Prequalification and ADP

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Ensuring Quality Priority Essential Medicines
Public Health Seminar Community involvement for
improved procurement, supply and pricing
Antiretroviral and Opioid Substitution
medicines. 5 7 March 2008 Kyiv, Ukraine
Dr Olexandr Polishchuk Adviser HTP/CPS/DCS World
Health Organization EURO Copenhagen,
Denmark apo_at_euro.who.int
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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? (1)

• 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

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How prequalification is organized? (2)

• 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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Steps in prequalification
Expression of Interest Product dossier SMF
Assessment
Inspections
Additional information and data
Corrective actions
Compliance
Compliance
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 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
• 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, 191.
• 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 WHOs
  Prequalifi cation Programme. Journal of Generic
  Medicines, 2006, 3(2)96105.

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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
• Monographs
• International Chemical Reference standards
• Sampling and testing of products on the
  market
• Training
• Capacity building
• . . .
• See also Annual Report

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Prequalification statistics
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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 24
• lumefantrine 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