Experience with Prequalification of Dossiers (quality part)

1. Experience with Prequalification of Dossiers (quality part) Workshop on GMP and Quality Assurance of Multisource Tuberculosis Medicines Kuala Lumpur – Malaysia 21-25 February 2005 Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa iiftgd@puk.ac.za

2. Abbreviations API Active pharmaceutical ingredient BP British Pharmacopoeia CEP EU certificate of suitability EOI Expression of interest FDC Fixed dose combination FPP Finished pharmaceutical product GMP Good manufacturing practices ICH International Conference onHarmonization Int.Ph. International Pharmacopoeia Ph.Eur.European Pharmacopoeia SmPC Summary of product characteristics TB Tuberculosis USP United States Pharmacopeia

3. Assessment procedures • Assessment according to the guidelines • Two assessors per quality (first & second) • Assessment outcome letter to applicant (manufacturer) • Applicant’s response, assessment of additional data. Repeat this step if necessary: • Approval of quality, with storage requirements and shelf-life • Approval safety/efficacy/CRO and GMP • Listing as prequalified on website

4. Well-established FPPs (Blue Book): • Have been marketed for at least five years in countries that undertake active post-marketing monitoring, • Have been widely used to permit the assumption that safety and efficacy are well known & • Have the same route of administration and strength, and the same or similar indications as in those countries All the FPPs on the 5th Invitation of EOI conforms to requirements, though innovator products are not always identifiable

5. General remarks Encouragement • Since the 1st invitation for EOI (Jan 2002) the quality of the dossiers (including DMFs) have notable increased (quality section) • DMFs accepted: 14 • Valid CEPs presented: 5 • One product registered via the route of registration in an ICH country

6. General remarks (2) Concerns • Supportive literature information absent in most dossiers (other than compendial data) • Literature information not professionally analysed & discussed in terms of the situation • Photocopies and/or full reference particulars of literature used in dossier are not presented • Responses to assessment reports not comprehensive • Resulting in multiple assessment/responses

7. General remarks (3) Concerns (continued) • FPPs not registered in country of origin • Marketing authorisation issued without assessment by national DRA • Only a small number of TB products appear on the prequalification list: • 8 anti-TB products by September 2004 (85 HIV/AIDS products by Nov. 2004) (2 antimalarial products by April 2004) • 4 suppliers/manufacturers

8. PQ list of TB products (09/2004) - tablets

9. Approach to deficiency discussion Deficiencies experienced with dossier (and additional data) assessments are discussed according to the points set out in the prequalification guideline (session 1): Guideline on Submission of Documentationfor Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs)used in the Treatment of HIV/AIDS, Malaria and Tuberculosis (hand-out)

10. Administrative 1/33 Poor organisation of the dossiers hampers the assessment. Examples: • Files are sometimes poorly bound(or not securely packed in the courier parcels) • Absence of table of contents • Absence of page numbers throughout dossier • It is recommended that sections be clearly indicted with securely fixed tags to assist cross-checking by assessors

11. Section 1. Characteristics of FPP 2/33 • Samples of FPPs are not always submitted • This is quite frustrating, since the samples are needed for instance: • To verify the description of the product • To inspect the packaging materials • To check correctness of the label • To check the data in the SmPC & PIL • For laboratory testing

12. Section 2. API deficiencies 3/33 • Full description of the reactions/steps used in the API synthesis not presented, including the purification step. Specifications of chemicals, catalysts & solvents used also absent. • Possible impurities cannot be established • Benzene (class 1 solvent, ≤ 2 ppm) in toluene • 1,2-dichloroethane used in the synthesis of ethambutol 2HCl not specified in API specs. • This is a class 1 solvent, ≤ 5 ppm (ICH) • Class 1 solvents acceptable only when unavoidable

13. Section 2. API deficiencies (2) • The open part of the DMF of the API is often incomplete and lacks information such as • Solubility properties (solubility in water, buffers at different pH values & organic solvents and partition coefficient) • Solid state properties (existence/absence of polymorphism, hygroscopicity, particle size, flowability, etc.) • API specifications lack attributes additional to compendial monograph, e.g. • Residual solvents (OVIs), particle size • USP OVIs (organic volatile impurities) not always covering specific synthesis OVIs

14. Section 2. API deficiencies (3) • The limits for assay in the API specifications not given to one decimal place, e.g. • Must be 98.0-101.0% (instead of 98-101%) • The same applies for the FPP specifications • Potency determination & CoAs not presented for secondary/working standards • Applies to both API and FPP manufacturer • Official standards available for all TB APIs, except moxifloxacin • Copies of API CoAs and stability data sheets not QA certified, signed or dated

15. Section 2. API deficiencies (4) • Degradation information not presented- through forced degradation studies and/or- from relevant literature / CEP • To identify possible degradants for stability studies • To verify specificity of stability assay method- Diode array detection for API peak purity not demonstrated in stability indicating assay validation!

16. Section 3. FPP deficiencies 8/33 • Pharmaceutical development reports are seldom included (done?) – a major problem • When provided often incomplete • Result: changes requested during assessment, for instance due to stability problems • Pivotal batches (BE, validation, stability) • Lack of table for comparison of formulas & discussion • Lack of comparative dissolution testing(f2 similarity calculations)

17. Section 3. FPP deficiencies (2) • The purpose of excipients not indicated in the unit and batch formula table • Overages not justified • Especially in case of rifampicin containing FPPs • Commercial colorant mixtures (e.g. Opadry) • Composition not indicated • Test methods not included • Microbial limit and colorants (skip-testing) not included in FPP specifications

18. Section 3. FPP deficiencies (3) • Documentation not in English, e.g. in • Manufacturing process documentation • Validation reports • Statements on adventitious agents not presented, e.g. • TSE/BSE (e.g. Mg-stearate from animal origin) • Asbestos in talc • Lack of validation data/reports on pilot and first 3 commercial batches

19. Section 3. FPP deficiencies (4) • Release/stability specifications & test methods of rifampicin containing FDC products are of MAJOR CONCERN: • Main degradant (> 5.0%?)not specified or tested►3-(isonicotinoylhydrazinomethyl)rifamycin • API peak purity (DAD) not demonstrated in stability indicating HPLC assay validation studies • USP monographs do not include degradants • Specificity of USP assay method for 4FDC must still be demonstrated (found specific for products tested on equipment in our laboratory)

20. Section 3. FPP deficiencies (5) • Stability specifications lack parameters that may be variables, e.g. • Tablet strength, friability & water content • These variables are interrelated, also with dissolution, and may show meaningful trends • Testing of these variables is inexpensive • Stability data presented in tables lack e.g. • Discussion of each parameter • Statistical analysis where required • Full details of batches tested

21. Section 3. FPP deficiencies (6) • Real-time stability studies carried out under Zone II conditions (25ºC / 60% RH) • Yet storage requirements indicated on labels, in SmPC & PIL often 30ºC !! • Storage requirements must be supported by stability studies • Zone IVstrongly recommended for procurement purposes (currently: 30ºC / 65% RH).- A large portion of medicines distributed to Zone IV areas

22. Section 3. FPP deficiencies (7) • Summary of product characteristics (SmPC): • Not included • Essential for FPP • Essential for WHOPAR • (1) Identification of dosage form and(2) presentation (packaging description) not given in detail in SmPC and PIL • Important in fighting counterfeit

23. Major conclusions • Expansion of the number of products and type of products in the prequalification list is of high priority for WHO • Development pharmaceutics studies (experimental and literature) will reduce the problems and increase the quality of the products / dossiers • API-API interactions in FDCs should be studied and resulting degradants identified and included in stability testing • Degradant analytical methods to be developed/validated

24. The mission The joint efforts of manufacturers & WHO • should cover all activities aimed at ensuring thatthe patient receives a product that meets established specifications and standards of quality, safety and efficacy. • It concerns both • the quality of the products themselves and • anything that might affect quality, • including information supplied with the product. (derived from Health Action International (Africa) definition for QA)