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 manufacturers compliance with regards to Good Manufacturing Practices (GMP). The goal of this document is to minimize consumers 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

purpose. Federal drug inspectors regulate the manufacturing processes of biological drugs while provincial drug inspectors monitor storage, transportation, and sale of these products under the supervision of National Regulatory Authority. This document focuses on six key systems and three critical elements within each system that are common for the establishment of biological drug products. Accordingly, this document also establishes two levels of inspectional coverage for evaluation of manufacturers compliance with applicable GMP regulations; Level-I includes all six systems in a comprehensive evaluation. Level II- includes two mandatory systems, plus one additional system on a rotating basis in a streamlined evaluation. OBJECTIVE:-

2.

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, efficacy and quality is assured. This document provides inspectional guidance to investigators assigned to perform biennial or for cause inspections of manufacturers producing regulated biological products, and provides administrative/ regulatory guidance for Drug Inspectors. It provides information necessary to inspect overall operation of manufacturing, quality assurance, quality control, facilities, and ensures that appropriate enforcement actions are initiated against non-compliance firm. 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; Increase communication between the industry and the Regulatory Agency, and Provide timely input to firms during inspections to improve their compliance with cGMP regulations. 3. SCOPE:-

Firms covered under this compliance programme include manufacturers of biological drug products, including source material manufacturers. 4. INSPECTIONAL PROCEDURES:

This guideline covers six key systems and three critical elements within each system for inspection. The six key systems are: 1. Quality System; 2. Facilities and Equipment System; 3. Materials System; The three critical elements are: 1. Standard Operating Procedures (SOPs) 2. Training 3. Documentation

4. Production System; 5. Packaging and Labeling System; 6. Laboratory Control System. 4.1 Inspection Options:-

The inspection of biological drugs manufacturers is conducted under either a Level- I or Level- II inspection options. A level-I inspection is an in-depth audit of the three critical elements in each of the six systems, and provides a comprehensive evaluation of the establishments compliance with cGMP. A level-II inspection is a streamlined evaluation of an establishments compliance with cGMP and provides coverage of the three critical elements in two mandatory systems, plus at least one additional system on a rotating basis during successive biennial inspections. 4.2 Frequency of GMP Inspections: GMP inspections are statutory obligations that are routinely conducted on a biennial schedule; however, inspections may be conducted more often if circumstances, such as the firms compliance history, so warrant. The inspection will be conducted using a team with the biological experts. 4.3 Other Inspections: NRA is responsible for the conduct of all pre-license inspections (PLI) and preapproval inspections (PAI) of regulated products. NRA identifies the scope and content of the inspection and invites Inspection Team to participate in the inspections. 5. THE SYSTEMS APPROACH:

Inspections of biological drug products manufacturers are to be conducted and reported using the systems and organization defined in this guidelines: 5.1 Quality System (Quality Assurance):

This system assures overall compliance with GMP, internal procedures, and adherence to specifications. The responsibilities of this system include all the reviews and approval of documents, release of components and in-process materials, change control, reprocessing, batch release, annual record review, preparation of validation protocols and validation reports. Batch Production Record (BPR) evaluations; and evaluation of returned and

salvaged products, including evidence of counterfeit products. 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, quality control and quality assurance, and to ensure that procedures are adequate for their intended use. This also includes the associated record keeping systems. Review document records related to product recall, product deviation complaints, out of specification results, rejects, and failure investigations. Verify that the firm routinely reviews records pertinent to the manufacture of lots or units prior to their release or distribution. Examine, report, and track counterfeit imported products, returned and rejected imported products, and complaint files concerning imported products. The second phase is to assess the data collected in order to identify quality problems that may be linked to other systems. Facilities and Equipment System: This system includes measures and activities that provide an appropriate physical environment, along with the equipment and resources that are used in the production of biological drug product. Coverage of this system includes verifying the appropriateness of buildings and facilities, including maintenance; equipment qualifications (installation qualification operation qualification and performance qualification); equipment calibration/ validation and preventative maintenance; cleaning and validation of cleaning processes as appropriate, and utilities that are not intended to be incorporated into the product; such as HVAC, compressed gases, and steam and water systems. Process performance should be evaluated as part of the inspection of the overall process, which is done within the system where the process is employed. 5.3 Materials System:

5.2

This system includes the measures and activities to control finished products, such as components, source materials, water or gases that are incorporated into the product, and containers and closures. The audit of this system should include examining the validation of computerized inventory control processes, product storage, distribution controls, records, and detection and prevention of counterfeiting, including counterfeit imported materials. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a walk-through of the facilities related to the materials system, a determination of significant physical changes, and an evaluation of routine monitoring of the utility systems. Equipment 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. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection. 5.4 Production System:

This system includes the measures and activities to control the manufacture of biological drug products, including following and documenting performance of approved manufacturing procedures. Inspection of this system should include, among other things, covering batch formulation; dosage form production; sterile filtration; aseptic filling; inprocess testing; lot release, and process validation. Review a sampling of records for operations performed. Verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries; show test results as well as the interpretation of results; show the expiration date assigned to specific products; and be as detailed as necessary to provide a complete history of the work performed. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a walk-through of the facility, a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment 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. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection. 5.5 Packaging and Labeling System:

This system encompasses the measures and activities that control packaging and labeling of biological drug products. Inspectional coverage should include review of the firms written procedures regarding packaging and labeling controls. The firms examination of labels and usage, and label storage and issuance should also be observed during the inspection. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a walk-through of the areas that house the packaging and labeling processes and systems, a determination of significant physical and/or manufacturing changes, and an

evaluation of routine monitoring of the utility systems. Equipment 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. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection. 5.6 Laboratory Control System:

This system includes all the various measures and activities that are related to laboratory procedures; analytical methods development; validation or verification; and the stability program. An in-depth audit of this system should include review of the firms SOPs for control of microbiological contamination and environmental monitoring; review of records for source materials, in-process and finished product testing; evaluation of the firms methods for sampling and testing products for identity, potency, safety, sterility and conformance with final specifications; and review of the firms test methods to ensure that they have been appropriately validated. Review a sampling of records for operations performed verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries. Facilities used in support of this system must be maintained in a clean and orderly manner, and must be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operation. The audit of this system should include a walk-through of the laboratories, a determination of significant physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility systems. Equipment 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. The audit of this system should include review of procedures and records of calibration and maintenance, verification that the firm is following procedures and that the procedures conform to the manufacturers recommendations and/or user manuals, and determination of any new equipment added, or if any modifications to existing equipment were made since the last inspection. 6. INSPECTION COVERAGE:

For each of the six systems defined above, the inspections must include coverage of the following three critical elements: Procedures Training of personnel Documentation

Actual observations of the processes applicable to each system should be performed whenever possible. Because most products covered by this program are aseptically processed, inspectional guidance for coverage of facilities, equipment calibration, and equipment maintenance has been incorporated into the systems, as appropriate. 6.1 Standard Operating Procedures (SOPs):

For each of the six-systems the firm should have approved written procedures and associated records, e.g., testing, maintenance, cleaning, etc., that document adherence to the procedures. Investigators should verify through actual observation, whenever possible, whether or not the firm adheres to the approved written procedures. Determine if the SOPs include all steps to be followed in the processing, testing, labeling, and distribution of biological drug products. Verify the most current version of approved SOPs is readily available for use by key personnel in the areas where the procedures are performed.

6.2

Training of Personnel:

The organization and personnel, including appropriate qualifications and training employed in any given system, should be evaluated as part of that systems operation. Determine if the firm has an adequate number of trained personnel, including supervisory, for all assigned functions and operations, for each of the six systems. Verify that all personnel responsible for supervising, processing, testing, packing, and distribution of biological drug products have the appropriate educational background, training and experience, including professional training as necessary, or any combination thereof, to perform their assigned functions. Training should also include cGMP regulations, as necessary; to ensure the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. If review of the facilitys discrepancy reports reveals recurring problems associated with one or more particular employees, review the relevant training records. 6.3. Documentation:

Records must be maintained concurrently with performance of each significant step in the processing, testing, and distribution of biological drug products so all steps can be clearly traced and recorded. If any records, which are required by regulation, are maintained in

an electronic format in place of paper format, the record keeping system should comply with regulations. All records must be legible and indelible, and must identify the person performing the work, including dates of the various entries; show test results as well as the interpretation of results; show the expiration date assigned to specific products; and be as detailed as necessary to provide a complete history of the work performed. Review a sampling records for operations performed in each system, verify that records are complete and maintained as required, and are related to the history and disposition of all products produced and distributed. Verify that the firm routinely reviews records pertinent to the manufacture of lots or units prior to their release or distribution. Review records related to product recall, product deviations, complaints, out of specification results, rejects, and failure investigations. INSPECTION APPROACHES:

7.

This compliance program provides two surveillance inspection options, Level-I, and Level-II; both options satisfy the biennial inspection requirement. 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 establishments 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. Level-II Inspection Option The Level-II inspection option is a focused surveillance cGMP inspection that covers three of the six key systems, and provides verification of an establishments continued compliance with cGMP. This option also includes inspectional coverage of any significant changes to the

facilities, manufacturing process, equipment, or license supplements since the preceding inspection. The Level II option includes an in-depth audit of the three critical elements of the following two mandatory systems: (1) Quality System, and (2) Production System; plus one additional system must be selected for coverage during the inspection, which will be determined during work planning. Coverage of additional systems should be rotated in successive Level-II inspections, unless otherwise indicated. In addition, during the course of a Level-II inspection, verification of QA activities may require limited coverage of other systems. Select a Level-II Option for any one of the following situations: The establishment has a satisfactory history of compliance, 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, product recalls, etc.). CONDUCTING INSPECTION:

8.

Inspectors should understand that employees at all levels of management feel under pressure during a regulatory inspection. It is important to be polite and to allow sufficient time for responses to be made. All questions should be answered, 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. Since companies vary in size and scope of their operations, the inspection approach should be tailored to the firm and should be carefully planned, preferably in advance of the actual inspection. It is generally recommended to perform a complete walk-through of the facility before entering into inspection of a specific system. However, in some cases, the walk-through may develop into a specific system inspection. Where this happens, the inspector should be careful to ensure that they later complete a walk-through of the entire facility. In some cases however, e.g. A for cause inspection, it may be more appropriate to review the Quality System or another system, thoroughly before entering production areas. 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, and altered as necessary during the course of the inspection. The inspector should conduct each inspection so that overall, a uniform assessment of GMP compliance is made at every facility inspected. 9. REPORTING:-

Each inspection should be documented during the course of the inspection in a bound notebook. Wherever possible observations should be recorded immediately.

Fast communication and evaluation of findings is essential especially in cases where a real or potential danger to public health is discovered. 9.1 Report Format

The report should begin with an overview of the all production, QC and QA List of participants in the inspection (Ministry of Health and company) should be provided. The purpose of the inspection should be stated and a list of systems inspected should be given. The product types covered during the inspection should be identified. Describe any significant changes that have occurred since previous inspections. Under inspectional observations or findings, report and discuss in full any adverse findings by systems. Add additional information as needed or desired to add clarity to the report. Inspectional observations noting cGMP deficiencies should be related to a specific requirement. cGMP requirements apply to all production documents as described in the scope of this document. 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. Major inspectional findings should be presented at this close-out meeting, but it should be stressed that an Inspection Report will follow. 9.2 Content and Style

The inspection report should be prepared as a brief, factual statement of findings, should be specific and accurate. Inspection observations should be organized under section headings according to the systems defined in this booklet. List of observations (Annex-II) in order of importance within each system in the checklist given as annex II. Where repeated or similar observations are made, they should be reported under a single observation or under a single heading. Avoid drawing unsubstantiated conclusions. Avoid using terms such as "inadequate" or unsatisfactory without qualification e.g. by explaining why and how a particular practice does not comply with the cGMP regulations. Report findings should be given as non-compliance events, without personal opinion and without reference to specific persons but rather to job functions.

The report should reflect performance of a thorough, professional and efficient cGMP inspection resulting in an impartial evaluation of the companys current state of compliance with cGMP requirements. The report should be submitted to the company within 90 days of the close-out meeting. 10. ENFORCEMENT:

Slightly low stability or potency at marginal level or low titer in seed virus should be given appropriate priority. Issues related to environmental monitoring must be thoroughly reviewed. . Where critical findings result from an inspection, management should be made aware of the severity of the observations at the close-out meeting. If appropriate, actions that may be implemented include: product(s) hold product(s) recall shut down of a production line, or lines Withdrawal of the Recognized Laboratory status of a facilitys Quality Control Laboratory completely or for a particular product or products. 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, the factory may be closed down through the Federal Drug Controller or through NRA.

Any of the above actions may continue until verification of implementation of satisfactory corrective action. Where required, 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 informed that they are expected to bring a written action plan for immediate and long term corrective action to come into full cGMP compliance. For major deficiencies, 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. The companys 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. Target dates must reflect a reasonable time frame. Each deficiency noted in the inspection report must be addressed. The firm's proposed corrective actions must be included in a written response to the NRA. 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. Enforcement may involve voluntary and non-voluntary action, or, in the case of suspected criminal activity, legal action.

When company management is unwilling or unable to provide adequate corrective actions in an appropriate time frame, formal non-voluntary enforcement actions will be demanded, as appropriate for the situation encountered. When deciding on the type of action, the initial decision should be based on the seriousness of the problem and the most effective way to protect the consumer. Laboratory tests that support observations of inadequate cGMP procedures are strong evidence for supporting enforcement actions. Where an inspection reveals deficiencies, sample collection should be considered if pertinent. However, 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. 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. The initial assessment and decision should be based on the seriousness and / or the frequency of the problem. 11. FOLLOW-UP INSPECTIONS:

Compliance Inspections are performed to evaluate or verify implementation of corrective actions after enforcement action has been taken. The coverage given in compliance inspections should be related first to those areas found deficient and being corrected. In addition a determination must be made on the overall compliance status of the firm after the corrective actions are 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. The level-I inspection option should be used for a compliance inspection, especially if the level-II inspection option was used during the prior inspection. 12. Grading system:

All points should be graded based on the following scheme: 1= If Tasks is fully implemented. 0.5= If Tasks is partially implemented. 0= If Tasks is not implemented. The score of 80% or better receive GMP compliance approval for biological drug manufacturing. The firm receives permission to manufacture, distribute, 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. The firm will not be permitted to manufacture, sell or distribute its product both domestically and internationally immediately. If scores does not reach 50% within 3 months, the regulatory body of Ministry of Health would issue a closure order of firm. The firm with the score of 50%-80% is allowed 6 months time to comply with cGMP regulations. Conditional production is permitted until the compliance of pending cGMP

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

Annex-1
GUIDANCE TO PREPARE QUALITY INSPECTION REPORT It is recommended that reports be divided into four parts: A. (a) (b) (c) (d) (e) (f) (g) (h) General information on the company or manufacturing facility Description of the inspection Observations Conclusions GENERAL INFORMATION: Manufacturers name. Address (including telephone, fax, email ). Address of manufacturing site if different from that given above. Manufacturing license number, if applicable. Activities Short description of site Number of employees engaged in production, QC, QA, storage and distribution. Use of outside scientific, analytical, or other technical assistance in relation to manufacture and analysis. . DESCRIPTION OF THE INSPECTION

B. B-1

(a) Date(s) of inspection(s). (b) Previous inspection date. (c) Type of inspection. (d) Scope of inspection. (e) (f) For foreign firms, record of inspection by proper authority is required. Brief report of inspection activities undertaken.

(g) Samples taken and results obtained. (h) Assessment of the site master file. (i) cGMP-related recalls from the market of any product in the last 2 years. B-2 Inspector(s)

(a) Name(s) of inspector(s) and accompanying experts. B-3 Introduction

(a) Brief summary of the manufacturing activities. (b) Other manufacturing activities carried out on the site (e.g. manufacture of cosmetics, research and development). (c) Use of outside scientific, analytical, or other technical assistance in manufacture and quality control. (d) Brief description of the quality management system of the firm responsible for manufacture. Reference can be made to a site master file if one is available. C. OBSERVATIONS:

The observations made during the inspection that are considered to be non-compliant with cGMP should be listed. Where positive observations are included in the report, clear distinction should be made between positive and non-compliant. Non-compliant observations can be classified, e.g. as critical, major and minor if the Member State concerned has defined these terms. The date by which corrective action and completion are requested in accordance with the policy of the national regulatory authority should be given. C.1 Quality assurance

(a) Quality system and documented quality policy of the manufacturer, e.g. as described in the quality manual. C.2 (a) (b) (c) (d) (e) C.3 (a) Organization and personnel Organizational chart showing the arrangements for quality assurance, including production and quality control. Qualifications, experience and responsibilities of key personnel. Outline of arrangements for basic and in-service training and method of keeping records. Health requirements for personnel engaged in production. Personnel hygiene requirements, including clothing. Premises Manufacturing areas (design, location etc.) used e.g. for storage and manufacturing (e.g. weighing, production, packaging) and flow of personnel and material. Special areas for the handling of highly toxic, hazardous and sensitizing materials. Nature of construction and finishes.

(b) (c)

(d)

(e) (f) (g) (h) C.4 (a) (b) (c) C.5 (a) (b)

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

C.6 (a) (b) (c) (d) C.7 (a) (b) (c) (d) (e)

(f) C.8 (a) (b) C.9 (a) (b)

Documentation (e.g. specifications, procedures, reports, records). Sanitation and hygiene Procedures for sanitation and/or cleaning (e.g. of premises and equipment) and records. Personal hygiene. Validation Validation master plan. Validation and qualification protocols and reports for qualification and validation (e.g. of premises, systems, equipment, process, computer, cleaning, analytical methods). Stages of validation. Types of validation. Documentation Documentation (e.g. specifications, procedures, records, protocols, reports). Preparation, revision and distribution of documentation. Reports on production, quality control (including environmental control), engineering and other relevant areas. Complaints Procedure, records and investigation. Product recalls Procedure, records and investigation. Contract production and analysis

(c) (d) C.10 (a) (b) (c)

C.11 (a) C.12 (a) C.13

(a) Responsibilities of contract giver. (b) Responsibilities of contract accepter. (c) Contract (containing clearly defined responsibilities). (d) GMP compliance of the contract accepter (initial assessment and continued compliance audited at regular intervals). C.14 (a) (b) (c) (d) Self-inspection and quality audits Procedure, program and compliance. Items for self-inspection. Self-inspection team. Frequency of self-inspection.

(e) (f) (g) (h) C.15

Self-inspection report. Follow-up action. Quality audit. Suppliers audits. Summary

Brief summary of the findings, and recommendations (where applicable). D. CONCLUSIONS

A statement regarding the GMP status.

Name: ______________________ Signature:_____________________

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, 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

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

SUMMARY OF COMPANY ORGANIZATION AND INSPECTION INSPECTION of _______________________________________________________; 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.) _____________________________ _____________________________ _____________________________ PRODUCTION DEPARTMENT Position Title (with phone No.) _____________________________ _____________________________ _____________________________ _____________________________ ANIMAL FACILITIES Position Title (with phone No.) _____________________________ _____________________________ ENGINEERING/MAINTENANCE Position Title (with phone No.) _____________________________ _____________________________ QUALITY CONTROL DEPT Position Title (with phone No.) _____________________________ _____________________________ QUALITY ASSURANCE DEPT Position Title (with phone No.) _____________________________ _____________________________ _______________ DEPARTMENT Position Title (with phone No.) _____________________________ _____________________________ _____________________________ _______________ DEPARTMENT Position Title (with phone No.) _____________________________ _____________________________ _____________________________ Name _______________________________________________________ _______________________________________________________ _______________________________________________________

Name _____________________________ _____________________________ _____________________________ _____________________________

Qualifications ___________________________ ___________________________ ___________________________ ___________________________

Name _____________________________ _____________________________

Qualifications ___________________________ ___________________________

Name _____________________________ _____________________________

Qualifications ___________________________ ___________________________

Name _____________________________ _____________________________

Qualifications ___________________________ ___________________________

Name _____________________________ _____________________________

Qualifications ___________________________ ___________________________

Name _____________________________ _____________________________ _____________________________

Qualifications ___________________________ ___________________________ ___________________________

Name _____________________________ _____________________________ _____________________________

Qualifications ___________________________ ___________________________ ___________________________

CHECK LIST FOR I NSPECTION AND PERPARATION OF REORT The following inspection check list is applicable to all biological drug establishments. 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, and who possess the scientific knowledge upon which the manufacture of these products is based. The personnel shall include specialists with training appropriate to the products made in the establishment.
S.No. 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, experience, training 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. Personnel hygiene requirements, including clothing.

QUALITY CONTROL Approved Incharge Pharmacist(s) Microbiologist(s) Chemist(s) Others (please specify numbers) Organizational Chart Record of Qualifications, 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 Production Health requirements for personnel engaged in QC. Personnel hygiene requirements, including clothing.

2. PREMISES:

Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid crosscontamination, buildup of dust or dirt and, in general, any adverse effect on the quality of products. (For premises where pathogenic organisms are utilized, see also 10.0 Containment Practices, A Facility Design).

S.No. 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. Defined & appropriately controlled area Prevent entry of pests. Plumbing, drains & traps Flow Charts showing patterns for material, personnel, product & waste movements Adequate Lighting

6)

7) 8) 9) 10) 11) 12) 13)

Building specification up-to-date. Paint work, cracks, Door seals-state of work Washing facilities-Adequacy Cleanliness, neatness, repair state Building plans approved as per drug rules Total covered area of building (in Sq. Ft.) Building being used for purposes other than those for which DML was granted (please give details if, 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, and capacity for carrying out manufacture of:Registered drugs. New drugs applied for registration Building condition. Entry of dust/birds/insects/rodents/other Worms adequately controlled Building properly constructed to facilitate smooth operations, adequate cleaning and disinfection.

20)

C) 1)

HVAC System Are pre-filters present in heating, 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, does the facility design permit effective fumigation? 4) Is the air flow adequate in all areas of production building?

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)

G. 1)

STERILE PROCESSING Are the aseptic manufacturing areas and operations consistent with the WHO guidelines for sterile biological products. Does the aseptic manufacturing area include :

2) a)

Smooth, hard non-particulate generating clean-able floors, walls and ceiling? Able to withstan

No horizontal pipes or conduits located over exposed components, in-process material, produ

Environmental controls, e.g. temperature, humidity and viable and non-viable particles? Are th b) Air supply through HEPA filters? Fixtures (electrical outlets and lighting, etc.) flush mounted and sealed to prevent air leakage, c) Identification of all pipes or conduits for air, clean steam or liquids? Properly equipped gowning area/air-lock? d) e) The ability to achieve appropriate air standards (Grade A,B,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)

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. EQUIPMENT:
This section deals with all the equipment used in the preparation, processing and control of intermediate, bulk and final product. Special consideration should be given to the capacity relative to the requirements of the establishment, about the ease of operation and cleaning/disinfect ion, the availability of spare parts, maintenance, validation and training of staff.

A) 1) 2)

EQUIPMENT Name, No., Total capacity & Operational/out of order.

Suitable for intended use. 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. 7) Balances, scales, measuring equipment of appropriate range. 8) 9) 10) Routinely calibrated/validated. Calibration and validation record available? Written standard Operating Procedures (SOPs) available

B) 1)

CLEANING DISINFECTION Availability of spares parts, Maintenance, validation & training of staff. Maintenance of equipment-SOP

2) Cleaning & maintenance 3) No cross contamination 4) Piping system, valves, vent filters. 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, Hot air oven SOPs 10) 11)

Supply and equipment which are exposed to pathogen during processing kept separate to avoid SOPs for utensils, autoclave, hot air oven should include.

Identification of responsible person for cleaning, defined schedule. Describe methods, procedure of clean equipment from contamination, inspect, before use, doc 12) Preventive maintenance program & record log book. 13) 14)

15)

4.

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. 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. Production steps should be effectively monitored and thoroughly documented to ensure safety, quality and efficacy of the final product.

A. 1)

ADEQUACY OF STARTING MATERIALS.

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, origin, 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, 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 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, alarms and backup power Inventory log? Adequately segregated storage to avoid mix-up or cross-contamination with other material?

g)

Check up on purity & identity at various intervals, write up.

h) B) 1) a) PROCESS Master Formula (MF) Does the MF adequately describe the complete production process? Is the MF up to date ;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, 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, if applicable? Are in-process intermediate materials tested for identity, quality, strength and purity? Alternat Process validation. Preparation & validation protocol.

b) 8) a) b) c) d) 9)

Such plan of production processing to be validated. Re-validation when required. Aseptic fill: SOP on aseptic filling process. Environment control of filling area. Validation by suitable media fills. Fill sufficient number of vials. Production plan Time & temperature Established for complete of product process

10) 11) 5. STARTING MATERIAL

In-process intermediate materials test for identity Quality purity, titre (Suppliers data on qualit Environmental monitoring

1.0 1) 2) 3) 4) 5) 6) 6. LABORATOR Y CONTROL: In-process controls testing may be performed by production staff under supervision of an independent QC department. Finished testing product is the responsibility of QC. The establishment of SOPs for all laboratory procedures is essential to ensure their accuracy and reproducibility. The QC laboratory demonstrates the consistency of

Specification & Q.C. release of raw/starting materials. Documentation for seed lot/cell bank. Documentation for raw materials for animal origin. Pre-testing and re-screening of biological material. Testing certificate of in-process intermediate History of cells including the number of generation doubling or passages of virus, is there a m

manufacturing by appropriate testing and review of historical records.

A 1) 2) 3)

Quality Control:

Does the quality control unit have adequate laboratory space and equipment? Are written calibration procedures available for instruments. Specification, standards, sampling plans. Test procedure and other laboratory control mechani

4)

Any change reviewed and approved by Q.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. Control include all required testing and documentation Reagent culture media, labeled and preparation recorded in lab. book with expiry date.

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, No. of samples and documentation required. All reference reagents kept secure properly stored identified and their integrity maintain. All retention samples, of each lot of final product stored under conditions consistent with prod Quarantine and release system Evaluation and investigation of complaints. Recall of products. Q.C. involved in decisions pertaining to product quality is Q.C. monitor consistency of produc Separate laboratory for microbiology and sterility testing. Animal test performed. Animal house maintained. Lab. Sufficiently equipped with suitable instruments/ equipments Separate laboratory for bacterial and viral vaccine test. Proper, clean and adequate facilities available for: Changing and storing clothes of personnel production

b)

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. Regular review of SOPs. Revisions to SOPs approved by an authorized person. System of distribution and control of SOPs. Validation and revalidation of all equipment. Calibration of all instruments. Reporting, investigating and recording all deviations. Frequency of environmental monitoring. Quarantine and release systems. Reprocessing of unsatisfactory and returned products. Evaluation and investigation of complaints. Recall of products. SOPs for all QC laboratory operations. Independence from QC department.

2) 3) 4) 5) 6) 7) 8) 9) 10)

11) 12) 13) 14)

15) 16) 17)

Self-inspection of each manufacturing and test area. Inspection follow-up to ensure action is taken. Follow-up of national control authoritys inspection and recommendations. Inspection system for contractors.

18)

7. FILLING AND PACKAGING PROCEDURE S:

A. 1) 2) 3) 4) 5) 6) 7) B. 1) 2) 3) 4) 5) 6) 7)

FILLING: Detailed, written procedures, followed for filling procedures; Q.C. approved and up-to-date. Record of filling signed by operators and reviewed by Q.C. Sterilizing records for equipment and components complete, signed and dated. Aseptic areas under positive HEPA filter air pressure, if installed. Laminar flow units validated regularly (at least every 6 months) if installed. Microbial count evaluation done routinely in aseptic work area. Aseptic filling operation (area and personnel) checked by routine sterile broth filling (at least LABELLING AND PACKAGING Labeling stored in a restricted access area. Labeling issued against individual work order. Used, returned and destroyed labeling reconciled and signed for. Records of labeling and packaging operations signed by operator and reviewed by Q.C. Labeling and packaging done according to Q.C. approved written procedures. Filling/labeling/packaging operations adequately separated. Adequate storage space for labeled and unlabelled products.

COMMENTS/REMARKS/RECOMMENDATIONS
1. Defects pointed out in the last inspection removed. Yes_______ No_______

General remarks/comments of the inspectors:

______________________________________________________________________________ ______________________________________________________________________________

3.

Recommendations

______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________

4. Comments of the firms representative ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________

Signature of the firms representative

_______________________ _______________________

Signatures of Inspectors