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BY: Wayne Kenny Date: 16/03/10
.................................................... .................................................................... 3........................................................................................... 15 Quality System ................ 16 References 17 1 .....................9..............................................................................8......... 5 A Brief History of Clean Rooms........................... 5 Environmental Control.. 2..........................................................................................14 Cleaning.................12 FDA Warning Letters ................................... 13...........................................7............ 11.............................................4 Introduction......................................TABLE OF CONTENTS Executive Summary:....................................... santization and sterilization ................................................ 16 Conclusion .......... 1............... 6.......................................................................................... 15 Maintenance ...........................10 Monitoring .........................................................
This is in effect a quality objective.42(c) states. However. To achieve this one must have a correctly implemented system of Quality Assurance incorporating CGMP(FDA 2l CFR parts 210 and 211) and thus Quality Control. It is a room in which the concentration of airborne particles is controlled to specified limits.for the most part. describe what needs to be accomplished rather than how to accomplish the requirement. poor maintenance and poor personal practices in clean room manufacturing can be high in both financial and regulatory terms. The main drive for this is not that the regulators are making new rules but rather technology has improved industries ability to address key issues in the regulatory world. On how to accomplish them we must first understand what a clean room is. process. a cleanroom is a controlled environment where products are manufactured. a means of conducting clean work in a small space. comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety. let air be the janitor ² a³janitor´ sweeping the premises every six seconds. Thus. in part. These contaminants are generated by people. All manufactures of medicinal products have to ensure that they products are fit for their intended use. Poor CGMP conditions at a manufacturing facility can ultimately pose a life-threatening health risk to a patient. quality or efficacy. To employ good operations one has to build quality into the premises and control the environment. There shall be separate or defined areas or such other 1 .. that "Operations shall be performed within specifically defined areas of adequate size. to prevent dust from falling on their sensitive timepieces when they were not being worked on. The costs for poor operations. In the late 1960¶s and early 1970¶s regulatory authorities had become more stringent. covered them with a small bell jar. These regulations. In the 1960 Willis Whitfield pioneered the clean bench. To keep a room very clean. its roots go back hundreds of years to Swiss watchmakers who.Executive Summary: The history of clean rooms dates back to Atomic Age and greatly enhanced in the Space Age. they change the nature of industry practice and thus change what is current from a regulatory view. This new technology was embraced by the sterile manufacturing industry as a means of compliance of GMP. facilities and equipment. FDA 21 CFR 211. the concept of the term ³current´ in current Good Manufacturing Practices is a reality which can be demonstrated when new technologies come into play. They must be continually removed from the air.
drug product containers."  21 CFR 211. product exposure. and drug products through the building or buildings shall be designed to prevent contamination. training. or any combination thereof. The more restriction of air flow the more turbulence. This air flow is called laminar flow. Any intervention or stoppage during an aseptic process can increase the risk of contamination. that "The flow of components. dust. These filters are essential for providing effective contamination control.42(b) states. Particles are significant because they can enter a product and contaminate it physically or by acting as a medium for microorganisms. microorganisms. In addition to the HEPA filters commonly used in cleanrooms. The control of this is achieved by HVAC systems Cleanrooms are designed to achieve and maintain a airflow in which essentially the entire body of air within a confined area moves with uniform velocity along parallel flow lines. as well as the operation in the area.3 microns with a 99. Turbulence can cause particle movement. or the surrounding environment. in-process materials. and experience. (iv) A system for monitoring environmental conditions. or holding of a drug product shall have the education. closures.46(b) states that "Equipment for adequate control over air pressure. Filtration is used such as HEPA(High Efficiency Particulate Air Filter). in part." Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product.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. (vi) A system for maintaining any equipment used to control the aseptic conditions. 21 CFR 211. the air quality. processing.97% minimum abilty to collect particles. and temperature shall be provided when appropriate for the manufacture.These filters are extremely important for maintaining contamination control. to perform assigned functions in such a manner as to 2 . depending on what is being done. 21 CFR 211. processing.25(b) states that "Each person responsible for supervising the manufacture. packing. containerclosures. in part. or holding of a drug product." The areas of manufacture must have a separate unit of operation that control to different degrees. including prefilters and particulate matter air filters. They filter particles as small as 0. humidity. Thus the use of automation and good engineering that increase process flow and reduce product handling should be incorporated. that "Air filtration systems. shall be used when appropriate on air supplies to production areas. The design of an area should be based on satisfying microbiological and particle standards defined by the equipment. there are a number of other filtration mechanisms used to remove particles from gases and liquids such as membrane filters which allow the filtering of compressed gases to meet an appropriate high-quality standard. which includes as appropriate: (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure. labeling. packing.46(c) states.
during or at the conclusion of operations). Such procedures shall include all requirements in this subpart. container. This is further reinforced by the FDA taking a ³risk assessment´ approach to enforcement of the regulations. walls. quality. WFI.22(c) states that "The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity.. operators involved in aseptic manipulations should adhere to the basic principles of aseptic technique at all times. As operator activities increase in an aseptic processing operation.g." All in-process data must be included with the batch record documentation. (4) sample size (e. The implemtation of a live and active quality system incorpating CGMP will ensure compliance. including the critical surfaces that come in contact with the product. quality. equipment.56(b) states that "There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules. strength. (6) alert and action levels.100(a) states that "There shall be written procedures for production and process control designed to assure that the drug products have the identity.e. These written procedures.. Personnel can significantly affect the quality of the environment in which the sterile product is processed. SOPs should be established in such areas ash as (1) frequency of sampling. as well as other data relating to acceptability of output from support systems (e. integrity of various filters). and closures. such written procedures shall be followed. and equipment surfaces. quality. and materials to be used in cleaning the buildings and facilities. and purity they purport or are represented to possess. surface area. including any changes.g. the risk to finished product sterility also increases. The monitoring program should cover all production shifts and include air. HEPA / HVAC. (3) duration of sampling. floors.g. reviewed. (5) specific sampling equipment and techniques. and purity that it purports or is represented to possess. and approved by the appropriate organizational units and reviewed and approved by the quality control unit. steam generator) and proper functioning of equipment (e. This means that the agency will target those products that 3 . methods. identity." 21 CFR 211. 21 CFR 211.provide assurance that the drug product has the safety. Review of environmental and personnel monitoring data. 21 CFR 211.. shall be drafted.. and (7) appropriate response to deviations from alert or action levels. and purity of the drug product. (2) when the samples are taken (i. batch alarms report." A well-designed aseptic process minimizes personnel intervention. air volume). Due to this personal micro monitoring should be carried out. To ensure maintenance of product sterility." Evaluating the quality of air and surfaces in the cleanroom environment should start with a welldefined written program and scientifically sound methods. strength. should be viewed as essential elements of the batch release decision.. strength.
reflect the greatest threat to the safety of public health. 4 . Sterile dosage forms will be high on the list.
i. loss of the business. It is a legal requirement to implement CGMP of the marketing authority. These documents stated principles which are still relevant today.II to assemble contamination-sensitive parts such as gyroscopes.Introduction This article will show that employing good operations. to prevent dust from falling on their sensitive timepieces when they were not being worked on. NASA SP-5045. covered them with a small bell jar. good maintenance and personal practices are essential in clean room manufacturing. 5 . "Clean Room Technology". Finally. The consequences of non compliance of CGMP has the possibility of being financially large. These rooms used filtered air but not as highly filtered as HEPA air. Willis Whitfield pioneered the clean bench. surgeons recognized the need for steps to prevent post traumatic infection. Lister and others developed methods to achieve this end and sterility became a watchword in operating suites. its roots go back hundreds of years to Swiss watchmakers who.e. Due to this compliance is of utmost importance.The final step. and AF-TO-0025-203. It can be achieved based on a correctly implemented system of Quality Assurance incorporating CGMP(FDA 2l CFR parts 210 and 211 or other marketing authority CGMP) and thus Quality Control. However. "Contamination Control Handbook". loss of market share. the development of the High Efficiency Particulate Air (HEPA) filter was developed at Sandia Labs for the Atomic Energy Commission after World War II.W. "Contamination Control Principles". US Air Force" were written. NASA SP-4074. White rooms had been used during W. Warning letters from FDA and some antidotal evidence. Quality Assurance. "Contamination Control of Aerospace Facilities. It is more importantly a morale issue that could pose a treet to human life. loss of public confidence. NASA SP-5076.In 1945 the need to test gas mask filters against particulate and biological materials led to the development of the aerosol particle counter. A Brief History of Clean rooms The field of contamination control is a recent technology coming to age as part of the Atomic Age and greatly enhanced in the Space Age. Through the 60's documents such as FED STD 209a. Due to the immense loss of life from bullet wounds.The American Civil War) gave impetus to the next phase in cleanliness. the Space Age with its requirements for both particulate and film cleanliness promoted contamination control technology. Nuclear particles which would have been deadly to personnel were isolated in process areas with HEPA filters while allowing air to circulate in them. The article will follow FDA regulations followed by the means and the µknow how¶ on achieving compliance. a means of conducting clean work in a small space. It will draw on the Regulations.
in part. zoning. Equipment placement and ergonomics are important in maintaining product/process integrity and operator safety. The microbiological impact have to be incorporated into the design of the space. that "Air filtration systems.The pharmaceutical industry embraced this new technology as a means of compliance of regulatory authorities drive of CGMP in the same period. (iv) A system for monitoring environmental conditions. in part. HVAC. or holding of a drug product. processing. 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. that "Operations shall be performed within specifically defined areas of adequate size. including prefilters and particulate matter air filters.46(b) states that "Equipment for adequate control over air pressure. minimal/no crevices. controls. and temperature shall be provided when appropriate for the manufacture. and pressurization are in place to protect product. Material and personal flow are unidirectional in critical area¶s. control contamination." 21 CFR 211. packing. Environmental Control FDA 21 CFR 211.and keep people comfortable. shall be used when appropriate on air supplies to production areas Clean rooms have to be separate to other operational procedures. which includes as appropriate: (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure ***."  21 CFR 211.46(c) states. *** (vi) A system for maintaining any equipment used to control the aseptic conditions. The air is classified by the following tables: 6 . Air Flow: unidirectional in critical operations to protect product exposed to the room environment. dust. Room finishes are hard and easily cleanable. humidity.42(c) states. microorganisms.
The diagram below demonstrates this in a Bio manufacturing plant 7 . where the room is designed to meet Grade D performance parameters but is not typically validated. Achieving a compliant cleanroom manufacturing operation requires the use of increasing levels of environmental cleanliness.´ The figure below a typical zoning.The people and material flow are controlled by airlocks with alarmed doors. or ³zones. it is important to achieve a proper airflow and a positive pressure differential relative to adjacent less clean areas. along with a typical air pressurization cascade from critical to noncritical zones. To maintain air quality in areas of higher cleanliness. In noncritical peripheral areas can be downgraded to a Controlled Not Classified (CNC).
 8 .
To detect integrity breaches around the sealing gaskets. Gases used such as air. the air most be filtered by HEPA filtration. Leak testing should be performed on filters as part of continuous maintenance program. maintenance or personnel practices 9 . Changes in velocity across the membrane of a filter can indicate a possibility of contamination. For example. Sterile membrane filters should be used for autoclave air lines.Pressure cascade below:  A differential of 15 Pascals between each air classifications. and carbon dioxide are often used in cleanrooms and are frequently employed in operations involving purging or overlaying. lyophilizer vacuum breaks. leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. To achieve this. even successfully qualified systems can be compromised by poor operational. or through various points on the filter media. Thereafter. Controlled by airlocks. and tanks containing sterilized materials. The number of air changes is determined by monitoring and justified for the area of classification. Smoke studies should be conducted that demonstrate unidirectional airflow and sweeping action over and away from the product. However. This is done by particle monitoring and velocity monitoring. such testing should be performed twice a year for the aseptic processing room. Holding tanks containing sterile product should be held under positive pressure to prevent micro biologicial growth  The above diagram is unidirectional flow cleanroom with HEPA and membrane filtration in the ceiling. nitrogen. through the frames. Different areas of classification require different HEPA filters and membrane filters which allow the filtering of compressed gases to meet an appropriate high-quality standard.
A zoning (criticial area) reduced with isolators above and below.  10 .The cost of A zoning is high to run and maintain. So the thinking would be to reduce the A zoning area with barrier isolators. The diagram below illustrates this.
including the critical surfaces that come in contact with the product. To maintain air quality in areas of higher cleanliness. that "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. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them. Montoring should be from contact plates used for flate surfaces such as walls.Adequately separating areas of operation is an important part of contamination prevention. and experience. Air and surface samples should be taken at the actual working site and at locations where significant activity or product exposure occurs during 11 . ceilings. Evaluating the quality of air and surfaces including personal in the cleanroom environment should start with a well-defined quality system and scientifically sound methods that are evaluated to ensure they operate as intended The monitoring program should cover all production shifts and include air. and closures. frequency.. container." Environmental monitoring programs for clean room manufacturing are composed from the analysis of personnel. It is especially important to monitor the microbiological quality of the aseptic processing clean area to determine whether or not aseptic conditions are maintained during filling and closing activities.25(a) states that "Each person engaged in the manufacture. and location should be carefully selected based upon their relationship to the operation performed. processing. floors. in part. quality. Samples should be taken throughout the aseptic processing facility (e. and purity of the drug product." 21 CFR 211. Difficult surfaces can be swabbed or rinse swabbed. training. or any combination thereof. and equipment surfaces. it is important to achieve a proper airflow and a positive pressure differential relative to adjacent less clean areas Monitoring 21 CFR 211. Sampling sizes should be sufficient to optimize detection of environmental contaminants at levels that might be expected in a given clean area. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. raw materials. which includes as appropriate: *** (iv) A system for monitoring environmental conditions***." 21 CFR 211. to enable that person to perform the assigned functions. or holding of a drug product shall have education.uniforms.22(c) states that "The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity. strength.g.Settle plates for air. processes.and finished products.42(c) states. Written procedures (SOP¶s) should include a list of locations to be sampled. aseptic corridors. walls. Sample timing. gowning rooms) using scientifically sound sampling procedures. Risk management should be incorporated to show area¶s that pose the most microbiological risk to the product and become a critical part of procedures. packing.
D C B A Hair net. The type of corrective actions that are implemented when an action level has been exceeded are typicially . A program of evaluation of training and support procedures should be implemented. neck. When identifying critical sites to be sampled. length of processing time. Critical surfaces that come in contact with the sterile product should be sterile. consideration should be given to the points of contamination risk in a process. The use of cosmetics and jewelry are not allowed. Critical surface sampling should be performed at the of the aseptic operation to avoid direct contact with sterile surfaces during processing. and testing. sampling and testing are immediately repeated if conditions indicate that the product quality has been compromised. hood with three seals. microbiological sampling of the personnel includes contact plate samples of. Alert and action limits are established after sampling. shoe covers. These investigations are usually completedwithin 1±3 months. lab coat. In general.right hand glove covers and left hand glove covers. analyzing. and pink eye must stay away from controlled environments. Routine microbiological monitoring of garments and finger impressions must be completed to determine general aseptic techniques. Once the trends are determined. Alert limits are values that when exceeded point towards a potential deviation from the system operating normally. regulatory. Sanitization of hands before and after every working day reduces the possibility of microbial contamination. Improper or late closure of an investigation is one of the major reasons for noncompliance with CGMP regulations. (optional cover of facial hair) Same as D but gloves and facial hair cover required Same as C with a coverall Same B but with facemask. left chest. boots. including factors such as difficulty of setup. and ankles Therefore training of personnel in aseptic techniques and proper gowning must be a priority. Some companies operated that if 2-3 alert limits are exceeded that this constitutes action limits. Retraining of personnel is performed if the investigation report indicates analyst error. The table below shows gowning requirements for zoning area¶s. impact of interventions. Hair and body must be cleaned daily. Basically. left sleeve. forehead . and corrective action must be completed within reasonable time. Personnel with a contagious disease such as cold. Sanitization procedures are reviewed and repeated. If an investigation is needed to investigate any deviations from the established values. Review of controlled environment certifications might indicate system breakdown during manufacturing.production. proper documentation of the investigation. If there is an indication that the product manufactured has 12 . flu. all thesystems and validation procedures are reviewed to determine the root cause ofthe action level. Action limits values when exceeded show the system is in non compliance and an investigation report and corresponding corrective actions must be performed and implemented.right sleeve. right chest. then limits are set upon historical. Personal are the highest risk in a clean room from both viable and non viable particles and hence µGowning¶. and trending the values obtained during at least 3 months of intensive microbiological testing of facilities and personnel. and industry guidelines. wrist. sampling. Gloves are either sanitized or a new pair before testing the next sample.
Which no doubt covered the procedures above. The FDA warning letter below enforces the points above.been compromised. 13 . An antidotal reference by a colleague who worked for An American company where one individual when de-gowning discovered a µcricket¶ on his shoe beneath his shoe cover. As it was put µall hell broke lose¶. the batches are placed on hold until the investigation is completed and the product is cleared for release.
are cleaned at intervals. As the equipment moves through the cleaning process. as well as other data relating to acceptability of output from support systems (e. Product contact equipment also consists of fixed and portable equipment. These written procedures. etc. pumps." While non-product contact. 21 CFR 211.Cleaning. sanitization and sterilization. Review of environmental and personnel monitoring data. and materials to be used in cleaning the buildings and facilities. racks. quality. such as tables.100(a) states that "There shall be written procedures for production and process control designed to assure that the drug products have the identity. such written procedures shall be followed. must be cleaned more frequently (typically between product batches or change-overs).. etc.. Quality System 21 CFR 211. Equipment that can not be sterilized in this manner are placed into grade A environment before process opertions." All in-process data must be included with the batch record documentation. equipment. piping. HEPA / HVAC.. and purity they purport or are represented to possess. WFI. chemical vapours. moist heat. Fixed equipment is disassembled with some components removed from the room for cleaning out of place (COP) in a purpose-built room. The sterilization of the end product if possible should be µterminal sterilizated¶ but not all products can be.56(b) states that "There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules. The non-product contact area¶s should be cleaned and disinfected. dry heat. They are either either be chemically sterilized.. the surrounding environment increases in cleanliness to correspond with the state of the equipment being cleaned. Equipment sterilized in place (SIP) is typically achieved through the introduction of pure steam in a closed system for a prescribed interval of time and temperature. carts. irradiated. with local B/A. shall be drafted. Remaining components are cleaned in place (CIP) by flushing the system with a series of solutions and rinses while the system is closed.Such methods as filtration. strength.g. or purchased as being sterilized. product contact equipment. methods. This typically means that the room(s) will be designed to meet a Grade D/C environment. and radiation should be employed. steam generator) and proper 15 . such as tanks. and approved by the appropriate organizational units and reviewed and approved by the quality control unit. Sterilization of equipment that is product contact is done but must be proven that the system effectively kills all viable micro organisms. reviewed. The cleaning process should be validated and recorded. The disinfectant should be rotated. Control of these fluids is managed by both the process equipment and a CIP system (typically a skid) control units. including any changes. Such procedures shall include all requirements in this subpart.
functioning of equipment (e. integrity of various filters). according to CGMP. Maintenance should be schduled and preventive in nature which in turn will save money in down time.e.g. batch alarms report. equipment etc. Good maintenance is at the heart of the overall system i. Technicial area¶s which allow access to maitance staff with out disruption to zoning.. It should be recorded and well documented. should be viewed as essential elements of the batch release decision. Clean rooms can have access to HVAC systems through walkable ceilings also instrumentioncan be housed there. A quality system incorporating CGMP will ensure continues compliance. Personal practices are utmost importance as they pose the largest micro biological risk in a clean room operation. Good operations encompasses the overall process. Manufacturing operations. valves etc and can be controlled unclassified. Maintenance Ease of maintenance is of importance. Personal should be trained and evaluation of the training effectiveness should be established. Maintenance chases or grey areas can be employed for piping . But the system will ultimately fail if poor maintenance is carried out and could potentially endanger life. people intervention in the process should also be kept to minimum. A sample can be seen below:  Conclusion. means that the process has a set of controls in the design and production processes to assure 16 . HVAC. The number of people who are in the rooms should be kept to minimum.
´ Part 210±211 (US Printing Office. Title 21. Code of Federal Regulations.Washington. Published by John Wiley & Sons. plant closure.Volume 142. the rest will follow. 17 .gov/history.a quality finished product. Edited by Luis Jinenez. The financial cost for non compliance is huge.fda. or Holding of Drugs. 2.White.htm 3. Clean room design. References 1. Volume 146. loss of market. Food and Drugs.Signore and Terry Jacobs. revised April 2000). 1999 4. ³Current Good Manufacturing Practice in Manufacturing. brand integrity etc. Processing. DC.www. Edited by A.Microbial Contamination Control in the Pharmaceautical Industry. 5. Good Design Practices for GMP Pharmaceutical Facilities. But more importantly is patient safety once this area is engraved into a quality policy and allowing the air to be the janitor. By W. Packing.