GUIDE LINES FOR cGMP INSPECTION OF BIOLOGICAL DRUGS

October, 2005 Version – I

Ministry of Health Government of Pakistan Islamabad

CONTENTS OF MANUAL

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Introduction 02 Objectives 02 Scope 03 Inspection Procedure 03 The Systems Approach 04 Inspection Coverage 07 Inspection Approaches 09 Conducting Inspection Reporting 10 Enforcement 11 Follow-up Inspections 13 Grading System 13 10

13. 14. 15.

Annex. I Guidance To Prepare Quality Inspection Report 14 Annex. II Inspection Checklist 19 References 35

GUIDE-LINES FOR GMP INSPECTION OF BIOLOGICAL DRUGS
1.
INTRODUCTION:-

This document serves as an inspection guidelines on manufacturer of biological products. It is prepared according to WHO and FDA guidelines. This document is intended to be used by the Ministry of Health inspectors as well as district inspectors-particularly those operating within National Regulatory Authority (NRA) to assist them in assessing manufacturer’s compliance with regards to Good Manufacturing Practices (GMP). The goal of this document is to minimize consumer’s exposure to adulterated biological products. National Regulatory Authority (NRA) regulates biological drugs including vaccines, blood products, immunological products, In-vivo diagnostics, toxins and venoms, immuno-stimulants. It is the responsibility of NRA to ensure that biological drugs are safe and effective and are prepared in compliance with GMP regulations. The Drug Act, 1976 emphasizes on regular GMP inspections of the premises where the biological products are manufactured, stored, distributed and sold. Drug inspectors having proper qualifications in Pharmacy with experience are appointed at Federal and Provincial levels for this

This document focuses on six key systems and three critical elements within each system that are common for the establishment of biological drug products.purpose. Facilities and Equipment System. transportation. This document provides inspectional guidance to investigators assigned to perform biennial or for cause inspections of manufacturers producing regulated biological products. plus one additional system on a rotating basis in a streamlined evaluation. This guideline represents a continuing compliance and surveillance activity conducted to ensure that regulated biological products are prepared in compliance with GMP guidelines and their safety. Level II. and Provide timely input to firms during inspections to improve their compliance with cGMP regulations. Federal drug inspectors regulate the manufacturing processes of biological drugs while provincial drug inspectors monitor storage.  Increase communication between the industry and the Regulatory Agency. It provides information necessary to inspect overall operation of manufacturing. quality assurance. Accordingly. Training 3.includes two mandatory systems. including source material manufacturers. 2. and provides administrative/ regulatory guidance for Drug Inspectors. INSPECTIONAL PROCEDURES: This guideline covers six key systems and three critical elements within each system for inspection. SCOPE:- Firms covered under this compliance programme include manufacturers of biological drug products. quality control. Standard Operating Procedures (SOPs) 2. Continued biennial inspections under this compliance program will:  Safeguard the public health by reducing the risk of adulterated or misbranded biological drug products reaching the marketplace. and sale of these products under the supervision of National Regulatory Authority. The six key systems are: 1. The three critical elements are: 1. 3.   Level-I includes all six systems in a comprehensive evaluation. and ensures that appropriate enforcement actions are initiated against non-compliance firm. 4. this document also establishes two levels of inspectional coverage for evaluation of manufacturer’s compliance with applicable GMP regulations. Documentation . facilities. 3. OBJECTIVE:- 2. Materials System. Quality System. efficacy and quality is assured.

internal procedures. NRA identifies the scope and content of the inspection and invites Inspection Team to participate in the inspections.1 Inspection Options:- The inspection of biological drugs manufacturers is conducted under either a Level. 4. preparation of validation protocols and validation reports.II inspection options. batch release.3 Other Inspections: NRA is responsible for the conduct of all pre-license inspections (PLI) and preapproval inspections (PAI) of regulated products. inspections may be conducted more often if circumstances. THE SYSTEMS APPROACH:  Inspections of biological drug products manufacturers are to be conducted and reported using the systems and organization defined in this guidelines: 5. and adherence to specifications. annual record review.4. 4. however. The inspection will be conducted using a team with the biological experts. 5. The responsibilities of this system include all the reviews and approval of documents. release of components and in-process materials. 4.1 Quality System (Quality Assurance): This system assures overall compliance with GMP. Packaging and Labeling System. Production System. reprocessing.I or Level.2 Frequency of GMP Inspections: GMP inspections are statutory obligations that are routinely conducted on a biennial schedule.  A level-I inspection is an in-depth audit of the three critical elements in each of the six systems. plus at least one additional system on a rotating basis during successive biennial inspections. A level-II inspection is a streamlined evaluation of an establishment’s compliance with cGMP and provides coverage of the three critical elements in two mandatory systems. Laboratory Control System. 5. and evaluation of returned and . change control. so warrant. and provides a comprehensive evaluation of the establishment’s compliance with cGMP. 6. such as the firm’s compliance history. Batch Production Record (BPR) evaluations.

5. This also includes the associated record keeping systems. Review document records related to product recall. a determination of significant physical changes. report. equipment calibration/ validation and preventative maintenance. cleaning and validation of cleaning processes as appropriate. Facilities and Equipment System: This system includes measures and activities that provide an appropriate physical environment. product deviation complaints. and steam and water systems. source materials. returned and rejected imported products. equipment qualifications (installation qualification operation qualification and performance qualification). including evidence of counterfeit products. The audit of this system should include a walk-through of the facilities related to the materials system. The audit of this system should include examining the validation of computerized inventory control processes. water or gases that are incorporated into the product. and failure investigations. and must be of suitable size. such as HVAC. quality control and quality assurance. and detection and prevention of counterfeiting. including counterfeit imported materials. Coverage of this system includes verifying the appropriateness of buildings and facilities. Facilities used in support of this system must be maintained in a clean and orderly manner. which is done within the system where the process is employed. Assessment of the Quality System is two-phased:  The first phase is to evaluate whether the QA unit has fulfilled its responsibility to review and approve all procedures related to production. Verify that the firm routinely reviews records pertinent to the manufacture of lots or units prior to their release or distribution. distribution controls. Process performance should be evaluated as part of the inspection of the overall process.3 Materials System:  5. Equipment used in support of this system must be maintained in a clean and . records. and an evaluation of routine monitoring of the utility systems. compressed gases. The second phase is to assess the data collected in order to identify quality problems that may be linked to other systems. along with the equipment and resources that are used in the production of biological drug product. out of specification results. and complaint files concerning imported products. rejects. and to ensure that procedures are adequate for their intended use. and utilities that are not intended to be incorporated into the product. including maintenance. and containers and closures. Examine. such as components. maintenance and proper operation.salvaged products. product storage. construction and location to facilitate adequate cleaning. and track counterfeit imported products.2 This system includes the measures and activities to control finished products.

lot release. Facilities used in support of this system must be maintained in a clean and orderly manner. and located so as to facilitate proper cleaning and maintenance. show the expiration date assigned to specific products. including following and documenting performance of approved manufacturing procedures. maintenance and proper operation. including dates of the various entries. and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible. 5. Inspectional coverage should include review of the firm’s written procedures regarding packaging and labeling controls. dosage form production. among other things. or if any modifications to existing equipment were made since the last inspection. 5. aseptic filling. Verify that records are complete and maintained as required. show test results as well as the interpretation of results. and located so as to facilitate proper cleaning and maintenance. verification that the firm is following procedures and that the procedures conform to the manufacturer’s recommendations and/or user manuals. and determination of any new equipment added.5 Packaging and Labeling System: This system encompasses the measures and activities that control packaging and labeling of biological drug products.4 Production System: This system includes the measures and activities to control the manufacture of biological drug products. and label storage and issuance should also be observed during the inspection. The audit of this system should include a walk-through of the areas that house the packaging and labeling processes and systems. Equipment used in support of this system must be maintained in a clean and orderly manner. sterile filtration. and determination of any new equipment added. verification that the firm is following procedures and that the procedures conform to the manufacturer’s recommendations and/or user manuals. The audit of this system should include a walk-through of the facility. and an . a determination of significant physical and/or manufacturing changes.orderly manner. and process validation. Facilities used in support of this system must be maintained in a clean and orderly manner. The firm’s examination of labels and usage. The audit of this system should include review of procedures and records of calibration and maintenance. and be as detailed as necessary to provide a complete history of the work performed. a determination of significant physical and/or manufacturing changes. or if any modifications to existing equipment were made since the last inspection. construction and location to facilitate adequate cleaning. Review a sampling of records for operations performed. covering batch formulation. Inspection of this system should include. The audit of this system should include review of procedures and records of calibration and maintenance. and an evaluation of routine monitoring of the utility systems. and must identify the person performing the work. inprocess testing. and must be of suitable size. construction and location to facilitate adequate cleaning. and must be of suitable size. maintenance and proper operation.

the inspections must include coverage of the following three critical elements:    Procedures Training of personnel Documentation . and an evaluation of routine monitoring of the utility systems. and determination of any new equipment added. a determination of significant physical and/or manufacturing changes. and must identify the person performing the work. safety. The audit of this system should include a walk-through of the laboratories. All records must be legible and indelible. and are related to the history and disposition of all products produced and distributed. and review of the firm’s test methods to ensure that they have been appropriately validated. or if any modifications to existing equipment were made since the last inspection. analytical methods development. and must be of suitable size. Facilities used in support of this system must be maintained in a clean and orderly manner. The audit of this system should include review of procedures and records of calibration and maintenance. construction and location to facilitate adequate cleaning. An in-depth audit of this system should include review of the firm’s SOPs for control of microbiological contamination and environmental monitoring. Review a sampling of records for operations performed verify that records are complete and maintained as required. 6.6 Laboratory Control System: This system includes all the various measures and activities that are related to laboratory procedures. evaluation of the firm’s methods for sampling and testing products for identity. Equipment used in support of this system must be maintained in a clean and orderly manner. verification that the firm is following procedures and that the procedures conform to the manufacturer’s recommendations and/or user manuals. potency. validation or verification. and located so as to facilitate proper cleaning and maintenance. Equipment used in support of this system must be maintained in a clean and orderly manner. in-process and finished product testing. 5. or if any modifications to existing equipment were made since the last inspection. verification that the firm is following procedures and that the procedures conform to the manufacturer’s recommendations and/or user manuals. and located so as to facilitate proper cleaning and maintenance. and determination of any new equipment added. maintenance and proper operation. including dates of the various entries. review of records for source materials. and the stability program. INSPECTION COVERAGE: For each of the six systems defined above. sterility and conformance with final specifications.evaluation of routine monitoring of the utility systems. The audit of this system should include review of procedures and records of calibration and maintenance.

testing. that document adherence to the procedures. processing. inspectional guidance for coverage of facilities.g.   Determine if the SOPs include all steps to be followed in the processing. Verify that all personnel responsible for supervising. 6. and distribution of biological drug products have the appropriate educational background. or any combination thereof. review the relevant training records. are maintained in . training and experience. Verify the most current version of approved SOPs is readily available for use by key personnel in the areas where the procedures are performed. packing. whether or not the firm adheres to the approved written procedures. testing.. to perform their assigned functions. potency.2 Training of Personnel: The organization and personnel. and distribution of biological drug products. 6. If any records. 6.. which are required by regulation. to ensure the final product has the safety. cleaning. etc. as appropriate. including supervisory. labeling. If review of the facility’s discrepancy reports reveals recurring problems associated with one or more particular employees. testing. purity.3. should be evaluated as part of that system’s operation. for all assigned functions and operations. identity and effectiveness it purports or is represented to possess. maintenance. Training should also include cGMP regulations. Documentation:   Records must be maintained concurrently with performance of each significant step in the processing. including professional training as necessary. equipment calibration. Investigators should verify through actual observation. including appropriate qualifications and training employed in any given system. and distribution of biological drug products so all steps can be clearly traced and recorded.Actual observations of the processes applicable to each system should be performed whenever possible. testing. Because most products covered by this program are aseptically processed. as necessary. e.  Determine if the firm has an adequate number of trained personnel.1 Standard Operating Procedures (SOPs): For each of the six-systems the firm should have approved written procedures and associated records. and equipment maintenance has been incorporated into the systems. whenever possible. for each of the six systems.

and are related to the history and disposition of all products produced and distributed. and provides verification of an establishment’s continued compliance with cGMP. and Level-II. verify that records are complete and maintained as required. both options satisfy the biennial inspection requirement. INSPECTION APPROACHES:   7. complaints.  All records must be legible and indelible. show test results as well as the interpretation of results. out of specification results. show the expiration date assigned to specific products. Level-II Inspection Option The Level-II inspection option is a focused surveillance cGMP inspection that covers three of the six key systems. Level-I. the record keeping system should comply with regulations. Review records related to product recall. and be as detailed as necessary to provide a complete history of the work performed. and failure investigations.an electronic format in place of paper format. and must identify the person performing the work. product deviations. This option also includes inspectional coverage of any significant changes to the . Verify that the firm routinely reviews records pertinent to the manufacture of lots or units prior to their release or distribution. This compliance program provides two surveillance inspection options. Review a sampling records for operations performed in each system. Level-I inspection option The Level-I inspection option is a surveillance or compliance inspection that is meant to provide a comprehensive evaluation of the establishment’s overall compliance with applicable cGMP requirements. Level-I inspections apply to one or more of the following conditions:       Initial inspection of a firm Firms that have a history of fluctuating compliance problems Compliance follow-up inspections Firms under Notice of Intent to Revoke and/or other administrative actions Firm that has implemented any significant changes since last inspection After conducting two previous inspections under a Level-II option The Level-I option includes an in-depth audit of the three critical elements in each of the six systems. including dates of the various entries. rejects.

REPORTING:- Each inspection should be documented during the course of the inspection in a bound notebook. unless otherwise indicated. It is important to be polite and to allow sufficient time for responses to be made. Coverage of additional systems should be rotated in successive Level-II inspections. Where this happens. e. the walk-through may develop into a specific system inspection. In addition. and (2) Production System. or license supplements since the preceding inspection. plus one additional system must be selected for coverage during the inspection. In some cases however. in some cases.). preferably in advance of the actual inspection.facilities. however there is always the possibility that a question has been misunderstood and therefore inspectors should be patient and willing to repeat and / or clarify a question until satisfied that an answer has been provided. and altered as necessary during the course of the inspection. Since companies vary in size and scope of their operations. The Level II option includes an in-depth audit of the three critical elements of the following two mandatory systems: (1) Quality System. equipment. Wherever possible observations should be recorded immediately. All questions should be answered.g. manufacturing process. The inspector should conduct each inspection so that overall. verification of QA activities may require limited coverage of other systems. during the course of a Level-II inspection. a uniform assessment of GMP compliance is made at every facility inspected. the inspection approach should be tailored to the firm and should be carefully planned. etc. Select a Level-II Option for any one of the following situations:    The establishment has a satisfactory history of compliance. CONDUCTING INSPECTION: 8. It is generally recommended to perform a complete walk-through of the facility before entering into inspection of a specific system. It is important that the inspector has a flexible inspection approach. The inspection focus and depth should be selected as appropriate for a specific firm. 9. However. Inspectors should understand that employees at all levels of management feel under pressure during a regulatory inspection. One of the two previous biennial inspections was a Level-I inspection The inspection preparation procedures revealed no specific trends that may have a significant impact on product safety or quality (review of BPRs. it may be more appropriate to review the Quality System or another system. thoroughly before entering production areas. . product recalls. which will be determined during work planning. the inspector should be careful to ensure that they later complete a walk-through of the entire facility. A for cause inspection.

The product types covered during the inspection should be identified. cGMP requirements apply to all production documents as described in the scope of this document. factual statement of findings. without personal opinion and without reference to specific persons but rather to job functions. should be specific and accurate. List of observations (Annex-II) in order of importance within each system in the checklist given as annex II. they should be reported under a single observation or under a single heading. Inspection observations should be organized under section headings according to the systems defined in this booklet. Add additional information as needed or desired to add clarity to the report.g. Major inspectional findings should be presented at this close-out meeting. but it should be stressed that an Inspection Report will follow. Under inspectional observations or findings. Describe any significant changes that have occurred since previous inspections. Report findings should be given as non-compliance events. . Where repeated or similar observations are made.2 Content and Style The inspection report should be prepared as a brief.1 Report Format The report should begin with an overview of the all production.Fast communication and evaluation of findings is essential especially in cases where a real or potential danger to public health is discovered. Inspectional observations noting cGMP deficiencies should be related to a specific requirement. QC and QA List of participants in the inspection (Ministry of Health and company) should be provided. Avoid drawing unsubstantiated conclusions. 9. 9. by explaining why and how a particular practice does not comply with the cGMP regulations. The purpose of the inspection should be stated and a list of systems inspected should be given. Avoid using terms such as "inadequate" or “unsatisfactory” without qualification e. On completion of the inspection a discussion should be held with the most senior management official available as well as with the top Quality Assurance functionary. report and discuss in full any adverse findings by systems.

legal action. or lines Withdrawal of the Recognized Laboratory status of a facility’s Quality Control Laboratory completely or for a particular product or products. 10. The company’s response to the inspection report should point out actions that have been taken or will be taken with target dates for implementation and follow-up. the factory may be closed down through the Federal Drug Controller or through NRA. actions that may be implemented include:       product(s) hold product(s) recall shut down of a production line. or. Target dates must reflect a reasonable time frame. Where critical findings result from an inspection. If appropriate.The report should reflect performance of a thorough. Enforcement may involve voluntary and non-voluntary action. firms are permitted 30 days to inform of corrective actions and for minor deficiencies a 90 days period is provided from the date of report issuance. Inspection findings that demonstrate that a firm is not operating in a state of control may be used as evidence for taking appropriate enforcement action. Management should be informed that they are expected to bring a written action plan for immediate and long term corrective action to come into full cGMP compliance. The firm's proposed corrective actions must be included in a written response to the NRA. The report should be submitted to the company within 90 days of the close-out meeting. Withholding approval of new products or renewal of licensing of existing Products In the event of breakdown of several systems and in particular where there is evidence of lack of authority and / or professionalism in the Quality System. Where required. For major deficiencies. in the case of suspected criminal activity. . . ENFORCEMENT: Slightly low stability or potency at marginal level or low titer in seed virus should be given appropriate priority. Any of the above actions may continue until verification of implementation of satisfactory corrective action. Each deficiency noted in the inspection report must be addressed. Issues related to environmental monitoring must be thoroughly reviewed. management will be requested to arrange meeting at senior level officers or departmental heads within up to one month from the date of the close-out meeting. management should be made aware of the severity of the observations at the close-out meeting. professional and efficient cGMP inspection resulting in an impartial evaluation of the company’s current state of compliance with cGMP requirements.

5= If Tasks is partially implemented. distribute. Laboratory tests that support observations of inadequate cGMP procedures are strong evidence for supporting enforcement actions. 12. When deciding on the type of action. Conditional production is permitted until the compliance of pending cGMP . The firm will not be permitted to manufacture. Where an inspection reveals deficiencies. However. sample collection should be considered if pertinent. 0. The score of 80% or better receive GMP compliance approval for biological drug manufacturing. The firm receives permission to manufacture. especially if the level-II inspection option was used during the prior inspection. as appropriate for the situation encountered. the initial decision should be based on the seriousness of the problem and the most effective way to protect the consumer. The level-I inspection option should be used for a compliance inspection. The firm with the score of 50%-80% is allowed 6 months time to comply with cGMP regulations. Failure of a system is considered to have occurred where there is an evidence to support significant and/or a trend of deficiencies within that system. In addition a determination must be made on the overall compliance status of the firm after the corrective actions are taken. the lack of violative samples (whether not collected or collected and found to conform) does not prevent initiation of enforcement action provided that cGMP deficiencies are well documented. FOLLOW-UP INSPECTIONS: Compliance Inspections are performed to evaluate or verify implementation of corrective actions after enforcement action has been taken. The firm is expected to address all of its operations in its corrective action plan not just the deficiencies noted in the audit report. formal non-voluntary enforcement actions will be demanded. 0= If Tasks is not implemented. and sell its product for domestic and international consumption The score of less than 50% receive warning letter allowing firm limited time (3 months maximum) for correction action. sell or distribute its product both domestically and internationally immediately.When company management is unwilling or unable to provide adequate corrective actions in an appropriate time frame. The coverage given in compliance inspections should be related first to those areas found deficient and being corrected. the regulatory body of Ministry of Health would issue a closure order of firm. If scores does not reach 50% within 3 months. 11. The initial assessment and decision should be based on the seriousness and / or the frequency of the problem. Grading system: All points should be graded based on the following scheme: 1= If Tasks is fully implemented.

Failure to comply with cGMP regulations after the specified time will result in closure of firm. .requirements.

fax. (h) Assessment of the site master file. QC. Activities Short description of site Number of employees engaged in production.Annex-1 GUIDANCE TO PREPARE QUALITY INSPECTION REPORT It is recommended that reports be divided into four parts:     A. Use of outside scientific. analytical. if applicable. record of inspection by proper authority is required. email ). (c) Type of inspection. B-1 (a) Date(s) of inspection(s). Address (including telephone. (b) Previous inspection date. Brief report of inspection activities undertaken. Manufacturing license number. (a) (b) (c) (d) (e) (f) (g) (h) General information on the company or manufacturing facility Description of the inspection Observations Conclusions GENERAL INFORMATION: Manufacturer’s name. (g) Samples taken and results obtained. (i) cGMP-related recalls from the market of any product in the last 2 years. or other technical assistance in relation to manufacture and analysis. storage and distribution. (d) Scope of inspection. DESCRIPTION OF THE INSPECTION B. . (e) (f) For foreign firms. Address of manufacturing site if different from that given above. B-2 Inspector(s) . QA.

g. Outline of arrangements for basic and in-service training and method of keeping records. weighing. (d) Brief description of the quality management system of the firm responsible for manufacture. packaging) and flow of personnel and material. as “critical”. Reference can be made to a site master file if one is available. C.(a) Name(s) of inspector(s) and accompanying experts. Qualifications. clear distinction should be made between “positive” and “non-compliant”. Non-compliant observations can be classified.2 (a) (b) (c) (d) (e) C. (b) (c) . research and development). Special areas for the handling of highly toxic. Premises Manufacturing areas (design. experience and responsibilities of key personnel.) used e.g. for storage and manufacturing (e. analytical. e. hazardous and sensitizing materials. production. Where positive observations are included in the report. or other technical assistance in manufacture and quality control. Nature of construction and finishes. e. location etc. C. manufacture of cosmetics. Health requirements for personnel engaged in production. as described in the quality manual. The date by which corrective action and completion are requested in accordance with the policy of the national regulatory authority should be given.g. (c) Use of outside scientific. Personnel hygiene requirements.g. “major” and “minor” if the Member State concerned has defined these terms.3 (a) Organization and personnel Organizational chart showing the arrangements for quality assurance. B-3 Introduction (a) Brief summary of the manufacturing activities. C. (b) Other manufacturing activities carried out on the site (e. including clothing. including production and quality control. OBSERVATIONS: The observations made during the inspection that are considered to be non-compliant with cGMP should be listed.1 Quality assurance (a) Quality system and documented quality policy of the manufacturer.g.

g. chemical and microbial analysis). finished products. reagents and culture media. location and adaptation of equipment used in production and control laboratories.4 (a) (b) (c) C. Organization and personnel. sampling. intermediate and bulk products. Detailed description of critical areas with potential risks of contamination and cross contamination. handling and use of starting materials. Good practices in production Transport. waste material. Planned preventative maintenance program for equipment and records. storage and handling of materials. Qualification and calibration. acceptance limits). Classification of the rooms used for the manufacture of products.(d) (e) (f) (g) (h) C. including: starting materials. air conditioning. Equipment Design. process). sampling. Validation (e. packaging materials. Change control and deviation reporting. reference standards. packaging materials.7 (a) (b) (c) (d) (e) . Materials Sourcing of materials. Control.6 (a) (b) (c) (d) C. Premises. returned and rejected materials. weighing. Materials. and bulk and finished products. ventilation. process operations and conditions. Planned preventative maintenance programme. Qualification of premises and systems as appropriate. Production operations and important parameters (e. including clean rooms. quarantine. Equipment and instrumentation. including records. and supply of steam and gas.5 (a) (b) Systems such as drainage. Quality control Activities of quality control (including quarantine control. C.g. Water systems.

specifications.g. records and investigation. Items for self-inspection. computer.12 (a) C. Self-inspection team.14 (a) (b) (c) (d) Self-inspection and quality audits Procedure. program and compliance. of premises.(f) C. procedures. Documentation Documentation (e. C. Contract production and analysis (c) (d) C. specifications. (d) GMP compliance of the contract accepter (initial assessment and continued compliance audited at regular intervals). Stages of validation.g. Validation Validation master plan. records. (c) Contract (containing clearly defined responsibilities). Sanitation and hygiene Procedures for sanitation and/or cleaning (e. Product recalls Procedure.g.g.8 (a) (b) C. Complaints Procedure.9 (a) (b) Documentation (e. reports). process. equipment. Preparation.11 (a) C. Personal hygiene. Reports on production. cleaning. protocols. analytical methods). revision and distribution of documentation.10 (a) (b) (c) C. Validation and qualification protocols and reports for qualification and validation (e. records). Frequency of self-inspection.13 (a) Responsibilities of contract giver. of premises and equipment) and records. reports. procedures. records and investigation. . (b) Responsibilities of contract accepter. Types of validation. systems. quality control (including environmental control). engineering and other relevant areas.

D. Quality audit. Summary Brief summary of the findings. Follow-up action. Name: ______________________ Signature:_____________________ . and recommendations (where applicable).15 Self-inspection report.(e) (f) (g) (h) C. CONCLUSIONS A statement regarding the GMP status. Suppliers’ audits.

Number and date of grant Total number of employees (Technical/Non Technical worker) Availability of technical persons (please give details of absent) Other Products of this Company (including bio-pharmaceuticals) Date of Last Inspection with brief report Abnormal Findings during last inspection Corrective Measures taken Measures still in pending along with reasons .ANNEX-II INSPECTION CHECK LIST FOR BIOLOGICALS MANUFACTUREING UNIT/PLANT Name of the unit Address Telephones: Fax and E-mail addresses Status of the unit Type of license.

Findings of Internal Audit (QA) [brief summary] Date of Present Inspection Reasons(s) for present inspection Type of Inspection [Level-I/Level-II] Floor plans of facility available? Name (s) of Inspector (s) Address (s) of Inspector (s) Other members of Inspection Team with designations and department names .

) _____________________________ _____________________________ QUALITY CONTROL DEPT Position Title (with phone No. Date _____________ SUMMARY OF SENIOR PERSONNEL: (use extra page if these departmental divisions are not appropriate. or for other department designations) ADMINISTRATION Position Title (with phone No.) _____________________________ _____________________________ _____________________________ _____________________________ ANIMAL FACILITIES Position Title (with phone No.) _____________________________ _____________________________ QUALITY ASSURANCE DEPT Position Title (with phone No.) _____________________________ _____________________________ _____________________________ PRODUCTION DEPARTMENT Position Title (with phone No.) _____________________________ _____________________________ _____________________________ Name _______________________________________________________ _______________________________________________________ _______________________________________________________ Name _____________________________ _____________________________ _____________________________ _____________________________ Qualifications ___________________________ ___________________________ ___________________________ ___________________________ Name _____________________________ _____________________________ Qualifications ___________________________ ___________________________ Name _____________________________ _____________________________ Qualifications ___________________________ ___________________________ Name _____________________________ _____________________________ Qualifications ___________________________ ___________________________ Name _____________________________ _____________________________ Qualifications ___________________________ ___________________________ Name _____________________________ _____________________________ _____________________________ Qualifications ___________________________ ___________________________ ___________________________ Name _____________________________ _____________________________ _____________________________ Qualifications ___________________________ ___________________________ ___________________________ .) _____________________________ _____________________________ ENGINEERING/MAINTENANCE Position Title (with phone No.) _____________________________ _____________________________ _______________ DEPARTMENT Position Title (with phone No.SUMMARY OF COMPANY ORGANIZATION AND INSPECTION INSPECTION of _______________________________________________________.) _____________________________ _____________________________ _____________________________ _______________ DEPARTMENT Position Title (with phone No.

QUALITY CONTROL Approved Incharge Pharmacist(s) Microbiologist(s) Chemist(s) Others (please specify numbers) Organizational Chart Record of Qualifications. experience. 1. PERSONNEL (Technical): The manufacturing establishment and its personnel shall be under the authority of persons who have been trained in management and in the techniques used in manufacturing biological substances. Personnel hygiene requirements. training and responsibilities of key personnel Job descriptions of each staff member Arrangements for basic and in-service training and method of keeping records.CHECK LIST FOR I NSPECTION AND PERPARATION OF REORT The following inspection check list is applicable to all biological drug establishments. 2. and who possess the scientific knowledge upon which the manufacture of these products is based. Personnel hygiene requirements. A) 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) B) 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) PRODUCTION Approved Incharge Pharmacist(s) Microbiologist(s) Chemist(s) Others (please specify numbers) Organizational Chart Record of Qualifications. PREMISES: . including clothing. S. experience and responsibilities of key personnel Job descriptions of each staff member Arrangements for basic and in-service training and method of keeping records. Independence from Quality Control Health requirements for personnel engaged in production. including clothing.No. Independence from Production Health requirements for personnel engaged in QC. The personnel shall include specialists with training appropriate to the products made in the establishment.

any adverse effect on the quality of products.Premises and equipment must be located. designed. (For premises where pathogenic organisms are utilized. A Facility Design). constructed. A) 1) 2) B) 1) 2) 3) 4) 5) LOCATION Site approved as per drug rules (Please give details if not) Surroundings hygienic conditions (please give details if not) BUILDING Suitability of Building. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid crosscontamination.0 Containment Practices. drains & traps Flow Charts showing patterns for material. buildup of dust or dirt and. product & waste movements Adequate Lighting 6) . see also 10. in general. Defined & appropriately controlled area Prevent entry of pests. Plumbing. adapted and maintained to suit the operations to be carried out. personnel.No. S.

does the facility design permit effective fumigation? 4) Is the air flow adequate in all areas of production building? .7) 8) 9) 10) 11) 12) 13) Building specification up-to-date. 20) C) 1) HVAC – System Are pre-filters present in heating. Entry of dust/birds/insects/rodents/other Worms adequately controlled Building properly constructed to facilitate smooth operations.) Building being used for purposes other than those for which DML was granted (please give details if. and capacity for carrying out manufacture of:Registered drugs. neatness. repair state Building plans approved as per drug rules Total covered area of building (in Sq. adequate cleaning and disinfection. ventilation and airconditioning (HVAC) Systems and replaced on a routine basis? Are HEPA filters terminally located? 2) Are duct works and filters located out side the clean rooms? 3) If fumigation procedures are used. Paint work. Ft. cracks. Door seals-state of work Washing facilities-Adequacy Cleanliness. New drugs applied for registration Building condition. Proper section/area segregation/arrangement to prevent mix-ups and cross contamination 14) Sewage / trash / effluent disposal is adequate 15) 16) Specifically designed as a biological unit 17) a) b) 18) 19) Building of suitable size.

Are room temperature and humidity effectively controlled? 5) 6) D) 1) 2) E) 1) F) 1) COMPRESSED AIR Is the air supply pass through filters in the sterile area? Are the air compressors properly maintained? CLEAN STEAM Is clean steam used for sterilization processes during manufacturing operations? WATER FOR INJECTION (WFI) SYSTEM Is the design of the WFI system adequate to supply sufficient water of (Pharmacopoeial) quality? Is there a holding tank for the WFI system? 2) .

1) STERILE PROCESSING Are the aseptic manufacturing areas and operations consistent with the WHO guidelines for sterile biological products.g.) flush mounted and sealed to prevent air leakage. in-process material.C. & D) during operation? The ability to maintain the appropriate pressure differentials between work areas with differen f) Dose the aseptic manufacturing area exclude: Access doors for servicing equipment and fixture? Drain? Sinks? i) g) h) 3) a) b) c) . hard non-particulate generating clean-able floors. produ Environmental controls. Does the aseptic manufacturing area include : 2) a) Smooth. etc. c) Identification of all pipes or conduits for air.B.G. humidity and viable and non-viable particles? Are th b) Air supply through HEPA filters? Fixtures (electrical outlets and lighting. walls and ceiling? Able to withstan No horizontal pipes or conduits located over exposed components. clean steam or liquids? Properly equipped gowning area/air-lock? d) e) The ability to achieve appropriate air standards (Grade A. temperature. e.

maintenance. EQUIPMENT: This section deals with all the equipment used in the preparation. . Special consideration should be given to the capacity relative to the requirements of the establishment. bulk and final product. about the ease of operation and cleaning/disinfect ion.4) Is the vaccine processing area isolated and independent of any space used for any other purpos Are the facilities appropriately designed and validated to comply with relevant containment le 5) Is the aseptic manufacturing area cleaned? 6) 3. the availability of spare parts. validation and training of staff. processing and control of intermediate.

Suitable for intended use. scales. 3) Installed and arranged in an organized manner 4) Adequately cleaned & maintained (Please also give details). 5) Equipment status identified by labeling 6) Clean/Defective/under maintenance etc.A) 1) 2) EQUIPMENT Name. measuring equipment of appropriate range. No. Total capacity & Operational/out of order. 7) Balances. Calibration and validation record available? Written standard Operating Procedures (SOPs) available . 8) 9) 10) Routinely calibrated/validated..

before use. Describe methods. vent filters. . doc 12) Preventive maintenance program & record log book. Identification of responsible person for cleaning. procedure of clean equipment from contamination.B) 1) CLEANING – DISINFECTION Availability of spares parts. validation & training of staff. inspect. defined schedule. 5) Cleaning & sterilization 6) Maintaining closed system “clean in place” 7) Sterilization place preferable (fermenters) 8) Filters-non fiber releasing calibration & validation-performance work 9) Autoclave. Maintenance of equipment-SOP 2) Cleaning & maintenance 3) No cross contamination 4) Piping system. autoclave. valves. hot air oven should include. Maintenance. Hot air oven SOP’s 10) 11) Supply and equipment which are exposed to pathogen during processing kept separate to avoid SOPs for utensils. 13) 14) 15) 4.

. Production steps should be effectively monitored and thoroughly documented to ensure safety.PROD UCTIO N AND INPROCE SS CONT ROL Production and in-process controls play a specially important role in ensuring the consistent quality of biological products. quality and efficacy of the final product. Tests that are crucial for quality control but that cannot be carried out on the finished product shall be performed at an appropriate stage of production.

Are there approved specifications for all starting material or raw material or raw material used To ensure the quality of raw materials: 2) Is there a quarantine and release system? a) Are the conditions of storage evaluated? b) c) For raw material of animal origin: 3) a) Are the details of source. alarms and backup power Inventory log? Adequately segregated storage to avoid mix-up or cross-contamination with other material? .A.and Seed Stocks have detailed records of: History of cells including the number of generation doublings or passages of virus? Is there a m b) c) Characterization according to the WHO TRS relevant to the product? Demonstration of purity? Manufacturing procedures? d) e) f) Appropriate storage and security with continuous monitoring of temperature. 1) ADEQUACY OF STARTING MATERIALS. origin. including reporting of changes in m Are biological materials that may contain infectious organisms screened or tested prior to entr e) 4) a) Do master/Working Cell Banks . and method of manufacture documented? Are they stored in controlled environments? Are the expiry dates given and is there a retest policy? b) Are rejected materials properly segregated from acceptable material? c) d) Do the contracts with vendors ensure quality and stability.

if applicable? Are in-process intermediate materials tested for identity. strength and purity? Alternat Process validation. Preparation & validation protocol.g) Check up on purity & identity at various intervals. h) B) 1) a) PROCESS Master Formula (MF) Does the MF adequately describe the complete production process? Is the MF up to date . write up. Environment control of filling area.and approved by QC/QA? b) c) Is the Batch Production Record form and adequate 2) a) Process validation: Has each phase of the production process been validated according to an approved validation protocol? Is re-validation done when required. Production plan – Time & temperature Established for complete of product process . Re-validation when required. Validation by suitable media fills. Aseptic fill: SOP on aseptic filling process. and performed appropriately? b) 3) a) Aseptic fill: Are suitable precautions taken to maintain aseptic conditions during the filling process? 4) 5) 6) 7) a) Are time and temperature limits established for the completion of production phases? Are viral removal and inactivation processes validated. b) 8) a) b) c) d) 9) Such plan of production processing to be validated. quality. Fill sufficient number of vials.

The establishment of SOPs for all laboratory procedures is essential to ensure their accuracy and reproducibility. Pre-testing and re-screening of biological material. Documentation for seed lot/cell bank. is there a m .0 1) 2) 3) 4) 5) 6) 6. The QC laboratory demonstrates the consistency of Specification & Q.10) 11) 5. release of raw/starting materials. STARTING MATERIAL In-process intermediate materials test for identity Quality purity. Testing certificate of in-process intermediate History of cells including the number of generation doubling or passages of virus. Finished testing product is the responsibility of QC.C. titre (Suppliers data on qualit Environmental monitoring 1. Documentation for raw materials for animal origin. LABORATOR Y CONTROL: In-process controls testing may be performed by production staff under supervision of an independent QC department.

of samples and documentation required. involved in decisions pertaining to product quality is Q. A 1) 2) 3) Quality Control: Does the quality control unit have adequate laboratory space and equipment? Are written calibration procedures available for instruments. No.C. Animal house maintained. Animal test performed. All retention samples. Specification. Written sampling and testing plan for raw materials intermediate and final product and precise Description of sampling and testing procedure for in-process material Retest policy and criteria for retest.A 5) Laboratory control established to ensure tested materials confirm to appropriate standards of id 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) a) These labs. book with expiry date. Lab.manufacturing by appropriate testing and review of historical records. Test procedure and other laboratory control mechani 4) Any change reviewed and approved by Q. sampling plans.C. of each lot of final product stored under conditions consistent with prod Quarantine and release system Evaluation and investigation of complaints. monitor consistency of produc Separate laboratory for microbiology and sterility testing. Sufficiently equipped with suitable instruments/ equipments Separate laboratory for bacterial and viral vaccine test. Recall of products. Proper. labeled and preparation recorded in lab. standards. All reference reagents kept secure properly stored identified and their integrity maintain. Q. clean and adequate facilities available for: Changing and storing clothes of personnel production b) . Control include all required testing and documentation Reagent culture media.

System of distribution and control of SOPs. Reporting.Washing and toilets with soap/detergent and air dryers c) / Retiring/Dining rooms B 1) Quality Assurance: Written and approved SOPs for all manufacturing and testing activities. investigating and recording all deviations. Recall of products. Reprocessing of unsatisfactory and returned products. Calibration of all instruments. SOPs for all QC laboratory operations. 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) . Revisions to SOPs approved by an authorized person. Frequency of environmental monitoring. Independence from QC department. Evaluation and investigation of complaints. Regular review of SOPs. Validation and revalidation of all equipment. Quarantine and release systems.

Microbial count evaluation done routinely in aseptic work area. Records of labeling and packaging operations signed by operator and reviewed by Q. Sterilizing records for equipment and components complete. approved written procedures. Adequate storage space for labeled and unlabelled products. followed for filling procedures. Labeling issued against individual work order. 1) 2) 3) 4) 5) 6) 7) FILLING: Detailed.C.C. if installed. Inspection follow-up to ensure action is taken. FILLING AND PACKAGING PROCEDURE S: A. . Inspection system for contractors. approved and up-to-date.15) 16) 17) Self-inspection of each manufacturing and test area. Used. 1) 2) 3) 4) 5) 6) 7) B. Labeling and packaging done according to Q. Aseptic areas under positive HEPA filter air pressure. Laminar flow units validated regularly (at least every 6 months) if installed. Q. signed and dated. Follow-up of national control authority’s inspection and recommendations. 18) 7. Filling/labeling/packaging operations adequately separated. written procedures. Record of filling signed by operators and reviewed by Q.C. returned and destroyed labeling reconciled and signed for. Aseptic filling operation (area and personnel) checked by routine sterile broth filling (at least LABELLING AND PACKAGING Labeling stored in a restricted access area.C.

Yes_______ No_______ General remarks/comments of the inspectors: ______________________________________________________________________________ ______________________________________________________________________________ 3. Defects pointed out in the last inspection removed.COMMENTS/REMARKS/RECOMMENDATIONS 1. Recommendations ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ 4. Comments of the firm’s representative ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ Signature of the firm’s representative _______________________ _______________________ Signatures of Inspectors .

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9.9:708413850.0 ****************************************************************************** ****************************************************************************** ****************************************************************************** ******************************************************************************      $3.42203/..9:704190172 8705708039.9478    ****************************************************************************** ******************************************************************************    #0.9438  ****************************************************************************** ****************************************************************************** ****************************************************************************** ******************************************************************************     42203984190172 8705708039.0$3.422039841903850.9.9478   *********************** ***********************  .

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