Ensuring Quality Priority Essential Medicines Public Health Seminar “Community involvement for improved procurement supply and pricing Ant by ohl18177

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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@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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Health Technologies and Pharmaceuticals
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Health Technologies and Pharmaceuticals
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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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Health Technologies and Pharmaceuticals
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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, 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
            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




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Health Technologies and Pharmaceuticals
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