Guide Lines for Cgmp Inspection

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GUIDE LINES FOR cGMPINSPECTION

OFBIOLOGICAL DRUGS

October, 2005

VersionI


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Ministry of Health

Government of Pakistan

Islamabad

CONTENTS OF MANUAL

1. Introduction

02

2. Objectives

02

3. Scope

03

4. Inspection Procedure

035. The Systems Approach

04

6. Inspection Coverage

07

7. Inspection Approaches

09

8. Conducting Inspection 10

9. Reporting

10

10. Enforcement11

11. Follow-up Inspections

13

12. Grading System

13


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13. Annex. I Guidance To Prepare Quality Inspection Report

14

14. Annex. II Inspection Checklist

19

15. References

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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 withinNational Regulatory Authority (NRA) to assist them in assessing manufacturers compliancewith 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, bloodproducts, 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 areprepared 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 properqualifications in Pharmacy with experience are appointed at Federal and Provincial levels for this


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purpose. Federal drug inspectors regulate the manufacturing processes of biological drugs while

provincial drug inspectors monitor storage, transportation, and sale of these products under thesupervision 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 alsoestablishes 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.

2. OBJECTIVE:-

This guideline represents a continuing compliance and surveillance activity conducted to ensure

that regulated biological products are prepared in compliance with GMP guidelines and theirsafety, 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 providesadministrative/ 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 drugproducts, 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: The three critical elements are:1. Quality System; 1. Standard Operating Procedures (SOPs)

2. Facilities and Equipment System; 2. Training

3. Materials System; 3. Documentation


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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 ineach 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 establishmentscompliance 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 inspectionwill 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 pre-approval inspections (PAI) of regulated products. NRA identifies the scope and

content of the inspection and invites Inspection Team to participate in theinspections.

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 tospecifications. 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 validationreports. Batch Production Record (BPR) evaluations; and evaluation of returned and


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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 itsresponsibility to review and approve all procedures related to

production, quality control and quality assurance, and to ensure thatprocedures 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 specificationresults, 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 counterfeitimported 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.

5.2 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 beevaluated as part of the inspection of the overall process, which is done within the

system where the process is employed.

5.3 Materials System:

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 andorderly 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 ofsignificant 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


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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 andmaintenance, 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; in-

process 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 productsproduced 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 aswell 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 awalk-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 shouldinclude 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 oflabels 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 facilitateadequate 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


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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 facilitateproper 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 stabilityprogram. An in-depth audit of this system should include review of the firms SOPs forcontrol 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 toensure 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 theperson 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 adequatecleaning, 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 orderlymanner, 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 newequipment 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 thefollowing three critical elements:

Procedures

Training of personnel

Documentation


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Actual observations of the processes applicable to each system should be performed whenever

possible. Because most products covered by this program are aseptically processed, inspectionalguidance 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 tothe 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 oris represented to possess.

If review of the facilitys discrepancy reports reveals recurring problems

associated with one or more particular employees, review the relevanttraining 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


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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 personperforming the work, including dates of the various entries; show test

results as well as the interpretation of results; show the expiration dateassigned 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 tothe 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.

7. INSPECTION APPROACHES:

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 sixsystems.

Level-II Inspection Option

The Level-II inspection option is a focused surveillance cGMP inspection that covers threeof

the six key systems, and provides verification of an establishments continued compliance withcGMP. This option also includes inspectional coverage of any significant changes to the


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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 thefollowing two mandatory systems: (1) Quality System, and (2) Production System; plus one

additionalsystem 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 asignificant impact on product safety or quality (review of BPRs, product recalls, etc.).

8. CONDUCTING INSPECTION:

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 torepeat 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 betailored 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 enteringinto 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 ofGMP 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.


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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 ofparticipants 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 inspectionalobservations 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 thescope 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 bestressed 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 thesystems 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 asingle heading.

Avoid drawing unsubstantiated conclusions.

Avoid using terms such as "inadequate" or unsatisfactory without qualification e.g. byexplaining 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.


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The report should reflect performance of a thorough, professional and efficient cGMP

inspection resulting in an impartial evaluation of the companys current state ofcompliance 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 longterm 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. Thefirm'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 usedas evidence for taking appropriate enforcement action. Enforcement may involve voluntary and

non-voluntary action, or, in the case of suspected criminal activity, legal action.


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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, asappropriate 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 collectionshould 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 optionshould 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 monthsmaximum) 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 cGMPregulations. Conditional production is permitted until the compliance of pending cGMP


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

closure of firm.


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Annex-1

GUIDANCE TO PREPARE QUALITY INSPECTION REPORT

It is recommended that reports be divided into four parts:

General information on the company or manufacturing facility

Description of the inspection

Observations

Conclusions

A. GENERAL INFORMATION:

(a) Manufacturers name.

(b) Address (including telephone, fax, email ).

(c) Address of manufacturing site if different from that given above.

(d) Manufacturing license number, if applicable.

(e) Activities

(f) Short description of site

(g) Number of employees engaged in production, QC, QA, storage and distribution.

(h) Use of outside scientific, analytical, or other technical assistance in relation tomanufacture and analysis. .

B. DESCRIPTION OF THE INSPECTION

B-1

(a) Date(s) ofinspection(s).

(b) Previous inspection date.

(c) Type ofinspection.

(d) Scope ofinspection.

(e) For foreign firms, record ofinspection by proper authority is required.

(f) Brief report ofinspection 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)


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(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. manufactureof 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 withcGMP 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 definedthese 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 thequality manual.

C.2 Organization and personnel

(a) Organizational chart showing the arrangements for quality assurance, including

production and quality control.

(b) Qualifications, experience and responsibilities of key personnel.(c) Outline of arrangements for basic and in-service training and method of

keeping records.

(d) Health requirements for personnel engaged in production.(e) Personnel hygiene requirements, including clothing.

C.3 Premises

(a) Manufacturing areas (design, location etc.) used e.g. for storage and

manufacturing (e.g. weighing, production, packaging) and flow of personnel

and material.(b) Special areas for the handling of highly toxic, hazardous and sensitizing

materials.

(c) Nature of construction and finishes.


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(d) Systems such as drainage, ventilation, air conditioning, and supply of steam

and gas. Detailed description of critical areas with potential risks ofcontamination and cross contamination.

(e) Classification of the rooms used for the manufacture of products, including

clean rooms.

(f) Water systems.(g) Planned preventative maintenance programme.

(h) Qualification of premises and systems as appropriate.

C.4 Equipment

(a) Design, location and adaptation of equipment used in production and controllaboratories.

(b) Planned preventative maintenance program for equipment and records.

(c) Qualification and calibration, including records.

C.5 Materials

(a) Sourcing of materials.(b) 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.

C.6 Good practices in production

(a) Transport, handling and use of starting materials, packaging materials, and

bulk and finished products.(b) Production operations and important parameters (e.g. sampling, quarantine,

weighing, process operations and conditions, acceptance limits).

(c) Validation (e.g. process).(d) Change control and deviation reporting.

C.7 Quality control

(a) Activities of quality control (including quarantine control, sampling, chemical

and microbial analysis).

(b) Organization and personnel.(c) Premises.

(d) Equipment and instrumentation.

(e) Materials.


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(f) Documentation (e.g. specifications, procedures, reports, records).

C.8 Sanitation and hygiene

(a) Procedures for sanitation and/or cleaning (e.g. of premises and equipment) and

records.(b) Personal hygiene.

C.9 Validation

(a) Validation master plan.(b) Validation and qualification protocols and reports for qualification and

validation (e.g. of premises, systems, equipment, process, computer, cleaning,

analytical methods).

(c) Stages of validation.(d) Types of validation.

C.10 Documentation

(a) Documentation (e.g. specifications, procedures, records, protocols, reports).

(b) Preparation, revision and distribution of documentation.

(c) Reports on production, quality control (including environmental control),engineering and other relevant areas.

C.11 Complaints

(a) Procedure, records and investigation.

C.12 Product recalls

(a) Procedure, records and investigation.

C.13 Contract production and analysis

(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 Self-inspection and quality audits

(a) Procedure, program and compliance.

(b) Items for self-inspection.

(c) Self-inspection team.

(d) Frequency ofself-inspection.


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(e) Self-inspection report.

(f) Follow-up action.(g) Quality audit.

(h) Suppliers audits.

C.15 Summary

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

D. CONCLUSIONS

A statement regarding the GMP status.

Name: ______________________ Signature:_____________________


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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


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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


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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)ADMINISTRATIONPosition Title (with phone No.)_______________________________________________________________________________________

Name_____________________________________________________________________________________________________________________________________________________________________

PRODUCTION DEPARTMENTPosition Title (with phone No.)____________________________________________________________________________________________________________________

Name____________________________________________________________________________________________________________________

Qualifications____________________________________________________________________________________________________________

ANIMAL FACILITIESPosition Title (with phone No.)__________________________________________________________

Name__________________________________________________________

Qualifications______________________________________________________

ENGINEERING/MAINTENANCEPosition Title (with phone No.)__________________________________________________________

Name__________________________________________________________

Qualifications______________________________________________________

QUALITY CONTROL DEPTPosition Title (with phone No.)__________________________________________________________

Name__________________________________________________________

Qualifications______________________________________________________

QUALITY ASSURANCE DEPTPosition Title (with phone No.)__________________________________________________________

Name__________________________________________________________

Qualifications______________________________________________________

_______________ DEPARTMENTPosition Title (with phone No.)_______________________________________________________________________________________

Name_______________________________________________________________________________________

Qualifications_________________________________________________________________________________

_______________ DEPARTMENTPosition Title (with phone No.)_______________________________________________________________________________________

Name_______________________________________________________________________________________

Qualifications_________________________________________________________________________________


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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 theseproducts 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 InchargePharmacist(s)

Microbiologist(s)Chemist(s)Others (please specify numbers)Organizational ChartRecord of Qualifications, experience, training and responsibilities of key personnel

Job descriptions of each staff memberArrangements for basic and in-service training and method of keeping records.Independence from Quality ControlHealth requirements for personnel engaged in production.Personnel hygiene requirements, including clothing.

QUALITY CONTROL

Approved InchargePharmacist(s)Microbiologist(s)Chemist(s)Others (please specify numbers)Organizational ChartRecord of Qualifications, experience and responsibilities ofkey personnel

Job descriptions of each staff memberArrangements for basic and in-service training and method of keeping records.Independence from ProductionHealth requirements for personnel engaged in QC.Personnel hygiene requirements, including clothing.

2.

PREMISES:


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Premises and

equipment must be

located, designed,

constructed,

adapted and

maintained to suit

the operationsto be carried out.

Their layout and

design must aim to

minimize the risk

of errors and

permit effective

cleaning andmaintenance in

order to avoid

cross-

contamination,

buildup of dust or

dirt and, in general,any adverse effect

on thequality of products.

(For premises

where pathogenic

organisms are

utilized, see also

10.0 Containment

Practices, AFacility Design).

S.No.A)

1)2)

LOCATIONSite approved as per drug rules (Please give details if not)Surroundings hygienic conditions (please give details if not)

B)

1)

2)

3)

4)

5)

6)

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


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7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

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 d

Proper section/area segregation/arrangement to prevent mix-ups and cross contamination

Sewage / trash / effluent disposal is adequate

Specifically designed as a biological unit

17)

a)b)

18)

19)

20)

Building of suitable size, and capacity for carrying outmanufacture 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 disinfect

C)

1)

2)

3)

4)

HVACSystem

Are pre-filters present in heating, ventilation and air-

conditioning (HVAC) Systems and replaced on a routine basis?

Are HEPA filters terminally located?

Are duct works and filters located out side the clean rooms?

If fumigation procedures are used, does the facility design permit effective fumigation

Is the air flow adequate in all areas of production building?


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5)

6)

Are room temperature and humidity effectively controlled?

D)

1)

2)

COMPRESSED AIR

Is the air supply pass through filters in the sterile area?

Are the air compressors properly maintained?

E)1)

CLEAN STEAMIs clean steam used for sterilization processes during

manufacturing operations?

F)

1)

2)

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?


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G.

1)

2)

a)

b)

c)

d)

e)

f)

g)

h)

i)

3)

a)

b)

c)

STERILE PROCESSING

Are the aseptic manufacturing areas and operations

consistent with the WHO guidelines for sterile biological products.Does the aseptic manufacturing area include :

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

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

Environmental controls, e.g. temperature, humidity and viable and non-viable particle

Air supply through HEPA filters?

Fixtures (electrical outlets and lighting, etc.) flush mounted and sealed to prevent air le

Identification of all pipes or conduits for air, clean steam or liquids?

Properly equipped gowning area/air-lock?

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

Dose the aseptic manufacturing area exclude:

Access doors for servicing equipment and

fixture?

Drain?

Sinks?


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4)

5)

6)

Is the vaccine processing area isolated and independent of any space used for any othe

Are the facilities appropriately designed and validated to comply with relevant contain

Is the aseptic manufacturing area cleaned?

3.

EQUIPMENT:

This section

deals with all the

equipment usedin the

preparation,

processing and

control of

intermediate,

bulkand final product.

Special

consideration

should be given

to the capacity

relative to therequirements of

theestablishment,

about the ease of

operation and

cleaning/disinfect

ion, theavailability of

spare parts,

maintenance,validation and

training of staff.


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A)

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

EQUIPMENT

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

Suitable for intended use.

Installed and arranged in an organized manner

Adequately cleaned & maintained (Please also givedetails).

Equipment status identified by labeling

Clean/Defective/under maintenance etc.

Balances, scales, measuring equipment of appropriate range.

Routinely calibrated/validated.

Calibration and validation record available?

Written standard Operating Procedures (SOPs) available


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B)

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

15)

CLEANINGDISINFECTION

Availability of spares parts, Maintenance, validation & training of staff.

Maintenance of equipment-SOP

Cleaning & maintenance

No cross contamination

Piping system, valves, vent filters.

Cleaning & sterilization

Maintaining closed system cleanin place

Sterilization place preferable (fermenters)

Filters-non fiber releasing calibration & validation-performance work

Autoclave, Hot air oven SOPs

Supply and equipment which are exposed to pathogen during processing kept separate

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

Preventive maintenance program & record log book.

4.


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PROD

UCTIO

N AND

IN-

PROCE

SSCONT

ROL

Production and

in-process

controls play aspecially

important role

in ensuring the

consistent

quality ofbiological

products. Teststhat are crucial

for quality

control but thatcannot be

carried out on

the finished

product shall beperformed at an

appropriate

stage of

production.Production

steps should be

effectivelymonitored and

thoroughly

documented toensure safety,

quality and

efficacy of the

final product.


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A.

1)

2)

a)

b)

c)

3)

a)

b)

c)

d)

e)

ADEQUACY OF STARTING MATERIALS.

Are there approved specifications for all starting material or raw material or raw mater

To ensure the quality of raw materials:

Is there a quarantine and release system?

Are the conditions of storage evaluated?

Do the contracts with vendors ensure quality and stability, including reporting of chan

For raw material of animal origin:

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?

Are rejected materials properly segregated from acceptable material?

Are biological materials that may contain infectious organisms screened or tested prio

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

b)

c)

d)

e)

f)

Characterization according to the WHO TRS relevant to the product?Demonstration of purity?

Manufacturing procedures?

Appropriate storage and security with continuous monitoring of temperature, alarms and back

Inventory log?

Adequately segregated storage to avoid mix-up or cross-contamination with other material?


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g)

h)

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

B)

1)

a)

b)

c)

2)

a)

b)

PROCESS

Master Formula (MF)

Does the MF adequately describe the complete production process?

Is the MF up to date ;and approved by QC/QA?

Is the Batch Production Record form and

adequate

Process validation:

Has each phase of the production process been validated according to an approved validation

Is re-validation done when required, and performed appropriately?

3)

a)

Aseptic fill:

Are suitable precautions taken to maintain aseptic conditionsduring the filling process?

4) Are time and temperature limits established for the completion of production phases?

5) Are viral removal and inactivation processes validated, if applicable?6) Are in-process intermediate materials tested for identity, quality, strength and purity?

7)

a)

Process validation.

Preparation & validation protocol.

b) Such plan of production processing to be validated.Re-validation when required.

8)

a)

b)

c)

d)

Aseptic fill:

SOP on aseptic filling process.

Environment control of filling area.

Validation by suitable media fills.

Fill sufficient number of vials.

9) Production planTime & temperature

Established for complete of product process


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10) In-process intermediate materials test for identity Quality purity, titre (Suppliers data o

11) Environmental monitoring

5.

STARTING

MATERIAL

1.0

1) Specification & Q.C. release of raw/starting materials.

2) Documentation for seed lot/cell bank.

3) Documentation for raw materials for animal origin.

4) Pre-testing and re-screening of biological material.

5) Testing certificate of in-process intermediate

6) History of cells including the number of generation doubling or passages of virus, is th

6.LABORATOR

Y CONTROL:

In-processcontrols testing

may be

performed by

production staffunder

supervision of

an independentQC department.

Finished testing

product is the

responsibility ofQC. The

establishment

of SOPs for alllaboratory

procedures is

essential to

ensure theiraccuracy and

reproducibility.

The QC

laboratorydemonstrates

the consistency

of


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manufacturing

by appropriate

testing and

review ofhistorical

records.

A

1)

Quality Control:

Does the quality control unit have adequate laboratory space and equipment?

2) Are written calibration procedures available for instruments.

3) Specification, standards, sampling plans. Test procedure and other laboratory control m

4) Any change reviewed and approved by Q.A

5) Laboratory control established to ensure tested materials confirm to appropriate standa

6) These labs. Control include all required testing and documentation

7) Reagent culture media, labeled and preparation recorded in lab. book with expiry date

8) Written sampling and testing plan for raw materials intermediate and final product and

9) Description of sampling and testing procedure for in-process material

10) Retest policy and criteria for retest, No. of samples and documentation required.11) All reference reagents kept secure properly stored identified and their integrity mainta

12) All retention samples, of each lot of final product stored under conditions consistent w

13) Quarantine and release system

14) Evaluation and investigation of complaints.

15) Recall of products.

16) Q.C. involved in decisions pertaining to product quality is Q.C. monitor consistency o

17) Separate laboratory for microbiology and sterility testing.

18) Animal test performed.

19) Animal house maintained.

20) Lab. Sufficiently equipped with suitable instruments/ equipments

21) Separate laboratory for bacterial and viral vaccine test.

22)a)

b)

Proper, clean and adequate facilities available for:

Changing and storing clothes of personnel

production


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c)Washing and toilets with soap/detergent and air dryers

/

Retiring/Dining rooms

B

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

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.


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15)

16)

17)

18)

Self-inspection of each manufacturing and test area.

Inspection follow-up to ensure action is taken.

Follow-up of national control authoritys inspection andrecommendations.

Inspection system for contractors.

7. FILLING

AND

PACKAGING

PROCEDURE

S:

A. FILLING:

1) Detailed, written procedures, followed for filling procedures; Q.C. approved and up-to

2) Record of filling signed by operators and reviewed by Q.C.

3) Sterilizing records for equipment and components complete, signed and dated.4) Aseptic areas under positive HEPA filter air pressure, if installed.

5) Laminar flow units validated regularly (at least every 6 months) if installed.

6) Microbial count evaluation done routinely in aseptic work area.

7) Aseptic filling operation (area and personnel) checked by routine sterile broth filling

B. LABELLING AND PACKAGING

1) Labeling stored in a restricted access area.

2) Labeling issued against individual work order.

3) Used, returned and destroyed labeling reconciled and signed for.

4) Records of labeling and packaging operations signed by operator and reviewed by Q.C

5) Labeling and packaging done according to Q.C. approved written procedures.6) Filling/labeling/packaging operations adequately separated.

7) Adequate storage space for labeled and unlabelled products.


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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

______________________________________________

Guide Lines for Cgmp Inspection

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