1. Introduction to WHO Prequalification of Medicines Programme Essential requirements Dr Milan Smid and many team colleagues WHO Prequalification of Medicines Programme Amman, June 2013

2. I Expression of Interest Compliance Additional information and data Corrective actions Compliance Assessment Inspections Steps in WHO prequalification Prequalification Maintenance and monitoring Product dossier SMF

3. Amman, June 2013 3 Application requirements - Full dossier Generic Product application Covering letter, in English, confirming that the information submitted in the product dossiers is true and correct. Product dossier (including full BE report where applicable), in English, in CTD format and the QOS- PD + QIS + BTIF/BW forms ALL completed in word format A product sample A site master file, for each manufacturing site

4. Amman, June 2013 How to Submit an application Submit electronic copy ONLY of Dossier in CTD format and Forms on CD/DVD To WHO Geneva After dossier has been accepted for assessment and has been allocated a WHO reference number you will be notified to proceed to step 2 Updated or finalised Dossier and Forms (paper copies + CD/DVDs) incorporating any improvements or changes requested in step 1 and samples To UNICEF- Copenhagen Submit Site Master File & Contract Research Organization Master File (CROMF) (hard copies +CD/DVDs) to Geneva address WHO/CF workshop, New Delhi, November 2012

5. Amman, June 2013 Data requested for prequalification 5 API FPP S & E + + An application to prequalify an FPP typically has three parts, relevant Good Practices have to be followed during manufacture and control: Information on the preparation and control of the API. Information on the preparation and control of the FPP. Safety and efficacy data, e.g. commonly replaced by demonstration of bioequivalence

6. Amman, June 2013 Data requested for prequalification guideline for applicants Consists of two parts: –Preparation of product dossiers (PDs) in Common Technical Document (CTD) format The preparation guideline –Guideline on submission of documentation on multisource (Generic) Finished Pharmaceutical Product (FPP): Quality part Main quality guide Being implemented since September 2010

7. WHO/UNFPA workshop, Nov 2012 7 Adapting the CTD-NDS (new drug) to CTD-ANDS (generic) Regional Admin Information Module 1 Nonclinical Overview Nonclinical Summary Clinical Overview Clinical Summary Quality Overall Summary Quality Nonclinical Study Reports Clinical Study Reports Module 3Module 4Module 5 Module 2 Not Part of the CTD The CTD

8. Amman, June 2013 Main sub-sections of 3.2.S. Drug Substance (API) 3.2.S.1 General information 3.2.S.2 Manufacture 3.2.S.3 Characterization 3.2.S.4 Control of the API 3.2.S.5 Reference standards or materials 3.2.S.6 Container closure system 3.2.S.7 Stability

9. Amman, June 2013 Main sub-sections of 3.2.P. Drug Product (FPP) 3.2.P.1 Description and Composition of the FPP 3.2.P.2 Pharmaceutical development 3.2.P.3 Manufacture 3.2.P.4 Excipients 3.2.P.5 Control of the FPP 3.2.P.6 Reference standards or materials 3.2.P.7 Container closure system 3.2.P.8 Stability

10. WHO/UNFPA workshop, Nov 2012 10 Specific quality documents: quality summaries (templates - QIS/QOS) The instructions for the QOS-PD (quality over all summary) run throughout the quality guideline Instructions for the QIS are in Section 3.2 and preface the QIS (quality information summary) template

11. Amman, June 2013 11

12. Amman, June 2013 Key aspects of quality assessment To ensure that all future batches, throughout their shelf life, will perform as the clinical/biobatch –Characteristics of the API batch used in the biobatch, details of FPP manufacturing process and quality attributes of the the biobatch are critical reference information To ensure that processes are adequately described and controlled and that they are validated To ensure that the level of impurities in the API and FPP are within safe limits To ensure that container closure system will protect the product from chemical, physical and biological deterioration and that it's compatible with the product To ensure that analytical methods used at different stages are reliable and reproducible

13. Amman, June 2013 FPP Prequalification and four options for submission of API information API FPPS & E 3.2.S ++ EDQM CEP APIMF Procedure WHO PQ API

14. Amman, June 2013 The APIMF Procedure The API manufacturer supplies the FPP manufacturer with the open part of their APIMF. The FPP manufacturer use this information to complete the necessary sections of their submission. The API manufacturer supplies the FPP with a letter of access. The FPP manufacturer attaches the open part of the APIMF and the letter of access to their FPP submission. The API manufacturer sends the open and closed sections of their APIMF directly to WHO. It is held in confidence.

15. WHO/UNFPA workshop, Nov 2012 15 The APIMF Procedure APIMF holderFPP applicant APIMF submission to APIMF focal point FPP submission APIMF assessment APIMF acceptanceFPP assessment FPP prequalification Letter of Access

16. Amman, June 2013 Advantages of the APIMF Procedure It allows the submission of confidential information by the API manufacturer without disclosure to the FPP applicant. One APIMF may be used to support multiple FPP applications without the need for repeated evaluations. It is applicable to both pharmacopoeial and non- pharmacopoeial APIs. The APIMF holder prepares and maintains the APIMF information and answers all queries directly. Normally all API-related changes would require the submission of a variation from associated FPP manufacturers.

17. Amman, June 2013 Notable Requirements –Number of batches required to establish the FPP shelf-life –Uniformity demonstration for the biolot instead of process validation report for pilot batches –process validation/pharmaceutical development requirements for “established” generics 17

18. Amman, June 2013 Accelerated procedure for accepting RH and 2 nd Line TB dossiers for assessment Stability Data at the time of submission only, may be reduced to no less than 3 months accelerated, plus 3 months long-term data, for not less than two primary batches of at least pilot scale. One of the primary batches should be the batch that was used for bioequivalence studies. In some cases, several years of long-term stability data on batches under uncontrolled storage conditions may also be accepted from Zone IV countries. NB all prequalification requirements for final acceptability of the dossier remain in effect, without exception, including but not limited to the submission of updated stability data during the assessment period as it becomes available, and a commitment to provide: –stability data on three production batches, and –process validation of three consecutive production batches to be completed prior to marketing. 18

19. Amman, June 2013 Scope of WHO PQ guidance on Variations to a Pre-qualified medicinal product applies to quality part of product dossiers for an API or an FPP. notification requirements for API-related changes differ depending on the manner in which API information was submitted with the original FPP application. FPPs that rely upon the APIMF or CEP procedure have reduced reporting requirements. Variations for FPPs prequalified on the basis of SRA approval should be approved by the same SRA and WHO PQP notified of the approval of the changes. 19

20. Amman, June 2013 Requalification Procedure for prequalification of pharmaceutical products requires holders of WHO-prequalified products to submit a quality review after five years from the date of prequalification of the product, or when requested to do so by PQP (whichever date is earlier) 20

21. 21 Jakarta, March 2013 Demonstration of bioequivalence PD studies Clinical studies In vitro methods Bioequivalence study ONLY EXCEPTIONAL! or

22. 22 Jakarta, March 2013 Comparators for the Prequalification Programme Innovator product with established Q,S, and E sourced from well regulated market (ICH process countries). Guidance on selection and the to be provided documents should be followed. The comparator should be selected from the comparator list (http://apps.who.int/prequal/info_applicants/info_for_applica nts_BE_comparator.htm)http://apps.who.int/prequal/info_applicants/info_for_applica nts_BE_comparator.htm Other comparators must be justified. Recommended to consult WHO at: prequalassessment@who.intprequalassessment@who.int Remember: Comparator is not always identical with a comparator required by national regulatory authority!

23. Amman, June 2013 Tested product  GMP  batch size  pilot batch  commercial batch  not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)  difference regarding the content of the investigative products (T and R) should preferably not be more than 5 %  strength with the largest sensitivity to detect differences in the two products

24. Amman, June 2013 Analytical methods FDA Guidance for Industry –Bioanalytical method validation, May 2001 ICH Guidance for industry –Validation of analytical methods: definitions and terminology, June 1995 –Validation of analytical procedures: methodology, November 1996 EMA guideline –Bioanalytical method validation, 2011

25. Amman, June 2013 Quality of Bioequivalence Studies Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trials subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

26. Amman, June 2013 Frequent GCP non-compliances No informed consent, complex language Ethics committee not independent Dosing procedure is inadequately documented, no drug accountability Certificates of analysis are not consistent with study products or not sufficiently detailed No testing on addictive substances performed Withdrawals are improperly documented Meals not standardized and not documented Storage of blood samples is not monitored Method of calculation of PK parameters is not specified Insufficient explanation of outliers Chromatograms not consistent with data

27. Amman, June 2013 WHO BCS-based biowaiver Active substances selected for biowaiving by WHO HIV/AIDS: Lamivudine (BCS 3) Stavudine (BCS 1) Zidovudine (BCS 1) Abacavir sulphate (BCS 3) Emtricitabine (BCS 1) TB: Levofloxacin (BCS 1) Ofloxacin (BCS 1) Ethambutol ((BCS 3) Isoniazid (BCS 3) Pyrazinamide (BCS 3)

28. Amman, June 2013 International norms, standards and guidelines used in inspection activities to ensure wide applicability HANDBOOK FOR GOOD CLINICAL RESEARCH PRACTICE (GCP) Guidance for implementation http://whqlibdoc.who.int/publications/2005/924159392X_eng.pdf Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. World Health Organization, 1995 (WHO Technical Report Series, No. 850), Annex 3. http://apps.who.int/prequal/info_general/documents/TRS850/WHO_TRS_850-Annex3.pdf Additional guidance for organizations performing in vivo bioequivalence studies. WHO Technical Report Series, No. 937, 2006, Annex 9 http://apps.who.int/prequal/info_general/documents/TRS937/WHO_TRS_937__annex9_eng.pdf Guidelines for the preparation of a contract research organization master file. World Health Organization, WHO Technical Report Series, No. 957, 2010 Annex 7, Page 271. http://www.who.int/medicines/publications/TRS957_2010.pdfhttp://www.who.int/medicines/publications/TRS957_2010.pdf 28

29. Amman, June 2013 Generics approved by SRA http://apps.who.int/prequal/info_applicants/Guidelin es/PQProcGenericSRA_July2011.pdfhttp://apps.who.int/prequal/info_applicants/Guidelin es/PQProcGenericSRA_July2011.pdf 1. Applicants should submit the following documentation: –A letter of undertaking (template attached) with a clear statement by the responsible person that the information submitted is true and correct. –A QA-certified copies of the Marketing and Manufacturing Authorizations issued by the relevant SRA. –An original or certified copy of WHO-type Certificate of a Pharmaceutical Product, issued by one of the SRAs, together with the –approved Summary of Product Characteristics (SPC), or an equivalent thereof, including Patient Information Leaflet (PIL) and Labelling. –Assessment report(s) issued by the relevant SRA (expected to be replaced by specifications and control methods). 2. Evidence of minimum five (5) years of current and continuous manufacturing experience and a copy of the last Annual Product Report. (expected to be deleted). 29

30. Amman, June 2013 Generics approved by SRA A sample of the FPP(s) in market packaging and certificate of analysis should be provided. Undertaking: –authorizes WHO PQP to publish "Main characteristics of the prequalified medicinal product" on its website; –will inform WHO prequalification programme with a copy of the regulatory acceptance letter of any change to the main characteristics of the product immediately after the variation has been approved by the relevant SRA. –if the change affects the information in SmPC, PIL and/or container labels (immediate and outer) in electronic format –c) has nominated a responsible employee for communication with WHO on any issues, including quality failures 30

31. Amman, June 2013 GMP Inspections by WHO Inspections are conducted before prequalification, on an on-going basis and in special circumstances Initial inspection target: <180days from dossier receipt Re-inspection frequency determined on a risk basis Inspections are normally announced 1-2 months in advance Inspections conducted by a Stringent Regulatory Authority are taken into account when planning inspections 31

32. Amman, June 2013 GMP inspections by WHO Inspections are conducted by a team –A WHO inspector leads the team –An inspector from another Regulatory Authority (usually a PIC/S member) assists –The Regulatory Authority of the country of manufacture is invited (and encouraged) to accompany the team –Inspection report provided within target of 30 days –Closed out after review of corrective actions 32

33. Amman, June 2013 Origin of Co-Inspectors 2011 2012

34. Amman, June 2013 Inspections of FPP 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 34

35. All FPP sites: Top 10 observation in 2011 -2012 35

36. Amman, June 2013 API Sites: Top 10 observation categories

37. 37 Jakarta, March 2013 Classification of observations Critical Observation An observation that has produced, or may result in a significant risk of producing, an API that, when used in a finished product, is harmful to the user. Major Observation A non-critical observation that has produced or may produce a product which does not comply with its prequalification application (including variations); and/or indicates a major deviation from the GMP guide; and/or indicates a failure to carry out satisfactory procedures for release of batches; and/or indicates a failure of the person responsible for QA/QC to fulfill his/her duties; and/or consists of several other deficiencies, none of which on its own may be major, but which may together represent a major deficiency and should be explained and reported as such. Other Observation An observation that cannot be classified as either critical or major, but indicates a departure from good manufacturing practice. 37

38. Analysis of inspection of observations Total number of Observations Average number of observations

39. Amman, June 2013 Thank you for the attention smidm@who.int 39 Ask if you are not sure, PQP contacts are: Dossiers and assessment: prequalassessment@who.intprequalassessment@who.int Inspections: prequalinspection@who.intprequalinspection@who.int Quality control: prequallaboratories@who.intprequallaboratories@who.int General: prequal@who.intprequal@who.int Tele/videoconferences are possible