Basic Principles of GMP Good Practices in Production and Quality Control Section 16 and 17 Module 13 | Slide 1 of 43 2013
Good Practices Objectives l Discuss aspects of good practices in production l Discuss aspects of good practices in quality control l Group session Module 13 | Slide 2 of 43 2013
Good Practices Manufacture l WHO Definition: All operations of purchase of materials and products, production, quality control, release, storage and distribution of pharmaceutical products, and the related controls l GMP applies to production and QC l Separate training module on QC Glossary Module 13 | Slide 3 of 43 2013
Good Practices l All activities in accordance with written SOPs l Records made at the time of action – and maintained l Deviations avoided – when occur, follow SOP – Quality unit involved l Checks on yields - reconciliation l One product at a time in an area 16. 2 – 16. 5 Module 13 | Slide 4 of 43 2013
Good Practices l All containers, equipment and areas labelled l Access to areas controlled l No non-medicinal products in the areas l In process controls performed l Prevention of mix-ups, contamination and crosscontamination kept in mind 16. 6 – 16. 9 Module 13 | Slide 5 of 43 2013
Good Practices Design of Premises l Design ä Walls, floors, ceilings, ledges, drains, air supply, dust extraction l Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination ä Cleaning programme, appropriate cleaning, cleaning records l Effective cleaning and disinfection ä choice of materials and chemicals, validation l Drains – prevent backflow 12. 2, 12. 3, 12. 7, 12. 9, 12. 29 l Protection from insects, birds, vermin and weather ä from receipt of raw materials to dispatch of released product Module 13 | Slide 6 of 43 2013
Basic Principles of GMP l Walls, floors, ceilings – smooth and easy to clean l No ledges or areas where dust can accumulate l Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination Module 13 | Slide 7 of 43 2013
Good Practices Avoidance of Cross-Contamination I l Special precautions to prevent generation and dissemination of dust l Proper air control – supply and extraction, suitable quality l Risk assessment l Avoid contamination by : ä dust, gas, ä particles, clothing, skin, ä vapours, sprays, ä organisms, residue, ä insects Module 13 | Slide 8 of 43 2013 16. 10 - 11
Good Practices Avoidance of Cross-Contamination II l Technical or organizational measures taken l Dedicated and self-contained areas for: ä Live vaccines ä Live bacterial preparations ä Certain other biological materials ä Penicillin products 16. 12(a) Module 13 | Slide 9 of 43 2013
Good Practices Avoidance of Cross-Contamination III l Campaign production: ä Separation in time ä Followed by appropriate cleaning ä Validated cleaning procedure 16. 12(b) Module 13 | Slide 10 of 43 2013
Good Practices Avoidance of Cross-Contamination IV l Ventilation systems and airlocks ä Appropriately designed ventilation system with air supply and extraction systems (See HVAC module) ä Supply or incoming air should be filtered ä Filtered recirculation of air or 100% fresh air supply ä Proper airflow patterns ä Pressure differentials ä Appropriately designed airlocks 16. 12 (c and d) Module 13 | Slide 11 of 43 2013
Good Practices Avoidance of Cross-Contamination V l Clothing ä Protection of operator and product ä Highly potent products or those of particular risk - need for special protective clothing ä Personnel should not move between areas producing different products ä Garments need to be cleaned 16. 12(e) Module 13 | Slide 12 of 43 2013
Good Practices Avoidance of Cross-Contamination VI l Cleaning and decontamination ä Procedure for removing soil and dirt ä Remove all cleaning chemical residues or disinfectant residues ä Remove and/or reduce micro-organisms ä Validated (known effectiveness of the procedure) ä Use cleanliness status labels ä Test for residues l Environmental monitoring (particles and micro) l Effectiveness of systems checked Module 13 | Slide 13 of 43 2013 16. 12(f, h and i), 16. 13, 16. 14
Good Practices Avoidance of Cross-Contamination -VII l Closed processing systems ä For example: totally enclosed water purification systems ä Tanks fitted with appropriate filtration - without removable lids ä Present special cleaning difficulties, sometimes use clean-in-place (CIP) 16. 12(g) Module 13 | Slide 14 of 43 2013
Good Practices Processing operations l Always ensure the work area is ready for the process (e. g. line opening) l Environmental and in-process controls done and recorded l Deviations and failures recorded l Cleaning performed within specified (validated) time limits 16. 15 – 16. 20 Module 13 | Slide 15 of 43 2013
Good Practices Processing operations l Use clean containers l All pipes, equipment, instruments are: – suitable for use, integrity checks – calibrated and verified / checked – in good state of repair – correct connections Module 13 | Slide 16 of 43 2013 16. 21 – 16. 24
Good Practices Packaging operations l No risk of mix-ups, contamination and cross-contamination l Preferrably physical separation between lines l Area indicates product under process l Filling followed by sealing and labelling- no delays l Correct performance e. g. overprinting, labels, leaflets – Automated checks preferred 16. 25 – 16. 30 Module 13 | Slide 17 of 43 2013
Good Practices Production Operations – Sanitation – IV Area clearance checks l The area clearance check should be carried out by two people ä between batches of same product, acceptable for both checks to be carried out by production personnel ä for product changeover, second check carried out by QC staff ä all checks carried out in accordance with written SOP and results recorded on the batch documentation. Module 13 | Slide 18 of 43 2013
Basic Principles of GMP Line opening: l Includes checks on materials and components l Batch number l Expiry date l Printed packaging material including cartons, leaflets, foil. . . Module 13 | Slide 19 of 43 2013
Good Practices Packaging operations l 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. l Samples taken away from the packaging line should not be returned. 16. 32 Module 13 | Slide 20 of 43 2013
Good Practices Packaging operations l Reintroduction - only after special inspection, investigation and approval. Detailed records of this operation. l Discrepancy in reconciliation investigated and recorded before release. l Unused batch-coded packaging materials destroyed. l Returning of unused materials to stores – SOP followed l Batch records reviewed as part of batch release l Investigation in case of discrepancies Module 13 | Slide 21 of 43 2013 16. 33 – 16. 36
Good Practices Production Operations – Sanitation – I l Work-flow ä designed to avoid potential contamination , mix-ups and errors l Access ä restricted to authorized personnel ä direct operators, QC staff, warehouse staff, maintenance personnel, cleaners ä the more critical the area - fewer number of persons there Module 13 | Slide 22 of 43 2013
Good Practices Production Operations – Sanitation – VII l Maintenance and repair ä activities inevitable in manufacturing area ä Should present no risk to product l Whenever possible, all planned maintenance outside normal operating hours l Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences l Area clearance by QC Module 13 | Slide 23 of 43 2013
Good Practices in Quality Control (QC) l Complete module on Quality Control Laboratories. This section only reflects some aspects of good practices in QC labs l QC concerned with sampling, testing, specifications l QC should be independent from production 17. 1. – 17. 2. l Involved in various areas – not confined only to the laboratory Module 13 | Slide 24 of 43 2013
Good Practices Each manufacturer should have a QC “function” l Supervised by a person with qualification and experience Resources should include: l Adequate facilities l Trained personnel l Approved procedures for all activities l Specifications and test procedures l Pharmacopoeia Module 13 | Slide 25 of 43 2013 17. 3(a)
Good Practices Basic Requirements for Quality Control – II 1. Sampling inspecting and testing of materials, bulk, finished products 2. Monitoring environmental conditions 3. Qualification and validation 4. Maintaining records of actions, deviations, investigations 5. Ensure ingredients and finished products are of the required quality and comply with marketing authorization 6. Keeping retention samples Module 13 | Slide 26 of 43 2013 17. 3.
Good Practices 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 6. Participate in environmental monitoring 7. Participate in Quality Risk Management programs 17. 4 Module 13 | Slide 27 of 43 2013
Good Practices QC Access l QC personnel must have access to production and other areas l Sampling e. g. water system, steam, environmental monitoring l For investigations Module 13 | Slide 28 of 43 2013 17. 5
Good Practices Sampling l Avoid contamination, cross-contamination and mix -ups during sampling - no adverse effects l Sampled containers labelled and re-sealed l Clean sampling equipment used - stored separately from other laboratory equipment 17. 8 – 17. 10 Module 13 | Slide 29 of 43 2013
Good Practices Control of starting materials and intermediate, bulk and finished products – and printed packaging material l Each lot/batch examined following receipt l Samples taken - representative of the batch l Samples tested according to test procedures l Results checked by supervisor prior to release or 17. 6 – 17. 7, 17. 15 rejection Module 13 | Slide 30 of 43 2013
Good Practices 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 Module 13 | Slide 31 of 43 2013
Good Practices Out of specification results l SOP for OOS investigation followed l OOS reported without delay l Investigated l Action taken – see also guidelines from stringent regulatory authorities) 17. 12 Module 13 | Slide 32 of 43 2013
Good Practices Test requirements: Starting and packaging materials l Materials tested prior to release l Results checked by QC manager (meet specification) l An identity test on a sample from each container normally required l Reduced sampling and testing subject to certain 17. 13 -17. 14 conditions in supplier qualification Module 13 | Slide 33 of 43 2013
Good Practices Reduced sampling: A validated procedure l Consider the nature and status of the manufacturer and supplier (GMP); l QA system of the manufacturer of the starting material; l Manufacturing conditions; 17. 14 l 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. Module 13 | Slide 34 of 43 2013
Good Practices Not applicable normally to: l starting materials supplied through agents and brokers where the source of manufacture is unknown or not audited; l starting materials for use in parenteral products 17. 14 Module 13 | Slide 35 of 43 2013
Good Practices Can results be taken from the Certificate of Analysis (from the supplier? ) l Subject to appropriate periodic validation l Reliability of the supplier’s analysis l On-site audits of the supplier’s capabilities l Original COAs (not photocopies) or authenticity assured l COAs must contain relevant information such as name and address of supplier; signatures, qualifications, materials, batch number, specifications, results, dates 17. 16 Module 13 | Slide 36 of 43 2013
Good Practices l In-process control records – keep as part of the batch records l Each batch of finished product – confirm compliance with specification before release l If a product does not meet the specification – rejected 17. 17 – 17. 19 Module 13 | Slide 37 of 43 2013
Good Practices Review of Records l QC records reviewed as part of batch approval process l Batch failure should be thoroughly investigated - written record of the investigation – extend to other batches if needed l Retention samples kept of finished product – in their final packaging – stored under the recommended conditions – Samples of active starting materials and excipients also kept 17. 20 - 17. 21 l Sufficient quantity to permit at least two full re-examinations. Module 13 | Slide 38 of 43 2013
Good Practices Stability studies l QC to evaluate the quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products l Establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions l Stability determined prior to marketing l Significant changes in processes, equipment, packaging materials, 17. 22 - 17. 23, 17. 25 etc. – stability testing. Module 13 | Slide 39 of 43 2013
Good Practices Written programme for ongoing stability consisting of: (a) complete description of the medicine involved in the study; (b) testing parameters and methods; (c) provision for the inclusion of a sufficient number of batches; (d) the testing schedule for each medicine; (e) provision for special storage conditions; (f) provision for adequate sample retention 17. 24 (g) data summary, evaluation and the conclusions of the study. Module 13 | Slide 40 of 43 2013
Good Practices Quality Control - summary l QC is part of GMP - refer to the handout ä sampling ä authorization ä specifications ä definition of product quality ä testing ä laboratory operations ä release procedures ä release decisions ä recalls and complaints ä investigation and reporting ä decision-making in all quality matters 2. 1, 17. 1 - 17. 3 Module 13 | Slide 41 of 43 2013
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