2. Why GMP? Provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy and quality Medicines are manufactured to comply with their marketing authorization Quality is built in Testing is part of GMP, but alone does not provide a good level of quality assurance

3. Why inspect? Verify compliance with GMP Verify compliance with marketing authorization Dossier: "Dedicated equipment is used" Inspection: Observation that this means "dedicated while used for the product or not being used for another product" Dossier: "The vials are removed from the lyophilliser and crimped in a grade A environment" Inspection: Correct, but before crimping they are stored in an uncontrolled corridor

4. 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 for active pharmaceutical ingredients - Annex 2, WHO Technical Report Series 957, 2010 (Based on ICH Q7)

5. Other WHO GMP Guidelines Pharmaceutical excipients Sterile pharmaceutical products Biological products Pharmaceutical products containing hazardous substances Investigational pharmaceutical products for clinical trials i Herbal medicinal products Radiopharmaceutical products Water for pharmaceutical use HVAC for non-sterile pharmaceutical dosage forms Validation

6. Good Manufacturing Practices (API): 1. Quality assurance 2. Good manufacturing practices for pharmaceutical products 3. Sanitation and hygiene 4. Qualification and validation 5. Complaints 6. Product recalls 7. Contract production and analysis General The contract giver The contract accepter The contract

7. Good Manufacturing Practices (cont'd) 8. Self-inspection and quality audits Items for self-inspection Self-inspection team Frequency of self-inspection Self-inspection report Follow-up action Quality audit Suppliers’ audits and approval 9. Personnel General Key personnel 10. Training

8. Good Manufacturing Practices (cont'd) 11. Personal hygiene 12. Premises General Ancillary areas Storage areas Weighing areas Production areas Quality control area 13. Equipment

9. Good Manufacturing Practices (cont'd) 14. Materials General Starting materials Packaging materials Intermediate and bulk products Finished products Rejected, recovered, reprocessed and reworked materials Recalled products Returned goods Reagents and culture media Reference standards Waste materials Miscellaneous

10. Good Manufacturing Practices (cont'd) 15. Documentation General Documents required: Labels Testing procedures Specifications for starting and packaging materials, for intermediate and bulk products and for finished products Master formulae and Batch Processing Records Packaging instructions and Batch Packaging Records Standard Operating procedures (SOP's) and records Logbooks

11. Good Manufacturing Practices (cont'd) 16. Good practices in production General Prevention of cross-contamination and bacterial contamination during production Processing operations Packaging operations 17. Good practices in quality control Control of starting materials and intermediate, bulk and finished products Test requirements Batch record review Stability studies

12. GMP is actually Good Common Sense Quality Management Quality Assurance GMP Production and Quality Control

13. Quality management in the drug industry Philosophy and essential elements: "The concepts of quality assurance, GMP, quality control and quality risk management are interrelated aspects of quality management, and should be the responsibility of all personnel. ……their relationship and their fundamental importance to the production and control of pharmaceutical products."

14. Quality Management The basic elements are: An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources 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”

15. The five P's Premises Primary materials People Procedure Processes defined and recorded

17. 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 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

18. Quality Assurance Wide-ranging concept covers all matters that individually or collectively influence the quality of a product Totality of the arrangements to ensure that the drug is continuously of the right quality for the intended use Quality Assurance incorporates GMP and also includes product design and development, with special focus on process design

19. The position of QA Director ProductionQC labOther Depts QA

20. Quality Assurance means to assure: Products are designed and developed correctly Complying with, e.g. GMP, GCP, GLP Production and control operations are defined Managerial responsibilities are defined In job descriptions The manufacture, supply and use of correct starting and packaging materials

21. 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 Complying with marketing authorization, production and QC requirements Proper storage, distribution and handling

22. 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

23. Quality Assurance means to (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

24. Quality Assurance includes: Responsibility of the Manufacturer for the quality of the product Fit for intended use Comply with marketing authorization 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

25. Good Manufacturing Practices That part of QA that ensures that products are consistently produced and controlled Quality standards Marketing authorization Aim: Diminishing risks that cannot be controlled by testing of product Contamination and cross-contamination Mix-ups (confusion)

26. Basic requirements for GMP: Clearly defined and systematically reviewed processes Qualification and validation is performed Appropriate resources are provided: Qualified and trained personnel Premises, space, equipment and services Materials, containers, labels Procedures, storage, transport Laboratories and in-process control

27. 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

28. GMP = continuous urge for improvement Involvement of the management Annual Product Quality Review Quality risk management Complaints handling Self-inspection

29. 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

30. Product Quality Review Objectives of 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

31. Product Quality Review (cont'd) Review of starting materials/ packaging materials, especially 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: Out-of-spec situations, rejections, deviations, changes Plus investigations and analysis of causes

32. Annual Product Quality Review (cont'd) Review of Marketing Authorization variations submitted, granted or refused (incl. third countries) Review of stability programme and 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)

33. 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.”

34. Complaints Procedure Designated responsible person: To handle complaint Decide on measure to be taken May be authorized person - if not, must advise authorized person of results Sufficient support staff Access to records Written procedure (SOP): Describes action to be taken Includes need to consider a recall (e.g. possible product defect)

35. Complaints Procedure – cont'd Thorough investigation: QC involved With special attention to establish whether "counterfeiting" may have been the cause Fully recorded investigation – reflect all the details Due to product defect (discovered or suspected): Consider checking other batches Batches containing reprocessed product

36. Complaints Procedure – cont'd Investigation and evaluation should result in appropriate follow-up actions May include a "recall" All decisions and measures taken should be recorded Referenced in batch records Records reviewed - trends and recurring problems

37. Complaints - other actions Inform competent authorities in case of serious quality problems such as: Faulty manufacture Product deterioration Counterfeiting ä Have a thorough recall procedure that is consistent with the complaints handling procedure ä Trend complaints, their investigations and results

38. Self-Inspection Purpose is to evaluate whether a company’s operations remain compliant with GMP The programme should cover all aspects of production and quality control be designed to detect shortcomings in the implementation of GMP recommend corrective actions set a timetable for corrective action to be completed Should be performed routinely Also on special occasions such as Recalls Repeated rejections

39. Self-Inspection (cont'd) Performed by team appointed by management, with: authority sufficient experience, expertise in their own field. knowledge of GMP may be from inside or outside the company Frequency should normally be at least once a year May depend on company requirements Size of the company and activities

40. Self-Inspection (cont'd) Report prepared at completion of inspection, including: results evaluation conclusions recommended corrective measures Follow-up action Effective follow-up programme Company management to evaluate both the report and corrective actions

41. Summary and conclusions: GMP compliance is not an option Quality should be built into the product GMP's are very similar and are really Good Common Sense Good Practices cover all aspects of manufacturing activities prior to supply The role and involvement of senior management is crucial