World Health Organization

World Health Organization
15 April, 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 15 April, 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 15 April, 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 GMP applies to production and QC 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 All activities in accordance with written SOPs
Records made at the time of action – and maintained Deviations avoided – when occur, follow SOP Quality unit involved Checks on yields - reconciliation One product at a time in an area 16.2 – 16.5

Good Practices 15 April, 2017 All containers, equipment and areas labelled Access to areas controlled No non-medicinal products in the areas In process controls performed Prevention of mix-ups, contamination and cross- contamination kept in mind 16.6 At all times during processing, all materials, bulk containers, major items of equipment, and where appropriate, the rooms and packaging lines being used should be labelled or otherwise identifi ed with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication should also mention the stage of production. In some cases it may be useful to also record the name of the previous product that has been processed. 16.7 Access to production premises should be restricted to authorized personnel. 16.8 Normally, non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products. 16.9 In-process controls are usually performed within the production area. The performance of such in-process controls should not have any negative effect on the quality of the product or another product (e.g. crosscontamination or mix up). 16.6 – 16.9

Good Practices 15 April, 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 15 April, 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 15 April, 2017 Avoidance of Cross-Contamination I Special precautions to prevent generation and dissemination of dust Proper air control – supply and extraction, suitable quality Risk assessment Avoid contamination by : dust, gas, particles, clothing, skin, 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 15 April, 2017 Avoidance of Cross-Contamination II Technical or organizational measures taken 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 15 April, 2017 Avoidance of Cross-Contamination III Campaign production: Separation in time Followed by appropriate cleaning Validated cleaning procedure Campaign production: The means that on product is separated form the other product by manufacturing several batches of one product, followed by thorough cleaning, before another product is manufactured. Validated cleaning procedure See also slide in sanitation and Hygiene 16.12(b)

Good Practices 15 April, 2017 Avoidance of Cross-Contamination IV Ventilation systems and airlocks Appropriately designed ventilation system with air supply and extraction systems (See HVAC module) Supply or incoming air should be filtered Filtered recirculation of air or 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 15 April, 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 15 April, 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 Environmental monitoring (particles and micro) Effectiveness of systems checked 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), 16.13, 16.14

Good Practices 15 April, 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) 16.12(g)

Good Practices 15 April, 2017 Processing operations Always ensure the work area is ready for the process (e.g. line opening) Environmental and in-process controls done and recorded Deviations and failures recorded Cleaning performed within specified (validated) time limits 16.15 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels or documents not required for the current operation. 16.16 Any necessary in-process controls and environmental controls should be carried out and recorded. 16.17 Means should be instituted of indicating failures of equipment or of services (e.g. water, gas) to equipment. Defective equipment should be withdrawn from use until the defect has been rectifi ed. After use, production equipment should be cleaned without delay according to detailed written procedures and stored under clean and dry conditions in a separate area or in a manner that will prevent contamination. 16.18 Time limits for storage of equipment after cleaning and before use should be stated and based on data. 16.19 Containers for fi lling should be cleaned before fi lling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles. 16.20 Any signifi cant deviation from the expected yield should be recorded and investigated. 16.15 – 16.20

Good Practices 15 April, 2017 Processing operations Use clean containers All pipes, equipment, instruments are: suitable for use, integrity checks calibrated and verified / checked in good state of repair correct connections 16.21 Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. 16.22 Pipes used for conveying distilled or deionized water and, where appropriate, other water pipes should be sanitized and stored according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 16.23 Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at prespecifi ed intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due should be clearly indicated on a label attached to the instrument. 16.24 Repair and maintenance operations should not present any hazard to the quality of the products. 16.21 – 16.24

Good Practices 15 April, 2017 Packaging operations No risk of mix-ups, contamination and cross-contamination Preferrably physical separation between lines Area indicates product under process Filling followed by sealing and labelling- no delays Correct performance e.g. overprinting, labels, leaflets Automated checks preferred 16.25 When the programme for packaging operations is being set up, particular attention should be given to minimizing the risk of crosscontamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation or an alternative system that will provide equal assurance. 16.26 Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents used previously and which are not required for the current operation. The line clearance should be performed according to an appropriate procedure and checklist, and recorded. 16.27 The name and batch number of the product being handled should be displayed at each packaging station or line. 16.28 Normally, fi lling and sealing should be followed as quickly as possible by labelling. If labelling is delayed, appropriate procedures should be applied to ensure that no mix ups or mislabelling can occur. 16.29 The correct performance of any printing (e.g. of code numbers or expiry dates) done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand, which should be rechecked at regular intervals. 16.30 Special care should be taken when cut labels are used and when overprinting is carried out off-line, and in hand-packaging operations. Roll feed labels are normally preferable to cut labels in helping to avoid mix ups. Online verification of all labels by automated electronic means can be helpful in preventing mix ups, but checks should be made to ensure that any electronic code readers, label counters, or similar devices are operating correctly. When labels are attached manually, in-process control checks should be performed more frequently. 16.31 Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. 16.25 – 16.30

Good Practices World Health Organization 15 April, 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 15 April, 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 15 April, 2017 Packaging operations Online control during packaging should include at least checks on: general appearance of the packages; whether the packages are complete; whether the correct products and packaging materials are used; whether any overprinting is correct; the correct functioning of line monitors. Samples taken away from the packaging line should not be returned. 16.32

Good Practices 15 April, 2017 Packaging operations Reintroduction - only after special inspection, investigation and approval. Detailed records of this operation. Discrepancy in reconciliation investigated and recorded before release. Unused batch-coded packaging materials destroyed. Returning of unused materials to stores – SOP followed Batch records reviewed as part of batch release Investigation in case of discrepancies 16.33 Products that have been involved in an unusual event during packaging should be reintroduced into the process only after special inspection, investigation and approval by authorized personnel. A detailed record should be kept of this operation. 16.34 Any signifi cant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated, satisfactorily accounted for, and recorded before release. 16.35 Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure requiring checks to be performed before returning unused materials should be followed if uncoded printed materials are returned to stock. 16.36 Production records should be reviewed as part of the approval process of batch release before transfer to the authorized person. Any divergence or failure of a batch to meet production specifi cations should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specifi c failure or discrepancy. A written record of the investigation should be made and should include the conclusion and followup action. 16.33 – 16.36

Good Practices World Health Organization 15 April, 2017 Production Operations – Sanitation – I Work-flow designed to avoid potential contamination , mix-ups and errors Access 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 15 April, 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 15 April, 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 QC concerned with sampling, testing, specifications QC should be independent from production Involved in various areas – not confined only to the laboratory 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). QC is the part of GMP concerned with sampling, specifications and testing, and with the organization and documentation which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be compliant with the requirements. QC is not confined to laboratory operations, but may be involved in many decisions concerning the quality of the product. 17.1. – 17.2.

Good Practices 15 April, 2017 Each manufacturer should have a QC “function” Supervised by a person with qualification and experience Resources should include: Adequate facilities Trained personnel Approved procedures for all activities Specifications and test procedures Pharmacopoeia Each manufacturer should have a QC function. The QC function should be independent of other departments and under the authority of a person with appropriate qualifications and experience. Adequate resources must be available to ensure that all the QC arrangements are effectively and reliably carried out. The basic requirements for QC are as follows: adequate facilities, trained personnel and approved procedures must be available for sampling, inspecting, and testing starting materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; samples of starting materials, packaging materials, intermediate products, bulk products and finished products must be taken by methods and personnel approved of by the QC department; 17.3(a)

Good Practices 15 April, 2017 Basic Requirements for Quality Control – II Sampling inspecting and testing of materials, bulk, finished products Monitoring environmental conditions Qualification and validation Maintaining records of actions, deviations, investigations Ensure ingredients and finished products are of the required quality and comply with marketing authorization Keeping retention samples 17.3 .

Good Practices 15 April, 2017 Other responsibilities include 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 Participate in environmental monitoring Participate in Quality Risk Management programs 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. 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. Participate in quality risk management exercises 17.4

Good Practices 15 April, 2017 QC Access QC personnel must have access to production and other areas Sampling e.g. water system, steam, environmental monitoring For investigations 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 certain hormones. 17.5

Good Practices 15 April, 2017 Sampling Avoid contamination, cross-contamination and mix-ups during sampling - no adverse effects Sampled containers labelled and re-sealed Clean sampling equipment used - stored separately from other laboratory equipment 17.8 Sampling should be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling. 17.9 Care should be taken during sampling to guard against contamination or mix up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean. Some particularly hazardous or potent materials may require special precautions. 17.10 Sampling equipment should be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment. 17.8 – 17.10

Good Practices 15 April, 2017 Control of starting materials and intermediate, bulk and finished products – and printed packaging material Each lot/batch examined following receipt Samples taken - representative of the batch Samples tested according to test procedures Results checked by supervisor prior to release or rejection Control of starting materials and intermediate, bulk and finished products 17.6 All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected. 17.7 Samples should be representative of the batches of material from which they are taken in accordance with the approved written procedure. 17.6 – 17.7, 17.15

Good Practices 15 April, 2017 Each sample container should bear a label indicating: (a) the name of the sampled material; (b) the batch or lot number; (c) the number of the container from which the sample was taken; (d) the number of the sample; (e) the signature of the person who has taken the sample; (f) the date of sampling. 17.11 Each sample container should bear a label indicating: (a) the name of the sampled material; (b) the batch or lot number; (c) the number of the container from which the sample has been taken; (d) the number of the sample; (e) the signature of the person who has taken the sample; (f) the date of sampling. 17.11

Good Practices 15 April, 2017 Out of specification results SOP for OOS investigation followed OOS reported without delay Investigated Action taken – see also guidelines from stringent regulatory authorities) Out-of-specification results obtained during testing of materials or products should be investigated in accordance with an approved procedure. Records should be maintained. See guidelines such as US FDA and UK MHRA. The trainer can explain that an OOS result should be reported without delay to the supervisor. A thorough investigation should be done to establish the reason for the OOS. This may include hypothesis testing. Laboratory investigations may be extended to production where necessary. Samples should not be tested into compliance 17.12

Good Practices 15 April, 2017 Test requirements: Starting and packaging materials Materials tested prior to release Results checked by QC manager (meet specification) An identity test on a sample from each container normally required Reduced sampling and testing subject to certain conditions in supplier qualification Test requirements Starting and packaging materials 17.13 Before releasing a starting or packaging material for use, the QC manager should ensure that the materials have been tested for conformity with specifi cations for identity, strength, purity and other quality parameters. 17.14 An identity test should be conducted on a sample from each container of starting material (see also section 14.14). It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled. This validation should take account of at least the following aspects: — the nature and status of the manufacturer and of the supplier and their understanding of the GMP requirements; — the QA system of the manufacturer of the starting material; — the manufacturing conditions under which the starting material is produced and controlled; and — the nature of the starting material and the medicinal products in which it will be used. Under such a system it is possible that a validated procedure for exemption from the requirement for identity testing of each incoming container of starting material could be accepted for the following: — starting materials coming from a single product manufacturer or plant; or — starting materials coming directly from a manufacturer, or in the manufacturer’s sealed container where there is a history of reliability, and regular audits of the manufacturer’s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an offi cially accredited body.

Good Practices 15 April, 2017 Reduced sampling: A validated procedure Consider the nature and status of the manufacturer and supplier (GMP); QA system of the manufacturer of the starting material; Manufacturing conditions; nature of the starting material and products in which it will be used coming from a single product manufacturer or plant; coming directly from a manufacturer, or in the manufacturer’s sealed container where there is a history of reliability, and regular audits of the manufacturer’s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body. 17.14 Starting materials 17.14 An identity test should be conducted on a sample from each container of starting material (see also section 14.14). It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled. This validation should take account of at least the following aspects: — the nature and status of the manufacturer and of the supplier and their understanding of the GMP requirements; — the QA system of the manufacturer of the starting material; — the manufacturing conditions under which the starting material is produced and controlled; and — the nature of the starting material and the medicinal products in which it will be used. Under such a system it is possible that a validated procedure for exemption from the requirement for identity testing of each incoming container of starting material could be accepted for the following: — starting materials coming from a single product manufacturer or plant; or — starting materials coming directly from a manufacturer, or in the manufacturer’s sealed container where there is a history of reliability, and regular audits of the manufacturer’s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an offi cially accredited body.

Good Practices 15 April, 2017 Not applicable normally to: starting materials supplied through agents and brokers where the source of manufacture is unknown or not audited; starting materials for use in parenteral products Reduced sampling and testing may not be appropriate in some cases. E.g if materials are supplied through brokers as repackaging may have taken place, and also if materials are used in sterile products Each batch (lot) of printed packaging materials must be examined following receipt. 17.14

Good Practices 15 April, 2017 Can results be taken from the Certificate of Analysis (from the supplier?) Subject to appropriate periodic validation Reliability of the supplier’s analysis On-site audits of the supplier’s capabilities Original COAs (not photocopies) or authenticity assured COAs must contain relevant information such as name and address of supplier; signatures, qualifications, materials, batch number, specifications, results, dates 17.16 In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the supplier’s analysis through appropriate periodic validation of the supplier’s test results (see sections 8.8 and 8.9) and through on-site audits of the supplier’s capabilities. (This does not affect section ) Certificates must be originals (not photocopies) or otherwise have their authenticity assured. Certificates must contain at least the following information (7): (a) identification (name and address) of the issuing supplier; (b) signature of the competent official, and statement of his or her qualifications; (c) the name of the material tested; (d) the batch number of the material tested; (e) the specifications and methods used; (f) the test results obtained; (g) the date of testing. 17.16

Good Practices 15 April, 2017 In-process control records – keep as part of the batch records Each batch of finished product – confirm compliance with specification before release If a product does not meet the specification – rejected In-process control 17.17 In-process control records should be maintained and form a part of the batch records (see section 15.25). Finished products 17.18 For each batch of medicines product, there should be an appropriate laboratory determination of satisfactory conformity to its fi nished product specifi cation prior to release. 17.19 Products failing to meet the established specifi cations or any other relevant quality criteria should be rejected. 17.17 – 17.19

Good Practices 15 April, 2017 Review of Records QC records reviewed as part of batch approval process Batch failure should be thoroughly investigated - written record of the investigation – extend to other batches if needed Retention samples kept of finished product in their final packaging stored under the recommended conditions Samples of active starting materials and excipients also kept Sufficient quantity to permit at least two full re-examinations. Batch record review 17.20 QC records should be reviewed as part of the approval process of batch release before transfer to the authorized person. Any divergence or failure of a batch to meet its specifi cations should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specifi c failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action. 17.21 Retention samples from each batch of finished product should be kept for at least one year after the expiry date. Finished products should usually be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials should be retained for at least one year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases and water) should be retained for a minimum of two years if their stability allows. Retention samples of materials and products should be of a size sufficient to permit at least two full re-examinations.

Good Practices 15 April, 2017 Stability studies QC to evaluate the quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products Establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions Stability determined prior to marketing Significant changes in processes, equipment, packaging materials, etc. – stability testing. Stability studies 17.22 QC should evaluate the quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products. 17.23 QC should establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions. 17.25 Stability should be determined prior to marketing and following any significant changes in processes, equipment, packaging materials, etc. , 17.25

Good Practices 15 April, 2017 Written programme for ongoing stability consisting of: complete description of the medicine involved in the study; testing parameters and methods; provision for the inclusion of a sufficient number of batches; the testing schedule for each medicine; provision for special storage conditions; provision for adequate sample retention data summary, evaluation and the conclusions of the study. Stability studies 17.24 A written programme for ongoing stability determination should be developed and implemented to include elements such as: (a) a complete description of the medicine involved in the study; (b) the complete set of testing parameters and methods, describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability; (c) provision for the inclusion of a suffi cient number of batches; (d) the testing schedule for each medicine; (e) provision for special storage conditions; (f) provision for adequate sample retention; (g) a summary of all the data generated, including the evaluation and the conclusions of the study. 17.24

Good Practices 15 April, 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. 2.1,

World Health Organization

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World Health Organization

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