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1 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines
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Good Manufacturing Practices – Part I Purpose and Principles of GMP Anton Norder, MSc Technical Officer WHO EMRO 1 st Workshop on the WHO Prequalification Programme: Priority Essential Medicines, Cairo, Egypt, 6 and 7 June, 2007 2 20 Avenue Appia CH-1211 Geneva 27 Switzerland E-mail: nordera@who.int
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3 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Guidelines and references GMP applies to both Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs) FPP: WHO Good Manufacturing Practices for pharmaceutical products: main principles. WHO Technical Report Series, No. 908, 2003, Annex 4. API: WHO Good Manufacturing Practices: starting materials. WHO Technical Report Series, No. 823, 1992. ä (ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization http://www.ich.org/cache/compo/276-254-1.html) http://www.ich.org/cache/compo/276-254-1.html
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4 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (FPP): 1. Quality assurance 2. Good manufacturing practices for pharmaceutical products (GMP) 3. Sanitation and hygiene 4. Qualification and validation 5. Complaints 6. Product recalls 7. Contract production and analysis ä General ä The contract giver ä The contract accepter ä The contract
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5 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd) 8. Self-inspection and quality audits ä Items for self-inspection ä Self-inspection team ä Frequency of self-inspection ä Self-inspection report ä Follow-up action ä Quality audit ä Suppliers’ audits and approval 9. Personnel ä General ä Key personnel 10. Training
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6 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd) 11. Personal hygiene 12. Premises ä General ä Ancillary areas ä Storage areas ä Weighing areas ä Production areas ä Quality control areas 13. Equipment
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7 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd) 14. Materials ä General ä Starting materials ä Packaging materials ä Intermediate and bulk products ä Finished products ä Rejected, recovered, reprocessed and reworked materials ä Recalled products ä Returned goods ä Reagents and culture media ä Reference standards ä Waste materials ä Miscellaneous
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8 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd) 15. Documentation ä General ä Documents required: l Labels l Testing procedures l Specifications for starting and packaging materials, for intermediate and bulk products and for finished products l Master formulae and Batch Processing Records l Packaging instructions and Batch Packaging Records l Standard Operating procedures (SOP's) and records l Logbooks
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9 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd) 16. Good practices in production ä General ä Prevention of cross-contamination and bacterial contamination during production ä Processing operations ä Packaging operations 17. Good practices in quality control ä Control of starting materials and intermediate, bulk and finished products ä Test requirements ä Batch record review ä Stability studies
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10 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines GMP is actually Good Common Sense Quality Management Quality Assurance GMP Production and Quality Control Section 1 and 2
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11 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Management: Philosophy and essential elements What is Quality Management? ä The aspect of management function that determines and implements the “quality policy” ä The overall intention and direction regarding quality, as formally expressed and authorized by top management
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12 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Management The basic elements are: ä An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources ä The systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for “Quality” The totality of these actions is referred to as “Quality Assurance”
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13 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Intermezzo: the five P's Premises Primary materials People Procedures Processes defined and recorded
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14 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance Quality assurance is a management tool In contractual situations, it also serves to generate confidence in a supplier QA, GMP and Quality Control are interrelated aspects of Quality Management ä They are described on the following slides in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products 1.1
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15 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance Wide-ranging concept ä covers all matters that individually or collectively influence the quality of a product Totality of the arrangements ä to ensure that the drug is continuously of the right quality for the intended use Quality Assurance incorporates GMP ä and also includes product design and development, with special focus on process design 1.1
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16 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines The position of QA Director ProductionQC labOther Depts QA
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17 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance means to assure: Products are designed and developed correctly ä Complying with, e.g. GMP, GCP, GLP Production and control operations are defined Managerial responsibilities are defined ä In job descriptions The manufacture, supply and use of correct starting and packaging materials 1.1 a- d
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18 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance means to assure: (cont'd) Controls are performed, including intermediates, bulk, calibration and validation Correct processing and checking of the finished product Products are sold/supplied only after review by the authorized person ä Complying with marketing authorization, production and QC requirements Proper storage, distribution and handling 1.1 e - h
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19 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance means to assure: (cont'd) Procedures for self-inspection and quality audits are applied Deviations are reported, investigated and recorded System for change control is applied Regular evaluation of product quality to verify consistency and continued improvement 1.1 i - l
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20 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance includes: Responsibility of the Manufacturer for the quality of the product ä Fit for intended use ä Comply with marketing authorization ä Safety, efficacy and quality Commitment of senior management and involvement of all staff Comprehensively designed and well implemented quality system Full documentation and monitoring of effectiveness Competent personnel, sufficient premises, equipment and facilities 1.3
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21 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices That part of QA that ensures that products are consistently produced and controlled ä Quality standards ä Marketing authorization Aim: Diminishing risks that cannot be controlled by testing of product ä Contamination and cross-contamination ä Mix-ups (confusion) 2.1
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22 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 1 10 100 Preliminary Design Code & Debug Validate Detailed Design IntegrateOperation 1.2 1.6 1.4 3 5 2 4 18 8 80 Relative Cost of Correcting Error Maximum Minimum The cost of change
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23 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Basic requirements for GMP: Clearly defined and systematically reviewed processes Qualification and validation is performed Appropriate resources are provided: ä Qualified and trained personnel ä Premises, space, equipment and services ä Materials, containers, labels ä Procedures, storage, transport ä Laboratories and in-process control 2.1 a - c
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24 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Basic requirements for GMP: (cont'd) Clear, written instructions and procedures Trained operators Records of actions, deviations and investigations Records for manufacture and distribution Proper storage and distribution Systems for complaints and recalls 2.1 d - j
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25 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines GMP = continuous urge for improvement Involvement of the management Annual Product Quality Review Complaints handling Self-inspection
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26 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Involvement of the management The senior management is responsible to attain the company's quality objectives All different departments and all levels within departments should be involved; and it's the senior management who should facilitate this Also suppliers and distributors should be involved The senior management should make available the required resources The basis of the quality system is the quality statement and quality policy, by the senior management
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27 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Annual Product Quality Review Objectives to do an Annual Product Quality Review: To review and verify the consistency and appropriateness of the existing process To identify and highlight any trends in the process, e.g. in analytical results, yields etc. To identify any possible product or process improvements Not yet mandatory in WHO GMP, but it is likely to become mandatory like it is in other GMP's
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28 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Annual Product Quality Review (cont'd) Review of starting materials/ packaging materials, esp from new sources Review of in-process control results and finished product analytical control results Amount of batches and packaging units produced and their yields Reviews of: ä Out-of-spec situations ä Rejections ä Deviations ä Changes ä Plus their investigations as well as a trend analysis of causes
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29 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Annual Product Quality Review (cont'd) Review of Marketing Authorization variations submitted, granted or refused (incl. third countries) Review of stability monitoring programme and its trends Review of adequacy of previous decisions on changes or improvements or corrective actions For new Marketing Authorizations (plus new variations) a review of post marketing commitment The qualification status of all relevant equipment and utilities (like water, HVAC, gases, etc.) Review of Technical Agreements (if applicable), to verify they are up- to-date.
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30 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.1 Complaints handling Complaints: Principle “ All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures and corrective action should be taken. ”
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31 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.2 – 5.3 Complaints handling (cont'd) Complaints Procedure: Designated responsible person: ä To handle complaint ä Decide on measure to be taken ä May be authorized person - if not, must advise authorized person of results ä Sufficient support staff ä Access to records Written procedure (SOP): ä Describes action to be taken ä Includes need to consider a recall (e.g. possible product defect)
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32 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.4 – 5.6 Complaints handling (cont'd) Complaints Procedure – cont'd Thorough investigation: ä QC involved ä With special attention to establish whether "counterfeiting" may have been the cause ä Fully recorded investigation – reflect all the details Due to product defect (discovered or suspected): ä Consider checking other batches ä Batches containing reprocessed product
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33 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.7 – 5.9 Complaints handling (cont'd) Complaints Procedure – (cont'd) Investigation and evaluation should result in appropriate follow- up actions ä May include a "recall" All decisions and measures taken should be recorded Referenced in batch records Records reviewed - trends and recurring problems
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34 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.10 Complaints handling (cont'd) Other actions Inform competent authorities in case of serious quality problems such as: ä Faulty manufacture ä Product deterioration ä Counterfeiting ä Have a thorough recall procedure that is fitting completely to the complaints handling procedure ä Keep track on trends in complaints, their investigations and results
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35 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Self-Inspection Purpose is to evaluate whether a company’s operations remain compliant with GMP The programme should ä cover all aspects of production and quality control ä be designed to detect shortcomings in the implementation of GMP ä recommend corrective actions ä set a timetable for corrective action to be completed Be performed routinely Also on special occasions such as ä Recalls ä Repeated rejections ä When a GMP inspection is announced by the national drug regulatory authority 8.1
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36 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 8.3, 8.4 Self-Inspection (cont'd) The Self-Inspection Team Team appointed by management, with: ä authority ä sufficient experience, expertise in their own field. knowledge of GMP ä may be from inside or outside the company Frequency should normally be at least once a year ä May depend on company requirements ä Size of the company and activities
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37 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 8.5, 8.6 Self-Inspection (cont'd) Carrying out a Self-Inspection Report prepared at completion of inspection, including: ä results ä evaluation ä conclusions ä recommended corrective measures Follow-up action ä Effective follow-up programme ä Company management to evaluate both the report and corrective actions
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38 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Summary and conclusions: GMP is mandatory in countries with a regulated pharmaceutical market, and in the WHO Prequalification Programme too. GMP's are very similar, they are nothing but Good Common Sense Good Practices cover all aspects of company's activities prior to sales GMP is not a reward, nor an external assignment, it should be built into the company Just like quality, which should be built into the product The role and involvement of senior management is crucial GMP means an urge for continuous improvement, 3 of the tools to do so are: ä Annual Product Quality Reviews ä Complaint handling and trending ä Self-inspection
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39 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines http://www.who.int/prequal
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