Prequalification of drugs for priority diseases EDM Technical Briefing March 2004 Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines Essential Drugs and Medicines Policy Health Technology and.
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Prequalification of drugs for priority diseases EDM Technical Briefing March 2004 Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines Essential Drugs and Medicines Policy Health Technology and Pharmaceuticals Cluster World Health Organization WHO - EDM 1 HIV/AIDS Crisis. Demand for affordable antiretrovirals is increasing. Numerous generic manufacturers offering products. Challenges for UN family and procurement agencies/organizations Which way to go to get the best possible protection of public health with the resources available? WHO - EDM 2 WHO/HTP/EDM/QSM Pre-qualification What is the problem? Sub-standard drugs purchased weak or absent quality assurance systems Lot of money invested in procurement no harmonized quality assurance system available for procurement organizations/initiatives Duplication of work lack of harmonized standards (GMP inspections) Risk: Sourcing sub-standard drugs, waste of money and, health risks to patientshe from: WHO - EDM 3 Joint project with other UN organizations Prequalification of HIV/AIDS Drugs - UN joint activity Partners* UNAIDS UNICEF UNFPA WHO With the support of World Bank * All organizations are also members of the International Pharmaceutical Coordination Group (IPC)m: WHO role Technical assistance based on WHO norms and standards, plus ICH and other standards, where applicable WHO - EDM 4 Procurement, Quality and Sourcing Project The prequalification part of the project has two major activities: countries are providing expertise I. Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc. : teams of professionals from national drug regulatory authorities: Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe ... II. Manufacturing site inspections: teamwork of inspectors: WHO representative (qualified GMP inspector), inspector from well-established inspectorate (Pharmaceutical Inspection Convention Scheme countries) and national inspector(s): Canada, France, Italy, Switzerland, The Netherlands … Quality control analysis - upon need but not always necessarily before prequalification and supply, increasingly as part of follow-up WHO - EDM 5 Procurement, Quality and Sourcing Project Prequalification basic principles Voluntary for participating manufacturers Legitimate - General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodies Widely discussed in many fora FIP Congress, Nice 2002 Supported by ICDRA in 2002 and 2004, representing more than 100 national drug regulatory authorities Transparent (all information available on the web site http://www.who.int/medicines/) Open to both innovators and multisource/generic manufacturers No cost for applicants during pilot phase WHO - EDM 6 WHO - EDM 7 Some relevant ICDRA 2004 recommendatins WHO is urged to create - as a matter of urgency - model guidelines for regulatory approval of prescription only fixed dose combination drugs with special emphasis on drugs for communicable diseases with high public health impact. Regulators have a role and responsibility to facilitate access to drugs of public health importance including proposing changes in the respective regulations in order to facilitate access without compromising on quality, safety and efficacy. WHO should continue pre-qualification of drugs for priority disease programmes, particularly HIV, malaria and TB. Countries should adopt the WHO Guidelines on Developing Measures for Combating Counterfeit Drugs, raise public and political awareness of the problem, increase national, international cooperation and data exchange between all stakeholders, including drug regulatory authorities , interested nongovernmental organizations , law enforcement agencies, industries, and relevant international organizations. … 8 WHO - EDM Procurement, Quality and Sourcing Project Prequalification: misunderstandings and critics Too high standards increasing prices … Too high and unnecessary standards for developing countries … Too bureaucratic and slow, not proactive and not able to provide products… Too low standards …. " This leaves the impression with readers that the ARVs approved by WHO are in fact generic products that are interchangeable with their innovator cousins. From available documents, however, we conclude that they are copy products with unknown quality, safety and efficacy profiles". WHO - EDM 9 Procurement, Quality and Sourcing Project Prequalification: generics or not? FDA requirements for generic drugs (www.fda.gov/cder/ogd) Thus, a generic drugs must: 1. contain the same active ingredients as the innovator drugs as the innovator drug 2. be identical in strength, dosage form, and route of administration 3. have the same use indications 4. be bio-equivalent 5. meet the same batch requirements for identity , strength, purity and quality 6. be manufactured under the same strict standards of GMP required for innovator products. WHO - EDM 10 WHO/HTP/EDM/QSM General procedure: Prequalification What will be required for generic drugs (1) ? 1. 2. 3. 3.1 3.2 3.3 3.4 Details of the product Regulatory situation in other countries Active pharmaceutical ingredient(s) (API) Properties of the active pharmaceutical ingredient(s) Sites of manufacture of API(s) Route(s) of synthesis Specifications – API described in a pharmacopoeia – API not described in a pharmacopoeia 3.5 Stability testing – WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-fourth report. Geneva, World Health Organization, 1996: 65-79(WHO TRS, No 863, as amended in 2002) http://www.ifpma.org/ich5q.html#stability WHO - EDM 11 WHO/HTP/EDM/QSM General procedure: Prequalification What will be required (2)? 4. 4.1. 4.2. 4.4. 4.5 4.6 4.7 4.8 Finished product Formulation Sites of manufacture Manufacturing procedure Specifications for excipients Specifications for the finished product Container/closure system(s) and other packaging Stability testing WHO - EDM 12 WHO/HTP/EDM/QSM General procedure: Prequalification What will be required (3)? 4.9 4.10 4.11 4.12 4.13 4.14 Container labelling Product information Patient information and package inserts Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) Interchangeability (bioequivalence studies) Summary of pharmacology, toxicology and efficacy of the product WHO - EDM 13 WHO/HTP/EDM/QSM General procedure: Prequalification Steps of the Procedure 1. Invitation for EOI - - Wide publication Open, transparent Specify products required 2. Guidelines for product dossier compilation and requirements available - Multi-source products Innovator products WHO - EDM 14 WHO/HTP/EDM/QSM General procedure: Prequalification 3. Receiving of dossiers 4. Screening of dossiers Screen for completeness Inform supplier Listed for a possible site inspection 5. Dossier evaluation Team of experts (quality, pharmaceutical development, bioequivalence etc) From national regulatory authorities Standard: Including, but not limited to WHO Manual and guidelines " Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority, WHO/DMP/RGS/98.5) Outcome of the evaluation communicated to supplier WHO - EDM 15 WHO/HTP/EDM/QSM General procedure: Prequalification 6. Site inspection WHO GMP Inspection team: - Appointed inspector - Experience, qualification, preferably from DRA - Local, national inspectorate - WHO representative 7. Report and outcome Reports on dossier evaluation and site inspection Communicated to supplier/manufacturer Compliance? Additional information to be submitted? WHO - EDM 16 Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality: Quality Problems (I) Assessment – from ABC to XYZ API source, impurities, lack of stability data … lack or defective bioequivalence data Manufacturing site inspections - - Manufacturers not ready, often non-compliance with WHO cGCP Upgrading of facilities to comply with WHO cGMP DRAs issued CPP – yet non-compliance Inspections reveal non-compliance, e.g. antibiotics (penicillin), hormones and other products manufactured in the same site No validation Time needed to respond to report “double standards” – local vs. international market WHO - EDM 17 Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems (II) Specific problems : Unacceptable chiral activity, stereo-isomerism of active pharmaceutical ingredient (API) - potentially inactive API CHIRALITY / ENANTIOMERIC PURITY Stavudine Lamivudine Indinavir (1/ 32 possible stereoisomers) Saquinavir mesylate (1/64 possible) Ritonavir Only one enantiomer registered and claimed in the innovator’s dossier EMEA/CPMP/375/96 EPAR : (-) Lamivudine selected because less cytotoxic than (+) Lamivudine and the racemate (50:50 mixture) WHO - EDM 18 Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems (III) CHIRALITY / ENANTIOMERIC PURITY: Lamivudine example (1): No information on the stereochemical configuration No information on how the synthesis can lead to the correct enantiomer evidence of structure / right enantiomer? No validation on manufacturing process of the API: only 2 batches with batch size unknown batch-to-batch consistency not demonstrated/ is the same enantiomer obtained each time? Is it contaminated with the same amount of the undesirable stereoisomer each time? Absence of control of the undesirable enantiomer in the finished pharmaceutical product including biobatch ... WHO - EDM 19 Problems encountered Access to HIV/AIDS Drugs and Diagnostics of Assured Quality: Quality problems (IV) BIOEQUIVALENCE Lamivudine examples 1 file for oral solution no BE study required 6 files for tablets from 4 manufacturers 2 manufacturers: no BE study 2 manufacturers: BE study included for at least one formulation strength Major deficiencies identified in BE studies from both manufacturers (assay validation, relevant test product?) WHO - EDM 20 Summary of Identified Deficiencies in all Files Requiring BE Studies (interim review, 64 files in total) Major deficiencies No bioequivalence study performed and no adequate justification for not performing a study (32 files) Inadequate validation data of bioanalytical method (14 files) No verification that test product used in bioequivalence study is identical to product intended for marketing (13 files) 90 % Confidence Intervals for pharmacokinetic parameters not presented (9 files) Non-assessable Comparative Efficacy Study (1 file) WHO - EDM 21 Summary of Identified Deficiencies in all Files Requiring BE Studies (interim review, 64 files in total) Minor deficiencies No information on batch size of test product Certificate of Analysis of test batch not submitted In-vitro dissolution profiles not submitted for test product for reference product for different strengths of the same product WHO - EDM 22 Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality Expanded Tuberculosis products: First line as well as second line treatment 119 Product dossiers Several inspections in various countries List of products and manufacturers not yet published – SERIOUS QUALITY PROBLEMS Malaria 27 Product dossiers, mainly artemesinin and combination products List of product(s) published in August 2003 HOW TO ASSESS? Some neither originators nor generics WHO - EDM 23 Pilot project Expansion to cover other important areas? Prequalification of QC laboratories Standards and procedure ready Two laboratories assessed, one approved Prequalification of procurement agencies Standards and procedure ready Model Quality Assurance System created, under finalization WHO - EDM 24 Pre-qualification of a triple FDC from generic manufacturers has caused a lot of "emotions" lamivudine + stavudine + nevirapine Issues: No originator FDC Regulatory principles the same as applied by FDA and EMEA to Trizivir from GSK ( lamivudine+zidovudine+abacavir) i.e. based on bioequivalnce studies against loose combination no additional clinical studies required WHO - EDM 25 Procurement, Quality and Sourcing Project Prequalification project Current status: Good news Relatively large number of ARV products and suppliers indicated Many potential suppliers appreciating feedback and willing to improve Unique knowledge obtained about generic ARVs and other products, including TB products “Quality” generic products do exist Bad news Only limited number of products have met the required standards Takes time to get into compliance Data to be generated, tests carried out GMP upgrade needed Bad quality generics may undermine the public confidence in generics Quality Assurance at a price! WHO - EDM 26 http://mednet3.who.int/prequal/default.shtml Quality can not be assessed, tested or inspected into the product. It has to be built into it. WHO - EDM 27