QUALITY OF PHARMACEUTICAL INGREDIENTS

1. QUALITY OF PHARMACEUTICAL INGREDIENTS WHO Prequalification Programme: Priority Essential Medicines WHO GMP and API Inspections Presented by Mr. Deus K Mubangizi Technical Officer mubangizid@who.int

2. In this presentation: • WHO-PQ: Inspection activities • WHO-PQ: Norms and standards • WHO-GMP for APIs versus ICH Q7A • Key elements of ICH Q7A • WHO-PQ API inspections: Observed trends and deficiencies • Conclusions

3. WHO Prequalification: Inspection activities APIs, FPPs BE/CROs

4. Prequalification: Inspection Processes • By a team of qualified and experienced inspectors • WHO representative (qualified inspector) • Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S) • National inspector/s invited to be part and observe the inspection • Observer from recipient/developing countries (nominated by DRA of the country) • Scope: • Compliance with guidelines: GMP (ICHQ7), GCP, GLP • Data verification – data manipulation, falsification, (validation, stability, clinical, bioanalytical) • Quality control (QC, BAL, NQCL, IQCL)

5. Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling

6. RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME(1 of 2)

7. RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME(2 of 2)

8. Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling

9. Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling

10. Risk-based approach in:definition and classification of deficiencies • Deficiencies are descriptions of non-compliance with GMP requirements. • A distinction is made between deficiencies as a result of: - • a defective system or, • failure to comply with the system. • Deficiencies may be classified as: • Critical Observation – potential risk harm to the user • Major Observation – major deviation from GMP • Minor or Other Observation – departure from good practice

11. Further considerations for classification 1. Classification of an observation is based on the assessed risk level and may vary depending on the nature of API manufactured, e.g. in some circumstances an example of an "other" deficiency may be categorized as "major". 2. A deficiency that was reported at a previous inspection and not corrected may be reported in a higher classification. 3. One-off minor lapses or less significant issues are usually not formally reported, but are brought to the attention of the manufacturer during the inspection.

12. Risk-based approach in:Conclusion following an inspection • When there are "other" observations only: • considered to be operating at anacceptable level of compliancewith WHO GMP/ICHQ7. • The manufacturer is expected to provide CAPAs. • CAPAs are evaluation and followed up during the next routine inspection. • When the are "other" and a few "major" observations: • compliancewith WHO GMP/ICHQ7 is madeafter the CAPAs have been assessed. • CAPAs for majors to include documented evidence of completion. • CAPAs paper evaluated ± an on-site follow up inspection. • When there are "critical" or several "major" observations: • considered to be operating at an unacceptable level of compliance with WHO GMP/ICHQ7 guidelines. • Another inspection will be required

13. Transparency: Information put in public domain - WHOPIRs and NOCs • These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO, among other actions: • "3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;" • A WHO Public Inspection Report (WHOPIR) reflects a positive outcome after an inspection • A Notice of Concern (NOC) is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or research organization.

14. Prequalification Programme: Use of Inspection reports from other NMRAs • An inspection by the PQP may be omitted when other acceptable evidence of GMP compliance (Report + CAPAs) is provided by the FPP or API manufacturer. • An inspection by another acceptable organization, such as a PIC/S member country, or US FDA or EU, may be considered in lieu of a PQP inspection when: • The inspection was conducted within the last 2 years, and • The scope of the inspection covered the specific API in question, and • The FPP or API manufacturer submits a copy of the last inspection report for review by the PQP. (During the review, the inspectors will determine whether the inspection was comprehensive, covered the relevant areas appropriate to the product in question and that the inspection report supports the final outcome in accordance with WHO GMP). • Irrespective of the above, the PQP reserves the right to inspect any API manufacturer if considered necessary (specific product issues). • Whether inspected by the PQP or GMP compliance is based on an inspection by another acceptable organization, on-going GMP compliance will be confirmed by WHO (also using update information from other NMRAs).

15. Prequalification Programme:International norms, standards and guidelines used in inspection activities to ensure wide applicability • Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol.2, GMP and inspection. WHO, Geneva, 2007. http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/index.html • ICH Q7: GMP Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization. http://www.ich.org/cache/compo/276-254-1.html • WHO GMP: water for pharmaceutical use. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3. http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf

16. Prequalification Programme:norms, standards and guidelines used… • WHO guidelines for sampling of pharmaceutical products and related materials. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 4. http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf • Supplementary GMP guidelines for HVAC systems. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 2. http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf • Supplementary GMP guidelines: validation. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4. http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf • Good Practices for National Pharmaceutical Control Laboratories. 36th Report. Geneva, WHO, 2002 (WHO TRS, No. 902), Annex 3. http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37 USP BP Ph. Eur. Ph. Int. Other guidelines e.g. ICH, ISO

17. Prequalification Programme:norms, standards and guidelines used… • WHO Expert Committee has revised WHO GMP for APIs at its meeting in October 2009 – adopted ICH Q7 principles. • Final editing going on but numbering of sections essentially similar to ICH Q7: • ICH Q7 is used in the discussions that follow.

18. WHO GMP and 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 • XIII. CHANGE CONTROL • XIV. REJECTION AND RE-USE OF MATERIALS • XV. COMPLAINTS AND RECALLS • XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) • XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS

19. WHO GMP for APIs / ICH Q7Key definitions: • ICH Q7A • API starting material (API SM): a raw material, intermediate or an API used in the production of an API and incorporated as a significant structural fragment into the structure of the API. API SM can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API SM are normally of defined chemical properties and structure. • Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API.

20. ICH Q7A : Introduction • From what point does ICHQ7A start to be applied ? • “ICH Q7A applies from the point at which production of the API begins”. • Some indications are provided in Table 1 of ICH Q7A. • For synthetic process, this corresponds to the introduction of the API starting material into the process; • For other processes, on a case by case basis.

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

22. Main issue : How to define the API SM ? RM (solvent, catalyst, reagent, filtration aid, decolorizing agent, chromatography phase, etc.) SM (Intermediates)n Active substance crude C, H, O, N Only flow chart GMPs do not apply Detailed description GMPs apply Active substance (pure) API SM Competent Authorities Industry Photo : Internet

23. Application of ICHQ7 • Companies should decide at which point ICH Q7A applies for their processes and should have documentation to support it. GMP applies from the declared and approved (API) SM in the registered file. • Stringency of GMP in API manufacturing increases from early steps to final steps • Advanced intermediates and crude APIs outsourced should be manufactured in compliance with GMP • This means that these “late intermediate and crude API” manufacturers should be considered as contract manufacturers (Q7A chapter 16 applicable). • Sterilisation and aspetic processing should be performed according to GMP related to Sterile pharmaceuticalproducts.

24. ICHQ7A: Scope • Q7A does not apply to : • vaccines, whole cells, whole blood and plasma • blood and plasma derivatives (plasma fractionation) • gene therapy APIs • bulk-packaged medicinal products • medical gases and manufacturing/control aspects specific to radiopharmaceuticals. • Q7A does not cover : • Safety aspects for the personnel engaged in the manufacture • and environmental issues.

25. Review of some ICHQ7A’s concepts • Quality management (Chapter 2) • Responsibilities of the Quality Unit • Sections 2.22-1 to 2.22-15 • Tools for surveillance, monitoring and continuous improvement: • Internal audits/Self inspection (section 2.4) • Product Quality review (section 2.5) • Complaints, returns and recall (sections 14.5 and 15) • Change control (section 13)

26. Review of someICHQ7A’s concepts Change control • Raw materials, specifications, analytical methods, facilities, support systems, equipment (including computerized systems), processing steps, labelling and packaging materials • That can impact the quality of the API Change control • Proposal drafted, reviewed and approved by the appropriate organisational unit • Change reviewed and approved by QU • Classification and impact assessment • Evaluation and monitoring + Notification

27. Review of some ICHQ7A’s concepts • Personnel (section 3) • Appropriate and regular GMP training periodically assessed (ICH 3.12) • Documentation (section 6) • Specifications for raw materials, intermediates, APIs, labelling and packaging materials (ICH 6.17) • Retention period specified for production, control and distribution records (ICH 6.13) • Contract manufacturers (section 16) • Contract manufacturers should comply with Annex 18 (ICH 16.10) • A contract or a formal agreement should exist between the contract acceptor and the contract giver (ICH 16.12).

28. Review of someICHQ7A’s concepts • Facilities,equipment and utilities system • Facilities designed to prevent mix-ups and contamination • Precautions implemented based on a risk assessment • Equipment cleaning methodology and intervals appropriate to prevent build-up and carry-over of contaminants (degradants) Critical operation with prolonged exposure to the environment Non critical operation with prolonged exposure to the environment Non critical or critical operation in a closed equipment

29. Review of some ICHQ7A’s concepts • HVAC systems (section 4.2) • Adequate ventilation, air filtration and exhaust systems should be provided where appropriate (ICH 4.21, 4.22) • Qualification and appropriate monitoring and operating range limits in place (ICH 4.20) • Water (section 4.3) • WHO potable water quality as a minimum (ICH 4.31) • Water for final isolation and purification steps for API for sterile products:test for microbial counts, objectionable counts and endotoxins.

30. Review of some ICHQ7A’s concepts • Material management (section 7.) • At least, identity testing of each batch on a sample representative of the batch (ICH 7.30) • Reduced testing for approved/validated suppliers (ICH 7.31) • Past quality history • Full analysis at least on three batches before starting reduced-testing • Reliability of the CoA checked at regular intervals • A documented supplier audit is not required but currently performed in the case of critical material by API manufacturers. • Precaution for bulk deliveries in non-dedicated tankers (ICH 7.22)

31. Review of some ICHQ7A’s concepts • Production (section 8) • Critical operations should be witnessed or subjected to an equivalent control (ICH 8.12) • Deviations should be documented, explained and/or investigated (ICH8.15) • Process time limits should be respected (ICH8.20) • Conditions and duration of storage of intermediates (ICH 8.21) • In-process sampling and controls (ICH 8.3) • approved written procedures, avoid risk of cross contamination during sampling, sample integrity

32. Review of some ICHQ7A’s concepts OOS batches blended with others to meet specifications • Production • Blending operations (section 8.4) • Only batches meeting established specifications • Expiry or retest date of the blended batch based on the manufacturing date of the oldest batch included. • Should be controlled and documented – traceability • Validation for homogeneity following blending 1. Blending small batches to ↑se batch size 2. Blending tailings APIs for OSDs/ Suspensions 1. Particle size distribution 2. Bulk density 3. Tap density

33. Review of some ICHQ7A’s concepts • Reprocessing or reworking for intermediates or APIs which do not conform to standards or specifications • Reworking (section 14.3) • Reason for non conformance determined prior to any reworking • Involves a “treatment” different from the established one • Recrystallization with a a different solvent • Reworked batches to be subjected to appropriate evaluation, testing ± stability testing • Concurrent validation • Should have comparable impurity profile • Reprocessing (s. 14.2) • Repeating a step of the established manufacturing process • Crystallization, distillation, filtration, chromatography, milling, etc • Continuation to completes process after IPQC in not reprocessing • Introducing unreacted material into reaction is reprocessing • Included in the standard manufacturing process if reprocessing used for a majority batches

34. Review of some ICHQ7A’s concepts • Recovery of Materials and solvents • Reactants, intermediates or APIs may be recovered from mother liquor or filtrates. • Must use approved procedures and specifications. • Recovered solvents may be reused in same process or in different process if confirmed to meet appropriate standards. • Fresh and recovered solvents and reagents if confirmed their adequacy 1. No approved procedures 2. Specs – carry over impurities 3. Not adequately tested 4. Use not documented 1. Approved procedures 2. Suitable specs 3. Adequate testing 5. Use documented

35. Review of some ICHQ7A’s concepts • Prospective validation (≥3 consec batches): • complete before commercial distribution • Current validation (≥3 consec batches): • For API produced infrequently • Batches may be released for commercial distribution after monitoring and testing • Retrospective Validation (10 - 30 batches): • Only in exceptional cases • For well established process • All batches, including failed ones • Validation (section 12) • Applies to • Analytical methods • Process • Cleaning • Computerized systems • Validate operations critical to the quality and purity of the API • Periodic review of validated systems

36. ICHQ7A : Conclusion • ICH Q7A is a “What to do document” • “How to do” is sometimes described • Flexibility • If necessary, when appropriate … • “Should” even if it could be interpreted mostly as “must” • Emphasis on the risks of • Contamination and cross contamination • Mix-ups, build-up and carry-over of degradants • Lack of traceability

37. WHO GMP and Inspection of API manufacturers Trends . . .

38. WHO GMP and Inspection of API manufacturers2002 - 2009 2002 to 2009 India (34) China (9) S. Korea (1) Vietnam (1)

39. WHO GMP and Inspection of API manufacturers • Most API inspections were conducted in India followed by China. • The number of China API sites inspected has increased of recent

40. WHO GMP and Inspection of API manufacturers Number of inspections per year • API inspections have been increasing over time. • Most API inspections were conducted in 2005, 2006, 2008 and 2009.

41. WHO GMP and Inspection of API manufacturers 2007 -2009. Inspections (disease areas) and number of observations • Most observations were observed in sites for TB APIs and these were the sites with most of the major observations. • Although sites for Malaria APIs had equally high number of observations, most of them were not major. • The sites for HIV APIs were generally in a reasonable shape.

42. WHO GMP and Inspection of API manufacturers • The most frequently found deficiencies were: • Material management • SOPs • Cleaning • Others included: • Batch records • Labelling • Cross contamination

43. Summary and Conclusions 谢谢！ • Inspection of API sites is part of the WHO-PQ procedures • International norms and standards are used during WHO-PQ inspections • Risk management principles are applied when: • scheduling inspections • conducting inspections • closing out inspections • Inspections of API sites has increased over time. Most of the API sites inspected by WHO-PQ are in India and China • Deficiencies have been observed mainly in: • Material management, SOPs, Cleaning, Batch records, Labelling, Cross contamination • Most deficiencies have been observed on sites for TB and Malaria APIs.