Inspection of pharmaceutical manufacturers
Inspection of drug distribution channels
These guidelines are intended to promote harmonization of pharmaceutical inspection practices among WHO Member States. They are directed to government inspectors—particularly those operating within small national regulatory authorities (1)—to assist them in assessing manufacturers' compliance with good manufacturing practices (GMP) (2). They will also be of value to manufacturers themselves when engaged in self-inspection or audit.
They cover inspection of the production and control of final dosage forms of pharmaceutical products destined for human and veterinary use and of drug substances (active pharmaceutical ingredients or bulk drug substances) employed in their manufacture. Within the national context their scope may need to be extended since similar regulations are often enforced to control pharmaceutical and biological products, medical devices, diagnostic products, foods, and food additives. In all cases the same fundamental principles apply.
Inspection and licensing of pharmaceutical manufacturing facilities on the basis of compliance with GMP are a vital element of drug control. They are also pivotal to the operation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (3), which requires an attestation by the competent regulatory authority in the exporting country that a given product is manufactured in premises and using operating practices that conform with GMP.
The guidelines also have relevance in various other contexts, including:
• self-inspection or internal audit of a factory or a part of it carried out by personnel of the company;
• inspection by an independent person or group of persons as a review of the quality system of a company in compliance with the standards issued by the International Organization for Standardization (ISO 9000–9004 (4)) or the British Standards Institution (BS 5750 (5)) or with other equivalent national standards;
• audit of a manufacturer or supplier by authorized agents of the customer.
The government inspectorate represents the enforcement arm of the national drug regulatory authority. Its function is to ensure adherence by manufacturers to all licensing provisions and specifically to GMP. The objectives are to control and enforce general standards of production and to provide authorization for the manufacture of specific pharmaceutical products. The first objective involves a sequential examination of production and control activities on the basis of the GMP guidelines issued by WHO or of nationally determined requirements. The second requires verification that production and quality control procedures employed in the manufacture of specific products are performed correctly and that they accord with data supplied in the relevant licensing applications.
Inspection will, of course, depend on national legislation and regulations and/or the resources available.
The role of the inspector
Inspectors should have previous training and practical experience in the manufacture and/or quality control of pharmaceutical products. Graduate pharmacists, chemists, or scientists with an industrial background in pharmaceutical production would qualify for consideration.
In-post training should include an element of apprenticeship gained by accompanying experienced inspectors on site visits as well as participation in courses and seminars on relevant subjects including modern pharmaceutical technology, microbiology, and the statistical aspects of quality control.
The primary responsibility of an inspector is to present a detailed factual report on standards of manufacture and control applied to specific products. However, inspection should not be limited to compilation of an inventory of faults, irregularities, and discrepancies. Provided it is in keeping with national policy and does not breach understandings regarding confidentiality of information having commercial value, advice may be offered on how production and control procedures can be usefully upgraded. An inspector should always be expected, for example, to offer advice on how to improve an in-process test procedure or to offer other assistance which, in his or her opinion, serves the public interest. An inspection should be regarded as an opportunity to assist and motivate a manufacturer to comply with GMP and to correct any specific deficiencies.
The inspection process
The planning, organization, method of work, and format of the resultant report should always be determined by the precise objective of the inspection. Inspections vary in nature according to the objective:
This is a full inspection of all applicable components of GMP and licensing provisions. It may be indicated when the manufacturer:
— is newly established;
— requests renewal of a licence to operate;
— has introduced new product lines or new products, or has made significant modifications to manufacturing methods or processes, or has made changes in key personnel, premises, equipment, etc.;
— has a history of non-compliance with GMP;
— has not been inspected during the last 3–5 years.
Manufacturers with a consistent record of compliance with GMP through previous routine inspections are eligible for concise inspection. The focus of a concise inspection is on a limited number of GMP requirements selected as indicators of overall GMP performance, plus the identification of any significant changes that could have been introduced since the last inspection. Collectively, the information obtained will indicate the overall attitude of the firm towards GMP. Evidence of unsatisfactory GMP performance observed during a concise inspection should trigger a more comprehensive inspection.
Follow-up inspection (reassessment or reinspection)
Follow-up visits are made to monitor the result of corrective actions. They are normally carried out from 6 weeks to 6 months after the initial inspection, depending on the nature of the defects and the work to be undertaken. They are limited to specific GMP requirements that have not been observed or that have been inadequately implemented.
Special visits may be necessary to undertake spot checks following complaints or recalls related to suspected quality defects in products. Reports of adverse drug reactions may also indicate that all is not well. Such inspections may be focused on one product, a group of related products, or specific operations such as mixing, sterilization, or labelling.
Special visits may also be made to establish how a specific product is manufactured as a prerequisite for marketing approval or issuance of an export certificate.
A further reason for special visits is to gather specific information on—or to investigate—specific operations and to advise the manufacturer of regulatory requirements.
Quality systems review
A quality systems review is a relatively new concept. Its purpose is to describe a quality assurance system that has been shown to operate satisfactorily. It entails a description of the quality system and the standards to be observed, normally in a manual containing a statement of the manufacturer's policy on quality assurance. It should also define the management structure needed to implement the policy, along with the procedures in each management area needed to ensure that adequate quality standards are set for the product, manufacturing processes are correctly defined, records are kept, and quality control and other quality assurance activities are carried out.
Frequency and duration of inspections
The frequency and duration of visits should be determined by the type of inspection required as well as by the workload and number of inspectors. New manufacturing establishments must be inspected before they are licensed, and new facilities must be inspected before production is started.
For all companies, inspections should be carried out on a regular schedule, ideally annually.
For large companies marketing a wide range of products, the inspection of the site may be split up into several visits over a longer period, e.g., 5 years where this is the period of validity of the manufacturing licence or the GMP certificates.
The length of a given inspection is determined by the size of the company and the purpose of the visit. It can extend from a few days to 2 weeks or more. The time taken also depends on the number of inspectors assigned to the visit.
In many countries, visits are made by one (or more) inspectors, sometimes accompanied by a specialist when production of biologicals, sterile production areas, or other special facilities are to be examined.
Preparing for the inspection
Drug inspection begins at the desk of the inspector. A review should be made of the documents relating to the company to be visited, available from the drug regulatory authority. These may include the manufacturing licence, the marketing authorization dossiers for leading products, reports of adverse drug reactions, complaints and recall records, the results of regulatory (surveillance) testing, and the previous inspection reports.
Company documents, including the annual report for the shareholders, the complaints file, and self-inspection/internal audit reports, are valuable sources of information. The last of these, depending on national legislation, may be withheld from the inspector. In some countries, a compromise is reached, the company presenting the internal audit reports to the inspector for general information after the latter's own report has been finalized. In any case, it should be possible to verify the frequency of self-inspections, and to which parts of the plant they have been applied.
Announced inspections cover regular visits to evaluate new plants and new production lines and to decide on the renewal of a licence.
Unannounced inspections are necessary for concise, follow-up, and special visits.
In certain countries regular inspections are unannounced as a matter of policy.
The visit usually begins with a meeting between the inspector(s), repre-sentatives of the company or plant management, and those responsible for the products or areas to be inspected. Credentials should be presented, letters of authority inspected, and an explanation given of why the inspection is being carried out.
It is advantageous for the company to appoint at least one "escort" who is directly involved in the preparation of the products that are the object of the inspection. Escorts should be chosen who are generally familiar with the quality systems of the company and who are involved in the self-inspection programme.
The meeting may be followed by a perusal of the company's documents by the inspector or by a walk-through visit, or both. This will permit the inspector to finalize the plan for the inspection. It is recommended that the inspector both develops and follows this plan independently, rather than accepting guidance from company management. Some basic rules for conducting the inspection are as follows:
• Inspection should follow the original plan as far as possible; items that are specific to certain areas of the facility, such as in-process testing and working documents, may need to be checked at the point of operation. Care should be taken to cover activities such as water production, sample storage, and validation.
• It is advisable to follow production flow from reception of the starting materials to the shipment of the finished products. The frequency of recalls and return of goods should be carefully noted.
• Documents such as master formulae, test specifications, standard operating procedures, and batch records (including protocols of analyses, etc. and documents relating to the control of printed materials and labelling operations) require close verification.
Without prejudice to the need to verify documentation, it is essential that the inspection be based largely on observation and cover the total working hours of the manufacturer. It is recommended that the inspector start the plant tour as soon as possible after arrival.
Inspectors can profitably use a short checklist to ensure that all areas of operations have been investigated. A very detailed checklist developed from GMP guidelines is of use specifically for the training of inspectors. Experience has shown that rigid adherence to a too-detailed checklist can lead to possible overlooking of vulnerable areas of a quality assurance system specific to the company/plant under investigation. For an experienced inspector, knowledge of the manufacturer's weak points allied with intuition may serve better than a checklist. Different checklists may be found in the recommended publications and documents listed.
Stability-testing programme. The inspector should be satisfied that there exists a documented ongoing programme specifying the regular withdrawal of samples of all products from the production line for stability testing. The testing schedule for stored samples should employ appropriate conditions of temperature and light stress, and suitable stability-indicating analytical methods that yield conclusions consistent with claimed shelf-life. The systems should permit re-evaluation of product stability following any changes in the manufacturing process or formula.
Significant changes in facilities, equipment, products, and senior personnel since the last inspection should be noted. The principle here is that changes represent possible areas of weakness or causes of non-compliance with GMP. For example, new equipment may require changes to be made in procedures; new product lines may require new product master files; and departures of senior personnel such as the quality control manager may result in behavioural or procedural changes.
Occasionally, an inspector may require access to other premises, documents, or information on the company. Ideally, the inspector's authority should be determined by legislation, but in the absence of clear legal or regulatory provisions, it is suggested that the GMP code is used as a guide and the inspector should have the right to verify compliance with every requirement listed in the code.
The inspector should not be concerned about information not covered by GMP—e.g., finance and personnel—where this does not infringe on the company's responsibilities or staff education and training.
Photographs or videos taken during the visit may be excellent illustrative material for the report. National legislation should stipulate that the inspector has the right to take visual records during the inspection to document the production premises or laboratories.
In many cases, an aerial photograph of the manufacturing site, possibly with surrounding grounds, may be obtained from the company together with other relevant materials for inclusion in the report.
Collecting samples. It is normal practice during the visit for the inspector to take samples for testing by the official quality control laboratory. Samples are usually taken from released products (e.g., from the finished-goods warehouse) but may also be taken from stocks of raw materials or in-process material. In order to protect sample integrity, any protocol meant for enforcement or legal purposes should set out the procedures for sample collection, analysis, and documentation. The following should be stated:
— name(s) of the sampled product(s), batch number(s), date, source, number of samples, and remarks on type of packaging and storage conditions;
— circumstances of sampling, e.g., suspected quality defects, routine surveillance, verification of compliance with GMP;
— instructions for the placing of seals on containers of sample materials;
— written confirmation of the receipt of the samples by the inspector (possibly together with the manufacturer's certificates of analysis and any other supporting documents).
The manufacturer, represented by the company escort, should be encouraged to take duplicate samples from the same batch(es), for "in-house" testing if a problem is later identified.
Before the inspector leaves the premises after the inspection, a final discussion with company management is recommended. If possible, the inspector should list any unsatisfactory findings and outline any irregularities or other observations to which management may wish to respond.
It is recommended that reports be divided into four parts: general information on the company or manufacturing facility, description of the inspection, observations, and conclusions. Annexes may contain supporting information (a list of products manufactured, an organization chart, the annual company report, photographs, etc.). The third and fourth parts may be combined. Appendix 2, which is an extract from a document prepared for the Pharmaceutical Inspection Convention, provides an example of the form and content of the inspector's report.
In order to save the inspector's time, the first part of the report containing basic data may be supplied by the company beforehand, provided that this fact is clearly stated in the report and the information supplied is verified by the inspector during the visit. An example of items that should be considered for inclusion is given in Appendix 2, section C "Site master file".
The second part should describe the complete progress of the inspection step by step, documenting which parts of the factory, warehouses, laboratories, records, documents, etc. were inspected.
The third part is devoted to observations. Changes, improvements, and examples of deterioration since the previous inspection should be noted by the inspector.
Positive observations should take the form of a description of the processes that the firm is carrying out particularly well and that may be considered examples of particularly good manufacturing practice.
Negative observations (non-compliance with GMP requirements) should distinguish between whether the defect lies in the system itself or in a failure to comply with the system. For instance, when cleaning is found to be suboptimal, it is important to know whether the standard operating procedures are inadequate or lacking, or whether adequate written procedures exist but are not being followed by personnel.
In the final part of the report, the inspector should summarize deficiencies, unsatisfactory practices, etc. (listed in decreasing order of importance), suggest corrective actions, and make recommendations. This part, together with the third part, should be discussed with the company management and responsible authorized persons at the end of the inspection.
A copy of the complete written report, after supervisory approval, should be provided to the company management with a covering letter. The corrective actions to be taken, together with a time limit for their execution, should also be presented to the management of the company.
Inspection reports may be treated as confidential documents depending on national legislation. Under certain international agreements, reports may be exchanged between drug regulatory authorities.
Depending on national legislation, regulatory authorities may take action to correct unsatisfactory practices and prevent the distribution of products with suspected quality defects or manufactured under conditions that do not comply with GMP requirements. In extreme cases, the closing down of operations may be required. In practice, these measures are used only in exceptional cases constituting a hazard to health.
In many countries, the drug regulatory authority has the legal power to suspend or revoke the marketing authorization for a product when the manufacturer does not comply with GMP. In addition, manufacturing or marketing authorizations (licences), the reregistration of products, and the issue of a variation licence or a GMP certificate may be delayed until appropriate measures have been taken by the company, and possibly have been confirmed by reinspection. As a rule, the manufacturer concerned has the right to appeal.
1. Guiding principles for small national drug regulatory authorities. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first report. Geneva, World Health Organization, 1990: 64–79 (WHO Technical Report Series, No. 790).
2. Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992: 14–79 (WHO Technical Report Series, No. 823).
3. WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first report. Geneva, World Health Organization, 1990: 57–63 (WHO Technical Report Series, No. 790).
4. International Standards: Quality management and quality assurance standards—Guidelines for selection and use (ISO 9000), Quality systems—Model for quality assurance in design/development, production, installation and servicing (ISO 9001); Quality systems—Model for quality assurance in production and installation (ISO 9002); Quality systems—Model for quality assurance in final inspection and test (ISO 9003); Quality management and quality system elements—Guidelines (ISO 9004). Geneva, International Organization for Standardization. 1987 (rev. 1990).
5. Quality systems. Part 2. Specification for manufacture and installation (BS 5750: Part 2). London, British Standards Institution, 1979.
Appendix 1. Recommended publications and documents
ASEAN manual for inspection of GMP. Association of South East Asian Nations, 1988.
Drug manufacturer's self-inspection manual as to conformity with GMP requirements. In: GMP regulations of Japan, 3rd ed. Tokyo, Ministry of Health and Welfare, 1988: 101–195.
Good drug manufacturing practices (GMP), audit check-list. Government of Brazil, Ministry of Health, 1983.
Grundregeln fьr die Herstellung von Wirkstoffen und die Sicherung ihrer Qualitдt; Fragebogen zu den Grundregeln fьr die Herstellung von Wirkstoffen und die Sicherung ihrer Qualitдt [Basic rules for the production of active ingredients and their quality assurance; audit checklist to the basic rules for the production of active ingredients and their quality assurance]. Pharmazeutische Industrie, 1981, 43: 537–542 (republished in: Oeser W, Sander A. Pharma-Betriebsverordnung, Kommentar [GMP comments]. Stuttgart, Wissenschaftliche Verlagsgesellschaft, 1988).
Guide to inspection of bulk pharmaceutical chemical manufacturing. Food and Drug Administration, US Department of Health and Human Services, Public Health Service, 1987.
Steinborn L. Quality assurance manual for the pharmaceutical and medical device industries. Buffalo Grove, IL, Interpharm Press, 1986.
Appendix 2. Form and content of the inspector's report
A. Inspector's information
1. Date of inspection(s) on which the information is based and name(s) of inspector(s).
2. Brief report of inspection activities undertaken.
3. Samples taken and results obtained.
4. Assessment of the site master file (see section C).
5. GMP-related recalls from the market of any product in the last two years.
B. Summary and conclusions
1. The inspector's general impression of the firm and his or her assessment of the acceptability of its GMP status for the range of products concerned.
2. Failures to comply with the PIC Guide to Good Manufacturing Practice (in order of importance) and with the time limits set for them to be corrected by the manufacturer.
C. Site master file
A site master file is a document prepared by the manufacturer containing specific and factual GMP information about the production and/or control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, the site master file need describe only those operations, e.g., analysis, packaging.
A site master file should be succinct and, as far as possible, not exceed 25 A4 pages.
1. General information
1.1 Brief information on the firm (including name and address), relation to
other sites, and, in particular, any information relevant to understanding the manufacturing operations.
1.2 Pharmaceutical manufacturing activities as licensed by the national authority.
1.3 Any other manufacturing activities carried out on the site.
1.4 Name and exact address of the site, including telephone, fax, and 24-hour telephone numbers.
1.5 Type of products manufactured on the site, and information about any specifically toxic or hazardous substances handled, mentioning the way they are manufactured (in dedicated facilities or on a campaign basis).
1.6 Short description of the site (size, location, and immediate environment and other manufacturing activities on the site).
1.7 Number of employees engaged in production, quality control, storage, and distribution.
1.8 Use of outside scientific, analytical, or other technical assistance in relation to manufacture and analysis.
1.9 Short description of the quality management system of the firm responsible for manufacture.
2.1 Organization chart showing the arrangements for quality assurance, including production and quality control.
2.2 Qualifications, experience, and responsibilities of key personnel.
2.3 Outline of arrangements for basic and in-service training and how records are maintained.
2.4 Health requirements for personnel engaged in production.
2.5 Personnel hygiene requirements, including clothing.
3. Premises and equipment
3.1 Simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings not required).
3.2 Nature of construction and finishes.
3.3 Brief description of ventilation systems. More details should be given for critical areas with potential risks of airborne contamination (schematic drawings of the systems are desirable). Classification of the rooms used for the manufacture of sterile products should be mentioned.
3.4 Special areas for the handling of highly toxic, hazardous, and sensitizing materials.
3.5 Brief description of water systems (schematic drawings of the systems are desirable), including sanitation.
3.6 Description of planned preventive maintenance programmes for premises and of the recording system.
3.7 Brief description of major equipment used in production and control laboratories (a list of equipment is not required).
3.8 Description of planned preventive maintenance programmes for equipment and of the recording system.
3.9 Qualification and calibration, including the recording system. Arrangements for computerized systems validation.
3.10 Availability of written specifications and procedures for cleaning manufacturing areas and equipment.
4.1 Arrangements for the preparation, revision, and distribution of necessary documentation for manufacture.
4.2 Any other documentation related to product quality that is not mentioned elsewhere (e.g., microbiological controls on air and water).
5.1 Brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters.
5.2 Arrangements for the handling of starting materials, packaging materials, and bulk and finished products, including sampling, quarantine, release, and storage.
5.3 Arrangements for the handling of rejected materials and products.
5.4 Brief description of general policy for process validation.
6. Quality control
6.1 Description of the quality control system and of the activities of the quality control department. Procedures for the release of finished products.
7. Contract manufacture and analysis
7.1 Description of the way in which the GMP compliance of the contract accepter is assessed.
8. Distribution, complaints, and product recall
8.1 Arrangements and recording system for distribution.
8.2 Arrangements for the handling of complaints and product recalls.
9.1 Short description of the self-inspection system.