DEHP. The prime candidate from U.02. Emery 3004. Concern about the potential health effects to people working with DOP test aerosols has led to a search for a safer equivalent replacement. The product of choice from US Army testing with assistance from various private companies was a Henkel Corporation (Emery Group) product called Emery 3004 PAO.fda. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 87 of 185 : 14 May 2007 HEALTH CANADA . NUMBER 01 (March 1994) Motise's Notebook NEW TECHNOLOGY EMERGING: 1) [VIP ID: 3769] “Substitute for DOP in HEPA filter Integrity Testing Reference (on HEPA filter integrity testing) Guideline on Sterile Drugs Produced By Aseptic Processing. used primarily as a lubricant base stock for oils.C. Emery 3004 (POA) can replace DOP in HEPA integrity testing. lubricants. NUMBER 04 (December 1996) Motise's Notebook POLICY QUESTIONS: Question 4 “Is there an acceptable substitute for DOP to integrity test HEPA filters? Reference: 21 CFR 211. Ref. Emery 3004 POA with the CAS number 68649-12-7 still remains an acceptable replacement for DOP. Dioctyl phthalate aerosols also called Di (2-ethylhexyl) phthalate. This product is a polyalphaoefin (POA) in the 4 centistoke (4 cSt) viscosity grade. air filtration.S. Contact for further information: Michael J.46. Verdi. The agency has recently accepted one of the alternatives. Other reported alternatives used in the industry include DOS (Di (2-ethylhexyl) sebacate) and Ondina Oil. di-sec octyl phthalate. no manufacturer has yet submitted all the necessary data to evaluate these alternatives. CDER has also compared the original specifications and the new site specifications along with data from the Material Safety Data Sheets and agrees that there is no significant difference in the product from either site. VOLUME 04. The Chemical Abstracts Service (CAS) number which identifies this product also remained as 68649-12-7. As such. However. based on data submitted to FDA we have concluded that Emery 3004 (POA) can replace DOP in HEPA integrity testing. or DEHP. As cited in the March 1994 Human Drug CGMP Notes.

Selected FDA 483 Observations (June 1998) Sterile Product Manufacture [VIP ID: 6379] “Documented evidence should be maintained.” 15. For example. Division Contact for Further Info: Terry Munson. demonstrating the proper qualification of contract employees responsible for replacing HEPA filters and repairing HEPA leaks in the aseptic core and depyrogenation tunnels.42(c)(10)(vi).22(a)]. manufactured by Henkel Corporation. : SGD-110-ENV Rev. and many other machines. and failure of the quality control unit to ensure that errors are investigated [21 CFR 211. Extracted from FDA warning letter MIN 06-36 (September 2006) Extracted from FDA warning letter MIN 06-36 USA 08-Sep-06 7 [VIP ID: 192524] “Failure to document that the pre and post-filters on the air handling units in your repackaging suites are changed according to the frequency specified in your SOP. We have concluded from the data that Emery 3004 performs at least as well as DOP in hot-smoke filter pentrometer machines.S. Documented evidence should be maintained. HFD-322.” 16. Army on the use of a compound called Emery 3004. on site. free of natural impurities. 2005 ([redacted]) the firm did not generate deviations even though the leaks violated the "Acceptance Criteria" in the firm's SOP (Number 21C22 Revision Number 06). as a substitute for DOP. Moreover. and (most important) not mutagenic. Extracted from FDA warning letter OEWL-06-01 (June 2006) Extracted from FDA warning letter OEWL-06-01 USA 30-Jun-06 2 [VIP ID: 192172] “Failure to establish a system for maintaining equipment to control aseptic conditions. when leaks were found in the HEPA filters for final product aseptic filling in room 181 in Building 37 on June 7 ([redacted]) and on December 5. Records should be maintained of the service and/or replacement of air filters.” © Validation in Partnership Ltd 2007 .” 14. clean to work with. failure to follow appropriate written procedures to prevent microbial contamination of drug products purporting to be sterile. the firm did not investigate to determine whether using those filters had any product impact.” Selected FDA 483 Observations (July 2002) Sterile Product Manufacture [VIP ID: 46810] “The pattern and magnitude of HEPA filter failures should be reported to Quality Assurance/Product Release personnel to assess any product impact. Emery 3004 is a poly-alpha olefin. Ref. non-corrosive. thermally and chemically stable. 08 Author : Validation in Partnership Ltd. demonstrating the proper qualification of contract employees responsible for replacing HEPA filters and repairing HEPA leaks in the aseptic core and depyrogination tunnels. (301-594-0095).Doc. simply by adjusting existing machine controls. on site. 211. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 88 of 185 : 14 May 2007 Various groups in FDA have reviewed data generated by a pharmaceutical company and the U. The material is inexpensive. Emery 3004 can replace DOP directly in existing penetrometer and other machines without machine modification. This means that there is no need to change the methods and procedures currently used to integrity test HEPA filters. Leaks found during HEPA filter integrity testing should be documented as deviations and should be investigated to assess any impact on product. and 211.113(b). …” Selected FDA 483 Observations (July 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 137800] “Records should be maintained of the service and/or replacement of air filters. that has physical properties similar to DOP. readily specifiable (unlike natural petroleum products).

” 19. Air velocity specifications at the filter face should be established for HEPA filters located in aseptic filling suites and should include an upper limit.” Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27170] “Air velocity specifications at the filter face should be established for HEPA filters located in aseptic filling suites. : SGD-110-ENV Rev. air velocity sampling points should be rotated to assure a comprehensive evaluation of the filter's performance.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Ventilation. [VIP ID: 194578] “Failure to establish an adequate air supply that is filtered through high-efficiency particulate air filter under positive pressure.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .42(c)(10)(iii). Ref. Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40710] “HEPA filter velocity specifications should include an upper limit. © Validation in Partnership Ltd 2007 . Buildings and Facilities D. Extracted from FDA warning letter CHI-3-07 (December 2007) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 3) a. 08 Author : Validation in Partnership Ltd. Air Conditioning (HVAC) System. Selected FDA 483 Observations (August 2007) Sterile Product Manufacture [VIP ID: 193768] “In the case of controls to verify and guarantee the functioning of the Heating. HEPA filter air velocity and pressure drop action and alert limits should be justified and should comply with the manufacturers recommendations. regardless of whether flow is laminar or non-laminar as required by 2I CFR 211. Velocity monitoring at suitable intervals can provide useful data on the critical area in which aseptic processing is performed. HEPA filter leak testing alone is insufficient to monitor filter performance. There should be specifications for air velocities at work surfaces and for the maximum divergence that can exist between the reading from different filters. For example. HEPA filters should be replaced when nonuniformity of air velocity across an area of the filter is detected or airflow patterns may be adversely affected. Velocity monitoring should also be performed and air velocity sampling points should be rotated to assure a comprehensive evaluation of the filter's performance.Doc. Variations in velocity can cause turbulence that increases the possibility of contamination. Velocities of unidirectional air should be measured 6 inches from the filter face and at a defined distance proximal to the work surface for HEPA filters in the critical area. It is important to conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters).” 18. there should be specifications for the maximum divergence that can exist between the reading from different filters. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 89 of 185 : 14 May 2007 17. The measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies. High-Efficiency Particulate Air (HEPA) \7\ (para 6) [VIP ID: 110410] “HEPA filter leak testing alone is insufficient to monitor filter performance. Selected FDA 483 Observations (March 2001) Sterile Product Manufacture [VIP ID: 27180] “In addition to air velocity specifications at the work surface. Air Filtration 2.” 20.

test methods.” 21. 3) [5] [4] High Efficiency Particulate Air filter [5] A velocity of 0.” 22. 21 CFR 211. The study documents a direct correlation between air flow rate and unacceptable ENSSP. processing.Doc. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref. Critical Area .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. with a range of plus or minus 20 percent around the setpoint.99% for particles greater than 0. packing. Buildings and Facilities A.” © Validation in Partnership Ltd 2007 .45 meters/second (90 feet per minute) has generally been established.3 microns at a face velocity of 90 FPM. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 90 of 185 : 14 May 2007 a) … The HEPA filters used in these areas are rated for an efficacy of 99. Please provide your rationale for continuing to operate the aseptic filling lines at these excessive velocities until replacing them with proper filters during your planned shut down in August 2006. but much higher face velocities (from [redacted] to [redacted]) are used in some of the aseptic filling rooms. HEPA filter velocity testing should be performed at work surfaces.” Selected FDA 483 Observations (December 2002) Sterile Product Manufacture [VIP ID: 51710] “HEPA filter velocity testing should be performed at the work surfaces. Higher velocities may be appropriate in operations generating high levels of particulates. Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171110] “2. HEPA filters should be validated and should be recertified at least annually in accordance with specifications.” Selected FDA 483 Observations (August 2002) Sterile Product Manufacture [VIP ID: 47720] “Air flow velocity checks should be measured near the work surface area (where vial filling occurs) rather than at the filter surface. or holding of a drug product. Ref. : SGD-110-ENV Rev. the procedures did not include a specification for the required distance for taking [redacted] test measurements. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . 08 Author : Validation in Partnership Ltd. and acceptance criteria defined by the drug manufacturer. There was insufficient evidence that ventilation and air filtration systems provided adequate control over microorganisms for the manufacture.46 The following deviations were noted regarding ventilation and air filtration systems: There was no scientific justification for testing of [redacted] filters in the Class A (ISO 5) area and sterile [redacted] only once annually.Class 100 (ISO5) (para 6) [VIP ID: 110230] “HEPA-filtered [4] air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. or for monitoring of pressure differentials between various operational areas. A study conducted for you by [redacted] as part of the investigation concluded that excessive non site specific penetration (ENSSP) of HEPA filters can result when filters are used at velocities for which they are not designed. …” Selected FDA 483 Observations (November 1997) Sterile Product Manufacture [VIP ID: 6249] “HEPA filter air velocity action and alert limits should be justified and should comply with the manufacturers recommendations.

air velocity studies. and in aseptic areas. 08 Author : Validation in Partnership Ltd. including necessary equipment.DRUG QUALITY ASSURANCE 7356. Buildings .iv. and that these essential certification activities are conducted satisfactorily. Inspection 9.Doc. High-Efficiency Particulate Air (HEPA) \7\ (para 7) [VIP ID: 110420] “Although contractors often provide these services.Inspectional B. : SGD-110-ENV Rev. as required by 21 CFR 820.” CPGM-DB CHAPTER 56 . Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19330] “There should be written procedures describing the calibration/certification methods and tolerance limits for all instruments used during production operations to include: (1) HEPA filters …” © Validation in Partnership Ltd 2007 . Specifically. dioctyl phthalate (DOP) or an alternative aerosol that has been determined to have similar or acceptable physical characteristics for detection of leaks. GMP b. Buildings and Facilities D.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Environmental control systems have not been inspected periodically to verify that the system. drug manufacturers are responsible for ensuring that equipment specifications. and acceptance criteria are defined. For example: c. Air Filtration 2. Procedures were not established or maintained to inspect the integrity or installation of the HEPA filters supplying air into the 'white area'. e. is adequate and functioning properly.” FDA Warning Letter 320-01-11 (September 2001) Extracted from FDA warning letter 320-01-11 USA 05/09/2001 [VIP ID: 43210] “The laminar flow hood in the micro lab and **** filters in the Class 100.g. Recertification should include integrity testing of the HEPA filters with an appropriate challenge aerosol. Failure to establish and maintain procedures to adequately control environmental conditions. test methods.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III . laminarity. Ref.000 production area had not been certified. particle counts.. There should be written procedures for the calibration of HEPA filter instrumentation. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 91 of 185 : 14 May 2007 FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 134970] “1. your firm has not conducted filter integrity inspections of the HEPA filters in the controlled environment room since it was installed sometime in 1996.70(c).” 23. HVAC systems (para 2) [VIP ID: 77690] “All HEPA filters should be validated and should be recertified at least annually.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.

000 (ISO 8) supporting rooms.Doc. The production area air supply lacks an appropriate air filtration system [21 CFR 211. Additionally.5. There should be a specification set for total air flow.70(c)1.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.5 Air Flow 1.” © Validation in Partnership Ltd 2007 . airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. packaging particles and flushing away microorganisms in the unlikely event they are present. FDA Warning Letter W/L 08-03 (November 2002) Extracted from FDA warning letter W/L 08-03 USA 19/11/2002 [VIP ID: 54430] “10. powder.5 The prevention of recontamination 9. Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6825] “Room filtered air flows should be monitored periodically and compared to those measured at the time of balancing. there is no data to support the specification set for total airflow. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. Five HEPA filter velocities in a clean room were recorded to have average flows outside of the specification. 9. Specifically.6. data to support the specification and data to support compliance with the specification.46] in that there were no specifications for velocity and pressure drop in the certification of the HEPA filters on the HVAC system.000 (ISO 8) supporting rooms.” Extracted from FDA Warning Letter CBER-00-011 (December 1999) Extracted from FDA warning letter CBER-00-011 USA 23/12/1999 [VIP ID: 160930] “4. Significantly higher air change rates are normally needed for Class 10. packaging particles and flushing away micro-organisms in the unlikely event they are present.000 and Class 100 areas. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. For Class 100.” 3. The HEPA filter in another clean room was observed to have flow less than the specification during air handling certificates testing conducted on 6/7/2002.1 [VIP ID: 190600] “The air change rate should be sufficient to ventilate the operation avoiding build up of aerosols. The air change rate should be sufficient to ventilate the operation avoiding build up of aerosols.46(c)] and [21 CFR 820. Clean Area Separation (para 4) [VIP ID: 110310] “Air change rate is another important cleanroom design parameter. your firm's specification states that HEPA filters used for clean rooms are to have an air flow between a high and low flow specification. For Class 100. Ref. 08 Author : Validation in Partnership Ltd. Significantly higher air change rates are normally needed for Class 10.” 2.” 4. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 92 of 185 : 14 May 2007 7. Failure to establish adequate control measures for air filtration systems [21 CFR 211. air flow sufficient to achieve at least 20 air changes per hour is typically acceptable. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . powder. Buildings and Facilities C.000 and Class 100 areas. : SGD-110-ENV Rev. Room filtered air flows should be monitored periodically and compared to those measured at the time of balancing.

PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . pathogenic.. e. Ref. … The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials. highly toxic. Sterile product manufacturing facilities should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. highly toxic. e.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . in that unidirectional airflow in the class #### aseptic filling suite has not been established [21 CFR 600.” © Validation in Partnership Ltd 2007 . 08 Author : Validation in Partnership Ltd.” 6. . radioactive or live viral or bacterial materials or products. .Doc.. FDA Warning Letter CBER-98-024 (August 1998) Extracted from FDA Warning Letter CBER-98-024 USA 14/08/1998 [VIP ID: 13000] “Failure to ensure that the ventilation system is arranged so as to prevent the dissemination of microorganisms from one manufacturing area to another and to avoid other conditions unfavorable to the safety of the product. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations. pathogenic.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . The ventilation system should be arranged so as to prevent the dissemination of micro-organisms from one manufacturing area to another.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 29 (para 2) [VIP ID: 63210] “A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. : SGD-110-ENV Rev.SUPERSEDED! (July 1996) Premises 29.g. radioactive or live viral or bacterial materials or products..11(a)].g. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 93 of 185 : 14 May 2007 5.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 29 [ViP ID: 186056] “A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials..MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 29 (para 2) [VIP ID: 63220] “… The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . [VIP ID: 1442] “A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively.

Doc. The air flow in critical areas should be laminar when delivered to the point of use.g. Qualification and Monitoring A. 08 Author : Validation in Partnership Ltd. operation or machine to a zone of higher product risk.SUPERSEDED! (July 1996) Premises 30. Aseptic Workstation para 3 [VIP ID: 187414] “We recommend laminar airflow velocities be monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area. Where a laminar air flow is required. : SGD-110-ENV Rev.” CPGM-DB CHAPTER 56 . . operation or machine to a zone of higher product risk.. SPECIAL PRODUCTION SITUATIONS D.APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. [VIP ID: 2180] “Is the air flow in critical areas laminar when delivered to the point of use? At what velocity? …” 9. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 94 of 185 : 14 May 2007 7. the air flow should not be interupted.Ensuring that items within a laminar airflow aseptic workstation not interrupt the airflow.. FACILITIES AND EQUIPMENT C. Personnel (para 3) [VIP ID: 110600] “… Unidirectional airflow design is used to protect sterile equipment surfaces. container-closures. e. Personnel Training.” © Validation in Partnership Ltd 2007 . operation or machine to a zone of higher product risk. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. GUIDANCE FOR INDUSTRY INDS . Thorough consideration should be given to controls for aseptic processing.. Disruption of the path of unidirectional flow air in the critical area can pose a risk to product sterility.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . Production Equipment para 6 b. [VIP ID: 1443] “It should be demonstrated that air-flow patterns do not present a contamination risk. GUIDANCE PET DRUG PRODUCTS .” 8. care should be taken to ensure that air flows do not distribute particles from a particle-generating person. Ref. Sterile Products/Aseptically Processed Products [VIP ID: 183918] “We recommend that special precautions be taken for investigational new drugs intended to be sterile.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . . e.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . The following examples are recommendations that should be considered: … .g.DRUG QUALITY ASSURANCE 7356.. Air flows should not distribute particles from a particle-generating person. Equipment 1.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 30 [VIP ID: 63230] “It should be demonstrated that air-flow patterns do not present a contamination risk. care should be taken to ensure that air flows do not distribute particles from a particle-generating person.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 28. and product.

Equipment 1. Inspectional Observations. Your firm's air flow patterns procedure lacked specific acceptance criteria. regardless of additional simulations performed under your current protocol.113(b)] For example. Selected FDA 483 Observations (February 2007) Sterile Product Manufacture [VIP ID: 194290] “Attributions of over action limit particulate levels in a Class 100 area to air disturbance caused by a cart in the Class 100 area are unfounded if no smoke studies have been performed with these carts in place.. . due to the equipment configurations within the Class [redacted] area.11(a)] For example. a) [VIP ID: 194674] “Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established. Air flow studies should be performed to determine air flow patterns in aseptic areas under dynamic conditions. unless substantial changes are made. response that your firm performed additional smoke studies including simulations of loading of the lyophilizer. We recommend that operators be trained on the importance of minimizing objects and equipment within the critical area so laminar airflow is not disrupted.. Your airflow study documentation included hand drawings that provided insufficient information to determine whether HEPA-filtered air used in the manufacturing area (and sterility test laboratory) robustly sweeps away particles and maintains unidirectional airflow protection under dynamic production conditions. We acknowledge receipt of your September 8th and October 20th 2006. FACILITIES AND EQUIPMENT C.” 10. : SGD-110-ENV Rev. your smoke study documentation is still considered inadequate. formulation rooms [redacted] and [redacted] do not meet manufacturing needs and prevent contamination.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI.Doc.” Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194250] “Where equipment is positioned within a Class 10. a) your firm failed to adequately document air flow (smoke) studies to demonstrate unidirectional airflow under dynamic conditions.. Production Equipment para 6 b.42(c) (10) and 600.” FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133220] “7. Your firm failed to establish separate or defined areas or other control systems for aseptic processing operations to prevent contamination or mix-ups.” © Validation in Partnership Ltd 2007 . there should be an evaluation performed in order to determine that there is appropriate unidirectional airflow within the Class 100 designated area to provide an adequate barrier between the two different air classifications.. written.” Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 6. 2006. Aseptic Workstation para 3 [VIP ID: 187414] “. [21 CFR § 211. Your hand drawings are insufficient documentation to determine if airflow is maintained under dynamic conditions. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 95 of 185 : 14 May 2007 GUIDANCE PET DRUG PRODUCTS . 08 Author : Validation in Partnership Ltd. is obstructed by the operators when making the connections. [21 CFR 211.000 designated area in a Class 100 fill room. and followed. in that the airflow. We have reviewed your responses and have the following comments: Observation 4 We note in your October 20. Records should be made of the studies and should be reviewed and approved by the quality unit. Therefore. above the critical area where multiple aseptic connections are made. Ref. letters in response to the Form FDA-483.

08 Author : Validation in Partnership Ltd. you did not commit to conducting enhanced air flow pattern studies (to include the activities identified above) in the Class 100 area until December 2006. Smoke studies should be performed in sterile filtration rooms and should ensure that: personnel are properly gowned. air returns are visible.” Selected FDA 483 Observations (November 2006) Sterile Product Manufacture [VIP ID: 194060] “Smoke studies should ensure that: technicians participating in the smoke study do not have exposed skin.” Selected FDA 483 Observations (January 2006) Sterile Product Manufacture [VIP ID: 179660] “There should be assurance. and any corrective actions resulting from the testing. and pooling and eddying is not visible in and around the sterile filling assembly. equipment and supplies normally present in the filling suite are present during the study. however. The [redacted] filling process was not adequately designed to permit unidirectional airflow protection of the bulk sterile drug. © Validation in Partnership Ltd 2007 . [VIP ID: 194580] “Failure to establish an adequate air supply that is filtered through high-efficiency particulate air filter under positive pressure. such as video records of smoke tests. : SGD-110-ENV Rev. technicians' activities are consistent with those during actual sterile operations. Your response to the FDA 483 indicates that you intended to conduct some additional air flow testing in August 2006. Please provide the results for the testing that occurred in August.” Selected FDA 483 Observations (January 2006) Sterile Product Manufacture [VIP ID: 179680] “Smoke studies should demonstrate the ability to maintain the integrity of laminar airflow within a critical area when Extracted from FDA Warning Letter 320-05-03 (July 2005) Extracted from FDA warning letter 320-05-03 Italy 21/07/2005 [VIP ID: 169310] “9. Please provide the timeframe for the review and assessment of the studies occurring in December. b) Air flow pattern testing done to demonstrate unidirectional airflow in the critical areas of the five aseptic fill lines are not done under simulated operating conditions with operators present performing routine and non-routine aseptic manipulations.” Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 3) b. adding stoppers to the hopper while in the Class 100 area. such as: adding vials to the line. For example. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 96 of 185 : 14 May 2007 Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194252] “Smoke studies should clearly or completely describe unidirectional airflow during real time conditions in order to determine that routine filling operations and personnel movement do not adversely impact upon the unidirectional flow of air during the filling process. there is no pooling between technicians and filling equipment and supplies.000 areas do not disrupt airflow. filling technicians are clearly visible.42(c)(10)(iii). removing fallen or defective vials while in the Class 100 area. filling activities are consistent with those performed during filling operations.Doc. removing vials from the line for weight checks while in the Class 100 area. or moving HEPA transfer carts fully into the Class 100 areas (Lines 2 and 6 only). regardless of whether flow is laminar or non-laminar as required by 2I CFR 211.” Selected FDA 483 Observations (October 2006) Sterile Product Manufacture [VIP ID: 193966] “There should be adequate exhaust systems or other systems to control contaminants in areas where air contamination occurs during production. and there is documentation to demonstrate that the studies are reviewed and evaluated. that gaps in strip curtains used to separate Class 100 areas from Class 10. Ref.

Air flow patterns inside shrouds. the testing of room particle counts.” Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128740] “Smoke studies should completely demonstrate that the air is moving away from the open product vials and work surfaces.g.” Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122660] “HVAC system qualification should include: a. Ref.” Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128730] “Where an aseptic filling process requires aseptic connections to be performed in a Class 100 area. but you also need to address these short term manufacturing issues. 08 Author : Validation in Partnership Ltd. video) to demonstrate that smoke tests are adequately executed.” Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121960] “Smoke stick studies conducted to demonstrate air flow patterns in aseptic filling rooms should show: a. Your response also does not address the dead air space inside the filling cabinet. and air-flow velocities at multiple times to demonstrate adequate performance over time.” Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 70940] “There should be evidence (e. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 97 of 185 : 14 May 2007 The smoke studies of your [redacted] filling operation indicated that unidirectional flow is not achieved in your current design. to include: (1) When opening and closing access doors in front of fill nozzles. the performance of smoke studies to determine air-flow patterns in aseptic processing areas. d. (4) During manual interventions with the particle control shields and air filtration devices.Doc. (2) When opening and closing access doors in front of stopper bowls. b. and information regarding the new layout of the filling area was not submitted. during personnel manual interventions.” Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 70930] “Determination of filter laminarity and air flow in filling rooms should be performed with the employees who are normally present during routine operations to determine if the laminarity and air flow is affected by their presence. We acknowledge your long-term goal of installing a [redacted] in this area. b. The effect the heat in the area has on the air patterns.” © Validation in Partnership Ltd 2007 . Documentation of the design of the [redacted] you propose to put in place. How the movement of equipment affects the air flow patterns. FDA-483 observations that dealt with this area remain a concern. (3) During the manual transfer of stainless steel 'Bleeding Pans' when positioned over fill nozzles. c. evaluations (smoke study) should be performed to demonstrate that the HEPA filtered air provides adequate unidirectional air flow and that the manual process does not produce air turbulences that can have a negative impact on the aseptic connections.” Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128750] “Evaluations (smoke study) should be performed for the pass throughs when opening and closing the doors in order to assure that the manual process does not negatively impact the unidirectional flow of air within Class 100 fill areas. : SGD-110-ENV Rev. number of air changes. Air flow patterns when the doors of the area are closed. and the turbulent airflow that can be created by repeatedly opening and closing the cabinet.

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Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72340] “Smoke tests conducted in class 100 parenteral filling areas should be performed under dynamic conditions to determine how the laminar flow is affected by the presence of operators (as observed during regular production) and equipment.” Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 70250] “Videotaped smoke testing performed to determine air circulation patterns, air recovery, and to ascertain the positive air pressure environment within dispensing rooms should be reviewed and approved by the Quality Unit.” Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70280] “Airflow patterns for the transfer to components (stoppers/plungers/etc.) from the Component Processor to bags and the sealing of filled bags should be adequately evaluated with smoke studies to assess turbulence, disruption of unidirectional airflow, and adequacy of aseptic technique.” Selected FDA 483 Observations (March 2003) Sterile Product Manufacture [VIP ID: 52210] “Smoke pattern studies (airflow pattern studies) should: (a) demonstrate that the air is moving away from open product vials, work surfaces and during manual interventions. (b) demonstrate that the movement of individuals who perform some of the manual operations during the filtration process does not produce air turbulence that could have a negative impact on the aseptic filling areas. (c) include a complete evaluation of the unidirectional flow of air during the manual transfer operations of the partially stoppered vials as the vials are transferred into the mobile transfer carts, used to transfer aseptically filled vials to the lyophilizer. (d) include simulations with transfer trays containing partially stoppered vials during the transfer process into the lyophilizer.” Selected FDA 483 Observations (January 2002) Sterile Product Manufacture [VIP ID: 46210] “Videotapes documenting the dynamic airflow assessments performed on filling lines should include simulation of operator interventions.” Selected FDA 483 Observations (September 2001) Product Manufacture [VIP ID: 41120] “The direction of air flow should be documented in weighing, blending and compression rooms.” Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40720] “Airflow (smoke) studies should include: (1) personnel performing stipulated activities …” Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26520] “Smoke tests used to determine air flow patterns in an aseptic core should be performed under dynamic conditions with video. The results should not be hand drawn.”

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Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 19420] “HEPA filter integrity testing should include: … d) the measurement of the distance between smoke entry and exit planes during laminar airflow (smoke) studies to ensure the flow is laminar e) more than just a narrative report to fully and accurately assess airflow patterns” Selected FDA 483 Observations (November 1999) Sterile Product Manufacture [VIP ID: 8790] “Air flow studies to assess turbulence and laminarity should be performed with personnel performing aseptic activities and when personnel traverse the filling area.” Extracted from FDA Warning Letter CHI-12-00 (February 2000) Extracted from FDA warning letter CHI-12-00 USA 07/02/2000 [VIP ID: 161610] “Failure to establish and follow procedures, designed to prevent objectionable microorganisms in drug products purporting to be sterile [21 CFR 211.113]. For example: There is no established procedure or written test method for conducting smoke pattern testing of the HVAC systems. There is no written document that defines terms, establishes acceptance criteria, or describes how the tests should be done, recorded and reviewed. The smoke pattern tests reviewed during this inspection were not completely described and/or documented. Employees have not received training on how to do airflow pattern tests.” Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7302] “Isolator airflow smoke studies should include: 1) the lower limit pressure differential 2) confirmation of unidirectional airflow 3) dynamic conditions (gloves in place etc.)” Extracted from FDA Warning Letter CBER-99-013 (March 1999) Extracted from FDA warning letter CBER-99-013 UK 17/03/1999 [VIP ID: 159560] “7. Failure to assure that air filtration systems are adequate [21 CFR 211.46(c) and 211.100(a)] in that smoke studies to evaluate laminar flow in the filling area have not been conducted since 1985, are not documented, and there are no written procedures for such studies.” Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136490] “Clean room smoke studies should include dynamic conditions such as equipment in operation and typical interventions simulated such as stopper staging and doors opening and closing.”

11. Determination has to be made of the air flow at the aseptic work surface.
FDA Warning Letter 2002-DT-21 (January 2002) Extracted from FDA warning letter 2002-DT-21 USA 30/01/2002 4 [VIP ID: 48290] “4) Failure to have separate or defined areas, or such other control systems as are necessary to prevent contamination during the course of aseptic processing operations, as required by 21 CFR 211.42(c)(10). For example: … b. No determination has been made of the airflow at the aseptic work surface.”

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12. A smoke stick is not always enough.
Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40720] “Airflow (smoke) studies should include: … (2) the generation of sufficient volumes of smoke to adequately evaluate airflow patterns across filter faces and filling lines (a smoke stick is not always enough)”

13. There should be documentation to demonstrate that Flo-Viz materials are equivalent to smoke.
Selected FDA 483 Observations (March 2001) Sterile Product Manufacture [VIP ID: 27300] “Where Flo-Viz materials (non-shedding monofilament nylon multi-strain mesh streamer material) are used in the determination of the direction of airflow, there should be documentation to demonstrate that they are equivalent to smoke.”

14. Laminar air flow protection may provide a suitable alternative to sterilisable systems.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS EQUIPMENT 23 [VIP ID: 186374] “… The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS STARTING MATERIALS Operating principles 50 [VIP ID: 186426] “When necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Operating principles 50. [VIP ID: 1649] “Where necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Equipment 23. (para 3) [VIP ID: 1615] “The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow.”

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The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref. A velocity of 0.Doc.” Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26440] “There should be specifications for the air velocity in an aseptic core. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . 3) [5] [4] High Efficiency Particulate Air filter [5] A velocity of 0.” 2.” Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 136310] “There should be a routine air velocity monitoring program to assure the maintenance of a 90 foot/minute +/.” 3. HEPA filtered air should be supplied at a sufficient and justified velocity to sweep particles away from areas where product is exposed.45 meters/second (90 feet per minute) has generally been established. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 101 of 185 : 14 May 2007 7.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Higher velocities may be appropriate in operations generating high levels of particulates.45 metres/second (90 feet per minute) ± 20 percent is generally accepted as appropriate. 08 Author : Validation in Partnership Ltd. Critical Area . Selected FDA 483 Observations (February 2002) Sterile Product Manufacture [VIP ID: 46020] “Written procedures for determining airflow velocities from HEPA filter units should require uniformity of air velocities between measuring points.6 Air Velocity 1.20% speed at critical filling sites during the filling operation. : SGD-110-ENV Rev. Ref. which should include the equipment to be used and re-installation of the air diffusers following testing. © Validation in Partnership Ltd 2007 .” Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26290] “There should be a written procedure describing how to obtain air velocity measurements from HEPA filters and air diffusion panels located above Class 100 aseptic filling areas. There should be a written procedure describing the frequency and method of obtaining air velocity measurements from HEPA filters and air diffusion panels located above Class 100 aseptic filling areas.Class 100 (ISO5) (para 6) [VIP ID: 110230] “HEPA-filtered [4] air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. Buildings and Facilities A. There should be specifications for the air velocity in an aseptic core and written procedures for determining and recording air flow velocities should require that all readings are within that specification prior to averaging the results. Selected FDA 483 Observations (February 2002) Sterile Product Manufacture [VIP ID: 46010] “Written procedures for determining airflow velocities from HEPA filter units should require that all readings are within specification prior to averaging the results. with possibly higher velocities where operations generate high levels of particulates. In critical areas. with a range of plus or minus 20 percent around the setpoint. This procedure should include: (a) the equipment to be used.

FACILITIES AND EQUIPMENT C.” Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7201] “Air velocity testing of HEPA filters used where parenteral product is exposed should be performed at the critical working level not at inches from the filter face. 08 Author : Validation in Partnership Ltd. Measurements taken from the filters face only should be correlated against those at the critical working level under dynamic conditions. GUIDANCE PET DRUG PRODUCTS . [VIP ID: 2186] “How often are air flow velocities checked for each HEPA filter?” 4. Measurements taken from the filters face only should be correlated against those at the critical working level under dynamic conditions.. : SGD-110-ENV Rev.g. Air velocities in Class 100 areas should be taken at work height. We recommend that operators be trained on the importance of minimizing objects and equipment within the critical area so laminar airflow is not disrupted.Doc.DRUG QUALITY ASSURANCE 7356. Production Equipment para 6 b.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 34.” Selected FDA 483 Observations (August 2002) Sterile Product Manufacture [VIP ID: 47720] “Air flow velocity checks should be measured near the work surface area (where vial filling occurs) rather than at the filter surface. not from the filter face. Ref. We recommend that microbiological monitoring (e. using settle plate) in the LAFW be conducted during sterility testing and critical aseptic manipulation. Equipment 1.” Selected FDA 483 Observations (December 1997) Product Manufacture [VIP ID: 6268] “Air velocities in Class 100 areas should be taken at work height. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 102 of 185 : 14 May 2007 (b) re-installation of the air diffusers following testing.” Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7201] “Air velocity testing of HEPA filters used where parenteral product is exposed should be performed at the critical working level not at inches from the filter face.” Selected FDA 483 Observations (June 1998) Sterile Product Manufacture [VIP ID: 6727] “The air velocity should be recorded at the aseptic filling work surfaces in accordance with a written procedure.CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. not from the filter face. Aseptic Workstation para 3 [VIP ID: 187414] “We recommend laminar airflow velocities be monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area.” CPGM-DB CHAPTER 56 .” © Validation in Partnership Ltd 2007 .

gowning rooms and general microbiology laboratory.” © Validation in Partnership Ltd 2007 . Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations. [VIP ID: 2180] “Is the air flow in critical areas laminar when delivered to the point of use? At what velocity? Is velocity determined at the critical area or at the filter face?” 5. e. gowning rooms and general microbiology laboratory. highly toxic.g. pathogenic. to assure that there is a sufficient velocity of air over the aseptic fill line.DRUG QUALITY ASSURANCE 7356. Differential pressure specifications should be documented for sterility test clean rooms.g. e. or an evaluation performed.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 28.” 7. the immediate environment to which a product and cleaned components which contact the product are exposed.” 3. Air velocities should be adequate to sweep over filling lines.” 2. highly toxic. radioactive or live viral or bacterial materials or products. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials. Adjacent rooms of different grades should have a pressure differential of 10 to 15 pascals (guidance values) but this recommendation may need to be modified for materials requiring containment.7 Pressure Difference 1.Doc. 08 Author : Validation in Partnership Ltd.MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 29 [ViP ID: 186056] “… Adjacent rooms of different grades should have a pressure differential of 10-15 pascals (guidance values). Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 2485] “Differential pressure specifications should be documented for all aseptic processing and / or ancillary clean rooms between which air may flow. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 103 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 . Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 136780] “Air velocity measurements should be taken. that is.” Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7560] “Air velocities should be adequate to sweep over filling lines. : SGD-110-ENV Rev. Particular attention should be paid to the protection of the zone of greatest risk. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . Differential pressure specifications should be documented for all aseptic processing and/or ancillary clean rooms between which air may flow. Ref. pathogenic. Selected FDA 483 Observations (November 1997) Sterile Product Manufacture [VIP ID: 2506] “Differential pressure specifications should be documented for sterility test clean rooms. radioactive or live viral or bacterial materials or products.

In any facility designed with an unclassified room adjacent to the aseptic processing room.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8.” Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7550] “Room differential pressures should be adequate to protect the integrity of the cleaner room. Ref. it is important that the environmental quality of the aseptic processing room be restored and confirmed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials. 08 Author : Validation in Partnership Ltd. As a minimum.5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination. and whether or not the reading is absolute or differential.2 [VIP ID: 190256] “There should be a pressure differential of not less than 10 to 15 Pascals (guidance value) between each of the areas. [6] Equal to 0. it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas. and it is critical that the time a door can remain ajar be strictly controlled (Ref.e. ambient/airlock and airlock/test room. at least 12. the immediate environment to which a product and cleaned components which contact the product are exposed.” © Validation in Partnership Ltd 2007 . e.1 CLEAN ROOM DESIGN 8. Buildings and Facilities C.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Buildings and Facilities C. To maintain air quality. radioactive or live viral or bacterial materials or products. a positive pressure differential of at least 10-15 Pascals (Pa) [6] should be maintained between adjacent rooms of differing classification (with doors closed).15 pascals (guidance values). highly toxic.2 Air Supply 8. a substantial overpressure (e.Doc.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. the aseptic processing room and adjacent cleanrooms have the same classification.1.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Maintaining a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide beneficial separation.2. Particular attention should be paid to the protection of the zone of greatest risk.06 inches of water gauge. readings should be taken prior to operator entry to the test suite. Clean Area Separation (para 1) [VIP ID: 110280] “An essential part of contamination prevention is the adequate separation of areas of operation. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations. Pressure gauges should be labelled to indicate the area served.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . 4). If this pressure differential drops below the minimum limit. For example. outward airflow should be sufficient to minimize ingress of contamination.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 29 (para 2) [VIP ID: 63220] “Adjacent rooms of different grades should have a pressure differential of 10 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 104 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .g. STERILITY TEST FACILITIES 8. that is. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness.g. the acceptable specification.. : SGD-110-ENV Rev. pathogenic. When doors are open. i.04-0. Pressure readings should be taken and recorded from externally mounted gauges unless a validated continuous monitoring system is installed.1. Clean Area Separation (para 2) [VIP ID: 110290] “In some cases.

Differential air pressures between aseptic processing areas and surrounding support areas of lower classification should be routinely monitored and recorded during dynamic operations.5 to 50 Pascals [22].113(b)] For example.5 The prevention of recontamination 7. The maintenance of positive pressure should be monitored and fitted with an alarm. 2006. Air balance between the isolator and other direct interfaces (e.5. Positive air pressure differentials from the isolator to the surrounding environment have largely ranged from approximately 17. supported by qualification studies. These pressure differences should be recorded regularly or otherwise documented. We agree an alarm is helpful.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 .g. b) [VIP ID: 194676] “Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established. however. written. Design 3.20" water gauge. dry heat tunnel) should also be qualified. no validation of your alarm system or approach to data recording was noted in your response. 7. and followed. : SGD-110-ENV Rev. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . We acknowledge receipt of your September 8th and October 20th 2006. as necessary. 08 Author : Validation in Partnership Ltd.MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 31 [VIP ID: 186060] “A warning system should be provided to indicate failure in the air supply. No system is in place to adequately monitor or record pressure differentials to assure that the rooms are maintained at the correct air pressure differential at all times. A positive air pressure differential adequate to achieve this separation should be employed and supported by qualification studies. An appropriate positive differential air pressure. [21 CFR § 211. [22] 0.. Indicators of pressure differences should be fitted between areas where these differences are important. should be assured as far as possible. should be maintained between the isolator and surrounding room and between different parts of the isolator system. b) air pressure differentials are not continuously monitored nor frequently recorded during aseptic filling operations. As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect against unforeseen circumstances. Ref. Inspectional Observations.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. We have reviewed your responses and have the following comments: Observation 5 Your October 20. The appropriate minimum pressure differential established by a firm will depend on the system’s design and. letters in response to the Form FDA-483.2 [VIP ID: 190492] “The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. when applicable. Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 6. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. response states your firm now has a visual and audible alarm in the aseptic fill room to signal aberrant air pressure differentials.07" to 0. Pressure Differential (para 1) [VIP ID: 111960] “Isolators that include an open portal should be designed to ensure complete physical separation from the external environment.Doc. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 105 of 185 : 14 May 2007 4. its exit port.” © Validation in Partnership Ltd 2007 .” 5.

processing. … [FDA-483 Item 4].” FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42790] “2.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 106 of 185 : 14 May 2007 Selected FDA 483 Observations (December 2004) Product Manufacture [VIP ID: 124720] “Pressure differentials between manufacturing rooms (encapsulation. including system errors. micro-organisms.Doc. : SGD-110-ENV Rev.” Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27720] “Differential pressures should be monitored continuously (not twice daily) in the aseptic fill controlled environment areas. Buildings and Facilities C.” © Validation in Partnership Ltd 2007 .” Selected FDA 483 Observations (May 2002) Sterile Product Manufacture [VIP ID: 46560] “Pressure differentials between fill rooms and adjacent uncontrolled room sealing and inspection rooms should be monitored and controlled directly to assure that a suitable pressure differential is maintained across these critical opening under all conditions.” Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26280] “Differential air pressures should be monitored between aseptic filling areas and surrounding support areas during dynamic aseptic filling operations.” Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124770] “Air pressure measurements should be taken and documented during dynamic filling processes to assure that the air pressures are maintained as required. packing or holding of a drug product [21 CFR 211.” Selected FDA 483 Observations (December 2003) Product Manufacture [VIP ID: 70530] “Pressure differentials between the classified and non. and temperature when appropriate for the manufacture. ****.” Selected FDA 483 Observations (June 2001) Sterile Product Manufacture [VIP ID: 27710] “Differential pressures should be monitored continuously (not twice daily) between the aseptic fill area and its adjacent gowning area. tableting) should be continually monitored to determine that the pressure specification is maintained during production. calibration accuracy and doors opening. Ref.46(b)].classified areas should be monitored to assure that the requisite air pressure is appropriately maintained. All alarms should be documented and deviations from established limits should be investigated. 08 Author : Validation in Partnership Ltd. the manufacturing and filling rooms of (a) ****.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. dust. granulation. Clean Area Separation (para 3) [VIP ID: 110300] “The Agency recommends that pressure differentials between cleanrooms be monitored continuously throughout each shift and frequently recorded. humidity. and **** are not equipped with differential pressure monitors. Failure to provide equipment for adequate control over air pressure. For example.

42(c)] in that data is not available to demonstrate that adequate pressure differential is maintained during filling operations.” FDA Warning Letter CBER-99-007 (December 1998) Extracted from FDA Warning Letter CBER-99-007 Canada 07/12/1998 [VIP ID: 13010] “Air pressure differential is not monitored in the manufacturing areas.” Selected FDA 483 Observations (August 1999) Sterile Product Manufacture [VIP ID: 7780] “Differential pressure should be monitored between filling rooms and neighboring unclassified rooms.” FDA Warning Letter CBER-99-002 (October 1998) Extracted from FDA warning letter CBER-99-002 UK 21/10/1999 [VIP ID: 13020] “Failure to establish separate or defined areas or other control systems for manufacturing and processing operations to prevent contamination or mix-ups [21 CFR 211.” Selected FDA 483 Observations (January 1997) Medical Device Manufacture [VIP ID: 135790] “Validation of positive air pressure in the manufacturing areas should take into account testing with various doors open to determine situations which may negate the positive air pressure. including the Vialing Rooms and the Monoclonal Production Room.” Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7128] “The pressure differentials for aseptic filling and compounding rooms should be documented more frequently than once a day. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 107 of 185 : 14 May 2007 Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19320] “Production room pressure differentials should be recorded each day for every room in use.” Selected FDA 483 Observations (June 1998) Sterile Product Manufacture [VIP ID: 6729] “Differential air pressure readings between filling rooms and support areas should be read during dynamic operations.Doc. 08 Author : Validation in Partnership Ltd.” Selected FDA 483 Observations (February 1997) Sterile Product Manufacture [VIP ID: 2473] “Air pressure differentials should be monitored or documented on a continuous basis to ensure a positive air pressure from the aseptic filling rooms to adjacent areas and to the uncontrolled environment outside the aseptic suite. Ref. : SGD-110-ENV Rev.” © Validation in Partnership Ltd 2007 .” Selected FDA 483 Observations (August 1998) Product Manufacture [VIP ID: 6797] “Room differential pressures should be routinely monitored.

” 7. Where plastic curtains are used to segregate areas of different classes. the differential pressure across the curtains should be measured. Selected FDA 483 Observations (February 1998) Sterile Product Manufacture [VIP ID: 6312] “Where plastic curtains are used to segregate areas of different classes. Facilities for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. problems with pressure differentials and sanitization have been encountered. For example. it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 . : SGD-110-ENV Rev. the differential pressure across the curtains should be measured.” Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6269] “Room pressure differential calculations should be recorded and the daily reading reviewed by someone other than the person taking the readings.MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Premises and equipment 3. However. These would include temperature. 08 Author : Validation in Partnership Ltd. it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 . it is still necessary to protect the product from environmental contamination.MANUFACTURE OF RADIOPHARMACEUTICALS PREMISES AND EQUIPMENT 3 [VIP ID: 186284] “In order to contain the radioactivity. it is still necessary to protect the product from environmental contamination. FACILITY (para 1) [VIP ID: 2017] “Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. However. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 108 of 185 : 14 May 2007 6. However. Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 14520] “Differential air pressure records and maintenance records for air pressure adjustments and repairs should be reviewed for completeness and accuracy by a second individual. it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas.” © Validation in Partnership Ltd 2007 .” 9. Because sterile bulk aseptic facilities are usually larger. The need to remove solvent vapors may also impact on area pressurization. In order to contain radioactive particles.” 8. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. humidity and pressure control. it is still necessary to protect the product from environmental contamination. a manufacturer was found to have the gowning area under greater pressure than the adjacent aseptic areas. Differential air pressure records and maintenance records for air pressure adjustments and repairs should be reviewed for completeness and accuracy by a second individual.Doc. including pressure control. [VIP ID: 1561] “In order to contain the radioactive particles. Ref.

For example.” 13. Failure to appropriately validate equipment. Failure to document the rationale behind established alarm times to monitor the specified differential air pressures within the manufacturing areas. between clean room pressure indicators and transmitters should be physically tagged. … B).” 11.Doc. [21 CFR 211.68]" [FDA Investigators: Thomas Arista. between clean room pressure indicators and transmitters should be physically tagged. 08 Author : Validation in Partnership Ltd. Selected FDA 483 Observations (January 2004) Product Manufacture [VIP ID: 70840] “HVAC pressure differential Alarm Logs should document the actual air pressure when the alarm was initiated and the actual value when the alarm is cleared.68)” 12. Failure to appropriately validate equipment. Air pressure alarm systems monitoring aseptic filling rooms should be tested periodically. Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136500] “Pneumatic lines in interstitial spaces.” Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 26990] “Air pressure alarm systems monitoring aseptic filling rooms should be tested periodically. Patricia Cochran and Jeffrey Sommers]” Extracted from FDA Warning Letter 2001-DT-12 (March 2001) Extracted from FDA warning letter 2001-DT-12 USA 02/03/2001 [VIP ID: 165740] “5. testing and challenge of data retrieval functions where used. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 109 of 185 : 14 May 2007 10. testing and challenge of data retrieval functions. For example. Unloading of centrifuges and loading of dryers should not be performed in close proximity (within 20ft) of reactor trains without physical separation or pressure differential control. There should be a rationale behind established alarm times and alarm logs should document the actual air pressure when the alarm is initiated and the actual value when the alarm is cleared.” FDA Warning Letter 01-NSV-09 (March 2001) Extracted from FDA warning letter 01-NSV-09 USA 02/03/2001 [VIP ID: 29080] “5. [21 CFR 211. Failure to document the rationale behind established alarm times to monitor the specified differential air pressures within the manufacturing areas. Pneumatic lines in interstitial spaces. where used. Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19760] “Unloading of centrifuges and loading of dryers should not be performed in close proximity (within 20ft) of reactor trains without physical separation or pressure differential control. Ref. Validation of pressure differential monitoring systems in sterile fill production areas should include the evaluation. … B).” © Validation in Partnership Ltd 2007 . Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72650] “Validation of pressure differential monitoring systems in sterile fill production areas should include the evaluation. : SGD-110-ENV Rev.

42 Design and construction features (c) [VIP ID: 20] “Operations shall be performed within specifically defined areas of adequate size. Aseptic processing should include systems for temperature and humidity control. For all other areas.CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: … (10) Aseptic processing. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 110 of 185 : 14 May 2007 7. If no temperature/humidity is specified.8 Temperature and Humidity 1. The following practices. which includes as appropriate: … (ii) Temperature and humidity controls.” 2.Doc. provided that all of the following conditions are met: … d) The repackaging and storage of the drug product is accomplished in a humidity controlled environment and within the temperature specified in the USP monograph or the product labeling. humidity and pressure control. These would include temperature. …” 3. follow guidance in 3a: Expiration Dating for Unit Dose Containers: A unit dose container is a non-reusable container designed to hold a quantity of drug intended for administration as a single dose. *Documentation must be on file to verify that all the conditions listed above are met. If no temperature/humidity is specified. Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. which is to be used promptly after the container is opened. : SGD-110-ENV Rev. with a relative humidity not exceeding 75 percent should be maintained.*” © Validation in Partnership Ltd 2007 . These would include temperature. .. FACILITY (para 1) [VIP ID: 2017] “Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. as defined by the USP. a controlled room temperature. a controlled room temperature. as defined by the USP. A firm may repackage solid oral dosage forms into unit dose containers and utilize an expiration date of not more than six months from the date of repackaging without conducting stability studies. humidity and pressure control.002B DRUG REPACKAGERS AND RELABELERS (December 1993) PART III .Buildings and Facilities Sec.DRUG QUALITY ASSURANCE 7356. Unit Dose Repackagers . Ref.. 211. CPGM-DB CHAPTER 56 . 21 CFR PART 211 .INSPECTIONAL OPERATIONS 3.1) [VIP ID: 4137] “For this program the full inspectional option provides specific policies for Unit-Dose Repackagers. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. if completely met. 08 Author : Validation in Partnership Ltd. A firm may repackage solid oral dosage forms into unit dose containers and utilise an expiration date of not more than six months from the date of repackaging without conducting stability studies. with a relative humidity not exceeding 75 percent should be maintained. are adequate to allow Unit Dose repackagers to comply with current good manufacturing practices in the specific areas described below. Full Inspectional Option *b. provided that the repackaging and storage of the drug product is documented as being accomplished in a humidity controlled environment and within the temperature specified in the USP monograph or the product labeling.

packing or holding of a drug product [21 CFR 211. 211.22. …” 7. (d) Personnel. Failure to provide equipment for adequate control over air pressure. The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual. and the air-handling system in the production area. Failure to establish written procedures (21 CFR 211. including operators and personnel responsible for monitoring. dust. equipment maintenance. humidity. Ref. the manufacturing and filling rooms of (a) ****.70 Production and process controls.198) for the following: … f. Extracted from FDA warning letter W/L 06-07 (February 2007) Extracted from FDA warning letter W/L 06-07 USA 02-Feb-07 5 [VIP ID: 194870] “Appropriate procedures have not been defined for controlling environmental conditions. Specifically your devices are labeled for room temperature or refrigerated storage. 211. needs special emphasis as people are potentially one of the main sources of microorganisms in the environment.QUALITY SYSTEM REGULATION (April 2006) Subpart G--Production and Process Controls 21 CFR 820.67. micro-organisms.122. [21 CFR 820. who work in a controlled environment. FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42790] “2. 08 Author : Validation in Partnership Ltd. There should be appropriate procedures defined for controlling and monitoring environmental conditions in production and storage areas.9 Training 1. and **** are not equipped with differential pressure monitors. Your current manufacturing and warehousing facilities do not have temperature controlling equipment and you have no assurance that devices are maintained below the labeled 86ºF. engineering. cleanliness.80. [VIP ID: 5807] “Each manufacturer shall establish and maintain requirements for the health. : SGD-110-ENV Rev. 211.” © Validation in Partnership Ltd 2007 . ****.70]” FDA Warning Letter 02-BLT-13 (January 2002) Extracted from FDA warning letter 02-BLT-13 USA 03/01/2002 5 [VIP ID: 48040] “5. humidity. The monitoring of temperatures.46(b)].” 5. and (b) **** and **** are not equipped with temperature and humidity control monitors [FDA-483 Item 4]. and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 111 of 185 : 14 May 2007 4.166. washing and preparation.Doc. The routine training of personnel. and 211. 21 CFR PART 820 . processing. Manufacturing and filling rooms should be equipped with temperature and humidity control monitors. 211. personal practices.100. and temperature when appropriate for the manufacture. 211. For example.

25(a). Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 112 of 185 : 14 May 2007 PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. The plastic curtains that surround the Class [redacted] area. STAFF TRAINING 8. equipment maintenance.113(b)]” © Validation in Partnership Ltd 2007 . Employees working in the sterile manufacturing area and sterility suite lack appropriate training in aseptic techniques and aseptic conduct. A formal personnel training programme is needed for all activities in each clean room.28(a). PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. these employees have failed to follow established SOPS designed to prevent microbiological contamination of drug products purported to be sterile as evidenced by FDA’s numerous inspectional observations. which are intended to protect the product from contamination. This means the programme has to be planned. Employees in room [redacted] aseptic filling room exhibited inappropriate aseptic conduct as evidenced by the observation of rapid movement throughout the Class [redacted] filling room. STAFF TRAINING 8.Doc.” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. This same employee was observed to be wearing safety glasses when the Gowning Procedures for the Parenteral Sterile Filling Area SOP 14-011-12 specifically states in bold letters that safety goggles are to be worn.3 [VIP ID: 188994] “A formal personnel training programme is needed for all activities in each clean room. Forceps used to remove fallen vials were brought out of the Class [redacted] room area into the Class [redacted] area and back into the Class [redacted] area. were displaced leaving gaps which could affect air flow in the Class [redacted] area. The inspectional observations include an employee entering the Class [redacted] filling suite with exposed skin between the hood and mask.” 3. 21 CFR 211. engineering. The above-referenced observations reveal significant problems in the training of the employees who perform activities in the sterile core. FDA Warning Letter RAN 2004-06 (March 2004) Extracted from FDA warning letter RAN 2004-06 USA 31/03/2004 [VIP ID: 126710] “2. 08 Author : Validation in Partnership Ltd. and 21 CFR 211. In addition. STAFF TRAINING 8. washing and preparation. An operator was observed to reach over uncovered vials being loaded onto the turntable while he was removing vials that had fallen over. Ref. This means the programme has to be planned.1 [VIP ID: 188990] “The routine training of personnel who work in a controlled environment needs special emphasis as people are potentially one of the main sources of microorganisms in the environment. documented and repeated at adequate intervals to ensure that the once trained individual meets the ongoing requirements for the work in a controlled environment.” 2. Employees working in a sterile manufacturing area should have appropriate training in aseptic techniques and aseptic conduct.2 [VIP ID: 188992] “Included are not only operators but also other personnel working in a controlled environment as staff responsible for monitoring. [21 CFR 211. An operator in the sterile filling suite was observed spraying her fingertips with isopropyl alcohol before collecting personnel environmental monitoring samples from her fingertips. documented and repeated at adequate intervals to ensure that the once trained individual meets the ongoing requirements for the work in a controlled environment. : SGD-110-ENV Rev.

g. Supervisors should ensure that all personnel are monitored and follow SOPs.2 AIRLOCK AND ASEPTIC GOWNING 8. : SGD-110-ENV Rev. Selected FDA 483 Observations (May 2004) Medical Device Manufacture [VIP ID: 121870] “The training of clean room personnel associated with out-of-specification particle counts and contact plates should be documented. or when operators perform the test infrequently. Personnel should undergo periodic re-certification. STERILITY TEST FACILITIES 8.Doc. Ref.g. Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.” 7. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 7. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.” © Validation in Partnership Ltd 2007 .” 8.” 6.2 Aseptic gowning 8.2 [VIP ID: 190242] “Supervisors should ensure that all personnel are monitored and follow Standard Operating Procedures (SOPs). TRAINING 7.2. or when operators perform the test infrequently. STAFF TRAINING 8.” 5. particularly when problems are detected during the course of routine environmental and negative control monitoring. particularly when problems are detected during the course of routine environmental and negative control monitoring. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8.2. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.2. Selected FDA 483 Observations (May 2001) Sterile Product Manufacture [VIP ID: 27160] “There should be documented evidence that outside contractors performing HEPA Filter testing have been trained to follow the established written procedure. and that they undergo periodic recertification. The training of clean room personnel associated with out-of-specification particle counts and contact plates should be documented. Each operator should be trained and certified in gowning procedures with training records maintained.5 [VIP ID: 188998] “Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.4 [VIP ID: 190270] “Each operator should be trained and certified in gowning procedures with training records maintained. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 113 of 185 : 14 May 2007 4. 08 Author : Validation in Partnership Ltd. There should be documented evidence that outside contractors performing HEPA filter testing have been trained to follow the established written procedure.

: SGD-110-ENV Rev. see 483 observations 9. 21 CFR 211. Personnel in clean rooms should be instructed to move slowly and carefully. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 114 of 185 : 14 May 2007 9. FDA Warning Letter 2002-DT-18 (January 2001) Extracted from FDA warning letter 2002-DT-18 USA 09/01/2001 [VIP ID: 42990] “Failure to evaluate and establish specifications for the building HVAC system. A preventative maintenance programme should be established for a building HVAC system. careful movement should be followed throughout the cleanroom. Such movements disrupt the unidirectional airflow.10 Calibration and Maintenance 1. humidity. 08 Author : Validation in Partnership Ltd. Extracted from FDA Warning Letter 320-06-02 (April 2006) Extracted from FDA warning letter 320-06-02 Croatia 28-Apr-06 1 [VIP ID: 191894] “Buildings used in the manufacture of injectable drug products are not always maintained in a good state of repair. and temperature. Qualification and Monitoring A. presenting a challenge beyond intended cleanroom design and control parameters.” 2. Personnel (para 3) [VIP ID: 110610] “ . and 21 CFR 211. 10 and 11.Doc. and to establish a preventative maintenance program for the HVAC system as required by 21 CFR 211.58. The principle of slow. Personnel (para 3) [VIP ID: 110590] “ . Ref. They should also be instructed to refrain from speaking when in direct proximity to the critical area.Move slowly and deliberately Rapid movements can create unacceptable turbulence in a critical area.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V.Approach a necessary manipulation in a manner that does not compromise sterility of the product To maintain sterility of nearby sterile materials.” 10. operators should refrain from speaking when in direct proximity to the critical area. Also. Personnel Training. For examples. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .58. as rapid movements can create unacceptable turbulence in a critical area. a proper aseptic manipulation should be approached from the side and not above the product (in vertical unidirectional flow operations). to provide for periodic checks to assure the system provides proper air flow. Personnel Training. Personnel involved in aseptic processing should be instructed that a proper aseptic manipulation should be approached from the side and not above the product in vertical unidirectional flow operations. A comprehensive preventative maintenance programme is essential in ensuring buildings used in the manufacture of injectable drug products are maintained in a good state of repair. and presenting a challenge beyond intended cleanroom design and control parameters.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. disrupting the unidirectional air flow.” 7.46. … © Validation in Partnership Ltd 2007 . Qualification and Monitoring A.

rust and mould. (Class 100. Information supplied to the FDA inspection team must be reliable and you should take immediate action to prevent this from recurring. The investigator states she was informed that production would cease until cleaning was performed. samples were taken. Failure to avert contamination in separate or defined areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211.Buildings and Facilities Sec. Your responses state that you have revised procedures.” FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 3 [VIP ID: 49890] “3. She later found out that production continued. 211. which includes as appropriate: … (vi) A system for maintaining any equipment used to control the aseptic conditions.000 processing rooms should be maintained free from damage. processing. Rust-like substance was observed on the metal frame surrounding the ceiling tiles and HEPA filters in the processing room (Class 100. For example.42 Design and construction features (c) [VIP ID: 20] “Operations shall be performed within specifically defined areas of adequate size.g. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: … (10) Aseptic processing. [21 CFR § 211. . provided training. Failure to have adequate systems to control contaminants in areas where air contamination occurs during production [21 CFR 211. There should be a system for maintaining equipment used to control aseptic conditions. and will develop a comprehensive preventative maintenance program. For example … . We are concerned that maintenance personnel did not notice the ripped exhaust when they had placed buckets in the same area. packing. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 115 of 185 : 14 May 2007 The flexible piping from the exhaust of the [redacted] was also ripped and observed to be taped in the same location from a previous tear.” 3. Equipment and fittings in Class 100. Two HEPA filter grills are bent and reveal a buildup of moldlike and other unknown material and these grills are located immediately above the **** filling zone” © Validation in Partnership Ltd 2007 . : SGD-110-ENV Rev. Part Fill Filling. replaced the flexible piping. Rotary **** Irrigation Filling. Please explain what you have done to prevent the condensate from dripping through the ceiling to the production area. c. and Manual Filling).CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -.The following is a summary list of the areas in **** rooms with rust build up: … Manual Fill Station **** and recirculating air unit **** …” FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 5 [VIP ID: 49910] “5. 21 CFR PART 211 . c.42(c)(5)]. Ref. 08 Author : Validation in Partnership Ltd.000)Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 3.000).Doc.There are numerous HEPA filter metal grills that have a build up of rust-like material and discoloration (e.46(c)].58] For example. or holding of a drug product in a good state of repair.” 4. [VIP ID: 194666] “Failure to maintain any building used in manufacture. and results were received.

” Selected FDA 483 Observations (January 2003) Sterile Product Manufacture [VIP ID: 51910] “Differential pressure gauges monitoring the pressure across prefilters in Air Handling Units (AHU) supplying sterile areas should be calibrated. Gauges used to measure the differential pressure across clean room prefilters and HEPA filters should be subject to periodic calibration. and system sanitization. [VIP ID: 1449] “All equipment such as sterilisers.MANUFACTURE OF STERILE MEDICINAL PRODUCTS . Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 47840] “Cleaning procedures should include air conditioning grills in solution preparation areas. Ref. Selected FDA 483 Observations (December 1999) Product Manufacture [VIP ID: 8620] “There should be calibration and maintenance procedures for HVAC equipment to include relative humidity and temperature sensors. water treatment. Air handling and filtration systems should be subject to validation and planned maintenance. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 116 of 185 : 14 May 2007 5. air handling and filtration systems. air handling and filtration systems. Planned maintenance procedures for clean room air handling units should require cleaning of the units. water treatment. storage and distribution systems should be subject to validation and planned maintenance. their return to use should be approved.” 7. storage and distribution systems should be subject to validation and planned maintenance. Cleaning procedures should include air conditioning grilles in solution preparation areas. Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 47810] “Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units. air vent and gas filters. the gauges used to measure the differential pressure across the cleanroom prefilter and HEPA filter are not subject to periodic calibrations. 08 Author : Validation in Partnership Ltd.” 6.72(a). and system sanitisation. There should be calibration and maintenance procedures for HVAC equipment to include relative humidity and temperature sensors. and their return to use should be approved.Doc.MANUFACTURE OF STERILE MEDICINAL PRODUCTS EQUIPMENT 36 [VIP ID: 186070] “All equipment such as sterilisers. as required by 21 CFR 820. : SGD-110-ENV Rev. generation. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated.” © Validation in Partnership Ltd 2007 .” 8. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . their return to use should be approved. air vent and gas filters. For example.” 9. FDA Warning Letter [Reference Obliterated] (July 2003) Extracted from FDA warning letter UK 07/11/2002 [VIP ID: 57380] “10.SUPERSEDED! (July 1996) Equipment 36. generation.

equipment has not been maintained or replaced as per SOP entitled "---" For example: … ii. and prefilters and filters for air handling units. which supply air to classified areas. to establish or maintain written procedures for cleaning and maintenance of equipment. FDA Warning Letter CBER-98-024 (August 1998) Extracted from FDA warning letter CBER-98-024 USA 14/08/1998 [VIP ID: 12170] “Failure to clean. : SGD-110-ENV Rev.” © Validation in Partnership Ltd 2007 . Laminar air flow hood prefilters.12]. the laminar air flow hood pre-filters have not been replaced. iii. which supply air to the classified areas. have not been replaced every . and to maintain records [21 CFR 211.” 11. Where instrumentation.” Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19330] “There should be written procedures describing the calibration / certification methods and tolerance limits for all instruments used during production operations to include: … (2) magnehelic gauges …” 10. strength quality or purity of the drug product.” Selected FDA 483 Observations (March 2001) Sterile Product Manufacture [VIP ID: 26880] “Magnehelic gauges used to monitor pressure differentials across pre-filters should be calibrated. Selected FDA 483 Observations (September 2002) Product Manufacture [VIP ID: 47470] “Records should be maintained of the equipment used to calibrate magnehelic gauges in tablet compression suites. utensils.” 12. are calibrated by outside contractors. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 117 of 185 : 14 May 2007 Selected FDA 483 Observations (October 2002) Sterile Product Manufacture [VIP ID: 51210] “Differential pressure gauges monitoring the pressure across prefilters in Air Handling Units (AHU) supplying sterile areas should be calibrated. and sanitize equipment.months. and supplies at appropriate intervals to prevent malfunctions or contamination that would alter the safety. the pre filters and filters for the air handling units. identity. Records should be maintained of the equipment used to calibrate magnehelic gauges in tablet compression suites.67 and 600. such as magnehelic gauges and balances. Ref. a responsible individual should review the calibration data provided. in that: a.Doc. Selected FDA 483 Observations (September 2002) Product Manufacture [VIP ID: 47480] “Where instrumentation such as magnehelic gauges and balances are calibrated by outside contractors a responsible individual from the firm should review the calibration data provided. should be maintained or replaced as per SOPs. maintain. 08 Author : Validation in Partnership Ltd.

Selected FDA 483 Observations (August 2007) Sterile Product Manufacture [VIP ID: 193770] “Where Heating. Environmental Monitoring 4. the user should assess the overall suitability of a monitoring device before it is placed into service. [20] For example. 08 Author : Validation in Partnership Ltd. Active Air Monitoring Assessing microbial quality of air should involve the use of active devices including but not limited to impaction. The movement and ingress of maintenance personnel. [20] Because devices vary. including maintenance personnel. and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency. into filling areas should be controlled and monitored to prevent contamination from occurring during manufacturing and processing operations. For example The controlling and monitoring of the movement and ingress of personnel. Each device has certain advantages and disadvantages. Air Conditioning (HVAC) System preventive maintenance is not performed due to the lack of personnel available or production taking place. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 118 of 185 : 14 May 2007 13. components. and disruption of unidirectional airflow. centrifugal.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Where HVAC system preventive maintenance is not performed. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures.” © Validation in Partnership Ltd 2007 . …” 15. reference should be made in the documents to any actions taken in response to the skipped work. Manufacturers should be aware of a device's air monitoring capabilities. Failure to avert contamination in separate or defined areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211. such as tools necessary for equipment repairs / adjustments into the **** filling areas is not being performed. Monitoring Methods b. Manufacturers should ensure that active air monitoring devices for assessing the microbial quality of air are calibrated. We recommend that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. due to the lack of personnel available or production taking place. cleanability. Active Air Monitoring [VIP ID: 111570] “b. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Ref.Doc. ability to be sterilized. and the tools and materials necessary for equipment repairs/adjustments. and ancillary materials.42(c)(5)].” 14. FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 3 [VIP ID: 49890] “3. reference should be made in the documents to any actions taken in response to the skipped work. : SGD-110-ENV Rev. and membrane (or gelatin) samplers. Ventilation. the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment. although all allow testing of the number of organisms per volume of air sampled.

6. NON-STERILE PROCESS VALIDATION 6. Ref. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality. product component. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 119 of 185 : 14 May 2007 7. 08 Author : Validation in Partnership Ltd. process equipment.SUPERSEDED! (October 1999) 3. [VIP ID: 21430] “Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material. process equipment. CLEANING VALIDATION ..” 2. Written procedures should be in place to describe the actions to be taken if a change is proposed to the process environment.6. method of production or testing or any other change that may affect product quality or reproducibility of the process. NON-STERILE PROCESS VALIDATION..7 Change Control 6. consistent with the approved specifications. NON-STERILE PROCESS VALIDATION 6. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component. …” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 . method of production or testing or any other change that may affect product quality or support system operation.” © Validation in Partnership Ltd 2007 . product component. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality. : SGD-110-ENV Rev.QUALIFICATION AND VALIDATION CHANGE CONTROL 43 [VIP ID: 187116] “Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material.4. process equipment.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 . method of production or testing or any other change that may affect product quality or reproducibility of the process.1 [VIP ID: 188620] “Change control is an important element in any Quality Assurance system.QUALIFICATION AND VALIDATION (September 2001) CHANGE CONTROL 43. The definition of what constitutes a change to a process environment needs to be agreed. DESIGN QUALIFICATION. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 6. [VIP ID: 68800] “The definition of what constitutes a change to a process or process environment needs to be agreed.7.Doc. process environment (or site).6. consistent with the approved specifications.6 Re-validation 6. process environment (or site).VALIDATION MASTER PLAN.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 6.4 [VIP ID: 188616] “The definition of what constitutes a change to a process or process environment needs to be agreed. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 . process environment (or site). NON-STERILE PROCESS VALIDATION 3. .11 Change Control 1. Re-validation 3. INSTALLATION AND OPERATIONAL QUALIFICATION.

INSTALLATION AND OPERATIONAL QUALIFICATION.5. Change Control 3. Normally process simulation tests should be repeated twice a year per shift and process. equipment.5 Test Frequency 5. PROCESS SIMULATION TEST CONDITIONS 5. The target should be zero growth but a contamination rate of less than 0. PROCESS SIMULATION TEST CONDITIONS 5. NON-STERILE PROCESS VALIDATION. For small batches. method of production or testing or any other change that may affect product quality or support system operation.[2] [2] For further details on the validation of aseptic processing. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system.7. Media fills should be performed after any significant modification to the HVAC system.5. equipment or environment or if processing lines stand idle for more than 6 months.1.” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 5.4 [VIP ID: 188932] “Start-up" simulation tests are performed for example for new processes. modifications in equipment directly in contact with the product or modifications in the HVAC system.” © Validation in Partnership Ltd 2007 . : SGD-110-ENV Rev. equipment or environment as for example significant personnel changes (a new shift). Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component. concentration and suitability for sterilisation of the nutrient medium. CLEANING VALIDATION . process environment (or site). please refer to the PIC/S Recommendation on the Validation of Aseptic Processing (PI 007)” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 5. 08 Author : Validation in Partnership Ltd.1% with 95% confidence limit is acceptable. The number of containers used for media fills should be sufficient to enable a valid evaluation.5 Test Frequency 5. Ref. DESIGN QUALIFICATION. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 120 of 185 : 14 May 2007 EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 . The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps.SUPERSEDED! (October 1999) 3. process equipment.” 3.MANUFACTURE OF STERILE MEDICINAL PRODUCTS SANITATION 42 [VIP ID: 186082] “Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). process and number of shifts.Doc. It should also take into account various interventions known to occur during normal production as well as worst case situations. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 .5 [VIP ID: 188934] “An "on-going" simulation test consists of one satisfactory simulation test per shift and is mainly performed for the periodic monitoring of aseptic conditions during routine manufacturing but also for example after less critical changes of processes.VALIDATION MASTER PLAN. NON-STERILE PROCESS VALIDATION 3. [VIP ID: 68820] “Change control is an important element in any Quality Assurance system. Any contamination should be investigated. clarity. the number of containers for media fills should at least equal the size of the product batch. Selection of the nutrient medium should be made based on dosage form of the product and selectivity.7. new equipment or after critical changes of processes. The manufacturer should establish alert and action limits.

ENVIRONMENT MONITORING REGULATORY GUIDANCE 8. It should address issues such as sample location. process and number of shifts. Ref. Buildings and Facilities E. stopper hopper. and the impact of construction activities on facility control.” 5. walls. Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194246] “The airborne particulate monitoring program should adequately monitor locations in the aseptic processing zone that pose a contamination risk to the product.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. A clean area environmental monitoring programme should include personnel monitoring and regular sampling and testing of the manufacturing environment. filling heads and accumulating table (empty vials).” 8. identification of microorganisms.9 [VIP ID: 188288] “The following elements should be carefully reviewed as they are often involved in loss of control of bioburden: … (g) Change control and validation. floors. size of sample.1 General 1. and equipment surfaces. limits. 08 Author : Validation in Partnership Ltd. : SGD-110-ENV Rev. trending systems. CONTROL OF PRESTERILIZATION BIOBURDEN 5. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system. duration of sampling. including air...MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Processing 42 (para 1) [VIP ID: 63350] “Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). . and procedures to promptly address out of limit results or adverse trends. specific sampling equipment and techniques. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Design (para 12) [VIP ID: 110540] “Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems or other utilities. using validated test methods. equipment. Selection of the nutrient medium should be made based on dosage form of the product and selectivity. concentration and suitability for sterilisation of the nutrient medium. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 121 of 185 : 14 May 2007 EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . e. clarity. Written procedures should address returning a facility to operating conditions following a shutdown. appropriate sampling frequency. timing of sample collection.Doc. It should also take into account various interventions known to occur during normal production as well as worst case situations. Change control should be carefully reviewed as it is often involved in loss of control of bioburden.” 4.g. PI 005-2 RECOMMENDATION ON GUIDANCE ON PARAMETRIC RELEASE (July 2004) APPENDIX I RECOMMENDATIONS FOR A GENERAL STERILITY ASSURANCE SYSTEM FOR TERMINALLY STERILISED PRODUCTS AND PROVISIONS FOR PARAMETRIC RELEASE 5.” Extracted from FDA Warning Letter 2006-NOL-04 (February 2006) © Validation in Partnership Ltd 2007 . Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems.

” FDA Warning Letter 2004-NOL-36 (September 2004) Extracted from FDA warning letter 2004-NOL-36 USA 17/09/2004 [VIP ID: 130040] “2. Observation 4]” © Validation in Partnership Ltd 2007 .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Sample sizes should be sufficient to optimize detection of environmental contaminants at levels that might be expected in a given clean area. : SGD-110-ENV Rev. General Written Program (para 1) [VIP ID: 111440] “In aseptic processing. Sample timing. 08 Author : Validation in Partnership Ltd. Review of environmental and personnel monitoring data. and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. frequency. processing area as required by 21 CFR 211.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Environmental Monitoring 1. aseptic corridors. you do not perform environmental monitoring for viable and non viable organisms in your aseptic areas.42(c)(10)(i).” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 122 of 185 : 14 May 2007 Extracted from FDA warning letter 2006-NOL-04 USA 15/02/2006 [VIP ID: 176710] “2. and closures. when a given batch is being manufactured) as well as environmental trends of ancillary clean areas. routine environmental monitoring of the aseptic filling area for viable and non-viable particulates is not done. You do not have control systems to prevent contamination.Doc. steam generator) and proper functioning of equipment (e. batch alarms report. Specifically. Environmental monitoring should promptly identify potential routes of contamination. [Reference: Form FDA 483. and location should be carefully selected based upon their relationship to the operation performed. This program provides meaningful information on the quality of the aseptic processing environment (e.. as well as other data relating to acceptability of output from support systems (e. WFI.g. General Written Program (para 2) [VIP ID: 111450] “Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and scientifically sound methods.g. operating parameters. Written procedures should include a list of locations to be sampled.g.. Environmental Monitoring 1.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . The requirement for review of all batch records and data for conformance with written procedures. floors.g.42 and 211.42(c)(10)(iv). gowning rooms) using scientifically sound sampling procedures. It is critical that these activities be maintained and strictly implemented on a daily basis. allowing for implementation of corrections before product contamination occurs (211. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211. Batch Record Review: Process Control Documentation (para 1) [VIP ID: 111860] “Manufacturers should build process and environmental control activities into their aseptic processing operation. walls. one of the most important laboratory controls is the environmental monitoring program..CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XII. Samples should be taken throughout the classified areas of the aseptic processing facility (e. Routine microbiological monitoring of the gowns and gloves of the employees working in the class 100 area is not done. and equipment surfaces. Your firm failed to establish a system for monitoring environmental conditions in the aseptic.. For example. Ref. including the critical surfaces that come in contact with the product.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. HEPA/HVAC. container. as required under 21 CFR 211.188. The monitoring program should cover all production shifts and include air. integrity of various filters) are considered essential elements of the batch release decision.113).

” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. Ispropyl alcohol was observed being sprayed directly over the [redacted] air samplers located in the Class [redacted] area during the media fill.” FDA Warning Letter RAN 2004-06 (March 2004) Extracted from FDA warning letter RAN 2004-06 USA 31/03/2004 [VIP ID: 126720] “3.Annex 1 of the EU/PIC/S Guide to GMP provides the basis for environmental and personnel monitoring requirements and recommendations. Annex 1 to the EU/PIC/S Guide to GMP provides the basic requirements for the manufacture of sterile products including those aseptically processed. : SGD-110-ENV Rev. carts. Environmental control systems have not been inspected periodically to verify that the system including necessary equipment is adequate and functioning properly [21 CFR 820. Environmental monitoring of personnel was not performed immediately after a significant intervention into the Class [redacted] area. Specifically.70(c)]. INTRODUCTION 2. 08 Author : Validation in Partnership Ltd.” FDA Warning Letter WL 09-04 (November 2003) Extracted from FDA warning letter WL 09-04 USA 24/11/2003 [VIP ID: 125200] “4. The environmental monitoring systems in the small volume parenteral manufacturing and filling areas are deficient in that your firm has not performed a scientific assessment to identify appropriate environmental monitoring sampling sites during the actual manufacturing and sterile filling operations that could pose the most microbiological risk to the products manufactured. ENVIRONMENTAL AND PERSONNEL MONITORING [VIP ID: 188970] “.3 General information 2. standards and recommendations. [21 CFR 211. Ref. for monitoring of the environment and of personnel.Doc.Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring. Equipment such as forceps. and tools used during the filling operation are not routinely monitored. ..000 cleanroom was not recertified between 3/97 to 9/2003 and no documented evidence that demonstrates that any environmental monitoring is conducted by the firm. intervention monitoring and staff training.” © Validation in Partnership Ltd 2007 . Inspectional observations include failure to perform air sampling in the area near the vial turntable to assess the condition of the air during manual loading of vials. The Annex includes requirements.3. the Class 100.1 [VIP ID: 188786] “..113(b)]” Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72670] “There should be a documented rationale and data to support the statistical validity of sampling frequencies for non-viable and viable particulates in critical filling zones. This occurred after intervention through the plastic curtains that surround the Class [redacted] area and after Rodac sampling of the plastic curtains was performed. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 123 of 185 : 14 May 2007 PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 2.” Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70260] “The environmental monitoring program should insure that batch related environmental data is generated for each aseptic stopper bagging and sealing activity. for example. Environmental monitoring for viable organisms in the manufacturing area is done in the center of the room at times when there is no activity in the room.

002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III .58 and 600. steps may be performed in unclassified. 08 Author : Validation in Partnership Ltd. Reference should be made to other documents such as the EN/ISO Standards. Actions taken when limits are exceeded should include adequate investigation into the source of the problem. Ref. As the process moves further downstream. less frequent monitoring is acceptable in areas in which upstream steps are performed. has not performed routine monitoring of the environmental controlled room for product bioburden. your firm: … b.211.DRUG QUALITY ASSURANCE 7356.DRUG QUALITY ASSURANCE 7356.)” FDA Warning Letter 2001-DAL-WL-35 (September 2001) Extracted from FDA warning letter 2001-DAL-WL-35 USA 07/09/2001 [VIP ID: 42520] “Failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications [21 CFR 820. Monitoring should be performed during production. Surface monitoring for microbial in critical areas is not performed. more frequent monitoring is expected.Doc. Environmental controls/monitoring (para 1) [VIP ID: 77130] “There should be a comprehensive environmental monitoring program. and room humidity [FDA-483 Item 1].” Selected FDA 483 Observations (October 2002) Sterile Product Manufacture [VIP ID: 47560] “Airborne particulate monitoring programs should adequately monitor all locations in the aseptic processing zone which pose a contamination risk to the product. Inspection 5.70].Inspectional B.” CPGM-DB CHAPTER 56 .11] … Non-viable particulate monitoring is not performed in critical or controlled production areas. Environmental controls/monitoring (para 2) [VIP ID: 77140] “Generally. which includes monitoring for non-viable and viable air particulates. There. alert. Buildings and Facilities [VIP ID: 78050] “[211.42 .Inspectional B. and measures taken to prevent recurrence. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 124 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 . surface viables and. surfaces etc. and action limits for each area.MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Principle Note: [VIP ID: 62310] “This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air. but "controlled" environments (ones with some level of particulate controls). room temperature. and corrective actions to be taken when limits are exceeded. for a fill room this may include the stopper hopper.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART V . Inspection 5.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III . For example. filling heads and the accumulating table.DRUG QUALITY ASSURANCE 7356. Procedures should address frequencies and locations for monitoring.REGULATORY/ADMINISTRATIVE STRATEGY Regulatory/Administrative Follow-Up Significant Deviations 2. …” © Validation in Partnership Ltd 2007 . (For example. Microbial and particulate counts are not performed during periods of activity. …” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . in the aseptic filling areas. potential impact on the product. personnel. : SGD-110-ENV Rev.” CPGM-DB CHAPTER 56 .

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FDA Warning Letter 01-NWJ-26 (June 2001) Extracted from FDA warning letter 01-NWJ-26 USA 08/06/2001 [VIP ID: 42000] “Failure to establish and monitor environmental conditions. For example, the inspection revealed that your employees used the manufacturing area as a lunchroom. In addition, you have not established or monitored product bioburden levels.” HUMAN DRUG CGMP NOTES, VOLUME 07, NUMBER 01 (March 1999) Motise's Notebook Policy Questions On: Question 7 [VIP ID: 6009] “What is the purpose of an environmental monitoring program in aseptic processing? What are some major factors that ensure the environment does not contaminate product throughout a batch's manufacture? Reference: 21 CFR 211.42, Design and construction features [Subpart C-Buildings and Facilities]; 211.113, Control of microbiological contamination; 211.22, Responsibilities of quality control unit; 211.46, Ventilation, air filtration, air heating and cooling; 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing; July 1994 Guide to Inspections of Sterile Drug Substance Manufacturers The environmental monitoring program is a vital part of a quality control unit's CGMP responsibility to monitor and ensure ongoing control of an aseptic process. The CGMP regulations, at section 211.113 require firms to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. This section is particularly applicable to sterile drug products made by aseptic processing, and the aseptic guideline addressed at length various aspects of environmental monitoring. An environmental monitoring program is vital for aseptic processing operations because it: 1) provides crucial information on the quality of the aseptic processing environment during manufacturing; 2) prevents release of a potentially contaminated batch if appropriate quality standards (defined by a firm's written procedures) are not fulfilled; and, 3) prevents future contamination by detecting adverse trends. In addressing the environmental monitoring program, the aseptic guideline discussed regular sampling and testing of the manufacturing environment, including air, floors, walls, and equipment surfaces. Evaluating the quality of air and surfaces in cleanrooms should start with a well-defined and specific written program, including validated test methods. As explained in the guideline, among issues normally addressed by an environmental monitoring program are: sample location, appropriate sampling frequency, timing of sample collection, duration of sampling, size of sample, specific sampling equipment and techniques, limits, identification of microorganisms, trending systems, and procedures to promptly address out of limit results or adverse trends. A number of major variables influence environmental control, all of which need to be addressed by appropriate written SOPs, in accordance with section 211.113. It is important that a personnel qualification and monitoring program address operator practices, critical in maintaining environmental control of the aseptic processing area. In addition, the CGMPs at section 211.46 require equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product. In this context, the Heating, Ventilation, and Air Conditioning (HVAC) system design and controls play a key role in providing an adequate environment (e.g., particulate cleanliness, air pressure, and airflow) for aseptic processing. Adequate cleaning and sanitizing procedures, facility design, equipment design, personnel flow, and material flow are among other key variables which significantly impact on the suitability of the environment in which aseptic processing operations are conducted. Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 35. [VIP ID: 2187] “Does the firm have a written monitoring program for classified areas that includes a scientifically sound sampling schedule that describes sampling locations, their relation to the working level, and frequency? Describe the basis for the sampling program. (21 CFR, 211.160)”

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 41. [VIP ID: 2193] “Report the actual volume of air sampled per location.” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 49. [VIP ID: 2201] “What sampling device is used? What volume of air is sampled?” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 50. [VIP ID: 2202] “How many samples are collected per location? Are results averaged?” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 51. [VIP ID: 2203] “When was sampling equipment last calibrated?” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 52. [VIP ID: 2204] “Were environmental sampling results within specifications during the manufacture of the batches of the selected drug product? (Describe any deviations and firm's response.)” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 55. [VIP ID: 2207] “What type of monitoring is done?” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) STERILIZATION SYSTEMS Filtration Sterilization II. Aseptic Filling 245. [VIP ID: 2397]

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“Briefly describe the aseptic filling processes from preparation of bulk liquid product to filling and sealing of final dosage form, including the environmental monitoring performed in critical areas during actual production (e.g., how are Class 100 conditions maintained; where are the sampling sites; is bioburden testing performed on the bulk product?)” CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) LABORATORY Environment 286. [VIP ID: 2438] “What type of environmental monitoring is performed in the laboratory (e.g., type and location of sampling; sampling equipment; frequency)?” BIOTECHNOLOGY INSPECTION GUIDE (November 1991) PROCESSING AND FILLING C. Filling (para 3) [VIP ID: 1098] “Problems that have been identified during filling include inadequate attire; deficient environmental monitoring programs; hand-stoppering of vials, particularly those that are to be lyophilized; and failure to validate some of the basic sterilization processes. Because of the active involvement of people in filling and aseptic manipulations, the number of persons involved in these operations should be minimized, and an environmental program should include an evaluation of microbiological samples taken from people working in aseptic processing areas. This program along with data should be reviewed during the inspection.”

2.

Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. STAFF TRAINING 8.5 [VIP ID: 188998] “Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.”

3.

Environmental monitoring should be performed under operational (dynamic) conditions.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.2 [VIP ID: 190296] “Environmental monitoring should be performed under operational (dynamic) conditions either within the isolator or in the laminar airflow and associated background areas.” Selected FDA 483 Observations (July 2004) Sterile Product Manufacture [VIP ID: 122400] “Viable and non-viable particulate monitoring should be performed during operations for all processing areas.” HUMAN DRUG CGMP NOTES, VOLUME 05, NUMBER 02 (June 1997) Motise's Notebook Active Pharmaceutical Ingredients (APIs) 3) [VIP ID: 3505] “Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?

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and in proximity to the work surfaces and exposed product or container/closures. Many firms now have the capability to monitor nonviables continuously. High levels of particulates generally represent a departure from processing norms. [VIP ID: 2190] “Report the limits used. It is therefore important that the Quality Control unit investigate such "particulate excursions.113. Contact for further information: Richard L.DRUG QUALITY ASSURANCE 7356. firms should obtain data from dynamic monitoring (during operations) as a routine batch control. indicating.fda. On the other hand. Aseptic processing operations are designed to exclude living microorganisms. 08 Author : Validation in Partnership Ltd. HFD-322. For example. and if sampling is done during production or at rest. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 128 of 185 : 14 May 2007 References: 21 CFR 211. 301-594-0095. However. Friedman. failure to monitor continuously is not objectionable. Ref.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) FREEZE-DRYING (LYOPHILIZATION) Lyophilization Validation 82.160(b). firms conduct studies to establish the room's air classification. It is generally accepted that monitoring of particulate concentration in classified (environmentally controlled) areas during operations serves as a direct indicator of changes in local air quality while indirectly indicating the increased potential for the introduction of microorganisms to the monitored area. in class 100 areas. and particulates from the finished product. when qualifying a cleanroom. 211.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 36.DRUG QUALITY ASSURANCE 7356." Finally. : SGD-110-ENV Rev. Sampling an environment for particulates during static (at rest) times is of minimal utility in assessing actual processing conditions.” CPGM-DB CHAPTER 56 . Firms should monitor frequently throughout manufacturing. e-mail: friedmanr@cder. unusual personnel activity which challenges the intended cleanroom design parameters. end toxins.DRUG QUALITY ASSURANCE 7356. however.DRUG QUALITY ASSURANCE 7356. length of sampling period. [VIP ID: 2234] “Is environmental monitoring performed during unloading of the chamber during production as well as during validation?” © Validation in Partnership Ltd 2007 . operational (dynamic) monitoring performed throughout aseptic processing is needed.gov” CPGM-DB CHAPTER 56 . Although the classification studies include assessment of particulate levels under static conditions. for example. Occasional static monitoring during periods of no operation to ensure particulate levels remain well below an area's classification level would be useful as a facility maintenance parameter.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 38. No. samples should be taken about one foot away from the work surface.Doc.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) FREEZE-DRYING (LYOPHILIZATION) Lyophilization Validation 80. 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing. Here's why. General requirements (Subpart I Laboratory Controls). [VIP ID: 2232] “Is environmental monitoring performed during loading of the lyophilizer both during production as well as during validation?” CPGM-DB CHAPTER 56 . [VIP ID: 2188] “Are both viable and non-viable particulate samplings performed in all classified areas during production?” CPGM-DB CHAPTER 56 . Control of microbiological contamination. the final classification should be derived from data generated while equipment is in place and operations are ongoing.

it is important to monitor and qualify cleanroom operations on each production shift. isolated. 211. Ref.42(c)(10). Ultimately. dried or packed.gov” 5. VOLUME 06.. not everyone will be suitable for cleanroom duty. … Note that because some people are found to be shedders. Personnel responsibilities. [VIP ID: 2369] “Briefly describe the environmental monitoring performed by the firm in critical areas during actual production. how are Class 100 conditions maintained? Where are the sampling sites? Is non-viable particulate monitoring performed?)” 4. HUMAN DRUG CGMP NOTES. NUMBER 03 (September 1998) Motise's Notebook POLICY QUESTIONS: Question 1 [VIP ID: 5959] “How would the CGMPs address the problem of cleanroom operators who are shedders or practice poor aseptic technique? References: See 21 CFR 211. 08 Author : Validation in Partnership Ltd. 211. (e.” © Validation in Partnership Ltd 2007 . Design and construction features. e-mail: friedmanr@cder. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 129 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 . dried and/or packed.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) STERILIZATION SYSTEMS Aseptic Sterilization Systems Dry Powder Filling 217. Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19770] “Environmental monitoring should be performed in milling.fda. Environmental monitoring should be performed in areas where parenteral grade APIs are milled.” Selected FDA 483 Observations (March 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7087] “Environmental monitoring should be performed in areas where parenteral grade APIs are isolated.Doc. : SGD-110-ENV Rev. Humans are a chief source of particulate contamination in the cleanroom. it is such differences among cleanroom personnel which underscore the need to monitor and qualify cleanroom operations on each production shift. HFD-322. Because some cleanroom operators may be shedders or practice poor aseptic technique.” Selected FDA 483 Observations (May 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7154] “Environmental monitoring should be performed in areas where parenteral grade APIs are isolated. environmentally monitored area.DRUG QUALITY ASSURANCE 7356. dried and packed. Contact for further information: Richard L. environmentally monitored area. 301-594-0095. Guideline on Sterile Drug Products Produced by Aseptic Processing.113 Control of microbiological contamination.g. June 1987 … Cleanrooms are defined by their low levels of both viable and nonviable particulates and these levels need to be monitored and kept under control.” 6. although these contaminants may originate from a number of other sources. Friedman. Active and excipient raw materials used in the manufacture of parenteral drugs should be sampled in a suitable. Personnel qualifications.28.25. Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7074] “Active and excipient raw materials used in the manufacture of parenteral drugs should be sampled in a suitable. blending and drying areas where APIs intended for parenteral use are exposed. 211. blended.

” © Validation in Partnership Ltd 2007 . compressed air.PERSONNEL Key Personnel 2. gases. subject to any national regulations: … . and action should be taken when limits are exceeded.g. ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. HVAC systems that could impact on product quality should be qualified and appropriately monitored. QA should review environmental monitoring data for excursions occurring during lot production to determine the potential impact on product quality. Drawings for these utility systems should be available.Doc.” 8. Routine environmental monitoring of filling areas should be performed by individuals from QC. EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 2 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 130 of 185 : 14 May 2007 7. or jointly exercised. steam.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4. …” 9. [VIP ID: 333] “The heads of Production and Quality Control generally have some shared. Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 14560] “Routine environmental monitoring of filling areas should be performed by individuals from QC. These may include. gases. Drawings for these utility systems should be available. steam.7. compressed air. and heating.” 10. The heads of Production and Quality Control may be jointly responsible for the monitoring and control of the manufacturing environment.20 [VIP ID: 24539] “All utilities that could impact on product quality (e.g.20 [VIP ID: 153710] “All utilities that could impact on product quality (e. ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. BUILDINGS AND FACILITIES 4. not by filling room operators. not by filling room operators. 08 Author : Validation in Partnership Ltd. and heating. Ref.2 Utilities 4. responsibilities relating to quality.2 Utilities 4. : SGD-110-ENV Rev. Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70300] “QA should review environmental monitoring data for excursions occurring during lot production to determine the potential impact on product quality.the monitoring and control of the manufacturing environment.

…” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION GENERAL 4.MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Production 7. and with the organisation. equipment operations. personnel and airborne particulates. Monitoring of the environment assumes particular importance.” 12. The basic requirements of Quality Control are that: i.g. in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 131 of 185 : 14 May 2007 11. and where appropriate for monitoring environmental conditions for GMP purposes. Ref. © Validation in Partnership Ltd 2007 . trained personnel and approved procedures are available for sampling. in-process controls and monitoring of process parameters and environment assume particular importance in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed. equipment to be used and records to be maintained. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 . inspecting and testing starting materials.26 [VIP ID: 185694] “There should be written procedures and the associated records of actions taken or conclusions reached. packaging materials. for: … . testing. adequate facilities. documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use. cleaning. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 1 QUALITY MANAGEMENT QUALITY CONTROL 1.MANUFACTURE OF RADIOPHARMACEUTICALS PRODUCTION 7 [VIP ID: 186292] “Process validation. test methods. sampling. environmental control. nor products released for sale or supply.4 [VIP ID: 185508] “Quality Control is that part of Good Manufacturing Practice which is concerned with sampling.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 . and following HVAC system failures. clothing. : SGD-110-ENV Rev.Doc. until their quality has been judged to be satisfactory. bulk. 08 Author : Validation in Partnership Ltd. intermediate. where appropriate. defining the specifications.1 [VIP ID: 185644] “… Procedures give directions for performing certain operations e. [VIP ID: 1565] “Process validation. Written procedures should be established and followed for the routine environmental monitoring of surfaces.environmental monitoring. in-process controls and monitoring of process parameters and environment assume particular importance in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed. and finished products. …” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION DOCUMENTS REQUIRED – PROCEDURES AND RECORDS (Other) 4. specifications and testing.

100 (b) … B. and includes accurate documentation for these products prior to shipment. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 132 of 185 : 14 May 2007 PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PROCESSING OPERATIONS . revision response does not explain how your firm knows whether [redacted] was added to the [redacted] prior to the revision.INTERMEDIATE AND BULK PRODUCTS 5. .38 [VIP ID: 185778] “Any necessary in-process controls and environmental controls should be carried out and recorded. which includes as appropriate: … (iv) A system for monitoring environmental conditions. The lack of documentation supporting the addition of [redacted] during the environmental monitoring calls into question whether or not this addition did indeed occur. : SGD-110-ENV Rev.188 A. Ref. The locations of [redacted] used for environmental monitoring during the execution of Protocol [redacted] were not documented until eight months after the execution of the record.” 21 CFR PART 211 .Doc. 21 CFR 211.CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department: … . (Observation #3 on the FDA-483) © Validation in Partnership Ltd 2007 . Although the revision of the SOP addresses this problem going forward. Without the [redacted] addition to the [redacted] the [redacted] nature of the drug may not have been inhibited. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: … (10) Aseptic processing. where required. 211. especially since other additions to the [redacted] were documented. …” Extracted from FDA Warning Letter WL: 320-06-01 (February 2006) Extracted from FDA warning letter WL: 320-06-01 India 21-Feb-06 1 [VIP ID: 191622] “Written production and process control procedures were not always followed and documented at the time of performance. …” Extracted from FDA Warning Letter WL: 320-06-01 (February 2006) Extracted from FDA warning letter WL: 320-06-01 India 21-Feb-06 2 [VIP ID: 191620] “Control records do not include complete and accurate information relating to the production and control of each batch. (Observation #4 on the FDA-483) Your response states that the SOP for "Storage.. Please demonstrate that the environmental monitoring of your [redacted] products is representative and accurate.Buildings and Facilities Sec.data from environmental monitoring.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 6 QUALITY CONTROL DOCUMENTATION 6. 21 CFR 211. The [redacted] preparation record did not include documentation to confirm the addition of [redacted] to the [redacted] used for environmental monitoring. Documentation reviewed during this inspection as well as the last inspection showed extremely low counts on your environmental monitoring.7 [VIP ID: 185848] “Laboratory documentation should follow the principles given in Chapter 4. preparation and sterilization of the [redacted] has been revised.42 Design and construction features (c) [VIP ID: 20] “Operations shall be performed within specifically defined areas of adequate size.. 08 Author : Validation in Partnership Ltd.

validating manufacturing processes. For example: a) Procedures outlining environmental monitoring of the clean room where the Heparin concentrate solutions were diluted and filled and Sodium Chloride solutions are filled into syringes have not been established. The observation is citing failure to define or document the location of the [redacted] prior to or during the study. h. …” © Validation in Partnership Ltd 2007 . Smoke studies were performed only under static conditions. as required by 21 CFR 820. e. purchasing controls. this drawing was prepared from memory. acceptance activities. no preventative actions were submitted for future protocols and studies. f. d. No documented action was taken when out of specification pressure differentials occurred. A review of Filling Room temperature records revealed several instances where the temperature range limits (on the form) were exceeded. Failure of the management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization. i. and document controls. your firm's corporate management and local management failed to (a) conduct management reviews at defined intervals. Your response also did not address the issue of preparing and approving validation protocols which lacked this important information. For example: a. humidity.” Extracted from FDA Warning Letter 2005-DAL-WL-22 (August 2005) Extracted from FDA warning letter 2005-DAL-WL-22 USA 04/08/2005 [VIP ID: 170680] “9. not sterilized. Filling room operators have exposed facial skin surfaces. There are no established personnel environmental monitoring specifications or limits for filling room operators. Failure to establish and maintain procedures to adequately control environmental conditions. Further. j. c. as required by 21 CFR 820. humidity. environmental monitoring. Ref. Item 4].70(c). Relying on the recollection of an employee eight months after the protocol was executed is not good practice. until the present were identified as alert notifications. Failure to establish and maintain procedures to adequately control environmental conditions that could adversely effect product quality. g.20 [FDA-483 Items 1 through 37]. Four out of five Alert/Action Level Notifications issued from January 31. Differential pressure between filling room and adjacent controlled environment is only monitored once daily. Surface monitoring procedures fail to provide quantitative assessment of the Class 100 and controlled environment surfaces.” FDA Warning Letter [NO REFERENCE] (September 2005) FDA Warning Letter [NO REFERENCE] USA 30/09/2005 [VIP ID: 173180] “9. as required by 21 CFR 820. b) Your firm has not monitored the temperature. and (c) establish and maintain procedures for complaint handling. although the results indicate all five met the criteria for action level notifications. (b) follow procedures for conducting quality audits. as required by 21 CFR 820.” Extracted from FDA Warning Letter 2005-DAL-WL-21 (August 2005) Extracted from FDA warning letter 2005-DAL-WL-21 USA 03/08/2005 [VIP ID: 170400] “1.Doc. 2001. however. corrective and preventive actions. For example. design controls.70(c) [FDA 483. and has not conducted routine bioburden testing to monitor and identify viable and non-viable particulates in the clean room. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 133 of 185 : 14 May 2007 Your response states that a drawing of the locations of the [redacted] during the [redacted] effectiveness study was prepared for the investigator. 08 Author : Validation in Partnership Ltd. b.70(c) [FDA-483 Item 26].” Extracted from FDA Warning Letter 05-ATL-21 (August 2005) Extracted from FDA warning letter 05-ATL-21 USA 11/08/2005 [VIP ID: 171010] “2. Your firm failed to establish and maintain procedures to adequately control environmental conditions which could reasonably be expected to have an adverse effect on product quality. : SGD-110-ENV Rev. …You have failed to establish formal parameters for temperature. Action levels for the RCS air sampling and the purified water bioburden allow for multiple days of air sampling or multiple unlimited bioburden counts before corrective action is taken. and pressure of the clean room. and pressure. Product contact surfaces are only sanitized. Sterile forceps used to manipulate sterile container components were placed on exposed surge tank surface when not in use.

70(e) [FDA-483. 08 Author : Validation in Partnership Ltd.” © Validation in Partnership Ltd 2007 .. and (7) appropriate response to deviations from alert or action levels.42(c)(10)]. your firm failed to conduct environmental testing on a [redacted] schedule as required by your firm's environmental testing procedures. (5) specific sampling equipment and techniques.DRUG QUALITY ASSURANCE 7356. Determine. (6) alert and action levels. Environmental controls/monitoring (para 3) [VIP ID: 77150] “Determine whether the firm has procedures in place for adequate environmental monitoring and if the procedures are followed and if the procedures describe what to do with any affected product. For example.e. Ref. Inspection 5. sample frequency. You have also not established any written procedures for environmental monitoring that specifically address issues such as sample location. Records of the monitoring should be maintained. as required by 21 CFR. (4) sample size (e. during or at the conclusion of operations).12 [VIP ID: 185052] “Access to temperature and pressure controlled areas should be restricted and controlled.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III .Inspectional B. sample size. and corrective actions in the event of failures.Doc.70(c) and to prevent contamination of equipment. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 134 of 185 : 14 May 2007 FDA Warning Letter SEA 05-16 (March 2005) Extracted from FDA warning letter SEA 05-16 USA 17/03/2005 [VIP ID: 135310] “3. Failure to have control systems for your firm's operations necessary to prevent contamination of drug product during aseptic processing [21 CFR 211.” CPGM-DB CHAPTER 56 . analytical techniques. Written SOPs should also address elements such as (1) frequency of sampling.” FDA Warning Letter 2005-DAL-WL-13 (February 2005) Extracted from FDA warning letter 2005-DAL-WL-13 USA 10/02/2005 [VIP ID: 134660] “8. : SGD-110-ENV Rev. our investigators noted that you do not perform environmental monitoring of your manufacturing area. item 7]. (2) when the samples are taken (i. air volume). determine the disposition of the product.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. "Furthermore. what steps the firm takes if action or alert limits are exceeded and review any investigations performed. PREMISES Environmental Control 7.g. or product as required by 21 CFR 820.. (3) duration of sampling.” PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. sampling technique. General Written Program (para 5) [VIP ID: 111480] “All environmental monitoring locations should be described in SOPs with sufficient detail to allow for reproducible sampling of a given location surveyed. If the limits were exceeded during any production runs." …. Environmental monitoring should be performed to demonstrate that the appropriate classification is consistently achieved. surface area.820. interpretation of results. Failure to establish and maintain procedures to adequately control environmental conditions to prevent their adverse effects on product quality. Environmental Monitoring 1.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . acceptance criteria.

Rice and Miah I. reviewed. and purity they purport or are represented to posses and to assure that such procedures. 211. : SGD-110-ENV Rev. including any changes. 08 Author : Validation in Partnership Ltd.46(c) Ventilation. your firm was cited for not providing HEPA-filtered air into the **** clean rooms as required by 21 CFR 211.” FDA Warning Letter CBER-01-023 (July 2001) Extracted from FDA warning letter CBER-01-023 USA 24/07/2001 [VIP ID: 43310] “Failure to maintain and/or follow written procedures for production and process control designed to assure that the drug products have the identity. was not followed in that monthly excursion status reports have not been generated since April 4.160(b)(1) … [FDA Investigators: Renee L.” FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28420] “3. Item 7.Doc. and (4) diagrams/charts of the HVAC system. Your justification is not adequate because you have not provided supporting documentation of (1) air cleanliness qualification data. for environmental monitoring for airborne contaminants or surfaces of laboratory equipment and benches. In addition. Some examples from the FDA483 are: … d.100]. strength.” Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7130] “HVAC failure during filling emergency procedures should include: 1) clearing filling lines of all product and open container closure systems 2) additional environmental testing after air flow is restored and prior to resuming operations (surface.” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 7305] “There should be SOPs for environmental monitoring in manufacturing and product filling areas. personnel. that were drafted by an appropriate organizational unit and reviewed and approved by a quality control unit. quality. Schneider] Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 136790] “Records documenting air sampling during media fills should include the individual times at which the samples are taken. (2) data from a routine environmental monitoring program. You disagreed with the investigator’s observation in that HEPA-filtered air is not necessary for each of the **** clean rooms (Class **** because the aseptic processing is being performed under the biological hoods that are equipped with HEPA filters. 2000. For example: … d. non-viable and viable particulate)” © Validation in Partnership Ltd 2007 . Ref. 211. no other procedures for tracking excursions have been implemented. (3) the specific ratings of each of the successive filters found in the HVAC system that serve the Class **** clean room. The SOP entitled Environmental Monitoring Sampling/Handling/Reporting. Your firm failed to have in place written procedures for many of the operations performed by your laboratory. nor is there any testing performed. There are no written procedures in place for. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 135 of 185 : 14 May 2007 FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42760] “With regard to the air filtration system. and approved by the appropriate organizational units and reviewed and approved by quality control [21 CFR 211. Air Filtration. are drafted.160 Laboratory Controls-General Requirements. Air Heating and Cooling [FDA-483 Item 3]. These procedures should include scientifically sound specifications and test procedures.

environmental control. Written procedures which describe steps to be taken when personnel exceed the action limits for environmental monitoring are not always followed.QUALITY MANAGEMENT Quality Control 1. bulk. quality.1. [VIP ID: 560] “Any necessary in-process controls and environmental controls should be carried out and recorded. adequate facilities. where appropriate. [VIP ID: 406] “Procedures give directions for performing certain operations eg cleaning.100] in that: … b. including any changes.PRODUCTION Processing operations: intermediate and bulk products 5. testing.DOCUMENTATION Documents required . Failure to establish and/or follow adequate written procedures for production and process control designed to assure that the drug products have the identity. nor products released for sale or supply. clothing. intermediate. inspecting and testing starting materials.Doc. and purity they purport or are represented to possess and to assure that such procedures. specifications and testing. strength. 08 Author : Validation in Partnership Ltd. : SGD-110-ENV Rev.” © Validation in Partnership Ltd 2007 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 136 of 185 : 14 May 2007 Selected FDA 483 Observations (December 1998) Sterile Product Manufacture [VIP ID: 6842] “Complaint investigations should include: … 3) investigations into environmental records and other manufacturing records …” Extracted from FDA Warning Letter CBER-99-005 (November 1998) Extracted from FDA warning letter CBER-99-005 Ireland 23/11/1998 [VIP ID: 158920] “3. …” EU GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 1 .DOCUMENTATION General 4. for: … . packaging materials.38. and where appropriate for monitoring environmental conditions for GMP purposes. and with the organisation.environmental monitoring. there was no evidence of retraining of aseptic operators in seven out of eight excursions occurring between August 1997 and June 1998. Ref. For example. until their quality has been judged to be satisfactory. …” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 . are reviewed and approved by the appropriate organizational units and reviewed and approved by quality control [21 CFR 211.Procedures and records (Other) 4. trained personnel and approved procedures are available for sampling.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 . sampling.26. documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use. equipment operation.4 [VIP ID: 297] “Quality Control is that part of Good Manufacturing Practice which is concerned with sampling. [VIP ID: 497] “There should be written procedures and the associated records of actions taken or conclusions reached. The basic requirements of Quality Control are that: i. EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 . and finished products.

These systems and others are discussed in the Basic Inspection Guide. and because of the complexity of the process.CGMPR'S (October 1993) 2. Also.” CPGM-DB CHAPTER 56 . and test data. INTRODUCTION (para 2) [VIP ID: 2012] “As with other inspections. Manufacturing Controls Report: 7. Inquire about the movement of large quantities of sterile drug substance and the location of pass-through areas between the sterile core and non-sterile areas.Doc. Also.” GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES (July 1993) 11. personnel.” GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS . [VIP ID: 4403] “Firm's procedures for monitoring the environment. Because some of the actual sterile bulk operations may not be seen. where required. specifications. along with the various reasons for rejection. 08 Author : Validation in Partnership Ltd.DRUG QUALITY ASSURANCE 7356. : SGD-110-ENV Rev. evaluate the methods used to test and establish bioburdens. This is particularly important for the foreign sterile bulk drug substance manufacturer where time is limited. Specifications for viable particulates must include provisions for both air and surface sampling of aseptic processing areas and equipment.” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. [VIP ID: 601] “Laboratory documentation should follow the principles given in Chapter 4. Review the firm's environmental control program.QUALITY CONTROL Documentation 6. Environmental Controls (para 1) [VIP ID: 2669] “Specifications for viable and non-viable particulates must be established. and various stages in processing for evidence of contamination by radioactive materials. such as wooden skids and forklift trucks.002C RADIOACTIVE DRUGS (September 1993) PART III .7.” © Validation in Partnership Ltd 2007 .INSPECTIONAL INVESTIGATIONAL C. glassware. FACILITY (para 2) [VIP ID: 2018] “Unnecessary equipment and/or equipment that cannot be adequately sanitized.data from environmental monitoring. Environmental Monitoring Summary Reports. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 137 of 185 : 14 May 2007 EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 6 . MICROBIOLOGICAL (para 2) [VIP ID: 118580] “Review bioburden (before filtration and/or sterilization) from both an endotoxin and sterility perspective. determine if review of environmental test data is included as a part of the firm's release procedures. endotoxin testing. any rejected batches. environmental monitoring. Ref. Observe these areas. should be identified. QA Investigation Logs. it is particularly important to review reports and summaries. and filter and filtration validation. etc. For drug substance labs evaluate methods validation and raw data for sterility. such as validation studies. For example. should be identified early in the inspection to provide direction for the investigator. Determine if the firm follows its procedure for reviewing out-of-limit test results. lists of batches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department: … . …” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) I. reject lists. equipment. review environmental monitoring results and sanitization procedures.

seats. : SGD-110-ENV Rev. Selected FDA 483 Observations (April 2005) Sterile Product Manufacture [VIP ID: 138140] “Where a proposed construction project may affect ongoing production. (b) monitoring of all frequently touched surfaces (e. a protocol should be developed to identify baseline viable microbial counts in the manufacturing areas adjacent to the construction. Selected FDA 483 Observations (December 2005) Sterile Product Manufacture [VIP ID: 179170] “Environmental monitoring action and alert limits for clean rooms should be based on historical data and/or statistical rationale” Selected FDA 483 Observations (September 2004) Medical Device Manufacture [VIP ID: 123400] “Environmental monitoring should include: a.” Selected FDA 483 Observations (July 2004) Sterile Product Manufacture [VIP ID: 122410] “Alert and action limits should be assigned for viable and non-viable particulate monitoring of controlled. nonclassified areas” © Validation in Partnership Ltd 2007 . so that action limits can be established.g. pens and seats etc.” 14.Doc. (c) complete investigation of personnel monitoring test results that exceed microbiological action limits. The identification of baseline viable microbial counts in the manufacturing areas adjacent to the construction so that action limits can be established c. non classified areas. 08 Author : Validation in Partnership Ltd. data and validation to support sampling sites and frequencies. There should be a procedure for routine environmental monitoring of manufacturing areas during times when the area has been idle. evidence to justify alert levels. based on validation studies. used by operators. Where a proposed construction project may affect ongoing production. Increased environmental sampling and additional sampling sites during construction …” 16. and complete investigation of personnel monitoring test results that exceed microbiological action limits. Environmental monitoring procedures for aseptic processing rooms should require the routine checking of air velocities in Class 100 areas at work height. and to include increased environmental sampling and additional sampling sites during construction. b. used by operators. a protocol should be developed to include: … b. Selected FDA 483 Observations (August 2003) Sterile Product Manufacture [VIP ID: 53070] “Environmental monitoring procedures for aseptic processing rooms should require: (a) the routine checking of air velocities in Class 100 areas of the rooms at work height. etc. Alert and action limits. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 138 of 185 : 14 May 2007 13. pens.” 15.). Selected FDA 483 Observations (March 1998) Sterile Product Manufacture [VIP ID: 6299] “There should be a procedure for routine environmental monitoring of manufacturing areas during times when the area has been idle. monitoring of all frequently touched surfaces (e. should be assigned for environmental monitoring of both classified areas and of controlled.g. Ref.

[redacted] processing areas were deficient regarding the system for monitoring environmental conditions. Corrective and preventative action procedures should include requirements for identifying. Medina and Elaine G.” © Validation in Partnership Ltd 2007 .” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III.70(c). FACILITY (para 4) [VIP ID: 2020] “Facilities used for the charge or addition of non-sterile components. … Failure to establish and maintain procedures to adequately control environmental conditions as required by 21 CFR 820. Monitoring of Bioburden on Lenses.” Selected FDA 483 Observations (March 1999) Sterile Product Manufacture [VIP ID: 7089] “Environmental monitoring warning and action limits should be established through validation. The concern is soluble extraneous contaminants. The "closed" system used to manufacture [redacted] is open at the time [redacted] is performed. Selected FDA 483 Observations (October 2004) Sterile Product Manufacture [VIP ID: 123480] “There should be a system in place for tracking open environmental and water monitoring excursions. Your response regarding monitoring the environmental conditions does not address the issue of failing to acknowledge and evaluate alert and action limits at the time they occur. 08 Author : Validation in Partnership Ltd. and it is necessary to monitor and control the environment in which this [redacted] is performed to ensure [redacted]. in a manner and amount sufficient to establish appropriate monitoring limits for routine production. Observe this area and review the environmental controls and specifications to determine the viable and non-viable particulate levels allowed in this area. such as the non-sterile drug substance.” 18." [Investigators: Lori A.Doc.” 17. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 139 of 185 : 14 May 2007 FDA Warning Letter DEN-03-11 (February 2003) Extracted from FDA warning letter DEN-03-11 USA 21/02/2003 [VIP ID: 59960] “7. non-viable monitoring before and after a campaign run does not give an accurate measure of the levels during the multi-week campaign. including endotoxins. 2001. It is important to assess an observation at or above established limits to determine if the process is still being performed under [redacted] conditions. should be similar to those used for the compounding of parenteral solutions prior to sterilization. that may be carried through the process.” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VII. VALIDATION (para 7) [VIP ID: 2047] “Environmental and personnel monitoring must be performed during validation. Stewart]. : SGD-110-ENV Rev. Also. Excursions beyond alert/action limits should be evaluated at the time they occur to determine if the process is still being performed and if there is any threat to the product. does not identify action or alert limits for aerobic and anaerobic bioburden. investigating and tracking environmental monitoring failures. For example. SOP 10-003-02. dated September 10. Ref. Extracted from FDA Warning Letter 320-05-03 (July 2005) Extracted from FDA warning letter 320-05-03 Italy 21/07/2005 [VIP ID: 169320] “10.

Doc. room. Ref. For instance. Batch and trending data that indicate whether utility and/or support systems are functioning properly. detailing data review frequency and actions to be taken. quarterly) and long-term trends in environmental and personnel monitoring data. weekly. Written procedures should be established. records of air quality monitoring for filling could show a time at which there was improper air balance or an unusually high particle count. For example. Establishing Levels and a Trending Program (para 2) [VIP ID: 111500] “Environmental monitoring data will provide information on the quality of the manufacturing environment. a search on a particular isolate over a year period) with the goal of investigating results beyond established levels and identifying any appropriate followup actions.” © Validation in Partnership Ltd 2007 . monthly. Production Record Review Complete batch and production control records should be reviewed to detect any signs of failures or anomalies that could have a bearing on product sterility. Whether construction or maintenance activities could have had an adverse impact. Each individual sample result should be evaluated for its significance by comparison to the alert or action levels. The quality control unit should be responsible for producing specialized data reports (e. shift.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A.” - Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121950] “Corrective and preventative action procedures should include requirements for identifying and investigating all nonconformities. or other parameters.. The quality control unit should provide routine oversight of near-term (e. Environmental Monitoring 2. [VIP ID: 111830] “6. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 140 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . including in-process sterility and environmental monitoring failures. Averaging of results can mask unacceptable localized conditions.” Selected FDA 483 Observations (March 2004) Sterile Product Manufacture [VIP ID: 71220] “There should be systems in place for tracking open environmental and water monitoring excursions describing responsibilities regarding timely review and closure of investigations. daily. Environmental Monitoring 2. A result at the alert level urges attention to the approaching action conditions. Sterility Testing C. the investigation should include elements such as: Events that could have impacted on the critical zone. A result at the action level should prompt a more thorough investigation. operator.g.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .g.. Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XI.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Investigation of Sterility Positives (para 3) 6. Establishing Levels and a Trending Program (para 3) [VIP ID: 111510] “Trend reports should include data generated by location. : SGD-110-ENV Rev.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . 08 Author : Validation in Partnership Ltd.

100 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 141 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 .” Selected FDA 483 Observations (September 2000) Sterile Product Manufacture [VIP ID: 19240] “When aseptic environmental monitoring results exceed action limits.115] … There were no records of investigations to determine sources of contamination associated with environmental monitoring excursions. …” FDA Warning Letter W/L 08-03 (November 2002) Extracted from FDA warning letter W/L 08-03 USA 19/11/2002 [VIP ID: 54380] “5.” © Validation in Partnership Ltd 2007 . together with an investigation in to the possible effect on product sterility. Specifically.Doc. Ref.” Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 2471] “The SOP for environmental monitoring should provide for additional sampling of critical sites where action limits are exceeded.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART V .Inspectional B.” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. 08 Author : Validation in Partnership Ltd.70(c)].211.DRUG QUALITY ASSURANCE 7356. : SGD-110-ENV Rev. Ensure that the impact of out-oflimit results on the product is adequately addressed.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III . an evaluation of what personnel were doing at the time of the excursion should be performed. GMP b. humidity. Aseptic processing areas are deficient regarding the system for monitoring environmental conditions [21 CFR 211. ENVIRONMENTAL MONITORING (para 6) [VIP ID: 2040] “In the management of a sterile bulk operation. and temperature. periodic (weekly/monthly/quarterly) summary reports of environmental monitoring are generated. Procedures should include actions to be taken when results are not within established limits.REGULATORY/ADMINISTRATIVE STRATEGY Regulatory /Administrative Follow-Up Significant Deviations 5.42(c) (10)(iv)] and [21 CFR 820.” Selected FDA 483 Observations (September 2000) Sterile Product Manufacture [VIP ID: 19250] “Procedures detailing the action to take when environmental monitoring limits in critical and non-critical areas are exceeded during aseptic fills should require comparing all environmental monitoring results (to include personnel monitoring). Buildings (para 6) [VIP ID: 77580] “Review procedures for controlling and monitoring pressure differentials. but there is no approved procedure to define this test method. Review the firm's investigation report and the disposition of batches processed when objectionable environmental conditions existed. the investigation process used to investigate environmental monitoring excursions and to determine release of product is based partly on results from "in house challenge studies". Production and Process Controls [VIP ID: 78080] “[211.DRUG QUALITY ASSURANCE 7356.” CPGM-DB CHAPTER 56 . Inspection 9. Review these reports to obtain those situations in which alert/action limits were exceeded.

9. 08 Author : Validation in Partnership Ltd. [VIP ID: 610] “For some kinds of data (e. Are results within specifications? If not. analytical tests results. and there should be comparison or trending of environmental data from year to year.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 6 . analytical tests results.” © Validation in Partnership Ltd 2007 . environmental controls.DRUG QUALITY ASSURANCE 7356. what action was taken by the firm with reference to: (a) environmental specifications.Doc. [VIP ID: 2439] “Compare the firm's written environmental specifications for the laboratory with sampling data for the previous three months. Worst case scenarios of simulations tests should also include monitoring activities. Worst case scenarios of simulations tests should also include monitoring activities.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) LABORATORY Environment 287. yields. environmental controls etc.g. ENVIRONMENTAL AND PERSONNEL MONITORING 7. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 142 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 .1.” 20. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 6 QUALITY CONTROL DOCUMENTATION 6. Ref.) it is recommended that records in a manner permitting trend evaluation be kept. (b) product undergoing testing at the time of the out-of-spec results?” 19.QUALITY CONTROL Documentation 6.. It is recommended that environmental control records be kept in a manner permitting trend evaluation and that environmental data is trended from year to year.” Selected FDA 483 Observations (January 1997) Sterile Product Manufacture [VIP ID: 135610] “Air pressure differential data throughout the clean room monitoring locations should be trended.” Selected FDA 483 Observations (December 1999) Sterile Product Manufacture [VIP ID: 8720] “Environmental monitoring results during dynamic and static conditions should be trended. : SGD-110-ENV Rev.9 [VIP ID: 185852] “For some kinds of data (e.1 [VIP ID: 188972] “It is important to state that the monitoring activity itself should not compromise the product quality. The monitoring activity itself should not compromise the product quality.1 Air Borne Microbial and Non-Viable Particle Monitoring 7.) it is recommended that records be kept in a manner permitting trend evaluation.” Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 14240] “Environmental monitoring data should be highlighted to indicate if it was obtained during static or dynamic conditions to enable meaningful trend analysis.g. yields. ..

Some manufacturers recirculate air without adequate filtration.15 [VIP ID: 24835] “Appropriate equipment and environmental controls should be used to minimize the risk of contamination. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.SUPERSEDED! (December 1996) Premises and equipment 7. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open.” 24. : SGD-110-ENV Rev. GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS II. CONTROL OF PRESTERILIZATION BIOBURDEN 5. Ref. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open.” 22.MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS (1997) . or contained systems). closed.” © Validation in Partnership Ltd 2007 . there should be data demonstrating the efficiency of air filtration including include surface and/or air sampling. the primary focus of attention should be on the details of determining and controlling presterilisation bioburden. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 143 of 185 : 14 May 2007 21. the primary focus of attention should be on the details of determining and controlling presterilization bioburden.2 [VIP ID: 188274] “Environmental control and its associated monitoring play a part in product bioburden control. in these cases the number of units filled may be the maximum number filled in production. enhanced attention should be given to environmental monitoring. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18. closed.1 General 18.15 [VIP ID: 156400] “Appropriate equipment and environmental controls should be used to minimize the risk of contamination. Filling and sealing is often a hand operation presenting great challenges to sterility so enhanced attention should be given to environmental monitoring. Environmental control and its associated monitoring play a part in product bioburden control. closed. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open.Doc. Hence. Hence.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. but it is often a relatively small part. [VIP ID: 4591] “Validation of aseptic processes presents special problems when the batch size is small. FACILITIES (para 3) [VIP ID: 3208] “The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage particularly where potent or highly sensitizing drugs are processed. Where potent or highly sensitising drugs are processed and air is recirculated.1 General 18. Where air is recirculated. or contained systems). or contained systems). EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 13 .” 23. but it is often a relatively small part. Where an aseptic process involves hand filling and sealing. 08 Author : Validation in Partnership Ltd. PI 005-2 RECOMMENDATION ON GUIDANCE ON PARAMETRIC RELEASE (July 2004) APPENDIX I RECOMMENDATIONS FOR A GENERAL STERILITY ASSURANCE SYSTEM FOR TERMINALLY STERILISED PRODUCTS AND PROVISIONS FOR PARAMETRIC RELEASE 5. review the firm's data which demonstrates the efficiency of air filtration such should include surface and/or air sampling.

rather than at a single time point. Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122660] “HVAC system qualification should include: … b. and air flow velocities should be tested at multiple times to demonstrate adequate performance over time. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 144 of 185 : 14 May 2007 25. Selected FDA 483 Observations (September 2000) Sterile Product Manufacture [VIP ID: 19830] “Environmental monitoring should require the following information to be recorded to support smoke studies: a) air velocities/volumes b) the exact placement of primary barriers” © Validation in Partnership Ltd 2007 . REG 07/01/93 GUIDE TO INSPECTIONS OF MICROBIOLOGICAL PHARMACEUTICAL QUALITY LABORATORIES (July 1993) IV. number of air changes. not just a check mark to indicate that they are acceptable. 08 Author : Validation in Partnership Ltd.Doc. therefore. : SGD-110-ENV Rev.” 3. Sterility Testing (para 2) [VIP ID: 2909] CONTROL “The USP points out that the facilities used to conduct sterility tests should be similar to those used for manufacturing product. Selected FDA 483 Observations (March 2001) Medical Device Manufacture [VIP ID: 27430] “Actual particle count and air velocity results should be recorded not just a check mark to indicate that they are acceptable. Environmental monitoring and gowning should be equivalent to that used for manufacturing product.” 8.” Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 179930] “Room particle counts. Ref. and air-flow velocities at multiple times to demonstrate adequate performance over time. the testing of room particle counts. Actual particle count and air velocity results should be recorded. to demonstrate adequate performance over time. The USP states. Facilities used to conduct sterility tests should have the same environmental monitoring and gowning standards as those used in aseptic processing production facilities. number of air changes and airflow velocities should be tested multiple times. Room particle counts. the number of air changes.2 Physical 1. Proper design would. "The facility for sterility testing should be such as to offer no greater a microbial challenge to the articles being tested than that of an aseptic processing production facility". Air velocities/volumes and the exact placement of primary barriers should be recorded to support environmental monitoring smoke studies. include a gowning area and pass-through airlock.” 2.

For Class 100 areas. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. 08 Author : Validation in Partnership Ltd. Critical Area . These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters.” Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124780] “There should be data to support the selected sampling points for environmental surface counts.Class 100 (ISO5) (para 4) [VIP ID: 110210] “We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product. See Section X. for additional guidance on particle monitoring. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift. it is recommended that measurements to confirm air cleanliness be taken at sites where there is most operator activity and most potential risk to the exposed sterilised product.46 The following deviations were noted regarding ventilation and air filtration systems: There was no scientific justification for testing of [redacted] filters in the Class A (ISO 5) area and sterile [redacted] only once annually. Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171110] “2. containers.” © Validation in Partnership Ltd 2007 . the procedures did not include a specification for the required distance for taking [redacted] test measurements. There was insufficient evidence that ventilation and air filtration systems provided adequate control over microorganisms for the manufacture.” Selected FDA 483 Observations (June 2005) Sterile Product Manufacture [VIP ID: 140120] “The location of particle counters in rooms should be demonstrated to provide an accurate representation of particle activity. Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 193732] “Non-viable monitoring probes for sterile connections for filtration and filling should be located to assure the connection areas are in control when connections are performed. and closures.E. There should be scientific justification for the frequency assigned to the testing of filters in sterile areas and procedures should include a specification for the required distance for taking test measurements.” 5.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . viable airborne microorganisms and non viable particulate matter in the areas used in the filling of sterile diluents. Ref. processing. containers. : SGD-110-ENV Rev. Regular monitoring should be performed during each production shift.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 145 of 185 : 14 May 2007 4. and not compromise the laminarity of the air flow.Doc. or for monitoring of pressure differentials between various operational areas. packing. 21 CFR 211. It is also recommended to conduct non viable particle monitoring with a remote counting system as these systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters. We recommend conducting nonviable particle monitoring with a remote counting system. and for monitoring of pressure differentials between various operational areas. and closures. or holding of a drug product. Buildings and Facilities A.

As examples.Class 100 (ISO5) (para 5) [VIP ID: 110220] “Some operations can generate high levels of product (e.100]. These may be reconfirmed during process simulation tests. by their nature.. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 146 of 185 : 14 May 2007 PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. packaging. Critical Area . do not pose a risk of product contamination.. by their nature. Initial qualification of the area under dynamic conditions without the actual filling function provides some baseline information on the non-product particle generation of the operation. : SGD-110-ENV Rev. and any corrective actions taken are not documented. this alarm system is unable to store more than [redacted] transgressions. Initial qualification of the area under dynamic conditions.” 7. powder) particles that. It may not.68]. Environmental monitoring systems (temperature and humidity) should be validated (IQ/OQ/PQ). For the filling environment the counts should be performed adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas.” Selected FDA 483 Observations (July 1999) Product Manufacture [VIP ID: 7207] “Environmental monitoring systems (temperature and humidity) should be validated (IQ/OQ/PQ). in these cases. a) Necessary actions have not been predetermined and documented when responding to alarms from the [redacted]. and purity they purport or are represented to possess [21 CFR Part 211. 08 Author : Validation in Partnership Ltd. However the location of the sample device should not compromise the laminarity of the air flow in the critical zone.. There is also no secondary review of such alarm events. to the extent possible.g. failure to establish and document procedures to assure that drug products have the identity. characterises the true level of extrinsic particle contamination to which the product is exposed. Ref. Extracted from FDA Warning Letter 2001-DAL-WL-04 (November 2000) Extracted from FDA warning letter 2001-DAL-WL-04 USA 17/11/2000 [VIP ID: 164920] “3) Failure to assure and document that automated equipment used in manufacturing. In these instances. be feasible to measure air quality within the one-foot distance and still differentiate background levels of particles from air contaminants. . GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Initial validation should be checked to confirm that worst case positions have been adequately identified.g. ENVIRONMENTAL AND PERSONNEL MONITORING 7.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. as well as failure to verify and document that equipment used for monitoring processing equipment and environmental conditions is adequate and functioning properly [21 CFR Part 820. do not pose a risk of product contamination. Similarly. be feasible to measure air quality within the one foot distance and still differentiate background levels of particles from air contaminants.70]. characterizes the true level of extrinsic particle contamination to which the product is exposed. processing. Buildings and Facilities A. the counts should be performed in locations where there is most operator activity. Monitoring with sampling probes located in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones should be avoided. provides some baseline information on the non product particle generation of the operation. strength.” 6. and these transgressions are not recorded. Some operations can generate high levels of product (e.” © Validation in Partnership Ltd 2007 .2. in these cases. quality.2 Non-viable monitoring 7.1 [VIP ID: 188974] “The location chosen for monitoring should be checked to ensure that the positions reflect the worst case. In these instances. to the extent possible. air can be sampled in a manner that.Doc. without the actual filling function. It may not. For room monitoring. powder) particles that. and holding of drug products will perform its intended function satisfactorily [21 CFR Part 211. Also. air can be sampled in a manner that.

pressure differential specifications should enable prompt detection (i. : SGD-110-ENV Rev. 08 Author : Validation in Partnership Ltd.)” Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14810] “The following activities should be routinely performed during aseptic filling operations: (1) non-viable particle counts . non-viable particulate monitoring of all areas where there are open containers and closures.” 9..” Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 136330] “Non-viable particle counts should be continuously monitored at critical sites in the aseptic filling rooms to assure the maintenance of Class 100 conditions at these sites during the aseptic processing of parenteral drug products. Buildings and Facilities C. (NOTE: Set up operations are generally personnel intensive operations that can be representative of worse case conditions.” © Validation in Partnership Ltd 2007 . An effective system facilitates restoration of operating conditions to established. For example. A suitable facility monitoring system will rapidly detect atypical changes that can compromise the facility’s environment.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121980] “Data collected from particle counters on aseptic filling lines should be archived. Data collected from particle counters on aseptic filling lines should be archived. pressure differential specifications should enable prompt detection (i.” 10. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 147 of 185 : 14 May 2007 8.. qualified levels before reaching action levels. alarms) of an emerging low pressure problem to preclude ingress of unclassified air into a classified room. Non viable particle counts should be routinely performed during sterile fill set-up operations for media fill runs and during aseptic filling operations and include all areas where there are open containers and closures. Ref. Clean Area Separation (para 5) [VIP ID: 110320] “A suitable facility monitoring system will rapidly detect atypical changes that can compromise the facility’s environment.Doc. …” Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72640] “Non-viable particulate monitoring should be performed during sterile fill set-up operations for media fill runs and routine manufacturing to demonstrate the maintenance of [sterile] conditions.e. An effective system facilitates restoration of operating conditions to established. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .. Selected FDA 483 Observations (September 2004) Sterile Product Manufacture [VIP ID: 123290] “Environmental monitoring programs in aseptic filling areas should include: … c. For example. qualified levels before reaching action levels. alarms) of an emerging low pressure problem to preclude ingress of unclassified air into a classified room.e.

: SGD-110-ENV Rev.” Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 128300] “lnvestigations should be conducted when alarms occur for non-viable particulate (NVP) monitoring in Class 100 fill areas.” Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 19960] “Environmental monitoring SOPs should specify the action to be taken when non-viable action limits are exceeded. and specifying the action to be taken when non viable action limits are exceeded.g.” Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 193664] “For all lots of product. There should be a written procedure that defines the method of establishing alert limits for airborne non viable particulate levels in classified areas and an established schedule calling for a periodic reevaluation of the alert limits based on historical data. should result in deviation reports. including lots with particle counts elevated above trend averages. There should be written procedures for reviewing particle count data. Particle Monitoring [VIP ID: 111650] “Routine particle monitoring is useful in rapidly detecting significant deviations in air cleanliness from qualified processing norms (e. Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194248] “There should be a written procedure that defines the method of establishing alert limits for airborne non-viable particulate levels in classified areas and an established schedule calling for a periodic re-evaluation of the alert limits based on historical data. Ref. Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121970] “There should be written procedures for reviewing particle count data. The extent of investigation should be consistent with the severity of the excursion and include an evaluation of trending data. Selected FDA 483 Observations (February 2007) Sterile Product Manufacture [VIP ID: 194290] “Attributions of over action limit particulate levels in a Class 100 area to air disturbance caused by a cart in the Class 100 area are unfounded if no smoke studies have been performed with these carts in place. clean area classification). potentially affected by repeated action level excursions for foreign matter in vials. to prevent future deviations. as necessary.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . investigations and corrective measures being undertaken in response to these events.” 12.” 13. See Section IV. Appropriate corrective action should be implemented. Instances of alert or action levels being exceeded for non viable particulates. there should be an investigation of the finished product lots manufactured between the two excursion events..” © Validation in Partnership Ltd 2007 .Doc.A for additional guidance on particle monitoring.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls E. 08 Author : Validation in Partnership Ltd. A result outside the established classification level at a given location should be investigated as to its cause. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 148 of 185 : 14 May 2007 11.

there was no review of environmental monitoring data that was obtained during manufacturing and filling operations for the referenced lot. . For example.Monitoring for non-viable particulates performed 10/26/01 in room 2217 (Part Fill filling area) recorded counts over the action limit in the **** area. Lot 19383 was released on 6/2/99.” © Validation in Partnership Ltd 2007 . For example: The written investigation [#032-99I] of the OAL (over-action-limit) non-viable particle counts in Fill Room 1 does not include justification for releasing lots 190365. four of the lots were released for distribution before the investigation was completed on 7/12/99. 190362.Doc. and Lot 190365 was released on 5/25/99. or corrective measure undertaken in response to this event. or control procedures [21 CFR 211. Failure to establish and follow adequate procedures describing the handling of complaints related to drug products [21 CFR 211. Four other lots made on the same equipment during the same time period were rejected. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 149 of 185 : 14 May 2007 FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 11 [VIP ID: 49970] “11. lot #74087-JT determined and / or confirmed metallic particles and synthetic fibers near the port. manufacturing. Failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications [21 CFR 211.180(e)]. These lots were aseptically filled on the [redacted] Filler. There was no deviation report. Failure to maintain records so that data therein could be used for evaluating. the quality standards of each drug product to determine the need for changes in drug product specifications. nor was any batch record review conducted. For example. . . Ref. However. at least annually. including conclusions and follow-ups [21 CFR 211. For example. In addition. Lot 190374 was released on 6/1/99.BQAOO14. investigation. which the investigation report identifies as the source of the high particle counts. : SGD-110-ENV Rev.192]. Lot 190389 was released for distribution on 6/4/99. does not describe the level of investigation to be performed when product complaints describing particulate matter in injectable products are received. . …” Extracted from FDA Warning Letter CHI-12-00 (February 2000) Extracted from FDA warning letter CHI-12-00 USA 07/02/2000 [VIP ID: 161520] “Failure of the quality control unit to assure that all unexplained discrepancies or failures of batches to meet specifications are thoroughly investigated and that the records of the investigations are complete.BQA0014 "Handling of Product Complaints and WIP Shipment Complaints" does not describe the level of investigation to perform when product complaints describing particulate matter in injectable products are received.” FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 8 [VIP ID: 49940] “8. 190383 and 190389.198].The investigation of PER #100361029. … . 190374. For example. 08 Author : Validation in Partnership Ltd.Environmental monitoring results are not routinely evaluated when complaints for metallic particles or other particulates are confirmed by analysis. …” FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 9 [VIP ID: 49950] “9.192]. there was no attempt to determine the source of the particulates at the manufacturing site. "Handling of Product Complaints and WIP Shipment Complaints" *.

The frequency for non viable particulate sampling in classified areas should be defined. The differential air pressure for aseptic filling areas and surrounding support areas should be monitored under dynamic conditions rather than at rest (static). Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 150 of 185 : 14 May 2007 14.DRUG QUALITY ASSURANCE 7356. For example. Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 179920] “Pressure differential and particle count trend reports included as part of the batch record should be documented as reviewed by quality assurance or production personnel. your firm: … (b) fails to follow the environmental control procedure (SOP# 3001. There should be assurance that the volume of air sampled for non viable particulates is adequate in relation to the time required to perform operations. : SGD-110-ENV Rev. Failure to follow appropriate written procedures and conduct adequate validation of the sterilization process designed to prevent microbial contamination in drug products purporting to be sterile [21 CFR 211.” 16. FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42800] “1.113(b)].” CPGM-DB CHAPTER 56 .” © Validation in Partnership Ltd 2007 . Pressure differential and particle count trend reports included as part of a batch record should be documented as reviewed by quality assurance or production personnel.” 17. corridors. and pharmacy rooms.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 48. dated 4/20/00) in that monitoring of non-viable particulate has not been performed in the manufacturing and filling rooms for ****. no monitoring of the system is conducted to demonstrate that the volume of air supplied is sufficient to maintain appropriate air pressure differentials between manufacturing rooms. ****. [VIP ID: 2200] “How often is non-viable particulate sampling performed in classified areas: a. Selected FDA 483 Observations (September 2005) Sterile Product Manufacture [VIP ID: 177960] “There should be assurance that the volume of air sampled for non-viable particulates is adequate in relation to the time required to perform operations. Exposed product areas b.42(c)(5)]. 08 Author : Validation in Partnership Ltd. Specifically. and ****[FDA-483 Item 2]. Surrounding areas” 15. Ref.Doc. Extracted from FDA warning letter 06-NWJ-14 (July 2006) Extracted from FDA warning letter 06-NWJ-14 USA 11-Jul-06 6) [VIP ID: 192240] “Failure to maintain separate or defined areas or other such control systems as are necessary to prevent contamination and mix-ups in the course of manufacturing and processing operations [21 CFR § 211. Filling areas c.” Selected FDA 483 Observations (June 2006) Active Pharmaceutical Ingredient Manufacture [VIP ID: 193574] “The routine monitoring of the differential air pressures between rooms should be documented.

used to clean production area floors. Your firm's response to observation 8 is inadequate. Specifically. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 151 of 185 : 14 May 2007 Extracted from FDA Warning Letter 320-99-04 (June 1999) Extracted from FDA warning letter 320-99-04 Netherlands 23/06/1999 [VIP ID: 159820] “3. These deviations violate Section 501(a)(2)(B) of the FD&C Act and Section 351(a) of the PHS Act. significant deviations in the manufacture of your monovalent concentrate that is used to formulate Influenza Virus Vaccine. Alarms should be adequately documented to assure that evaluation of the impact on product quality and trending can be conducted. the vacuum's HEPA filter has not been evaluated to ensure that airborne particulates are not dispersed into the production areas.” 20. : SGD-110-ENV Rev. 08 Author : Validation in Partnership Ltd. but are not limited to: … 6. temperature conditions within the aseptic processing area are not being documented to ensure such conditions are consistently within established specifications of [redacted] degrees Celsius. pressure. The HEPA filters of vacuum cleaners. Aseptic processing area temperature conditions should be documented to ensure they are consistently within established specifications. as required by 21 CFR 820. Extracted from FDA warning letter OEWL-06-01 (June 2006) Extracted from FDA warning letter OEWL-06-01 USA 30-Jun-06 6 [VIP ID: 192180] “… Additionally. Fluzone® were observed during the inspection. Systems used to monitor temperature.70(c).” 18. Ref. used for aseptic manufacturing should be able to produce alarm reports for critical and sub-critical areas. Extracted from FDA warning letter 07-ATL-01 (October 2006) Extracted from FDA warning letter 07-ATL-01 USA 31-Oct-06 9 [VIP ID: 192634] “Failure to establish and maintain procedures to adequately control environmental conditions.” © Validation in Partnership Ltd 2007 . humidity and alarm conditions for environmentally classified areas.Doc. The wet/dry vacuum is used to clean the floors of your production areas. Selected FDA 483 Observations (March 2007) Sterile Product Manufacture [VIP ID: 194384] “Building Monitoring SCADA Systems used to monitor temperature. pressure. …” 19. However. used for aseptic manufacturing should be able to produce alarm reports for critical and sub-critical areas. Your firm has not provided the updated task list to FDA and the temperature audit has not been completed. Specific areas of concern include. should be evaluated to ensure that airborne particulates are not dispersed into the production areas. Your firm has stated that it has updated the Preventative Maintenance Task List to include space to record specific temperature readings on April 27. The differential air pressure for the aseptic filling areas and surrounding support areas is monitored at rest (static) rather than under dynamic conditions. humidity and alarm conditions for environmentally classified areas. which should be adequately documented to assure that evaluation of the impact on product quality and trending can be conducted. Your company has stated that it will conduct an audit to identify and enhance other temperature documentation practices and will install a continuous temperature and humidity recording system. 2006.

” 3 Manufacturing processes for products intended to be sterile. For example.Doc. © Validation in Partnership Ltd 2007 . responsibilities relating to quality. should include environmental monitoring to assess the microbial contamination in the manufacturing area during typical operating conditions. the monitoring and control of the manufacturing environment. subject to any national regulations: the authorisation of written procedures and other documents. There should be procedures for the review and/or approval of major quality decisions by Senior Quality Management. in order to monitor factors which may affect product quality. including justification for continued operations when microbial action limits are exceeded in the environment.” FDA Warning Letter 02-PHI-03 (February 2002) Extracted from FDA warning letter 02-PHI-03 USA 22/02/2002 [VIP ID: 48520] “The Quality Unit failed to adequately investigate the impact of the presence of **** in **** drug products when environmental monitoring samples taken in the **** facility were found positive for **** [21 CFR 211. investigation. … training. : SGD-110-ENV Rev. including amendments. 08 Author : Validation in Partnership Ltd.22].” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 12 .” 2. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 2 PERSONNEL KEY PERSONNEL 2. or jointly exercised.USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS INTRODUCTION MICROBIOLOGICAL MONITORING 46 [VIP ID: 186814] “Microbiological monitoring is the responsibility of the pharmaceutical manufacturer. It may include environmental monitoring where product is manufactured and pre-irradiation monitoring of the product as specified in the marketing authorisation. … the monitoring of compliance with the requirements of GMP. Selected FDA 483 Observations (May 2005) Sterile Product Manufacture [VIP ID: 138850] “There should be procedures for the review and/or approval of major quality decisions by Senior Quality Management. and taking of samples. including justification for continued operations when microbial action limits are exceeded in the environment. … the designation and monitoring of storage conditions for materials and products. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 152 of 185 : 14 May 2007 8. your firm possessed no validated analytical method to determine if **** drug products were crosscontaminated with ****.7 [VIP ID: 185524] “The heads of Production and Quality Control generally have some shared. Ref.3 Microbiological 1. the inspection. These may include. Microbiological monitoring is the responsibility of the pharmaceutical manufacturer and the heads of Production and Quality Control have shared responsibility for the monitoring and control of the manufacturing environment.

defined areas to prevent microbiological contamination.Doc.007 & C. 08 Author : Validation in Partnership Ltd. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 153 of 185 : 14 May 2007 HEALTH CANADA .4 SANITATION .” FDA Warning Letter CHI-10-01 (January 2001) Extracted from FDA warning letter CHI-10-01 USA 11/01/2001 [VIP ID: 28240] “Airborne bioburden sampling of class 100 filling areas does not assure that results obtained reflect environmental conditions present during routine manufacture. For example..008 2. closures.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2. only **** cubic meters of air are taken for each airborne bioburden sample in class 100 filling areas and adjacent class 10. labeling). [VIP ID: 1815] “Microbiological monitoring is the responsibility of the pharmaceutical manufacturer.000 areas. this **** filling room is used for other functions such as storage. or mix-ups (e. Environmental monitoring has shown this section of the room to be a persistent source of microbiological contamination over the last 18 months.g.02. containers.8 [VIP ID: 65760] “CAN THE SAMPLING FOR THE MICROBIAL MONITORING OF AIR IN NON-STERILE AREAS WHERE SUSCEPTIBLE PRODUCTS ARE PRODUCED BE CONDUCTED WHEN THERE ARE NO MANUFACTURING OR PACKAGING ACTIVITIES? The sampling should occur during actual manufacturing or packaging in order to reflect the conditions to which the products being produced are really exposed.02.. Ref. ." [FDA Investigators: Bruce McCullough. processing operations must be performed within separate.C. In addition. It may include environmental monitoring where product is manufactured .” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 12 ..4. At least **** filling machines are located and run simultaneously in the same room.USE OF IONIZING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS (January 1993) Microbiological monitoring 46. Monitoring between production runs is also advisable in order to detect potential problems before they arise. Alicia Mozzachio and Jason Chancey]” Selected FDA 483 Observations (May 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 15020] “Manufacturing processes for API's which are pyrogen tested and intended for use in the manufacture of intravenous solutions and injectable finished products should include: … (3) environmental monitoring to assess the microbial contamination in the manufacturing area” Selected FDA 483 Observations (June 1999) Sterile Product Manufacture [VIP ID: 7165] “Sterile manufacturing process validation should include microbiological evaluation of: … 4) environment …” FDA Warning Letter M2329n (January 1999) Extracted from FDA warning letter M2329n Canada 08/01/1999 [VIP ID: 12570] “A single filling room contains multiple filling lines and is used for additional ancillary processing facility functions. cross-contamination.. : SGD-110-ENV Rev. Each **** processing room should be designed to minimize personnel load and activity adjacent to its filling line. our investigators cited several examples of months where approximately **** of the airborne bioburden samples collected were taken with no operators in the class 100 filling area. there is unnecessary equipment and extra personnel load in the room in which injectable products are produced. Also.” © Validation in Partnership Ltd 2007 . As a result..

Additional microbiological monitoring is also required outside production operations. after validation of systems. Surfaces and personnel should be monitored after critical operations. volumetric air and surface sampling (e. 90 mm) cfu/4 hours (b) <1 5 50 100 Contact plates (diam.g. b) … the stopper hopper is not a site selected for environmental monitoring. cfu/glove <1 5 - © Validation in Partnership Ltd 2007 . as appropriate. Ref. Where operations requiring high degrees of cleanliness are performed.Doc.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 . such as operators making aseptic connections at pre and post filtration sites. [VIP ID: 194568] “Failure to establish and follow written procedures designed to prevent microbiological contamination of drug products purporting to be sterile and failure to validate sterilization processes as required by 21 CFR 211. microbiological monitoring of the environment. cleaning and sanitisation. : SGD-110-ENV Rev. swabs.g. Sampling methods used in operation should not interfere with zone protection. Such methods should include.” Selected FDA 483 Observations (September 2005) Sterile Product Manufacture [VIP ID: 177930] “Active air sampling should be routinely monitored while critical operations are taking place. surfaces and personnel should be performed frequently according to a programme using methods. contact plates.113(b). cfu/plate <1 5 25 50 Glove print 5 fingers. viable monitoring should be performed during set-up of the sterile connections for filtration and filling. Recommended limits for microbiological monitoring of clean areas during operation: Recommended limits for microbial contamination (a) Grade Air sample cfu/m A B C D Notes: (a) These are average values (b) Individual settle plates may be exposed for less than 4 hours.” Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 193730] “In the case of aseptic processing. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 154 of 185 : 14 May 2007 4. swabs and contact plates).” <1 10 100 200 3 Settle plates (diam. Results from monitoring should be considered when reviewing batch documentation for finished product release. which do not interfere with zone protection. 55 mm).MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 5 [VIP ID: 185994] “Where aseptic operations are performed monitoring should be frequent using methods such as settle plates. settle plates. 08 Author : Validation in Partnership Ltd. dynamic air samplers. Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 1) b. e.

CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VIII. b. including factors such as difficulty of setup. We recommend that microbiological testing of aseptic workstations be performed during sterility testing and critical aseptic manipulation. PRODUCTION AND PROCESS CONTROLS C. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production. 21 CFR 211.Doc. Detection of microbial contamination on a critical site would not necessarily result in batch rejection.” GUIDANCE PET DRUG PRODUCTS . and impact of interventions. Environmental Monitoring 1.” Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171120] “3.” Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 124990] “Sampling procedures for environmental surface sampling in the filling and packaging suites should be representative of the entire work areas to include: a. It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities. three individuals were observed in the Class A/B (ISO 5) room with exposed eye and partial forehead areas. autoclave doors etc. General Written Program (para 3) [VIP ID: 111460] “It is important that locations posing the most microbiological risk to the product be a key part of the program. there was no assurance that irradiated caps were exposed to [redacted] for [redacted] minutes as required by the batch production record and environmental monitoring did not include the area where duct tape surrounds the hole where bottles exit the Class A (ISO 5) filling area. consideration should be given to the points of contamination risk in a process. The contaminated critical site sample should prompt an investigation of operational information and data that includes an awareness of the potential for a low incidence of false positives. vinyl curtains. Critical surface sampling should be performed at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing. We acknowledge that you have updated standard operating procedures and batch production records. re-trained personnel and provided face covering and eye protection to those working in the [redacted] area. length of processing time. Methods can include using swabs or contact plates for surfaces and settling plates or dynamic air samplers for air quality. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 155 of 185 : 14 May 2007 Selected FDA 483 Observations (September 2005) Sterile Product Manufacture [VIP ID: 177940] “Viable active air sampling should be performed at the area where most critical operations occur.g. : SGD-110-ENV Rev.)” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . dry heat oven doors. However. Microbiological Control on Aseptic Processing and Sterilizing Filtration 8. all portions of the rooms. chairs positioned in front of three exhaust vents were obstructing air flow in the Class A/B (ISO 5) room. Ref. 08 Author : Validation in Partnership Ltd. When identifying critical sites to be sampled. rather than the air sampler being placed on a table in the corner of the room.” © Validation in Partnership Ltd 2007 .CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. An operator was observed spraying [redacted] near a [redacted] intended for environmental monitoring. Critical surfaces that come in contact with the sterile product should remain sterile throughout an operation. critical areas that are most often in contact with personnel (e. Control procedures were inadequate to prevent microbiological contamination of sterile eye drops. due to the limited amount of time the inspection team had available to observe aseptic practices and the number and significance of the deviations.113 (b) There were several deviations in aseptic practices and technique. we have no assurance that all control procedures are adequate and suggest that a more comprehensive assessment of aseptic practices and techniques at your firm is needed to provide greater assurance of microbiological control. Environmental and personnel monitoring [VIP ID: 187516] “Environmental monitoring is crucial to maintaining aseptic conditions.

The wall phone that is used in the aseptic fill room.Doc. c. The interior surface of the rubber stopper access door that comes into contact with the back of the operator's upper right side shoulder.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. [20] Because devices vary. Surface Monitoring Environmental monitoring involves sampling various surfaces for microbiological quality. Active Air Monitoring Assessing microbial quality of air should involve the use of active devices including but not limited to impaction. The areas of the rubber stopper transfer equipment that are handled by the operators. cleanability. b. : SGD-110-ENV Rev. and disruption of unidirectional airflow. The back of the operator's upper right side shoulder. swabs. The surfaces of the stainless steel writing bench. conditions of aseptic processing areas.” © Validation in Partnership Ltd 2007 . Environmental Monitoring 4. although all allow testing of the number of organisms per volume of air sampled. Manufacturers should be aware of a device's air monitoring capabilities. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 156 of 185 : 14 May 2007 Selected FDA 483 Observations (March 2005) Sterile Product Manufacture [VIP ID: 128950] “Environmental Monitoring (EM) programs for aseptic filling areas should include obtaining EM samples from the following locations to demonstrate that there are no microbial contaminants present: a. The stainless steel "bleed pan:' f. h. Active Air Monitoring [VIP ID: 111570] “b. j. d. walls. Environmental Monitoring 4. i. the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment. We recommend that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. and equipment should be tested on a regular basis.42(c)(10)(iv)] For example. For example. Each device has certain advantages and disadvantages. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures. the user should assess the overall suitability of a monitoring device before it is placed into service. The fill equipment access door handles. [21 CFR 211.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . centrifugal. and contact plates can be used for such tests. Viewing light buttons located on the top of tanks. routine viable air sampling does not encompass aseptic activities including the times and locations where the critical operations are performed. The air hose touching the black tubing that connected the SMA outlets. floors.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Monitoring Methods b. Surface Monitoring [VIP ID: 111560] “Acceptable methods for monitoring the microbiological quality of the environment include: a.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Touch plates. e. product contact surfaces. Your firm failed to establish an adequate system for monitoring environmental. and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency. ability to be sterilized. and membrane (or gelatin) samplers. Monitoring Methods a. Ref. The writing pens.” FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133210] “6. [20] For example. g. 08 Author : Validation in Partnership Ltd.

settling plates can be used as qualitative. microbiological monitoring of all surfaces that have direct contact with stoppers. Monitoring Methods c. : SGD-110-ENV Rev. Their value in critical areas will be enhanced by ensuring that plates are positioned in locations posing the greatest risk of product contamination. glove monitoring of operators performing aseptic weighing of bulk product before the operators have changed gloves or sanitized their hands. active environmental viable monitoring (slit-to-agar) at multiple points. …” Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122650] “Environmental monitoring of aseptic processing areas should include: … e.” Selected FDA 483 Observations (September 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 123340] “Products manufactured or repackaged which are labeled as being pyrogen tested and are intended for use in injectable drug formulations should be validated from an endotoxin perspective to include: … c. monitoring for anaerobic organisms. Passive Air Monitoring (Settling Plates) [VIP ID: 111580] “c. Because only microorganisms that settle onto the agar surface are detected. environmental monitoring of the manufacturing and packaging area. such as settling plates (petri dishes containing nutrient growth medium exposed to the environment).CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. slit-to-agar monitoring during setup line adjustment and fill weight check operations. As part of methods validation. or semi-quantitative.g. b. e. not just at filling needles. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 157 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . the only breach of the integrity of the system is during the act of blood collection and does not require to be carried out in a classified clean room). the quality control laboratory should evaluate what media exposure conditions optimize recovery of low levels of environmental isolates. which inhibits recovery of microorganisms.” PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 11. COMPONENT PREPARATION Preparation of Components 11.6 [VIP ID: 185162] “The premises used for the preparation of blood components in a closed-system should be kept in a clean and hygienic condition and the microbial contamination load on critical equipment.” © Validation in Partnership Ltd 2007 . surfaces and the environment of the preparation areas should be monitored. Ref. The data generated by passive air sampling can be useful when considered in combination with results from other types of air samples. Environmental Monitoring 4.. caused by lengthy sampling periods and / or high airflows).” Selected FDA 483 Observations (September 2004) Sterile Product Manufacture [VIP ID: 123290] “Environmental monitoring programs in aseptic filling areas should include: a. f. and sanitized utensils used for aseptic manipulations. … d. routine monitoring of sterilized. Exposure conditions should preclude desiccation (e. 08 Author : Validation in Partnership Ltd. routine. (As closed-system processing involves the use of pre-configured multiple bag systems. Passive Air Monitoring (Settling Plates) Another method is the use of passive air samplers.Doc. air monitors.

3. (b) Individual settle plates may be exposed for less than 4 hours. CONTROL OF PRESTERILIZATION BIOBURDEN 5.Doc. such as: active air sampling. 08 Author : Validation in Partnership Ltd.9 [VIP ID: 188288] “The following elements should be carefully reviewed as they are often involved in loss of control of bioburden: … (d) Microbiological monitoring. : SGD-110-ENV Rev.” <1 10 100 200 3 Settle plates (diam.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 158 of 185 : 14 May 2007 PI 005-2 RECOMMENDATION ON GUIDANCE ON PARAMETRIC RELEASE (July 2004) APPENDIX I RECOMMENDATIONS FOR A GENERAL STERILITY ASSURANCE SYSTEM FOR TERMINALLY STERILISED PRODUCTS AND PROVISIONS FOR PARAMETRIC RELEASE 5. 55 mm).MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 5 [Table and Notes] [VIP ID: 62680] “Recommended limits for microbiological monitoring of clean areas during operation are provided in the table below. Ref.1 [VIP ID: 190294] “Environmental microbiological monitoring should include a combination of air and surface sampling methods. swabs or flexible films. operators' gloved hand plates.3 Microbial Monitoring 7. settle (exposure) plates.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. 90 mm) cfu/4 hours (b) <1 5 50 100 Contact plates (diam. …” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.1 [VIP ID: 188976] “It is usually expected that a combination of the methods identified in the Annex 1 of the EU/PIC/S GMP guide for monitoring microbial levels is used in environmental monitoring programmes where appropriate. Recommended limits for microbial contamination (a) Grade Air sample cfu/m A B C D Notes (a) These are average values. cfu/glove <1 5 - © Validation in Partnership Ltd 2007 . surface contact (RODAC) plates. cfu/plate <1 5 25 50 Glove print 5 fingers. ENVIRONMENTAL MONITORING 10.

Failure to establish an adequate system for monitoring environmental conditions of aseptic processing areas [21 CFR 211. 1987 "Guideline on Sterile Drugs Produced by Aseptic Processing" Yes..BMFG1413.100(b)]. …” Extracted from FDA Warning Letter CBER-99-013 (March 1999) Extracted from FDA warning letter CBER-99-013 UK 17/03/1999 [VIP ID: 159510] “2.100 and/or failure to establish procedures designed to prevent microbiological contamination as required by 21 CFR 211. strength. However. which was observed in use in the critical manufacturing areas. tools.” Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 137550] “Environmental monitoring sampling should include curtains at locations where personnel move through to perform activities along a fill line. and purity they purport or are represented to possess as required by 21 CFR 211.” FDA Warning Letter CBER-00-017 (March 2000) Extracted from FDA warning letter CBER-00-017 USA 16/03/2000 [VIP ID: 12690] “Failure to establish separate or defined areas or other control systems for manufacturing and processing operations to prevent contamination or mix-up [21 CFR 211. .42(c)(10)(iv) and 600.. …” Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19770] “Environmental monitoring should be performed in milling. quality."helps control particulate counts". Failure to follow written production and process control procedures [21 CFR 211. furniture etc. equipment no. VOLUME 05.. "General Good Employee Practices".42(c)(10)(iv)] in that surface environmental monitoring was not performed in the **** hoods where aseptic filling occurs. For example.” HUMAN DRUG CGMP NOTES.Doc. No microbial monitoring of air is done in the Class 100 area in the Smeja unloading rooms. For example: … j. blending and drying areas where APIs intended for parenteral use are exposed.11(a)] in that active air sampling is not performed during aseptic filling but rather immediately after every filling operation.. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 159 of 185 : 14 May 2007 FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 6 [VIP ID: 49920] “6. in the clean areas". : SGD-110-ENV Rev. Ref.” Extracted from FDA Warning Letter CHI-27-99 (July 1999) Extracted from FDA warning letter CHI-27-99 USA 09/07/1999 [VIP ID: 159920] “Failure to have sufficient production and process controls or to establish procedures to assure that drug products have the identity. © Validation in Partnership Ltd 2007 . … Rust and corrosion was observed on the base and impeller blades on active air sampler.113. 08 Author : Validation in Partnership Ltd. states: do not "bring in or use rusty racks. NUMBER 04 (December 1997) Motise's Notebook POLICY QUESTIONS: 4) [VIP ID: 4054] “Has FDA identified an appropriate microbiological specification for monitoring critical surfaces in an aseptic area used to make sterile drug products? Reference: June.

[VIP ID: 17430] “11.g.g. Water systems © Validation in Partnership Ltd 2007 . swabs and contact plates). D. volumetric air and surface sampling (e.” GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. Firms often express this action limit as <1 CFU. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates." Microbiological monitoring of critical surfaces should yield zero colony forming units (CFUs). [VIP ID: 17470] “1. Microbiological Monitoring of the Environment. Ref. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. Results from monitoring should be considered when reviewing batch documentation for finished product release. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. cleaning and sanitisation. Additional microbiological monitoring is also required outside production operations. of course. Microbiological Methods The microbiological materials and methods used in the environmental monitoring program should be described. Microorganisms on personnel d. be sterile. Surfaces and personnel should be monitored after critical operations.322. FDA's 1987 "Guideline on Sterile Products Produced by Aseptic Processing" states: "Equipment surfaces which contact sterilized drug product or sterilized container/closure surfaces should.Doc. neutralization of sanitizers. incubation. e. HFD. It is just as important in aseptic processing to properly validate sterilization processes applied to these equipment surfaces as it is to validate such processes for the drug product and container/closures.SUPERSEDED! (July 1996) General Microbiological Monitoring Of Graded Areas [VIP ID: 1393] “5. Viable air samples and settling plate samples should be collected at locations where personnel are actively loading bottles onto the turntable and making adjustments to filling nozzles b. 08 Author : Validation in Partnership Ltd. and closure contact surfaces are known as "critical surfaces.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 .gov” Selected FDA 483 Observations (January 1997) Sterile Product Manufacture [VIP ID: 135620] “Environmental monitoring samples of critical aseptic filling areas should be collected at worst case locations and times.g. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 160 of 185 : 14 May 2007 Product. The following are sources of microbial contamination and their monitoring that should be addressed. Methods may include sample collection. Airbourne microorganisms b. container. Contact for further information: Richard L.F. Surface samples should be collected from areas where activity is performed. Procedures and Specifications for Media Fills 11. after validation of systems." This standard can also be found in international publications such as the European Union's "Manufacture of Sterile Medicinal Products" (Annex I to the European Union Guide to Good Manufacturing Practice).” GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. Microorganisms on inanimate surfaces c.: a. of this guidance).MANUFACTURE OF STERILE MEDICINAL PRODUCTS .fda. 301-594-0095. and calculation of results. Microbiological monitoring The microbiological monitoring data obtained during the media fill runs should be provided (see section IV. Sampling methods used in operation should not interfere with zone protection. e. e-mail: friedmanr@cder. Viable air samples should be collected during aseptic connections c. transport. F. : SGD-110-ENV Rev. Friedman. including specifications: a.

filling areas 3.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 39. : SGD-110-ENV Rev. [VIP ID: 2192] “Does the firm have data on the ability of these samplers to recover organisms without deleterious effect on survivability such as through impact or dessication of organisms or media?” CPGM-DB CHAPTER 56 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 161 of 185 : 14 May 2007 e. Centrifugal sampler.)?” 5.Doc. Molds. [VIP ID: 2189] “Report the frequency of viable sampling using "active" sampling methods for: 1. F.” © Validation in Partnership Ltd 2007 .DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 57.DRUG QUALITY ASSURANCE 7356. Yeasts. swabs. Microbiological Monitoring of the Environment. Product component bioburden” GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. etc. and anaerobes should be provided. surrounding areas” CPGM-DB CHAPTER 56 . Ref.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 37. and Anaerobic Microorganisms A description of periodic or routine monitoring methods used for yeasts.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 40.” CPGM-DB CHAPTER 56 . INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing.). [VIP ID: 2191] “Report the type of viable sampling equipment used (STA.” CPGM-DB CHAPTER 56 . 08 Author : Validation in Partnership Ltd. molds. etc.DRUG QUALITY ASSURANCE 7356. [VIP ID: 2209] “What type of contact surface monitoring devices are used (RODAC.DRUG QUALITY ASSURANCE 7356. The exteriors of environmental monitoring plates should be sanitised before being set out in the aseptic areas. exposed product areas 2. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 19930] “The exteriors of environmental monitoring plates should be sanitized before being set out in the aseptic areas. [VIP ID: 17480] “2.

the source or location from where the sample was obtained.” © Validation in Partnership Ltd 2007 . There should be incoming checks of Petri dishes to be utilised in preparation of environmental monitoring plates. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . the date and time the sample was taken and verification that the samples are incubated within the established period of time. Laboratory records should include a description of the sample received for testing. a unique identifier for the sample. the lot number or other distinctive code of the sample. Ref. the user should assess the overall suitability of a monitoring device before it is placed into service. : SGD-110-ENV Rev. are incubated within the established period of time. [20] For example. and disruption of unidirectional airflow. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 19940] “Suppliers of environmental monitoring plates should be audited.” 8. cleanability. incubator logbooks should include sample identification to assure that the incubated samples. Environmental Monitoring 4. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures. and the laboratory should have an accurate inventory of the samples incubated in each incubator. Active air samplers should be evaluated for their suitability for use in an aseptic environment based on collection efficiency. the source or location from where the sample was obtained. ability to be sterilised. Active Air Monitoring . the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment. Suppliers of environmental monitoring plates should be audited. 08 Author : Validation in Partnership Ltd. such as environmental and media fill samples. and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency. and disruption of unidirectional airflow. and the date the sample was taken. [20] Because devices vary. Selected FDA 483 Observations (August 2006) Laboratories [VIP ID: 193804] “Laboratory records should include a description of the sample received for testing.” Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124750] “Read times and dates should be documented for environmental monitoring viable surface count plates and viable active air count plates to assure incubation times have been met. Active Air Monitoring [VIP ID: 111570] “b.” 9. cleanability. and for Petri dishes utilized in preparation of environmental monitoring plates.Doc.. Monitoring Methods b. Selected FDA 483 Observations (October 2006) Sterile Product Manufacture [VIP ID: 193928] “There should be incoming checks or specifications for filters used in sterile filtration and tubing used in the manufacturing of product. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 162 of 185 : 14 May 2007 6.” 7. Manufacturers should be aware of a device's air monitoring capabilities.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. ability to be sterilized. For example..

. Selected FDA 483 Observations (October 2004) Sterile Product Manufacture [VIP ID: 123790] “SOPs for the viable sampling of Glove Boxes and Laminar Flow Hoods should provide for the collection of surface samples at the conclusion of aseptic activity. Environmental microbiological monitoring should include details of the testing locations and the identification of all isolated organisms in a format that facilitates early detection of trends. Failure to follow written production and process control procedures [21 CFR 211. equipment no. : SGD-110-ENV Rev.. such as USP. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . in the clean areas". GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. Other suitable microbiological test methods."helps control particulate counts".” © Validation in Partnership Ltd 2007 . INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. Alternate Microbiological Test Methods [VIP ID: 111640] “Other suitable microbiological test methods (e. if it is demonstrated that the methods are equivalent or better than traditional methods.” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI.BMFG1413. An environmental monitoring programme should include alert/action limits and appropriate follow-up actions to be taken when they are reached..Doc. which was observed in use in the critical manufacturing areas. and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e. USP). This includes the daily use of surface plates and the monitoring of personnel.100(b)].g.. states: do not "bring in or use rusty racks.g... [VIP ID: 17490] “3.” 11. in-process control testing. Microbiological Monitoring of the Environment. furniture etc. "General Good Employee Practices". 08 Author : Validation in Partnership Ltd. Exceeded Limits A description of the actions taken when specifications are exceeded should be provided. ENVIRONMENTAL MONITORING (para 1) [VIP ID: 2035] “The environmental monitoring program for the sterile bulk drug substance manufacturer should be similar to the programs employed by the SVP industry. For example. F.. tools. As with the SVP industry.” 12.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls D. can be considered for environmental monitoring. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 163 of 185 : 14 May 2007 FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 6 [VIP ID: 49920] “6. rapid test methods) can be considered for environmental monitoring. …” 10. However. alert or action limits should be established and appropriate follow-up action taken when they are reached. Ref. … Rust and corrosion was observed on the base and impeller blades on active air sampler.

and the overall environmental picture provides valuable information for an investigation.000 (ISO 8). such as curtains. and plexiglass doors.” Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15660] “Environmental monitoring should include: (1) trending of isolates …” Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14670] “Organisms isolated during personnel bioburden monitoring. genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid. where appropriate. genus) level. can often be instrumental in detecting such trends. colony morphology is not enough.. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or.” Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 14540] “Environmental monitoring of filling areas should include: (1) class 100 plastic curtains (2) entry ways for the filling area (3) product filling nozzles © Validation in Partnership Ltd 2007 . Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure. In some cases. identification of organisms isolated from Class 100 locations. . environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 164 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Microbiological Media and Identification (para 1) [VIP ID: 111590] “Characterization of recovered microorganisms provides vital information for the environmental monitoring program.” Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122650] “Environmental monitoring of aseptic processing areas should include: … d. At minimum. should be included in the environmental monitoring program. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments. chairs. such as Class 100.” Selected FDA 483 Observations (December 2003) Sterile Product Manufacture [VIP ID: 70670] “Surfaces in aseptic processing rooms that are frequently contacted by filling operators during production.6 [VIP ID: 190304] “Records should be maintained of the numbers and type of organisms isolated and results presented in a format that facilitates early detection of trends. current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).Doc. : SGD-110-ENV Rev. Routine identification of environmental micro-organisms to at least the genus level should assist in detecting trends. ENVIRONMENTAL MONITORING 10. where appropriate.1). the program should require species (or.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls B. gowning validation and routing gowning monitoring should be identified.. Sensitive techniques such as molecular typing techniques will be required for identification of micro-organisms if equivalence of identity of environmental and test isolates is the sole rationale used to invalidate the original sterility test (refer to clause 13.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. 08 Author : Validation in Partnership Ltd. Ref.

” FDA Warning Letter CBER-99-002 (October 1998) Extracted from FDA warning letter CBER-99-002 USA 06/10/1998 [VIP ID: 12160] “Failure to establish an adequate system for maintaining equipment used to control the aseptic process [21 CFR 211.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 43. These should be based on a scientific rationale. There is no documented explanation or justification for the selection of the surfaces defined in SOP [redacted] Monitoring of Surfaces. recording requirements. as "Class 100 Critical Sites. which specify the frequency of all types of monitoring. 2006.42(c) (10)(vi) and 600. exposure durations and the test media to be used. Ref. : SGD-110-ENV Rev.42(c)(10)(iv). Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 5) [VIP ID: 194586] “Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area as required by 21 CFR 211." dated May 23.” Selected FDA 483 Observations (July 1997) Medical Device Manufacture [VIP ID: 2535] “Airborne and Surface Bioburden Monitoring of production areas should include: (1) a documented schedule and frequency for the monitoring and testing of the controlled environment (2) identification of the location and specific areas in which microbial sampling is performed (3) identification of isolated microorganisms” CPGM-DB CHAPTER 56 .DRUG QUALITY ASSURANCE 7356." The four sites described as critical are surfaces on the in-feed turntable. Your response indicates that you will continue to monitor the same sites until at least February 2007. including inactivating agents. There should be written procedures covering the microbiological monitoring of the environment and surfaces in manufacturing areas. the vibratory bowl is not included in the routine environmental monitoring program. and makes no commitment to monitor equipment surfaces that come in direct contact with the sterile product or sterile. The critical sites listed in the SOP do not include any surfaces that come in direct contact with the sterile product or sterile components. species)?” 13.Doc.” Selected FDA 483 Observations (January 1998) Sterile Product Manufacture [VIP ID: 6248] “Environmental monitoring of production areas and systems should include routine speciation of all organisms. 08 Author : Validation in Partnership Ltd. not just those at or above alert/action levels. two equipment platforms and the conveyor motor cover. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 165 of 185 : 14 May 2007 (4) rubber stopper bowl” Selected FDA 483 Observations (June 1999) Sterile Product Manufacture [VIP ID: 7179] “Plastic curtains enclosing class 100 laminar air flow areas should be included in environmental monitoring during filling. [VIP ID: 2195] “Are recovered microorganisms routinely identified? To what level (genus. where required.11(b)] in that there is no cleaning / sanitization validation for the non sterilizable vibratory bowl (stopper hopper) in the aseptic filling suite.” © Validation in Partnership Ltd 2007 . In addition. test location maps.

: SGD-110-ENV Rev. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 166 of 185 : 14 May 2007 Selected FDA 483 Observations (December 2006) Sterile Product Manufacture [VIP ID: 194098] “Procedures for monitoring environmental conditions within aseptic areas should address when viable air monitoring is to be conducted (i. d.Doc. which can result in instances when more than 30 days can elapse without monitoring. The SOP only requires monthly monitoring of the Class 10.” Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124780] “There should be data to support the selected sampling points for environmental surface counts. Monitoring for anaerobic organisms is not performed.” © Validation in Partnership Ltd 2007 . It is insufficient only to determine colony morphology.” Selected FDA 483 Observations (September 2005) Medical Device Manufacture [VIP ID: 178230] “Procedures should be defined and documented for controlling environmental conditions. For example: a. b. 08 Author : Validation in Partnership Ltd.000 room directly adjacent to the fill room.” Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124760] “There should be SOPs requiring the recording of read times and dates for environmental monitoring viable surface count plates and viable active air count plates. Organisms isolated from Class 100 locations are not identified. e.” Selected FDA 483 Observations (January 2006) Sterile Product Manufacture [VIP ID: 179430] “Aseptic processing areas are deficient regarding the system for monitoring environmental conditions if: a. dated August 2. during dynamic or static operations) and should provide a scientific rationale to support surface sampling sites.g. In addition. c.e.” Extracted from FDA Warning Letter 06-NWJ-09 (December 2005) Extracted from FDA warning letter 06-NWJ-09 USA 14/12/2005 [VIP ID: 175560] “7. which could reasonably be expected to have an adverse affect on product quality as required by 21 CFR 820. the monitoring of bioburden levels throughout the production areas.70(c). the procedure does not specify the number of air samples that need to be collected (the procedure does not specify the specific sampling sites in each location for manufacturing and final packaging operations). viable airborne microorganisms and non viable particulate matter in the areas used in the filling of sterile diluents. Ref. 2002) failed to explain how and when environmental monitoring of the packaging room [redacted] would be performed. The SOP requires the initiation of an investigation and corrective action only after two consecutive action levels are exceeded as the schedule for sampling may result in long periods of time between consecutive samplings of the same area. Growth promotion is not performed on the media used for sampling. Failure to establish and maintain procedures to adequately control the environmental conditions. e.” Selected FDA 483 Observations (June 2005) Sterile Product Manufacture [VIP ID: 140130] “There should be a scientific rationale for the locations of the placement of viable air samplers and settling plates in aseptic filling suites. Your firm's sampling of airborne and surface microbes procedure (Document #060018.

For example. The frequency of monitoring.” GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. type of monitoring. exposure duration. location (including proximity to critical operations).” Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121920] “Microbiological surface sampling procedures should provide instructions regarding the frequency of sampling and the sites for sampling.” GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 167 of 185 : 14 May 2007 PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. Environmental Controls (para 2) [VIP ID: 2670] “Note: In the preparation of media for environmental air and surface sampling. ENVIRONMENTAL MONITORING 10. [VIP ID: 2194] “Are settling plates used? Describe the length of exposure period. 08 Author : Validation in Partnership Ltd. F. Ref. : SGD-110-ENV Rev. suitable inactivating agents should be added. [VIP ID: 17460] “The microbiological monitoring program used during routine production and media fills should be described.4 [VIP ID: 190300] “The media used for each type of monitoring should be specified and the recovery of micro-organisms on the chosen media should be validated. sampling frequency. ENVIRONMENTAL MONITORING 10.DRUG QUALITY ASSURANCE 7356.” © Validation in Partnership Ltd 2007 . the addition of penicillinase to media used for monitoring sterile penicillin operations and cephalosporin products.Doc. Suitable inactivators of disinfectants and cleaning solutions may need to be incorporated into recovery media used for samples taken from surfaces. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing.3 [VIP ID: 190298] “Location maps.CGMPR'S (October 1993) 2.” Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 16150] “Environmental monitoring procedures should include monitoring compounding and other manufacturing areas for the presence of objectionable organisms. sites monitored. Microbiological Monitoring of the Environment. microbial limits. and precise descriptions of the actions taken when specifications are exceeded should be included. and frequency of all types of microbiological environmental monitoring should be specified in written procedures. alert and action level specifications.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 42.” CPGM-DB CHAPTER 56 .

08 Author : Validation in Partnership Ltd.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 45. anaerobes.DRUG QUALITY ASSURANCE 7356. and precise descriptions of the actions taken when specifications are exceeded. Include the frequency of monitoring. F. Exact descriptions of the microbiological methods used in the environmental monitoring program should be provided so that an assessment of the results can be made in relationship to the methods used in obtaining the results.Doc. alert and action level specifications.” © Validation in Partnership Ltd 2007 . Include air. penicillinase) used for antibiotics or other bacteriocidal/bacteriostatic substances? Has the firm shown that these are effective? (Are records available? Are calculations correct?)” CPGM-DB CHAPTER 56 . [VIP ID: 3035] “Describe the microbiological monitoring program used during routine production (and media fills if the monitoring program for media fills differs from routine monitoring). A description of the actions taken when specifications are exceeded should be provided. [VIP ID: 2208] “Does the firm have written procedures for the monitoring of product contact surfaces?” STERILIZATION PROCESS VALIDATION . Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. type of monitoring.” 14. A description of periodic or routine monitoring methods used for yeasts. : SGD-110-ENV Rev. 1. should be provided.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 56. 2. Descriptions of the bioburden monitoring program should also be provided.g.DRUG QUALITY ASSURANCE 7356.DRUG QUALITY ASSURANCE 7356. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 168 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 . [VIP ID: 2197] “What media are used?” CPGM-DB CHAPTER 56 . personnel.SUPERSEDED! (January 1993) II. Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 7157] “Incidents which may cause environmental monitoring plates to be compromised should be recorded at the time they occur. surfaces.. [VIP ID: 2198] “Are deactivators (e. sites monitored. Include specifications as applicable. and water monitoring programs. including specifications. Incidents which may cause environmental monitoring plates to be compromised should be recorded at the time they occur. 3. Ref. molds.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 46. or other microbes.

Ref. 600. therefore.Doc. It is not unusual to see settle plates and air sample locations well away from such areas. and care. …” 16. It is important to observe operator activity over a period of time and ensure that microbial monitoring sites are located in and around areas of high operator activity. Thus. A typical example is where settle plates are located well to the rear of the filling machine where there is little or no operator activity. facilities. : SGD-110-ENV Rev. These procedures must provide for adequate removal or decontamination of the spore-forming microorganisms on and within manufacturing equipment.BIOLOGICAL PRODUCTS: GENERAL (April 2006) Subpart B--Establishment Standards Sec. animals. (i) Manufacturing processes using spore-forming microorganisms conducted in multiproduct manufacturing site must be performed under appropriate controls to prevent contamination of other products and areas within the site. ENVIRONMENTAL AND PERSONNEL MONITORING 7. The same may be true for air sampling.” 18. There should be validation data to establish surface sampling sites and frequencies. They may even contribute to the generation of a resistant (flora) organism. For manufacturing processes using spore-forming micro-organisms. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 169 of 185 : 14 May 2007 15.2 [VIP ID: 188978] “Microbial monitoring should be performed in and around areas of high operator activity. environmental monitoring specific for the spore-forming micro-organism(s) must be conducted in adjacent areas during manufacturing operations and in the manufacturing area after completion of cleaning and decontamination. Prevention of spore contamination can be achieved by using a separate dedicated building or by using process containment if manufacturing is conducted in a multiproduct manufacturing building. (ii) If process containment is employed in a multiproduct manufacturing area. The use of ultraviolet lights in operating areas may mask a contaminant on a settling or aerobic plate.3. ENVIRONMENTAL MONITORING (para 2) [VIP ID: 2036] “There are some bulk drug substance manufacturers that utilize UV lights in operating areas. They may mask a contaminant on a settling or aerobic plate.” 17. It is important. and ancillary room items as well as the removal of diposable or product dedicated items from the manufacturing area. 08 Author : Validation in Partnership Ltd. equipment. to observe operator activity over a period of time and ensure that the monitoring sites are so located as to monitor operator activity. Environmental monitoring specific for the spore-forming microorganism(s) must be conducted in adjacent areas during manufacturing operations and in the manufacturing area after completion of cleaning and decontamination.3 Microbial Monitoring 7. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. They may even contribute to the generation of a resistant (flora) organism. procedures must be in place to demonstrate adequate removal of the sporeforming microorganism(s) from the manufacturing area for subsequent manufacture of other products. the use of Rodac or surface plates will provide more information on levels of contamination. the use of Rodac or surface plates will provide more information on levels of contamination. (e) [VIP ID: 1854] “Restrictions on building and equipment use … (3) Work with spore-forming microorganisms. 21 CFR PART 600 .11 Physical establishment. Thus.” © Validation in Partnership Ltd 2007 . Such lights are of limited value. All product and personnel movement between the area where the sporeforming microorganisms are manufactured and other manufacturing areas must be conducted under conditions that will prevent the introduction of spores into other areas of the facility. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121930] “There should be validation data to establish surface sampling sites and frequencies.

Condensate and excessive moisture can result in increased humidity and increases in levels of microorganisms on surfaces of equipment.” 21. Environmental monitoring samples should be taken from the areas of the filling equipment most likely to be contaminated and contain bioburdens. : SGD-110-ENV Rev. including those in product contact. and that investigations are performed into the causes of contamination at the time of inspection. it is not unusual to see the highest level of contamination on the surfaces of equipment shortly after systems are steamed. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 170 of 185 : 14 May 2007 19.3 Microbial Monitoring 7. Ref.. Sites prone to spillage).” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) V.” © Validation in Partnership Ltd 2007 . such as sites prone to spillage. 08 Author : Validation in Partnership Ltd.” GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. it should be identified and investigated at the time of inspection.e. not at the beginning (before processing) or end of a shift (following sanitisation). Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 16520] “Environmental monitoring of critical surfaces (to include product contact) should be performed during or at the conclusion of operations. It is important that alert and action levels for all microbiological contaminants found in monitoring samples are established and defined. If this occurs. Selected FDA 483 Observations (February 2007) Sterile Product Manufacture [VIP ID: 194332] “If an out-of-specification environmental monitoring result is obtained for viable particulates during routine monitoring. should be performed during or at the conclusion of operations.” Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15370] “Environmental monitoring samples should be taken from the areas of the filling equipment most likely to be contaminated and contain bioburdens (i.3. ENVIRONMENTAL MONITORING (para 4) [VIP ID: 2038] “As previously discussed.Doc. the cause is usually the inadequate removal of condensate. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. it is particularly important to review Environmental monitoring after sterilization of the system. Environmental monitoring of critical surfaces. Therefore.” Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 14250] “Routine personnel viable monitoring programs within environmentally controlled areas for aseptically processed and terminally sterilized products should include the routine sampling of: … (2) contact surfaces (such as filling heads and the inside the stopper bowl)” 20.4 [VIP ID: 188982] “A useful monitoring technique is to monitor the filling needles at the end of the filling session. ENVIRONMENTAL AND PERSONNEL MONITORING 7. based on validation studies and historical data. EQUIPMENT (para 6) [VIP ID: 2033] “Another potential problem with SIP systems is condensate removal from the environment. not at the beginning (before processing) or end of a shift (following sanitization).

Your facility’s quality control unit failed to review production records to assure that no errors have occurred or. However. October 9.22 and 211.000 to 100. 2004) concluded that [redacted] fumigation of your facility’s formulation areas on May 17. 2004 'was successful' as confirmed by your ongoing environmental monitoring program. processes. between [redacted] through [redacted] your firm took four corrective actions as a result of high microbial counts found in the controlled environment room but failed to investigate the root cause of the high counts. the Investigator observed that your firm failed to investigate the root cause of high microbial counts noted during the monthly environmental monitoring program although corrective action was taken.For example.192 Microbiological test results for personnel and environmental monitoring that exceed your firm's action level were not investigated and were inadequately investigated.” FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133130] “1.000 areas and the action limits for personnel gowning should be based on historical Environmental Monitoring (EM) data. during our review of 5 of your firm's 140 Quality Strategic Response (QSR) reports. We acknowledge your statement that you will conduct an internal review of your deviation reporting and to investigate all OOS results. 21 CFR 211. …” Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128770] “Microbial operational alert limits for Class 1. if errors have occurred. including but not limited to Serratia spp.192] For example: a) The quality control unit’s investigation of Fluvirin sterility failures (Fluvirin Sterility Failure Investigation Report #R/0198/04.” FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 135000] “3. respectively. that they have been fully investigated. : SGD-110-ENV Rev. as required by 21 CFR 820.” Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 125000] “Microbial "alert" and "action" levels should be based on historical environmental monitoring program data. Failure to establish and maintain procedures to investigate the cause of nonconformities relating to product. Unexplained discrepancies were not adequately investigated by the quality control unit. Also.Doc. the quality control unit also failed to investigate thoroughly any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR 211. and the quality system. we want to emphasize the importance of good documentation in relation to investigating deviations. Yet environmental data from April 2004 through September 2004 for formulation rooms [redacted] and [redacted] indicate continued alert and action level excursions for gram negative organisms.” FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133150] © Validation in Partnership Ltd 2007 .” Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124540] “Microbial action levels for manufacturing aseptic areas and surrounding support areas should be based on current historical Environmental Monitoring (EM) data. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 171 of 185 : 14 May 2007 Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171150] “6. 08 Author : Validation in Partnership Ltd. Ref.100(a)(2).

and which subsequently resulted in the rejection of the lots.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. The quality control unit did not thoroughly investigate the environmental monitoring excursions during filling for Fluvirin lots [redacted] and [redacted]. Ref. cleanroom qualification. 08 Author : Validation in Partnership Ltd.192] For example: c) The Fluvirin sterility failure investigation conducted by the quality control unit failed to address the fact that numerous monovalent blend pools (over 50%) used from March 2004 through October 2004 exceeded your firm’s bioburden alert level ([redacted] cfu / ml).CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV.22 and 211. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 172 of 185 : 14 May 2007 “1.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . remedial measures should be taken in response to unfavorable trends.” Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 70910] “Warning and action limits for sampling plates used to monitor the bioburden on the floors. and sanitization studies.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . low-level contamination can be particularly difficult to detect.” © Validation in Partnership Ltd 2007 . walls.Class 100 (ISO5) (para 8) [VIP ID: 110250] “Air monitoring samples of critical areas should normally yield no microbiological contaminants. : SGD-110-ENV Rev. Environmental Monitoring 1. General Written Program (para 4) [VIP ID: 111470] “Environmental monitoring methods do not always recover microorganisms present in the sampled area. In the absence of any adverse trend.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . We recommend affording appropriate investigative attention to contamination occurrences in this environment. if errors have occurred. media fills. Critical Area . that they have been fully investigated. Because false negatives can occur. especially for a new operation. Data from similar operations can also be helpful in setting action and alert levels. a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate. consecutive growth results are only one type of adverse trend. Establishing Levels and a Trending Program (para 1) [VIP ID: 111490] “Microbiological monitoring levels should be established based on the relationship of the sampled location to the operation. One should also consider environmental monitoring data from historical databases. The non-conformance reports were limited to review of the filling activity for each specified lot. There was no investigation in these non-conformance reports of aseptic filling area environmental monitoring excursions that occurred for other lots between September 2004 and October 2004. Buildings and Facilities A. Your facility's quality control unit failed to review production records to assure that no errors have occurred or. The levels should be based on the need to maintain adequate microbiological control throughout the entire sterile manufacturing facility. In all room classes.Doc. Environmental Monitoring 2. Increased incidence of contamination over a given period is an equal or more significant trend to be tracked.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. the quality control unit also failed to investigate thoroughly any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR 211. in developing monitoring levels. and machinery surfaces in the manufacturing areas should be based on the results of validation studies. In particular.

” © Validation in Partnership Ltd 2007 . For example. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 173 of 185 : 14 May 2007 FDA Warning Letter DEN-03-16 (May 2003) Extracted from FDA warning letter DEN-03-16 USA 08/05/2003 [VIP ID: 56180] “Failure to establish and maintain procedures to adequately control environmental conditions. this procedure does not define what is meant by "overgrown. : SGD-110-ENV Rev.70(c). Our review of the literature found that [redacted] spp. east. contamination of the air system and the HEPA filters in a hospital’s oncology-hematology special care unit." "lawn. the [redacted] will complete a "White Room Discrepancy Notice" and forward it to the White Room Supervisor. such monitoring cannot provide a complete overview of the room conditions. 08 Author : Validation in Partnership Ltd. personnel.198]. Ref. there is a potential for impact to the critical surfaces.” FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 9 [VIP ID: 49950] “9. In a previous inspection. The procedure. as part of a trend in the sterile environment between [redacted] and [redacted]. We believe that cGMP requires additional vigilance in this area. and has identified the presence of [redacted] spp." indicated several instances of "uncountable overgrown" and "lawn" plates. For example. on the floor which exceeded your firm’s action levels for that surface. Four bone marrow transplant recipients were subsequently infected. … This appears to be a persistent problem. Your firm maintains that a ceiling or HEPA filter route of contamination is not likely because air and surface monitoring. documentation for samples taken during filling shows that the areas where positive growth was found prior to filling (south. Medina]. can contaminate water damaged. the presence of mold was confirmed by analysis. west." The procedure also does not describe what corrective actions the White Room Supervisor is to take if the monitoring limits are exceeded. However. the results of environmental testing performed in 2001 and 2002 as listed in the "Viable Air/ Surface Plate Survey Report. we have concerns regarding the source of the contamination. The investigation did not indicate any review or evaluation of environmental monitoring data as a result of the confirmation that there was mold growth on the caps or any attempt to ascertain the source of the mold. after a complaint was received regarding mold in the product. The literature reports it can be an opportunistic pathogen in immunocompromised individuals and references a 1988 incident regarding [redacted] spp. If it is above the sterile core ceilings. received any information from your firm regarding any investigation into possible contamination in the ceilings and/or HEPA filters or other potential source of this mold. Post-inspectional correspondence from your firm states that the exceeded action levels were associated with environmental sampling conducted prior to filling the meperidine HCl and that floor samples taken during filling were negative for growth. cellulose-containing building materials. and center floors) were not sampled. "Validation of Limited Access Areas" states if the test results are over the maximum microbiological contaminant level [redacted]. Although your firm believes that these floor counts did not impact the aseptic filling operations because of negative environmental monitoring results for critical surfaces.Doc. Failure to establish and follow adequate procedures describing the handling of complaints related to drug products [21 CFR 211. as required by 21 CFR 820. The inspection revealed that your firm’s environmental monitoring found mold. BQA0014 "Handling of Product Complaints and WIP Shipment Complaints" does not describe the level of investigation to perform when product complaints describing particulate matter in injectable products are received. Failure to thoroughly investigate exceeded environmental monitoring action levels in the sterile filling room in which meperidine HCI injection lot [redacted] was filled. We note that the West Chester facility has had water leaks above the ceilings in the sterile core." or "too numerous to count.” - Extracted from FDA Warning Letter 99-PHI-36 (September 1999) Extracted from FDA warning letter 99-PHI-36 USA 28/09/1999 [VIP ID: 160120] “3. There is no documentation that additional disinfection was done between samplings. contamination. and air. Given that mold spores can become aerosolized. to date. has had periodic breaks in sterile conditions (to change HEPA filters or otherwise access ceilings). However. with the exception of the floors. We have not. have been negative for [redacted] spp. [redacted] species." [Investigator: Lori A.

work sequence. 08 Author : Validation in Partnership Ltd. [redacted] CFU on the turntable. If indicated. preparation. and test procedures designed to ensure that components.” Selected FDA 483 Observations (June 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6368] “Gram staining should be routinely conducted when environmental limits are exceeded.” GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) II. contact time) to enable reproducibility. A description of the actions taken when specifications are exceeded should be provided. Microbiological Monitoring of the Environment (para 1) [VIP ID: 17030] “Section 211. closures. Once the procedures are established. action levels.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. standards.160 of the Code of Federal Regulations requires. methods used. sampling plans. [redacted] of which involved contamination of the filling needle area. [redacted] CFU on the [redacted]. INFORMATION FOR TERMINAL MOIST HEAT STERILIZATION PROCESSES The following information should be submitted for each facility to be used in the manufacture of the proposed drug product: D.. . Environmental Monitoring 3.” 22. For example.” Selected FDA 483 Observations (April 1997) Medical Device Manufacture [VIP ID: 136380] “Surface bio-burden should be used to determine the effectiveness of cleaning and sanitization procedures in maintaining controlled environment conditions. their adequacy should be evaluated using a routine environmental monitoring program. in-process materials.Doc. On 8/28/98 microbial contamination was identified on five critical sites in fill room 3. The adequacy of disinfection procedures should be evaluated using a routine environmental monitoring programme. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .g. [redacted] CFU on the alcohol container. [redacted] CFU on the filling needle area. Applicants should provide information concerning this program. and data summaries should be included. drug product containers.” © Validation in Partnership Ltd 2007 . Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 174 of 185 : 14 May 2007 Selected FDA 483 Observations (April 1999) Sterile Product Manufacture [VIP ID: 7129] “Microbial contaminant limits for surface counts should be based on historical trending of environmental monitoring data. Therefore..” FDA Warning Letter [NO REFERENCE] (January 1999) FDA Warning Letter [NO REFERENCE] USA 14/01/1999 [VIP ID: 159200] “1) Quality Control/Assurance has not consistently discharged their responsibilities for overseeing procedures impacting on quality and purity as follows: a) They failed to recognize and investigate significant environmental trends and out-of-specification microbial results in sterile areas. and drug products conform to appropriate quality standards. Process water includes autoclave cooling water.. the establishment of scientifically sound and appropriate specifications. including [redacted] CFU on one employee’s gloves. : SGD-110-ENV Rev. Ref. a microbiological monitoring program for production areas along with a bioburden monitoring program for product components and process water should be established. environmental monitoring data identifies [redacted] instances of microbial contamination of critical equipment surfaces during the prior 9 months. in part. Disinfection Efficacy (para 3) [VIP ID: 111550] “Disinfection procedures should be described in sufficient detail (e. microorganisms associated with adverse trends can be investigated as to their sensitivity to the disinfectants employed in the cleanroom in which the organisms were isolated. Frequency.

PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. 08 Author : Validation in Partnership Ltd. Microbiological monitoring The microbiological monitoring data obtained during the media fill runs should be provided (see section IV. D. which should include the various interventions that are known to occur during normal production runs. should be provided.3 [VIP ID: 188980] “The process simulation test provides an ideal opportunity to confirm that worst case locations have been identified by the use of additional monitoring during the test. ENVIRONMENTAL AND PERSONNEL MONITORING 7. microbial sampling by monitoring personnel and sampling device. of this guidance).4. ENVIRONMENTAL AND PERSONNEL MONITORING 7.5 [VIP ID: 188984] “Additional monitoring around the affected area prior to disinfection may provide useful information as to the cause.Doc. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 175 of 185 : 14 May 2007 23. ENVIRONMENTAL AND PERSONNEL MONITORING 7. will provide an ideal opportunity to confirm that worst case locations have been identified. See F below for further details. Microbiological monitoring data obtained during the media fill run.g. Additional monitoring around the affected area prior to disinfection may provide useful information as to the cause.SUPERSEDED! (January 1993) II. The following details should be included with the data summary for each media fill run described: … 11.3 Microbial Monitoring 7. [VIP ID: 3033] “Provide procedures and specifications used for media fills. by the use of additional monitoring during the test. These data should be obtained using the same filling line(s) that are to be used for the product in question. repair or replacement of needles/tubes.1 [VIP ID: 188986] “It is essential to include in a simulation test the various interventions that are known to occur during normal production runs.” STERILIZATION PROCESS VALIDATION . The process simulation test. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing.3. Ref.” GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. D.3. Procedures and Specifications for Media Fills 11.F. Briefly describe the routine media fill program for existing filling lines including acceptance specifications. replacement of on-line filters. filling and handling of stoppers etc. duration of stops on the line. [VIP ID: 17430] “11. : SGD-110-ENV Rev. …” © Validation in Partnership Ltd 2007 . and summaries of results for validations using the same container/closure system and filling process that is to be used for the product in question.” 24.3 Microbial Monitoring 7. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. Provide details of the microbiological testing method(s) used.” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. e. A summary of recent media fill results.4 Intervention Monitoring 7. Any procedural differences between the media fill and the production process should be indicated. including failures.

CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. However. TRAINING 7.” HEALTH CANADA . such as dedicated shoes and garments providing a higher level of protection.007 & C. Personnel Training. as well as protective garments. Personnel (para 5) [VIP ID: 110640] “There should be an established program to regularly assess or audit conformance of personnel to relevant aseptic manufacturing requirements. Monitoring should be accomplished by obtaining surface samples of each operator's gloves on a daily basis. Supervisors should ensure that all personnel are initially qualified in gowning procedures. that out-of-specification results are trended and that personnel undergo periodic recertification. periodic requalification will provide for the monitoring of various gowning locations over a suitable period to ensure consistent acceptability of aseptic gowning techniques. : SGD-110-ENV Rev. or in association with each lot.2 [VIP ID: 190242] “Supervisors should ensure that all personnel are monitored and follow Standard Operating Procedures (SOPs).e. Personnel Training. Qualification and Monitoring A. Personnel should undergo periodic re-certification.02.Doc. chest). A vigilant and responsive personnel monitoring program should be established. mustache and beard covering. that alert and action limits are established for personnel monitoring. a firm may decide to apply more stringent requirements for operators. For any aseptic processing operation.” © Validation in Partnership Ltd 2007 . Sampling sites should be justified. We recommend that this assessment include microbiological surface sampling of several locations on a gown (e. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . Qualification and Monitoring C. facemask. Following an initial assessment of gowning.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . forearm.008 2. The quality control unit should establish a more comprehensive monitoring program for operators involved in operations which are especially labor intensive (i. 08 Author : Validation in Partnership Ltd. such as hair.C. There are basic clothing requirements for any person entering the manufacturing areas.g.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 7.e. 5). those requiring repeated or complex aseptic manipulations).GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2. Ref.4 SANITATION .0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.. An aseptic gowning qualification program should assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures.. if adverse conditions occur. glove fingers. ONE LEVEL FOR OPERATORS WITH FULL GOWNING AND COVERALLS AND ANOTHER LEVEL FOR QA AUDITORS AND VISITORS? WHAT ENVIRONMENTAL MONITORING DATA IS REQUIRED? Yes.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. additional or more frequent requalification could be indicated. that they are monitored to verify they follow Standard Operating Procedures (SOPs). Monitoring Program (para 1) [VIP ID: 110670] “Personnel can significantly affect the quality of the environment in which the sterile product is processed.7 [VIP ID: 65750] “CLOTHING: IS IT ACCEPTABLE TO HAVE TWO LEVELS OF CLOTHING IN THE NON-STERILE MANUFACTURING AREAS. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 176 of 185 : 14 May 2007 25.4. There are no specific environmental monitoring requirements for clothing worn in the non-sterile manufacturing areas. This sampling should be accompanied by an appropriate sampling frequency for other strategically selected locations of the gown (Ref. particularly when problems are detected during the course of routine environmental and negative control monitoring. or when operators perform the test infrequently. palm (left and right) and fingertips (left and right) of personnel returning from lunch breaks.” Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72330] “Gowning Monitoring Programs for Parenteral Aseptic Areas should consider sampling the chest.02. i. Annual requalification is normally sufficient for those automated operations where personnel involvement is minimized and monitoring data indicate environmental control.

Both employees continued to work in the sterile core before retraining occurred. one employee failed gown testing on 7/22/98 and was not retrained until 10/9/98.. This employee also exceeded action limits for gloves during actual product filling on [redacted] other occasions in the 9 months before the date of retraining. One of these employees repeatedly exceeded microbial action limits but was permitted to routinely operate in the sterile core without consideration of the potential impact on finished product. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 177 of 185 : 14 May 2007 Selected FDA 483 Observations (July 2000) Sterile Product Manufacture [VIP ID: 15800] “Environmental monitoring of personnel should trend out-of-specification results between employee gloves and gowns.” Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 7158] “Gloves used for aseptic addition of sterile powder should be tested prior to changing. including a microbial count of [redacted] on 9/14/98. This is the same employee mentioned in 1(a) above who had [redacted] CFU on gloves on 8/28. …” Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 137560] “Finger dab samples should be collected from personnel performing aseptic connections on filling equipment immediately after the connections are made.” Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136540] “Environmental monitoring procedures should include periodic monitoring of personnel after performing aseptic connections. Ref. . another employee failed gown testing on 7/23/98 and was not retrained until 10/5/98. For example.” Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 14250] “Routine personnel viable monitoring programs within environmentally controlled areas for aseptically processed and terminally sterilized products should include the routine sampling of: (1) operators gowns and masks.” Selected FDA 483 Observations (October 1999) Sterile Product Manufacture [VIP ID: 7750] “Personnel monitoring SOPs should require an action condition for a single excessively high glove count or any adverse trend. : SGD-110-ENV Rev..” © Validation in Partnership Ltd 2007 .Doc.” FDA Warning Letter [NO REFERENCE] (January 1999) FDA Warning Letter [NO REFERENCE] USA 14/01/1999 [VIP ID: 159200] “1) Quality Control/Assurance has not consistently discharged their responsibilities for overseeing procedures impacting on quality and purity as follows: … b) They failed to assure that SOPs are followed which prohibit employees who fail gown testing during media fills from working in the sterile core until they are retrained. … The failure to recognize serious environmental trends and make informed judgments is very clearly demonstrated when employees were permitted to work in the sterile core despite known problems with maintaining sterile technique.” Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136530] “Environmental monitoring procedures should include periodic monitoring of the back and wrist areas of gloved hands. 08 Author : Validation in Partnership Ltd.

records of operators. 08 Author : Validation in Partnership Ltd. [VIP ID: 2206] “What are the firm's alert and action limits for personnel monitoring?” GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 3) [VIP ID: 2755] “Because of the active involvement of people in filling and aseptic manipulations. regulatory situations have resulted. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 178 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 .002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 54. gloves. For example © Validation in Partnership Ltd 2007 . or monitoring has shown unacceptable levels of contamination. to include personnel who enter the aseptic processing areas but do not directly perform work in the filling area (examples included engineering and equipment preparation personnel).” Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 50990] “Systems should be in place to assure that all personnel are monitored at exit from the aseptic zone and where self monitoring is performed proper procedures are followed for monitoring of gloves and gowns. It states under the heading of "Interpretation of Quality Control Tests" that review consideration should be paid to environmental control data. where self monitoring is performed. [VIP ID: 2205] “How often is monitoring performed on filling room personnel?” CPGM-DB CHAPTER 56 .. Manufacturers are actively sampling the surfaces of personnel working in aseptic processing areas. : SGD-110-ENV Rev. proper procedures are followed for monitoring of gloves and gowns.DRUG QUALITY ASSURANCE 7356. Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 125010] “Microbial environmental monitoring samples should be routinely taken from production personnel working in filling operations. Failure to avert contamination in separate or defined areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211.” FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 3 [VIP ID: 49890] “3. microbial monitoring.” Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70270] “All personnel entering aseptic processing areas should be monitored at least once each day. gowns. A reference which provides for this type of monitoring is the USP XXII discussion of the Interpretation of Sterility Test Results. an environmental program should also include an evaluation of microbiological levels on people working in aseptic processing areas. In those situations in which manufacturers have failed to perform some type of personnel monitoring.” 26. Systems should be in place to assure that all personnel are monitored at exit from an aseptic zone and.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 53. One method of evaluation of the training of operators working in aseptic processing facilities includes the surface monitoring of gloves and / or gowns on a daily basis.DRUG QUALITY ASSURANCE 7356. Ref.42(c)(5)].Doc.. and garbing practices. including .

'white area' wear shoe covers. 08 Author : Validation in Partnership Ltd. as required by 21 CFR 820. if justified from the results of microbiological monitoring and validation studies.” 30.2 [VIP ID: 190266] “Protective garments should be changed for each work session or at least once a day if justified from the results of microbiological monitoring and validation studies. components. Protective garments should be changed for each work session or at least once a day. …” 27. monitoring surfaces and personnel during the second and third shifts should be routine. Our Investigator observed employees who did not wear shoe covers and wore the same shoes as they wore outside the facility into the 'white area. Environmental monitoring media residues should be removed from operator gowns prior to them returning to a production area. such as tools necessary for equipment repairs / adjustments into the **** filling areas is not being performed.2.70(c). Your firm stated that [redacted] evaluated the effects of shoe covers on the environment in the clean room and on product bioburden and determined that eliminating the practice of wearing shoe covers appeared to have reduced the product's bioburden and recommended that this employee gowning practice be eliminated.” © Validation in Partnership Ltd 2007 .” 28.2 AIRLOCK AND ASEPTIC GOWNING 8. Selected FDA 483 Observations (April 1999) Sterile Product Manufacture [VIP ID: 7117] “Environmental monitoring media residues should be removed from operator gowns prior to them returning to a production area. Selected FDA 483 Observations (June 2001) Sterile Product Manufacture [VIP ID: 27780] “Environmental monitoring gowning failures should be evaluated against product sterility issues.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. If processing of a sterile bulk drug substance occurs around the clock. Failure to establish and maintain procedures to adequately control environmental conditions. ENVIRONMENTAL MONITORING (para 5) [VIP ID: 2039] “Since processing of the sterile bulk drug substance usually occurs around the clock. : SGD-110-ENV Rev. STERILITY TEST FACILITIES 8. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. Environmental monitoring gowning failures should be evaluated against product sterility issues. For example: b.2. FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 134960] “1.' [redacted] does not require that employees working in the.Doc. microbiological monitoring of surfaces and personnel during the second and third shifts should be routine. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 179 of 185 : 14 May 2007 .The controlling and monitoring of the movement and ingress of personnel.2 Aseptic gowning 8. Ref. including maintenance personnel.” 29. and ancillary materials.2.

and manufacturing environments to determine the extent of bacterial contamination in your devices and where and why the contamination occurred in your device manufacturing process or the compounding pharmacy's drug manufacturing process. …” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . dated January 31. reassignment of the individual to operations outside of the aseptic manufacturing area. For the sampling of critical surfaces. 2005.” © Validation in Partnership Ltd 2007 .Doc. FDA and CDC notified your firm of a report of patient infections associated with your devices contaminated with fluorescens.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Monitoring Program (para 2) [VIP ID: 110680] “Asepsis is fundamental to an aseptic processing operation. all device components and raw materials. and February 8. At the conclusion of our inspection. This information was communicated to your firm by our office and during the inspection and was communicated to the public in three FDA press releases. Microbiological trending systems. Ref. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. An ongoing goal for manufacturing personnel in the aseptic processing room is to maintain contamination-free gloves and gowns throughout operations. Extracted from FDA Warning Letter 2005-DAL-WL-22 (August 2005) Extracted from FDA warning letter 2005-DAL-WL-22 USA 04/08/2005 [VIP ID: 170620] “3. ENVIRONMENTAL MONITORING (para 3) [VIP ID: 2037] “There are some manufacturers that set alert/action levels on averages of plates. and evaluating complaints by a formally designated unit and to ensure that all the requirements of 21 CFR 820. Sanitizing gloves just prior to sampling is inappropriate because it can prevent recovery of microorganisms that were present during an aseptic manipulation. the averaging of results on plates is unacceptable. Qualification and Monitoring C. When operators exceed established levels or show an adverse trend. an investigation should be conducted promptly. including recalled devices. Personnel Training.” 33. reviewing.198(a) through (e) are met [FDA-483 Items 4 and 5]. when repeated alert and action limits are reported for them over time. Since the initial FDA and CDC notifications to your firm. such as operators' gloves.” 32. Environmental monitoring procedures should address the actions to be taken when operators exceed specified levels of contamination. Laboratory Controls. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 180 of 185 : 14 May 2007 31. Failure to establish and maintain adequate complaint handling procedures for receiving. For the sampling of critical surfaces. the average of results on plates is unacceptable. : SGD-110-ENV Rev. increased observation. Clean room personnel should not sanitise their hands immediately prior to touching finger touch plates used for personnel monitoring. February 4. additional cases of patient infections were reported. and in certain instances. Follow-up actions can include increased sampling. prior to our current inspection. and the disqualification and subsequent requalification of aseptic operators. The primary concern is any incidence of objectionable levels of contamination that may result in a non-sterile product. your firm had not … (b) conducted microbiological testing of the quarantined devices. retraining. For example. such as operators' gloves.” Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15640] “Environmental monitoring procedures should address the disqualification and subsequent requalification of aseptic operators when repeated alert and action limits are reported for them over time. are discussed in more detail under Section X. 08 Author : Validation in Partnership Ltd. and assessment of the impact of atypical trends. Selected FDA 483 Observations (October 2007) Sterile Product Manufacture [VIP ID: 193922] “Clean room personnel should not sanitise their hands immediately prior to touching finger touch plates used for personnel monitoring. gowning requalification.

: SGD-110-ENV Rev. a) Investigations of two positive sterility tests did not determine conclusive or probable root causes for the contamination. … [1]. such trends can appear to be more indicative of laboratory error as a possible source of a sterility test failure.1 [VIP ID: 190378] “A test may be repeated only when it can be demonstrated that the test was invalid for causes unrelated to the product being examined. The European Pharmacopoeia[1] restricts criteria to one or more of the following conditions only: (a) the data of the microbiological monitoring of the sterility testing facility show a fault. The investigation of this sterility failure fails to mention this correlation and does not discuss the impact of a new adverse trend with regard to the detection of this problematic organism. The organism was detected nine times in 2006. …” © Validation in Partnership Ltd 2007 . However. Ref. Sterility Testing C. whether or not the batch has been distributed. and the failure to extend the investigation to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy as required by 21 CFR 211. …” 35. but not be limited to. and notably. Although root causes were not determined. and corrected. Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 2) a.192. to properly extend failure investigations to all associated batches or product are discussed below. 2006. Examples of your failure to conduct adequate investigations. which is one of the primary microbiological contaminants identified in the multiple media fill failures investigated under [redacted]. were not detected by those reviewing and approving the final report. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 181 of 185 : 14 May 2007 34. Record of Laboratory Tests and Deviations … Microbial monitoring of the aseptic area of the laboratory and personnel can also reveal trends that are informative. including a viable air sample in the aseptic core of an adjacent filling line the day after the manufacture of this batch. The contaminating organism was identified as Bacillus pumilus.Doc. Third Edition.” 36. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 13. including the data of the microbiological monitoring of the sterility testing facility showing a fault. Investigation of Sterility Positives (para 3) 2. Lot [redacted]. which also have a bearing on the scope of lots potentially implicated by the sterility failure. [VIP ID: 111790] “2. and seven of the nine samples were in the same month of manufactures as the failed lot. European Pharmacopoeia. The European Pharmacopoeia only permits a repeat sterility test if certain criteria are satisfied. significant errors that impact directly on the determination of the potential scope of the sterility assurance problem were noted with each investigation as follows. and corrected. Supplement 1998. ii) [VIP ID: 194572] “Failure to thoroughly investigate or maintain a written record of the investigation of any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications. These deficiencies in the investigation. Sterility Test Failure investigations should include. 08 Author : Validation in Partnership Ltd. Upward trends in the microbial load in the aseptic area of the laboratory should be promptly investigated as to cause. Strasbourg. INTERPRETATION AND REPEAT TESTS 13. … ii) Progesterone Injection. both investigations conclude that "the impact of the sterility test positive was isolated to the affected batch" and all other batches placed on hold when the test failures were found were released for distribution.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XI. USP. In some instances. Council of Europe. Microbiological monitoring should also include the aseptic area of the laboratory and personnel and any upward trends in its microbial load should be promptly investigated as to cause. The lot was aseptically filled on Line 4 on April 26. a review of environmental monitoring results at the time of failure. The investigation also also incorrectly associates this sample result with the detection sample. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING .

results showing little or no recovery of microorganisms can be misleading. Item 11.and long-term environmental trend analyses.194(a)(8) … f. analytical method used 211.” Selected FDA 483 Observations (October 1999) Sterile Product Manufacture [VIP ID: 7980] “Sterility Test Failure investigations should include: (1) review of environmental monitoring results for the failing day (2) corrective actions (3) indication of probable causes and corrective action where no identifiable cause is determined” 37. Procedure (CM 1) for the quality control of media was not always followed in that expired media was used. Investigation of Sterility Positives (para 3) 3. 08 Author : Validation in Partnership Ltd.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XI. [VIP ID: 111800] “3. (3) address corrective actions relating to personnel” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . especially when preceded or followed by a finding of an adverse trend or atypically high microbial counts.Doc. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 182 of 185 : 14 May 2007 Extracted from FDA Warning Letter 320-05-03 (July 2005) Extracted from FDA warning letter 320-05-03 Italy 21/07/2005 [VIP ID: 169250] “7. different test organisms than specified were used as positive controls. Monitoring of Production Area Environment Trend analysis of microorganisms in the critical and immediately adjacent areas is especially helpful in determining the source of contamination in a sterility failure investigation. For example. Sterility complaint investigation reports failed to identify and discuss any possible correlation of the sterility test isolate with microorganisms found in your firm's environmental and personal monitoring.194(a)(7) 2. Consideration of environmental microbial data should not be limited to results of monitoring the production environment for the lot. person performing the analysis 211. 211. FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28430] “4. 21 CFR 211. Quality control procedures for the control of media to be used in microbiological monitoring should be strictly followed. Sterility Testing C.198” Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 128310] “lnvestigations into initial sterility test failures should: (1) include an evaluation of environmental monitoring conducted at the time of the filling operation (2) include an attempt to associate the organisms isolated from the sterility failures to organisms isolated previously from the environment. or shift associated with the suspect lot. It is therefore important to look at both short. day. media and inhibitory agents used including lot numbers and dates made 211. Analysts notebooks failed to always document the following pertinent information: 1.194(a)(3) © Validation in Partnership Ltd 2007 .194(a)(2) 3. 211. Ref. sample amount used for analysis 211. Item 16.194(c) 4. and negative and positive control testing was not performed. : SGD-110-ENV Rev. Examples from the FDA-483 are: … d.194 Laboratory Controls-Laboratory Records The laboratory records fail to consistently and accurately include complete data derived from all tests necessary to assure compliance with specifications and standards.

strength. It is important to note that failure to conduct growth promotion testing is another example where you are missing a large body of data that is important for microbiological investigations where environmental results exceeded your firm's action level. Item 17.194(4)&(5) … [FDA Investigators: Renee L. yeasts and molds) as well as bacteria and incubated at appropriate conditions of time and temperature..194(d) 6. Rice and Miah I. Tests should be performed on media to assure that it is capable of supporting microbial growth and details of media handling and incubation methods should be available.e. 21 CFR 211.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls B.” © Validation in Partnership Ltd 2007 . Data should be established to demonstrate the suitability of methods of transportation and incubation of environmental monitoring agar plates for surface and air monitoring. quality. Selected FDA 483 Observations (June 2005) Sterile Product Manufacture [VIP ID: 140110] “Data should be established to demonstrate the suitability of using film wax sheets in the transportation / incubation of environmental monitoring agar plates for surface and air monitoring. should be based on data supporting the upper time limit specified.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . and purity.” Selected FDA 483 Observations (March 2005) Sterile Product Manufacture [VIP ID: 137990] “Procedures specifying the submission of environmental samples to the laboratory for incubation within a set time period of collection. and the [redacted] analytical method used on eye drops and nasal spray was not fully validated. We acknowledge you have now committed to conducting growth promotion testing. As mentioned above. microorganisms found during environmental testing were not identified. Ref. Analysts notebooks fail to document individual plate results when an average of the two was reported as the test result. The microbiological culture media used in environmental monitoring should be validated as capable of detecting fungi (i. 08 Author : Validation in Partnership Ltd. Your proposed corrections appear acceptable pending our receipt and review of supporting documentation. incubator used and its temperature 211. C for 48 to 72 hours.194(d) g. Consistent methods will yield a database that allows for sound data comparisons and interpretations. Laboratory controls did not include scientifically sound and appropriate test procedures designed to assure that components.160 Growth promotion testing was not performed on microbiological testing media. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 183 of 185 : 14 May 2007 5. : SGD-110-ENV Rev. Microbiological Media and Identification (para 3) [VIP ID: 111610] “The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control.Doc. but we would like to emphasize that this is an important body of information that is missing for all investigations in the past. the incubation start and end date 211. Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171160] “7. we encourage you to maintain the necessary documents and data to determine the root causes of failures. 211. or other wrap techniques (that completely seals the Petri dishes so to minimize the availability of oxygen to the growing microorganisms on the agar surface). Schneider]” 38. and drug products conform to appropriate standards of identity. in-process materials. Total aerobic bacterial count can be obtained by incubating at 30 to 35 deg. Total combined yeast and mold count can generally be obtained by incubating at 20 to 25 deg C for 5 to 7 days.” 39. there was no assurance that yeast and mold will grow at the [redacted] incubation temperature used to detect bacteria growth.

.DRUG QUALITY ASSURANCE 7356.” Selected FDA 483 Observations (June 1999) Sterile Product Manufacture [VIP ID: 7176] “Strains of factory isolates from firms controlled environments should be used in the performance of growth promotion testing of media used for media fills and environmental monitoring. Ref. Where appropriate..002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 44.g. Growth promotion testing should be performed on all lots of prepared media..” Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14820] “Growth promotion tests should be performed on sterility media to assure the media is capable of supporting microbial growth. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 184 of 185 : 14 May 2007 GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING . .” Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14800] “Validation studies should be completed to assure that the microbial settle plates are capable of supporting microbial growth after the exposure time in class 100 rooms. antibiotics).” CPGM-DB CHAPTER 56 .” Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 16480] “TSA media used in environmental monitoring should be qualified to show it can support growth at the specified action levels.Doc. [VIP ID: 2196] “Are the culture media used in the viable monitoring program shown to be capable of detecting molds and yeasts as well as bacteria by means of growth promotion tests? Is anaerobic monitoring performed?” © Validation in Partnership Ltd 2007 . 08 Author : Validation in Partnership Ltd. growth promotion testing of the media used for sampling. Microbiological Media and Identification (para 4) [VIP ID: 111620] “Incoming lots of environmental monitoring media should be tested for their ability to reliably recover microorganisms.CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls B.” Selected FDA 483 Observations (December 2003) Sterile Product Manufacture [VIP ID: 70570] “Environmental monitoring programs should include the use of microbial growth media that is optimum for the propagation of yeast or mold contaminates.” Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122650] “Environmental monitoring of aseptic processing areas should include: a. inactivating agents should be used to prevent inhibition of growth by cleanroom disinfectants or product residuals (e. : SGD-110-ENV Rev.

Biological and Biotechnological Products 1. mycoplasm. Environmental monitoring should include periodic challenging of sanitisers with new resistant isolates. Validation in Partnership Limited 34 Chester Road Maccesfield Cheshire SK11 8DG. VIP CONTACT DETAILS Bound copies of this guidance document can be purchased directly from Validation in Partnership Limited.g. or to find out more about us and the services we offer please visit the ViP Web Site: www.” 9.ViPltd. if required.co. : SGD-110-ENV Rev.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 47.uk www. bacterial. viral.APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI.co. For details of price and delivery.Sides@ViPltd.uk or contact us directly at the address below.DRUG QUALITY ASSURANCE 7356. Guidance Document HVAC Systems & Environment Control/Monitoring Page Date: : 185 of 185 : 14 May 2007 CPGM-DB CHAPTER 56 . such as Bacillus lichenformis and Bacillus thurigenesis. bacterial. Of particular importance in evaluating the environment to be used for production of biological and biotechnological products is the susceptibility of biotechnology and biological products to contamination with biological substances including microbial adventitious agents. Ref.Doc. [VIP ID: 2199] “What incubation periods are used and at what temperature?” 40. UK Telephone : Facsimile : Email : Web Page : +44 (0)1625 660880 +44 (0)1625 660881 Kieran. mycoplasm) that may remain from previous research or production activities.g. General Considerations para 4 [VIP ID: 183908] “Of particular importance in evaluating the environment to be used for production (see section V) is the susceptibility of biotechnology and biological products to contamination with biological substances including microbial adventitious agents (e. e. Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15660] “Environmental monitoring should include: … (2) periodic challenging of sanitizers with new resistant isolates such as Bacillus lichenformis and Bacillus thurigenesis” 41.uk © Validation in Partnership Ltd 2007 . GUIDANCE FOR INDUSTRY INDS . SPECIAL PRODUCTION SITUATIONS C..co. viral. 08 Author : Validation in Partnership Ltd.ViPltd.