1. 1 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines

2. 2 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 – Part III Inspection experience 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

3. 3 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Inspections done in the PQ Programme  GMP inspections at all API manufacturers and all FPP manufacturers ä Routine: full inspection, aiming to cover all parts of GMP ä Concise: focused on limited number of requirements, e.g. in cases of consistent record of GMP compliance or in cases of one major change that leads to an extra inspection ä Follow up: to monitor corrective actions ä Special: following complaints, recalls etc.  Normally a Routine inspection every 2 years.

4. 4 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Guiding principles for inspection  Risk based orientation when planning inspections  Science based policies and standards  Integrated quality systems  International standards  Public interest  Quality systems approach  Modern challenges including risk assessment by manufacturers

5. 5 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Process of risk management acc to ICH Q7A Ref. ICH Q9, Quality Risk Management

6. 6 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality by design (QbD)  Means designing and developing formulations and manufacturing processes to ensure predefined product quality  Understanding and controlling formulation and manufacturing process variables affecting the quality of a product  Product and process specifications ä Understanding of affect of formulation and process factors on product quality and performance  Quality built into the product  Interaction between review, compliance and inspection

7. 7 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Planning an inspection  Manufacturer's file incl. previous inspection reports and corrective actions taken  Site Master File  Type(s) of product(s) and their dossiers  Type of material(s)  Premises  Changes (deviations, additional products, cleaning procedure, campaigns etc)  Utilities and applications  Proposed programme for the inspection (sent by e-mail)

8. 8 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Classification of Observations  A critical deficiency was defined as a deficiency which had produced, or led to a significant risk of producing, either a product which was harmful to the human patient or a product which could result in a harmful residue in a food producing animal.  A major deficiency was defined as a non-critical deficiency, which had produced or might produce a product which did not comply with its marketing authorisation.  A minor deficiency was defined as a deficiency where an observation made could improve the quality system and quality assurance approach of the manufacturer, but which did not have a major impact on the quality of the product.

9. 9 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Inspection reports  After inspection: Inspection report, including a List of Observations  Conclusion stated: essentially compliant / non-compliant  Manufacturers requested to respond to the report by submitting a Corrective Action Plan  Reviewed by the inspectors  If further correspondence required: Interim Conclusion  If no further correspondence required: Final Conclusion

10. 10 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Performing the inspection Where to start in the inspection to assess GMP compliance?

11. 11 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Drawings of lay out of premises Example of Materials and People Flow Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods Material Flow People Flow Zone: Clean Zone: Packaging Zone: Controlled

12. 12 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Tour around the facilities

13. 13 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Equipment Contents and direction of flow indicated  e.g. water lines, equipment components, air-handling systems

14. 14 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Equipment All aspects including  Design, installation, operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc…

15. 15 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Qualification and Validation

16. 16 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Other topics to be inspected  Utilities: ä HVAC (Heating, Ventilation and Air Conditioning systems) ä Water ä Gases ä Compressed air ä Steam...  Batch documentation  Log books  Etc.

17. 17 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Prefilter Air flow patterns AHU Main filter Uni-directional Turbulent 1 23 HVAC

18. 18 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines + Production Room Exhaust air treatment Central air handling unit Terminal air treatment at production room level Fresh air treatment (make-up air) HVAC Main subsystems

19. 19 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Differential pressure on filters Turbulent / mixed airflow Description Uni-directional airflow / LAF Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Air flow pattern 22 N/A2, 3 Optional 22 2N/A 23 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) HVAC

20. 20 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Water for Pharmaceutical Use

21. 21 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Start at laboratory, walk through; assessing Organization and management:  Suitable size, construction and location - safety requirements considered in the design  Adequate degree of separation of the activities  Sufficient number of rooms or areas to assure the isolation of test systems.  Suitable testing and safety equipment ä E.g. voltage stabilizers should be installed where needed  Storage rooms or areas for supplies and materials with protection against infestation, contamination, and/or deterioration. Quality Control Part One. 7.1. – 7.5.

22. 22 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Storage areas and central store  Separate for secure storage of samples, retained samples, reagents, laboratory accessories, reference materials  Appropriate storage conditions e.g. refrigeration where necessary  Restricted access to designated personnel  Organized to accommodate incoming and outgoing samples, reagents, equipment, instruments and other devices  Appropriate storage conditions.  Storage area with clean bottles, vials, spoons, funnels, and labels required for dispensing reagents from larger to smaller containers Quality Control Part One. 7.7.1.1. – 7.7.1.4

23. 23 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Personnel  Sufficient number, with necessary education, training, technical knowledge and experience  No conflict of interest or other pressure  Competence ensured for activities, performing tests and/or calibrations, validations or verifications, evaluation of results and signing test reports and calibration certificates  Staff undergoing training - supervised, with formal assessment after training  Personnel must be qualified on the basis of appropriate education, training, experience and/or demonstrated skills Quality Control Part One. 6.1 – 6.3.

24. 24 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Personnel (2)  Permanently employed, or under contract  Contracted personnel to be supervised and sufficiently competent, motivated – work complying good practice of the laboratory.  Current job descriptions for managerial, technical and key support personnel  Records of competence, educational and professional qualifications, training, skills and experience ä Readily available, and include date of confirmation of competence, plus criteria for confirmation and name of the confirming authority. Quality Control Part One. 6.4 – 6.5

25. 25 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Verify compliance (in practice)  From register, select a batch of API, excipient and finished product  Request specifications and test methods  Retention samples  Verify information in register against sampling sheet, PO, delivery note, incoming goods register, analytical report, sampling SOP etc Quality Control

26. 26 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Specifications archive  Current versions of all specifications  Pharmacopoeia compendia or in manufacturers' registration documents. Archive must contain:  List of all pharmacopoeias in the laboratory ä all updates and corrections must be noted; ä adequate numbers of supplements and addenda.  File of non-pharmacopoeia quality specifications ä numbered and dated, latest version; ä information relevant to the status of the quality specifications; ä corrections or changes appropriately handled, including producing a revised document as soon as possible. Part Two. 9.1. – 9.2. Quality Control

27. 27 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Specifications archive  Use of the master copy ä photocopies accounted for and controlled for use  Confidentiality of specifications Responsibility defined for:  Updating all pharmacopoeias - including supplements, addenda, and corrective measures used in the laboratory;  Maintaining a specifications file Part Two. 9.3. – 9.5. Quality Control

28. 28 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Incoming samples (Sampling plan and procedures)  Sample size sufficient for: ä the tests to be performed ä replicate tests ä retained / retention sample  The laboratory must have a sampling plan and internal procedure for sampling, available to all analysts and technicians within the laboratory  Sample registration  Labelling of samples Part Three. 14.1.1. – 14.4.3. Quality Control

29. 29 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines  Identification on sample from each container  Verify spectrum and or chromatogram (number of containers)  Traceability to instrument used, reference standard used, analyst, date, source data (preparation of sample e.g. logbook or worksheets)  Refer to the test method for materials required Quality Control

30. 30 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Laboratory Records  All original observations, calculations and derived data, calibration, validation and verification records etc. and final results must be retained on record for an appropriate period of time e.g. ä whole length of time the drug is on the market  Records to contain sufficient information to permit repetition of tests and include e.g.: ä identity of the personnel involved in sampling, preparation and testing of the samples ä Instruments, equipment etc. Quality Control Part One. 4.1 – 4.2.

31. 31 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Analytical worksheet  An internal document in a printed form for recording information  Complemented by the raw data obtained in the analysis  One used for each numbered sample  A further set of analytical worksheets in duplicate can be used for a collaborating unit (after testing, all results are assembled in one analytical worksheet, using the data from all collaborating units). Part Three. 15.1. – 15.3.2. Quality Control

32. 32 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Reference materials  Used for testing and/or calibration, validation or verification of a sample or equipment, instruments or other devices  Responsibility must be assigned to a specific person  Registration and labelling with an identification number assigned ä A new identification number to each new batch ä Number marked on each vial ä Quoted on the analytical worksheet at every use Part Two. 11.1. – 11.2.4. Quality Control

33. 33 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Data processing equipment Includes computers, automated tests or calibration equipment; used for collection, processing, recording, reporting, storage or retrieval of test- and/or calibration-data  Where used, requires systematic verifications of calculations and data transfers  For computer software developed by the user: ä this documented in detail ä validated or verified as being adequate for use Quality Control Part One. 5.1.

34. 34 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Reagents  Reagents, chemicals, including solvents and materials used in tests and assays - of appropriate quality and supplied with COA  List of pre-qualified suppliers  Clear responsibility in job descriptions for the preparation of reagents in the laboratory  SOPs according to pharmacopoeia or other standards  Records for the preparation, and standardization of volumetric solutions Quality Control Part Two. 10.1. – 10.3.

35. 35 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines  Reagent labels must clearly specify: ä the contents, the manufacturer, the date received, and as appropriate, the concentration, standardization factor, shelf-life and storage conditions (purchased) ä date of preparation, name and initials of person (if prepared in the laboratory)  Volumetric solutions: ä the name of the manufacturer of the original reagent (where diluted), the date of preparation, the date of standardization and factor, and identify the responsible technician  Reagents must not be moved unnecessarily from unit to unit  Whenever possible, transportation in original containers  Subdivided in scrupulously clean, fully labelled containers Part Two. 10.4-10.5.3. Quality Control

36. 36 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Calibration, validation and verification of equipment, instruments and other devices  Regular calibration, validation and verification of all equipment, instruments and other devices used to measure the physical properties of substances must be performed  Specific procedures for each type of equipment, instrument and other devices must be established, having regard to the extent of which they are used, verified and calibrated at regular intervals according to SOP Part Two. 12 -12.2. Quality Control

37. 37 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Evaluation of test results  Results must be reviewed and evaluated – do they meet specifications  Consider the results of all tests  Doubtful results should be investigated (Internal quality system, OOS investigation etc)  Doubtful results can be rejected only if they are clearly due to error, which has been identified.  All conclusions entered on the analytical worksheet by the analyst and initialled by the supervisor Part Three. 17.1. – 17.2. Quality Control

38. 38 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Traceability  Analytical specificities of each measurement procedure and reference material that is used to ascertain traceability, must be known.  Traceability chain, including measurement procedures and reference materials at all levels, must be prepared  Laboratory investigations - applies to measurement procedures as well as to reference materials used Part Two. 13.1. – 13.3. Quality Control

39. 39 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Dissolution Testing errors are caused by:  Temperature variations  Rotational speed variations  Vibration  Wobble  Shaft perpendicularity  Tension on the chain or belt  Bubbles  Shaft centering Quality Control

40. 40 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Control Quality control (also micro, water, environment…)  Sampling and testing  Reference Standards  Specifications  Stability testing  Source/raw data  Qualification and validation

41. 41 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Other topics to inspect may include  Organization, job descriptions  Training programme and qualification of personnel  Contract production and analysis  Documentation system  Validation (process, cleaning etc)  CAPA, failure investigation  Change control  Deviations  Self-Inspection  Complaints handling and recall  Product quality review  Supplier evaluation

42. 42 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Some observations most often made  Management expects GMP compliance to be achieved just like that  Documentation seems OK, but is actually not followed  Documents completed after the actual action  Changes made without review of the impact of a change on the system  Deviations not documented in a systematic manner  Computer systems not validated  Re-use of materials without proper assurance  Training programme or Job descriptions not accurate  Contract manufacturing or analysis without up-to-date Technical Agreements

43. 43 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Former experience  First submissions of generic HIV/AIDS medicines (in 2001) were mostly of poor quality  However, several HIV/AIDS products manufacturers were able to upgrade the quality of the dossiers submitted significantly  Subsequently the quality of the products manufactured has improved as well  This reduces the average number of assessment sessions necessary to get the product prequalified

44. 44 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Customized technical assistance  Technical assistance can be organized by WHO, for which an external technical expert is used outside the Prequalification team  It can relate to dossier development, GMP implementation or both  The type, length and the content of the support given will be decided case by case based on: ä The assessment reports ä The inspection reports ä The needs of the manufacturer Always in agreement between WHO and the manufacturer  A report will be issued to the manufacturer and to WHO.  The results of the support will be monitored by WHO  When relevant the technical assistance can be continued.

45. 45 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Criteria for giving technical assistance to manufacturers Absolute criteria:  Participation in the prequalification programme (currently HIV/AIDS, Malaria, Tuberculosis, Reproductive Health)  At least an application/submission of "promising quality"  Found to be capable and having a record of willing to improve Relative criteria:  Preferably manufacturing priority product or product, for which there is no / limited number of prequalified products  Location preferably in a developing country  Preferably national Government support for improving quality

46. 46 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Principles of avoiding conflict of interest in giving Technical Assistance  Provisions for the experts : ä Qualification and experience in the area where expertise is needed ä Absence of conflict of interest (competing companies etc.) ä Total intellectual independence from the prequalification programme, no participation in inspections or assessments or any product related decision making

47. 47 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Many training slides on our web site: http://www.who.int/prequal

48. 48 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines

49. 49 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines

50. 50 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Discussion Any questions?