Prequalification Programme: Priority Essential Medicines Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations 15 October 2007 Tallinn, Estonia Dr A J van Zyl Technical Officer HTP/PSM/QSM World Health Organization (WHO) Geneva, Switzerland vanzyla@who.int 1 Quality of medicines remains a problem in many countries Oct 2006. Panama: More than 30 died - cough syrup containing diethylene glycol – industrial solvent (in antifreeze) – kidney failure 1999. Belgium: Two babies died. Injected KCl (supposed to be glucose) 2000. USA: 17 children died. No active ingredient in inhalers Picture. New York Times 2007 Death by GMP: MH Anisfeld. GMP Review. Vol 4 No 4 2006 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 2 What is WHO doing to help the countries? Normative functions – setting norms and standards Including GMP Capacity building Prequalification Programme: Priority Essential Medicines "Three in one" – more tuned to real public health problems, immediate feedback, better quality, higher efficiency Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 3 In this presentation… What is "prequalification" and how does it work Steps in prequalification Norms and standards used Evaluations (dossiers and site inspections) Outcome of assessment Capacity building and improvements Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 4 Prequalification of essential medicines The UN prequalification program: Is an action plan for expanding access to medicines for patients with: HIV/AIDS Tuberculosis Malaria And access to Reproductive Health Products Ensures quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM) Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 5 How prequalification is organized? Role of WHO: Managing and organizing the project on behalf of the United Nations. • Provides technical and scientific support • Ensures that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP, GLP) and quality control Partners: • UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank • Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department Actors: Mainly qualified assessors and inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 6 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 7 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 8 Steps in prequalification I Expression of Interest Product dossier SMF Assessment Inspections Additional information and data Corrective actions Compliance Compliance Prequalification Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 9 Monitoring Quality Assurance (QA) of WHO prequalification process PQ team has its own Quality Assurance system: Quality Assurance and Safety: Medicines (QSM) Standard Operating Procedures (SOPs) Manuals and guidelines General Procedure for Prequalification Norms and standards (product dossiers, manufacturers etc) Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 10 Product dossier assessment Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 11 Reproductive Health Products Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 12 Evaluation procedure Assessment of product dossiers (Quality specifications, pharmaceutical development, production, control, stability, bioequivalence etc). Teams of professionals from national Drug Regulatory Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ... • • • • • Copenhagen assessment week 8 to 20 assessors together during one week at least every two months at UNICEF in Denmark Every dossier is assessed by at least four assessors. An assessment report is issued - signed by assessors Letter summarizing the findings and asking for clarification and additional data if necessary Letter is sent first by e-mail to the applicant followed by surface mail Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 13 Assessment procedure- Product dossiers Innovator products • • • Multisource (generic) products • • Abridged procedure if approved by stringent authorities like EMEA and US FDA Assessment reports from Drug Regulatory Authorities (DRSs), WHO Certificate of Pharmaceutical Product (CPP), batch certificate, update on changes Trusting scientific expertise of well-established DRAs Full dossier with all the data and information requested Quality: • Information on starting materials and finished product, including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc Efficacy and safety: • Bio-equivalence study or clinical study report Commercial sample Requested, but not always analysed before prequalification. US FDA tentative approvals for ARVs – recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach will soon apply for EU Art58 and Canadian JCPA procedure) Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 14 Prequalification: generics and not generics Generic medicines: 1. To contain the same active ingredients as the innovator drugs as the innovator drug 2. To be identical in strength, dosage form, and route of administration 3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality 5. To be manufactured under the same strict standards of GMP required for innovator products. 6. To be bio-equivalent Prequalification requirements for generics What if not generics Fully in line with major regulatory agencies Full data to prove safety (including preclinical toxicology) and efficacy has to be presented Not all non-innovator products in prequalification pipeline can be defined as generics – no innovator may be available See also FDA requirements for generic drugs (www.fda.gov/cder/ogd) Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 15 Norms and standards used Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 16 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 17 Prequalification: where the technical documents come from? International consultation process The WHO Expert Committee – review and adopts Executive Board World Health Assembly Printed in respective TRS and WHO web site Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 18 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 19 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 20 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 21 Publications 2005/2006 New, user friendly prequalification web site launched in November 2006: http://who.int/prequal/ Articles: 1. Prequalifi cation of medicines. WHO Drug Information, 2005, 19:1. 2. WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2. 3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105. Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 22 Problems encountered with product dossiers General HIV/AIDS: Initially – few monographs (Official Pharmacopoeia) Malaria - very few innovator products, many not typical generics as well Very few antimalarials approved in ICH and associated countries Limited DRAs and regulatory experts having experience Fixed dose combinations more complicated than single component products TB: Old products, low profits – lack of data meeting current requirements General Quality related issues Manufacturers do not comply with GMP Products not controlled - registered and produced only for export Lack of specifications or poorly defined manufacturers specifications Stability data missing or not meeting requirements No method validation etc. Mostly manufacturers can overcome these problems if motivated. However, it may take a lot of time Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 23 Problems encountered with product dossiers Lack of reference products for bioequivalence studies For generic products: Bioequivalence studies to show the same blood concentrations (assume same safety and efficacy profile) Often unclear which comparator product to be used BE not a requirement in all countries Safety and efficacy related issues Insufficient data submitted Incomplete protocols and trial reports Incomplete evaluation of published literature No characterisation of pharmacokinetic properties of the product General statements made: No interaction known (clearly not true); No (or minimal) adverse events (literature survey if no original data) Too broad efficacy claims Galenical development history not provided Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 24 Inspection of sites Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 25 Inspections: Team of inspectors for each inspection WHO PQ inspector plus PIC/S member country plus local country inspector (observer) Some cases – capacity building (recipient country) Preparation includes SMF, product information, inspection reports, complaints etc APIs, Finished products Clinical studies: Mostly Bioequivalence studies (generic products Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 26 Inspections: Assess compliance with WHO norms and standards: GMP GCP GLP GSP GDP… Organizations conducting clinical trials WHO training materials Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 27 Where are the inspections performed? India, Bangladesh, Pakistan China Belgium Canada Malaysia France South Africa Switzerland United States Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda … Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 28 Inspections: Production and control activities: Normally over 3 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 ... Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 29 Inspections: Bio-equivalence studies GCP and GLP About 2 days per study including Clinical part Bio-analytical part Clinic, Pharmacy and related areas, data verification Laboratory and data verification Statistical analysis Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 30 Problems identified in GMP inspections: Various including validation, ventilation, equipment, quality risk management… 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 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 31 Problems identified in GMP inspections: No URS for HVAC, water and computer systems Incomplete (not detailed) or "no" qualification of HVAC / water / computers Insufficient filtration of air to production areas No prevention of possible cross-contamination and contamination. No authorized schematic drawings "As built" AHUs lacked components reflected in the schematic drawings, including filters Temperature and RH mapping studies incomplete, or results not applied HVAC systems not controlled or monitored Filters: not planned, classified, tested (including installed filter leakage test), monitored Pressure differential gauges not controlled, including calibration and zero checks Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 32 Problems identified in GMP inspections: Wrong sequence of components (e.g. after filtration) Inappropriate AHU for equipment e.g. coaters, FBD Claim "wet scrubbers" – but not functional Inappropriate change control No quality risk management documented Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 33 Problems identified in GCP inspections: Volunteers Ethics committee Independence Supportive documentation Clinic Archives Pharmacy Number of volunteers in a study No control for participating in several studies in a short period Supportive documentation – DOB, identification, ECGs Screening ICF Documentation, randomization, dispensing CRFs Analytical method validation Stability (stock solutions, samples) Source data including chromatograms Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 34 Outcome Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 35 Outcome List of prequalified products New and revised guidelines, norms and standards Monographs International Chemical Reference standards Sampling and testing of products on the market Training Capacity building ... See also Annual Report Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 36 List of prequalified products Disease 2001 HIV/ AIDS TB Malaria … 2002 2003 2004 2005 2006 2007 … … … … 25 19 (excluding US FDA, Canada) (excluding US FDA) … (5) 2 1 0 4 0 2 3 0 3 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 37 Examples of Antimalarials prequalified so far Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12 Artemether/ lumefantrine 20mg 120mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24 Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml Artesunate 50mg Guilin Pharmaceutical Co Ltd Tablets PVC/AI Blister 12 Some other manufacturers may have also achieved GMP level but GMP alone is not enough for prequalification Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 38 Monitoring… Ongoing assessments and follow-up • • • • Products Manufacturing sites (both for APIs and finished dosage forms) CROs Sampling and testing • Data verification inspections Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 39 Since 2005: PQ Annual report Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 40 Capacity building and improvement Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 41 Capacity building of DRAs and Manufacturers Both remain important components and need strengthening Both need improvement and new approaches From 2006 - in addition - provide (to selected manufacturers): Technical Assistance Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 42 Measures taken to get more products prequalified Action taken. . . Formerly very limited resources vs huge obligations and scope Initially only ONE professional - today at least 15 (including 4 secondments from Governments such as France and China) Business plan and funding proposals – now funds received (Gates) and (UNITAID) Internal SOPs and work procedures "Note for Applicants" (anti-malaria products) New regulatory guidance documents created and started Specific guidance on comparator products More direct discussions with manufacturers started Regulatory advice on complicated cases including BE Pharmaceutical development, technology transfer, paediatric formulations "Notes to consider" Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 43 Measures taken to get more products prequalified Action taken (2) . . . Additional funding (e.g. Gates, UNITAID) Additional training workshops Additional staff to be recruited Communication to be improved Regulators Manufacturers Donors and partners More proactive approach towards potential suppliers – new elements Regulatory advice Technical assistance Strengthening links with WHO regions Taylor made approach to different regions Building capacity in countries Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 44 Alternative regulatory pathways USA FDA tentative approvals linked to PEPFAR EU Article 58 Included in WHO PQ List Confidentiality agreement with US FDA in place For products exclusively to be used outside EU Canadian Access to medicines scheme WHO cooperation with the above mentioned Confidentiality agreement in preparation Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 45 Thank you Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 46