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Prequalification Programme: Priority Essential Medicines
Dr A J van ZylTechnical OfficerHTP/PSM/QSM
World Health Organization (WHO)Geneva, Switzerland
vanzyla@who.int
Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations
15 October 2007
Tallinn, Estonia
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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
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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
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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
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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)
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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
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I Expression of InterestProduct dossier
SMF
Compliance
Additional informationand data Corrective actions
Compliance
Assessment Inspections
Steps in prequalification
Prequalification Monitoring
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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)
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Product dossier assessment
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Reproductive Health Products
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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
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Assessment procedure- Product dossiers
Innovator 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
Multisource (generic) products 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)
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Prequalification: generics and not generics
Generic medicines: 1. To contain the same active ingredients as the innovator drugs as the innovator drug2. To be identical in strength, dosage form, and route of administration3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality5. To be manufactured under the same strict standards of GMP required for innovator products.6. To be bio-equivalent
Prequalification requirements for generics Fully in line with major regulatory agencies
What if not generics 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)
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Norms and standards used
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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
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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.
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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
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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
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Inspection of sites
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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
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Inspections:
Assess compliance with
WHO norms and standards: GMP GCP GLP GSP GDP…
Organizations conducting clinical trials WHO training materials
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Where are the inspections performed?
India, Bangladesh, Pakistan China Belgium Canada Malaysia France South Africa Switzerland United States Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda
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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 . . .
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Inspections:
Bio-equivalence studies GCP and GLP
About 2 days per study including
Clinical part Clinic, Pharmacy and related areas, data verification
Bio-analytical part Laboratory and data verification
Statistical analysis
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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
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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
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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
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Problems identified in GCP inspections:
Volunteers Number of volunteers in a study No control for participating in several studies in a short period Supportive documentation – DOB, identification, ECGs Screening ICF
Ethics committee Independence Supportive documentation
Clinic Archives Pharmacy
Documentation, randomization, dispensing CRFs Analytical method validation Stability (stock solutions, samples) Source data including chromatograms
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Outcome
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Outcome
List of prequalified products New and revised guidelines, norms and standards
MonographsInternational Chemical Reference standards
Sampling and testing of products on the marketTraining
Capacity building. . .
See also Annual Report
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List of prequalified products
Disease 2001 2002 2003 2004 2005 2006 2007
HIV/
AIDS
… … … … … 25(excluding US FDA, Canada)
19 (excluding US FDA)
TB … (5) 2 1 0 4
Malaria 0 2 3 0 3
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Examples of Antimalarials prequalified so far
Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12
Artemether/ 20mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24lumefantrine 120mg
Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml
Artesunate 50mg Tablets Guilin Pharmaceutical Co Ltd PVC/AI Blister 12
Some other manufacturers may have also achieved GMP level but GMP alone is not enough for prequalification
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Monitoring…
Ongoing assessments and follow-up
• Products• Manufacturing sites (both for APIs and finished dosage forms) • CROs• Sampling and testing
• Data verification inspections
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Since 2005: PQ Annual report
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Capacity building and improvement
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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
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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"
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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
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Alternative regulatory pathways
USA FDA tentative approvals linked to PEPFAR Included in WHO PQ List Confidentiality agreement with US FDA in place
EU Article 58 For products exclusively to be used outside EU
Canadian Access to medicines scheme WHO cooperation with the above mentioned Confidentiality agreement in preparation
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Thank you