Good Manufacturing Practices: WHO Inspections

1. Good Manufacturing Practices: WHO Inspections Tony Gould (Slides provided by Dr Andre van Zyl)

2. Inspections To get started: • Risk assessment (SOP) • Scheduling • Preparation • Announce inspection • Provide tentative inspection plan • Inspect, prepare inspection report • Review corrective action

3. Inspections Inspections • Done by teams of inspectors • WHO inspector plus appointed from DRA (PICS member) • Invite local inspector (DRA) • Some cases observers and technical advisors • Technical assistance (independent, no conflict of interest)

4. Current trends in Inspections Guide to Manufacturer Risk Classification

5. APIs Why inspect? • Quality • Heparin • Baxter – 2008, more than 80 deaths in USA • Investigated – FDA (GMP – sourcing of starting material, lack of control) • Nelfinavir, Lopinavir /Ritonavir • Roche – 2008, global recall of batches • genotoxic substance (GMP, cleaning of tanks) • Morphic forms • European law – FPP manufacturer's responsibility • Self, contracted party, DRA • Rationalization, economy • Initially mostly in Europe – now Asia (India and China) – control?

6. API Parameters considered: • Polymorphism • Solubility in water • Route of Synthesis • Solvents used • Impurities • Sterile API • Fermentation • Toxicity • Activity/potency • Particle size • Other properties to be considered • Site compliance information (WHO/EDQM/Other)

7. WHO GMP for APIs – ICH Q7 • II. QUALITY MANAGEMENT • III. PERSONNEL • IV. BUILDINGS AND FACILITIES • V. PROCESS EQUIPMENT • VI. DOCUMENTATION AND RECORDS • VII. MATERIALS MANAGEMENT • VIII. PRODUCTION AND IN-PROCESS CONTROLS • IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES • X. STORAGE AND DISTRIBUTION • XI. LABORATORY CONTROLS • XII. VALIDATION

8. API • XIII. CHANGE CONTROL • XIV. REJECTION AND RE-USE OF MATERIALS • XV. COMPLAINTS AND RECALLS • XVI. CONTRACT MANUFACTURERS • XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS

9. WHO GMP and Inspection of API manufacturers Increasing GMP requirements

10. APIs Why inspect? • Variations • Change manufacturers and suppliers • Different specifications, route of synthesis, impurity profile • Stability, re-test dates vs expiry dates • Incomplete dossier, DMF, APIMF

11. API Examples of observations of non-compliance in 2007 Batch records and SOPs • Before steps were processed… a complete centrifugation operation before actual operation; • BMR was not completed, although the step was already in progress... No start time of the cooling process … no records of the temperature … for every 30 minute as required in the BMR… equipment logbook no entry… • The SOP “cleaning of centrifuge bag” was incomplete…No evidence of: • dedicated bags • labeling of storage drums • Also for fluid bed bags • Risk of cross contamination

12. API Examples of major non-compliances (2009) • Quality management • Lack of knowledge and experience • Deviations not reported • Change control incomplete • Documentation • Recording of operations, also not reflecting all steps and full of errors • Incomplete process validation • Materials management • Sampling (number of samples, release date before manufacturing date) • Storage and use - FIFO • Buildings and facilities • Water systems; HVAC – poor design and controls • equipment cleaning – show product residue after cleaning, equipment cleaned in outside environment

13. Inspection of API manufacturers

14. Inspection of API manufacturers Areas of non-compliance 2007 -2009. Inspections (disease areas) and number of observations

15. Inspection of API manufacturers Summary of trends • Number of inspections between '05 and '09 – 9 to 12. Low number in 2007 • Highest number of inspections in India, followed by China • Observations range between 20 and 28 (low number in 2007) • Lower number of observations in ARV manufacturers, but lower number of major non compliances at malaria manufacturers • Observations relating to material management, SOPs and documents, cleaning

16. Inspection of FPP manufacturers To get started (FPP manufacturer): • Product dossier submitted • Listed as a manufacturer in a product dossier • Assessment in progress • Risk assessment • Submit a SMF • Announce inspection • Provide tentative inspection plan • Inspect, prepare inspection report – corrective action

17. Manufacturers: Normally over 4 days Covers all aspects of GMP Quality management, Quality assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel Utilities (e.g. HVAC, water) . . . Also data verification (dossier) including stability data, validation (process), development batches and bio batches Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification Inspection of FPP manufacturers

18. FPP Findings • Validation and qualification work was often incomplete • Validation Master Plans (VMP) lacked details • Validation policies as defined in the VMPs were not implemented • Process validation was lacking • Validated procedures (e.g. environmental monitoring) were lacking • Incomplete (not detailed) qualification of HVAC, water and computer systems

19. FPP Findings • Insufficient filtration of air to production areas • No prevention of possible cross-contamination and contamination. • "As built" AHUs lacked components reflected in the schematic drawings, including filters • No qualification of sampling areas and reverse unidirectional air flow units • Temperature and RH mapping studies incomplete, or results not applied • HVAC systems not controlled or monitored, start up, shut down • Filters: • not planned, classified, tested (including installed filter leakage test), monitored • Pressure differential gauges not controlled, including calibration and zero checks

20. GMP ... • PQR • Not done annually • Not all data reported including starting materials, commitments, variations • Trends not reviewed / discussed – results merely reported • Deviations • Not reported, some are opened, new deviations opened on a deviation • Not authorized by production manager or QA prior to implementation • No assessment on impact, not additional testing • Change control procedures not followed • No assessment on impact, no routing to responsible persons • No qualification or validation • Wrong materials used (e.g. MOC extension of PW loop)

21. GMP ... • In process controls • Some less critical ones reported • Wrong results represented • Even though "fail" – reported as "pass" • Qualification • Often incomplete • Wrong sequence • Unreliable data • "approved" and signed off despite non compliance with specifications, errors not picked up • Computers, software, excel calculations • Process validation • Lacking • Unreliable results

22. FPP OOS • SOP for the reporting and investigation of Out of Specification (OOS) results not implemented • No record of OOS results • In case of an OOS, re-testing was done, however, the results were recorded on a loose piece of paper, other sheets were not appropriately completed e.g. method number, no of samples, LIMS number

23. FPP Reworking materials / products: • GMP allows in exceptional cases - reworks were done on a routine basis. • Inappropriate authorization for the reworks including no prior authorization by QA, authorization by production supervisors up to 7 weeks after the rework was initiated. • A rework was even initiated prior to the conclusion of the OOS investigation. • Reworked batches were not subjected to additional testing including stability studies • Only one of all the reworked batches was subjected to stability testing according to the stability plan.

24. Inspection of FPP manufacturers

25. Inspection of FPP manufacturers

26. Inspections of Contract Research Organizations (CROs) • Clinical sites: Normally over 2 days • Started 2004 -Covers all aspects of GCP and GLP • Ethical considerations, Protocol, Volunteers etc • Data verification – identified misrepresentation of data • Clinical part • Clinic, Pharmacy and related areas, data verification • Bio-analytical part • Laboratory and data verification • Statistical analysis New York Times 2007

28. Inspections of Contract Research Organizations (CROs) Also: Guidance for Industry Bio-analytical Method Validation U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) May 2001

29. Inspections ofContract Research Organizations (CROs) Clinical Part of the study • Protocol, Ethics committee • Volunteers • Informed consent • Source data and CRFs Bio-analytical part of the study • Sample management • Method validation and sample analysis

30. Inspections ofContract Research Organizations (CROs) Main problems in some CROs: • Many haven't done studies for "regulated market" submissions • Lack of GCP and GLP regulations, requirements, enforcement and compliance • IEC not independent – set up by sponsors • Manipulation of data • No source data / records available (CRO and Sponsor)

31. Inspections ofContract Research Organizations (CROs) Examples of observations • Half of the CRFs "missing" • Source data destroyed accidently by fire or "monsoon" • Sponsor claims the data were kept by the CRO, and the CRO claims the data were kept by the sponsor • All data and retention samples destroyed as the product "expired" – even though the submission is still under evaluation

32. Inspections of Contract Research Organizations (CROs) Examples Half of the CRFs "missing" (at sponsor / CRO?), source data destroyed accidently by fire or "monsoon", destroyed as the product "expired" Out of 95 ECGs copied by the inspectors, 43 appear to have been recorded from the same and single subject during a single session Manual integration and results not real

33. Inspections ofContract Research Organizations (CROs) Example: Numerous improper manual integrations were noted by the inspectors for QC samples. • Such integrations were found both for the method validation and for the trial phase. These integrations were corrected during the inspection by one staff member under control of one inspector. • The status of the results of several QC samples was affected by these improper manual integrations • Taking these corrected results into consideration the results of subjects No. 5 and 20 should be rejected: • subject No. 5: results were only obtained for 4 of the 6 QC samples and the results of 2 of these 4 samples fall out of acceptance limits; • subject No. 20: the results of both LQC samples fall out of acceptance limits..

34. Example discrepancies

36. Inspections ofContract Research Organizations (CROs) Recent observations included unreliable data such as: • Discrepancies between electronic raw data files and data submitted in study reports for assessment; • Improper manual integration of chromatograms observed during inspections even as "no manual integration" was reported; • Differences in chromatogram peak areas between the electronic raw data files and the printouts submitted to the WHO; • Batches that fail when data is calculated from raw data files during inspections (e.g. for QC samples) even as these batches were presented as "passing" with values different from those actually obtained during subject sample analysis; • Inappropriate bio analytical method validation.

37. Number of inspections

38. That’s all…