World Health Organization

World Health Organization
28 March, 2017 Basic Principles of GMP Good Practices in Production and Quality Control In this session, we are going to deal with an area of importance to the good functioning of a pharmaceutical factory, and look specifically at practices that are considered to be "good" in the production and quality control environment This will be a quarter-day session with the following approximate timings: Presentation 45 minutes Group session 45 minutes Group feedback minutes (Timings are approximate and should be adjusted to suit the class and the course structure.) Section 16 and 17

Good Practices World Health Organization 28 March, 2017 Objectives Discuss aspects of good practices in production Discuss aspects of good practices in quality control Group session There are two main objectives to this session: Firstly, Discuss aspects of good practices in production Secondly, Discuss aspects of good practices in quality control And then we will have a group session.

Good Practices 28 March, 2017 Manufacture WHO Definition: All operations of purchase of materials and products, production, quality control, release, storage and distribution of pharmaceutical products, and the related controls Production and QC are parts of GMP Separate training module on QC WHO defines manufacture as "all operations of purchase of materials and products, production, quality control, release, storage and distribution of pharmaceutical products, and the related controls". Production and QC are parts of GMP Note: There is a separate training module on QC Glossary

Good Practices 28 March, 2017 Design of Premises Design Walls, floors, ceilings, ledges, drains, air supply, dust extraction Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination Cleaning programme, appropriate cleaning, cleaning records Effective cleaning and disinfection choice of materials and chemicals, validation Drains – prevent backflow Protection from insects, birds, vermin and weather from receipt of raw materials to dispatch of released product The trainer should discuss general elements of good design features of the premises. Use practical examples to illustrate the points in the slide. 12.2, 12.3, 12.7, 12.9, 12.29

Basic Principles of GMP
World Health Organization 28 March, 2017 Walls, floors, ceilings – smooth and easy to clean No ledges or areas where dust can accumulate Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination Walls, floors, ceilings – smooth and easy to clean No ledges or areas where dust can accumulate Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination

Good Practices 28 March, 2017 Avoidance of Cross-Contamination I Special precautions should be taken to prevent generation and dissemination of dust Proper air control – supply and extraction, suitable quality Due to uncontrolled release of: dust, gas, particles, vapours, sprays, organisms, residue, insects Special precautions should be taken to prevent generation and dissemination of dust Proper air control – supply and extraction, suitable quality Due to uncontrolled release of: dust, gas, particles, vapours, sprays, organisms, residue, insects, operators

Good Practices 28 March, 2017 Avoidance of Cross-Contamination II Dedicated and self-contained areas for: Live vaccines Live bacterial preparations Certain other biological materials Penicillin products Certain products, such as live vaccines and other biological materials need to be produced in separated areas. In particular, penicillin should be produced in a separate facility. 16.12(a)

Good Practices 28 March, 2017 Avoidance of Cross-Contamination III Campaign production: Separation in time Followed by appropriate cleaning Validated cleaning procedure Campaign production: Separation in time Followed by appropriate cleaning Validated cleaning procedure See also slide in sanitation and Hygiene 16.12(b)

Good Practices 28 March, 2017 Avoidance of Cross-Contamination IV Ventilation systems and airlocks Appropriately designed ventilation system with air supply and extraction systems Supply or incoming air should be filtered Recirculation of air versus 100% fresh air supply Proper airflow patterns Pressure differentials Appropriately designed airlocks An important measure against cross-contamination is the design of the ventilation system. All incoming air should be filtered to an appropriate standard to achieve the grades of cleanliness specified for the room being supplied. The use of appropriate pressure differentials and air extraction, together with airlocks, is one of the main ways of achieving control over cross-contamination. (Airflow patterns and equipment design are other considerations.) Additionally, the recirculation of air must be examined carefully. If a ventilation system supplies 100% fresh air, then different rooms can be used for different products at the same time. However, if a system includes recirculation, then all rooms supplied by that system must be processing the same product, or the air must be filtered to an appropriate standard. If no filters are installed, then all ductwork will have to be cleaned during product changeover. 16.12 (c and d)

Good Practices 28 March, 2017 Avoidance of Cross-Contamination V Clothing Protection of operator and product Highly potent products or those of particular risk - need for special protective clothing Personnel should not move between areas producing different products Garments need to be cleaned Clothing relates to the protection of both the operator and the product. For highly potent products or those that create a particular risk of cross-contamination, special protective clothing needs to be worn. Decontamination processes for these clothes need to be in place. For all manufacturing areas where there is any risk of the product contaminating the clothing, the simple precaution of not moving between areas producing different products should be adopted. 16.12(e)

Good Practices 28 March, 2017 Avoidance of Cross-Contamination VI Cleaning and decontamination Procedure for removing soil and dirt Remove all cleaning chemical residues or disinfectant residues Remove and/or reduce micro-organisms Validated (known effectiveness of the procedure) Use cleanliness status labels Test for residues Cleaning should be a procedure for removing soil and dirt. It should not add or leave behind anything, including cleaning, chemical or disinfectant residues. It must remove or reduce micro-organisms. Cross reference to the module on validation can be mentioned if questions arise on how and what is cleaning validation. 16.12(f, h and i)

Good Practices 28 March, 2017 Avoidance of Cross-Contamination -VII Closed processing systems For example: totally enclosed water purification systems Tanks fitted with appropriate filtration - without removable lids Present special cleaning difficulties, sometimes use clean-in-place (CIP) Increasingly, facilities are being designed with closed processing systems. This trend is obviously one that should be encouraged, as it is a major element in the avoidance of cross-contamination. 16.12(g)

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – I Work-flow designed to avoid potential contamination Access to production areas restricted to authorized personnel direct operators, QC staff, warehouse staff, maintenance personnel, cleaners the more critical the area - fewer number of persons there The work-flow has to be designed in such a way as to avoid any potential contamination. Access to production areas should be restricted to authorized personnel only. These will include direct operators, QC staff, warehouse staff, maintenance personnel and cleaners. The more critical the area, the fewer the people that should be in there during processing operations.

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – II Simultaneous operations not permissible to process different products in different areas with a common ventilation system permissible to carry out secondary packaging activities for different products within a packing hall with adequate physical separation Processing of different products simultaneously within a single room or area supplied by the same ventilation system must not be carried out unless there is no risk of cross-contamination. Hence, it is permissible to dispense materials for different products within adjacent down-flow booths in a dispensary. This is because each booth creates its own protected environment. That is, it is not permissible to process different products in different parts of a tabletting facility, if the area is supplied by a single unfiltered recirculating air system It is also permissible to carry out secondary packaging activities for different products within a packing hall, provided there is adequate physical separation, such as a partition, since the product is sealed and there is no risk of airborne contamination. However, it is not permissible to process different products in different parts of a tabletting facility, if the area is supplied by a single recirculating air system, unless appropriate air filtration is used. .

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – III Area clearance checks Process of checking all materials and documentation from the previous batch removed all plant and equipment thoroughly cleaned and appropriate status labelling checklist useful The first step in any batch processing operation is the area clearance check. This is the process of checking that all materials and documentation from the previous batch have been removed, and that all plant and equipment has been thoroughly cleaned. A useful group exercise is to use a flipchart to get the trainees to list all the requirements for a cleaning status label. Items can include: name of the equipemnt, cleaned or not clean, date cleaned, who cleaned, who passed, how long will the cleaned equipment remain clean before rrequiring recleaning, etc.,

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – IV Area clearance checks The area clearance check should be carried out by two people between batches of same product, acceptable for both checks to be carried out by production personnel for product changeover, second check carried out by QC staff all checks carried out in accordance with written SOP and results recorded on the batch documentation. The area clearance check should be carried out by two people (one performing the check and the other confirming the result). Between batches of the same product, it is acceptable for both checks to be carried out by production personnel. However, where there has been a product changeover as well, the second check should be carried out by QC staff. All checks should be carried out in accordance with a written SOP and the results recorded on the batch documentation and cleaning record. A checklist is very useful for this purpose. Discuss with the trainees the requirement for QC to do the second check for the area clearance check.

Basic Principles of GMP
World Health Organization 28 March, 2017 Line opening: Includes checks on materials and components Batch number Expiry date Printed packaging material including cartons, leaflets, foil . . . Explain the process of line opening, documents to be checked, quantities, correct documents and materials, signatures and relevant procedure and checklists.

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – V Cleaning and cleaning validation degree of cleaning depends on whether consecutive batches are of same or different product Check cleaning agent is fully removed If possible hot water alone used for cleaning all cleaning and disinfecting solutions carefully prepared and expiry dated Final rinse with purified water, or water for injection (for sterile products) Full records kept We have already talked about cleaning of premises. Another important point is the cleaning of the equipment in which products are manufactured. The degree of cleaning will depend on whether consecutive batches are of the same product or of different products. It is important that any cleaning agent introduced is also fully removed so that it does not contaminate the product. Wherever possible, hot water alone should be used for cleaning. The final rinse should be with purified water or water for injection in the case of equipment used for processing sterile products. A validation programme should be based on the worst case situation, e.g. a relatively insoluble material that is active at low levels of concentration. Additionally, full records should be kept of cleaning and sanitation.

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – VI Water systems Water - major constituent of most products SOP for cleaning and sanitization of the water purification system should include distribution pipework Validation and removal of disinfectant before reuse The sanitation of water systems is particularly important, as water is such a major constituent of most products. Hot water (normally >75oC) and recirculated is a good sanitising agent. There should be a written standard procedure for cleaning and prevention of contamination, which should include not just the purification system but also the distribution pipework. The procedure should be validated, especially the removal of disinfectant before the system is put back into use. This is important because formaldehyde and peracetic acid are often used to disinfect water systems

Good Practices World Health Organization 28 March, 2017 Production Operations – Sanitation – VII Maintenance and repair activities inevitable in manufacturing area Should present no risk to product Whenever possible, all planned maintenance outside normal operating hours Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences Area clearance by QC Repair and maintenance activities are inevitable in a manufacturing area. However, they should be carried out in a way that does not present any risk to the product. Therefore, whenever possible, all planned maintenance should be done outside of normal operating hours. Any emergency work in a working area should be followed by a thorough clean down and disinfection of the area before manufacturing recommences, AND area clearance by QC

Good Practices 28 March, 2017 Good Practices in Quality Control (QC) Complete module on Quality Control Laboratories. This section only reflects some aspects of good practices in QC labs Each manufacturer should have a QC Department Independence from production and other departments is fundamental Under the authority of an appropriately qualified and experienced person with one or several control laboratories at his or her disposal The trainer should remind the participants that there is a complete module on Quality Control Laboratories. This section only reflects some aspects of good practices in QC labs. Each holder of a manufacturing authorization should have a quality control department (except for a holder performing only a fraction of the manufacturing process under a contract). The independence of quality control from production is considered fundamental. The quality control department should be independent fromother departments and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. 17.3

Good Practices 28 March, 2017 Basic Requirements for Quality Control Resources Adequate facilities Trained personnel Approved procedures The quality control department must have adequate resources. This means: Adequate laboratory facilities or access to them e.g. government or contract laboratories Appropriately qualified, trained and experienced personnel Approved written procedures. 17.3(a)

Good Practices 28 March, 2017 Basic Requirements for Quality Control Tasks Sampling Inspecting Testing Monitoring Releasing/rejecting The operational tasks of the quality control department are: Sampling Inspecting Analytical testing Monitoring of all materials and environmental conditions in the factory Releasing or rejecting materials for production use and finished products 17.3(a)

Good Practices 28 March, 2017 Basic Requirements for Quality Control - I Objects Starting materials Packaging materials Intermediates Bulk products Finished products Environmental conditions The objects of these activities are: Starting materials Packaging materials Intermediates Bulk products Finished products Environmental conditions 17.3(a)

Good Practices 28 March, 2017 Basic Requirements for Quality Control – II 1. Sampling: Methods and personnel approved by QC department 2. Qualification and validation done 3. Making records 4. Ensure ingredients and finished products are of the required quality and comply with marketing authorization, are in correct containers and have correct labels Let’s look at some of these basic requirements for quality control in greater detail: 1. Sampling should be undertaken by methods and personnel approved by the QC department. We described a little earlier the key issues around sampling. It is not a requirement that all sampling needs to be done by quality assurance or quality control personnel. The important point is that it is carried out in such a way that it is representative of the batch and in accordance with an SOP. QC personnel must have access to the production area to undertake sampling when necessary. 2. Validated test methods should be applied. The validation of test methods includes verification of: accuracy, precision, linearity, repeatability, robustness, specificity. This means that the test methods should be challenged to be able to demonstrate that the tests are able to give an accurate result on a repeatable basis. The methods must be capable of being applied with precision. The results obtained must be linear over a range of acceptable responses. Finally, the results must be repeatable over a number of identical tests. 3. Records for sampling, inspecting, testing of materials, intermediates and bulk and finished products need to be kept. It is essential too that the inspector assesses the records of the work done during processing. This means that there will be traceability on what happened. 4. The QC department should review and evaluate the relevant production documentation. This review needs to cover all quality aspects. As part of the documentation procedure, it is important that the quality control department approves all the documentation. This ensures that the manufacturing documentation and the quality assurance documentation are in harmony. 5. The QC department should generate or review records for deviations and failure investigations. As batches are produced, it is important that all deviations from the normal manufacturing procedure are recorded or documented. Any impact on product quality must be assessed. It may be that additional product testing is required. It may be that additional stability testing is necessary. 6. Ingredients must comply with the qualitative and quantitative composition of the finished product as approved in the marketing authorization. It is most important that the materials used in manufacture comply with the details registered in the marketing authorization. It is on this basis that the product was developed and that all the stability testing has been carried out. All the clinical trials have also been completed using materials of a consistent specification. The product has been registered using those sources and quality of materials. 17.3 b- e

Good Practices 28 March, 2017 Basic Requirements for Quality Control – III 5. Records of tests made 6. Review production documentation 7. Assess deviations 8. Retain samples of starting materials and products 9. Release of batches together with the authorized person Successful quality control also requires that: 7. Ingredients are of the required purity. We have already talked about the reasons for ensuring that the starting materials are of the specified quality. Without it the company will be unable to ensure that the rest of the process can be carried out with success. 8. Proper containers are used. During development of the product, care will have been taken to test the compatibility of the product with the container. Testing will have been undertaken to determine the effectiveness of the container in ensuring that product stability is maintained. The use of non-compliant or non-approved containers would mean that the product shelf-life cannot be guaranteed. 9. Labelling of in-house materials and finished product is correct. In some countries more than half of all product recalls are caused by incorrect printed components. These failures can be due to a variety of causes. These range from mix-ups in the printed components during printing or labelling and packing, to text errors in the printing which have not been identified. These same errors can also occur in-house if insufficient care is taken. 10.Batches are released by the authorized person. Release of batches of finished product should only occur after the authorized person has certified that production and quality control have been completed in accordance with the requirements of the marketing authorization. 11. Samples of starting materials and products and retained. Sufficient retention samples of the starting materials and the finished product in its final pack should be kept for one year past the expiry date. This is to allow for an evaluation of the product after it has been distributed should there be a need. It will also allow ongoing stability trials to be done. These samples help to control that the product conforms with the requirements during the entire shelf-life. 17.3 f- h

Good Practices 28 March, 2017 Other Duties of the Quality Control Department 1. Establish, validate and implement QC procedures 2. Evaluate, store and maintain reference standards 3. Correct labelling of containers and materials and products 4. Monitor stability of APIs and products 5. Participate in complaint investigations 6. Participate in environmental monitoring In addition to those already mentioned, the QC department has other duties to carry out, including: 1. Establishing, validating and implementing all QC procedures. All QC procedures need not only to be established in the first instance but also to undergo exactly the same critical review and maintenance process as operating procedures in all other areas. 2. Evaluating, maintaining, storing reference standards. Reference standards are among the most critical materials that QC has to handle. After all, the results of much testing rely upon comparison with an analytical reference standard. If that reference standard has not been looked after properly then all the test results may be incorrect. 3. Ensuring correct labelling of containers of materials and products. We have already mentioned just how critical this activity is. The major difficulty is the problem of seeing that an error has occurred. You are looking at a situation where there are thousands of components often being processed at high speed. It is nearly impossible for operators to see that an error has occurred. Systems must be in operation as the main safeguard. If equipment such as bar code readers are in operation it must be regularly checked for effectiveness. 4. Stability testing of active ingredients and finished products. A stability-testing programme should be developed for all products, described in the form of an SOP. Stability of active pharmaceutical ingredients should be monitored. Active ingredients should be regularly tested within their shelf-life to confirm suitability for continued use. The quality control department should have a very clear role in ensuring that samples are taken for the ongoing stability testing programme and that analysis is undertaken at the right time. 5. Participating in complaint investigations. We will be devoting a whole module to the importance of complaint and recall handling. It is worth repeating that complaints offer an opportunity for the company to learn from mistakes or product design failures. In this way actions can be taken to prevent re-occurrence. 6. Participating in environmental monitoring. There are many sides to environmental monitoring. With regard to products, the environment that we are referring to here is that which can immediately affect product quality. E.g.., swab testing and settle plates in a sterile area, testing of temperature and humidity control. There is another environment that needs to be looked at. External environment checks may be needed. 17.4

Good Practices 28 March, 2017 Assessment of Finished Products Should embrace all relevant factors, including: production conditions in-process test results manufacturing documentation compliance with finished product specification examination of the finished pack Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packing), documentation, compliance with the specification for the finished product, and an examination of the finished pack. 17.5

Good Practices 28 March, 2017 QC Access QC Personnel must have access to production areas: for sampling and investigation As appropriate QC personnel must have access to production areas for, for example, sampling and inspection. However, this must be balanced because it may not be appropriate, for instance, to have QC staff enter aseptic filling suites, or areas where there is highly potent dangerous material such as oncology (or cytotoxic material) or anovulent hormones. 17.6

Good Practices 28 March, 2017 Quality Control - summary QC is part of GMP - refer to the handout sampling specifications testing release procedures recalls and complaints decision-making in all quality matters authorization definition of product quality laboratory operations release decisions investigation and reporting Quality control is the part of GMP that is concerned with sampling, specifications, testing and with organization, documentation and release procedures, using validated methods implemented by trained and experienced personnel. The quality control process is not confined to laboratory operations, but must be applied to all decisions concerning the quality of a product. Quality control staff must therefore sign all manufacturing procedures that are relevant to product quality. Quality control staff will also monitor environmental conditions that have an effect on product quality. Each holder of a manufacturing licence should have a quality control department. This department must have staff who are clearly responsible for all quality control activities. They must have access to suitable facilities to perform all the testing that is required. The independence of quality control from production is considered fundamental. This means that the quality control manager should not report to the production manager. Likewise, the production manager should not report to the quality control manager. Legislation in different countries deals with this issue in different ways. Quality control departments need sufficient resources to carry out their responsibilities. Adequate resources should include: sufficient numbers of trained and experienced staff an appropriately designed laboratory, suitably equipped to enable all the quality control functions to be carried out in accordance with specifications. Ideally, the head of the quality control department should report directly to the managing director of the company. This means that for key decisions on product quality there is no interference from manufacturing staff. An alternative to this, which might in some circumstances be preferable, is that the quality controller reports to a professionally qualified technical director who is also responsible for production activities. This position does rely on the professionalism of the jobholder. The advantage of this second arrangement is that it encourages a scientific and professional review of the product quality against the standards and product use. This scientific evaluation of the product may not be possible for a chief executive who has no scientific background. All samples must be taken by methods and trained personnel approved by the quality control department. Records must be made of all sampling and testing and any deviations fully recorded and investigated. Samples (when taken) must be representative of the whole batch under consideration. The samples must be taken in accordance with a sampling plan, and in such a way as not to change the quality of the material being sampled. When containers have been sampled, they need to be labelled as such. The equipment used for sampling should be carefully cleaned between use, to ensure that it has no adverse affect on the result of the testing to be done. This cleaning will also assist in preventing cross-contamination. All activities relating to sampling should be described in a SOP, together with the safety precautions required. The quality control department should authorize all documentation that has an effect on product quality. This will include all SOPs as well as master documents for production and quality control batch documentation. A complete review of all batch documentation, relating to production and quality control, should be undertaken before the decision to release the product for sale is taken by the authorized person. The authorized person must check that the product conforms to the established specifications and the registered product details before releasing the product for distribution. The quality control department must retain sufficient samples of all materials in the batch and of the finished product, as described in the relevant SOP. The retained sample is used for ongoing stability testing and to permit, as necessary, a future examination of the product in case of a product complaint or recall. The quantity of the product to be retained will be determined by reference to the stability testing programme and the extent of testing required. Generally, the quantity is at least twice that required for full testing. The quality control department has the responsibility for handling all product complaints and recalls, including the management of any recall procedure, which must be available in the form of a written SOP. This area of activity deals with the less positive aspects of quality management. However, professional handling of any complaints or recalls is extremely important. There is a complete module devoted to this issue in this training programme. Part One 3.1, 3.2

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