Presentation on theme: "PREQUALIFICATION General overview and procedures"— Presentation transcript:
1 PREQUALIFICATION General overview and procedures and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement agencies involved in procurementTechnical Briefing Seminar for Consultants on Procurement and Supply Managementfor HIV/AIDS, TB and MalariaOrganized by WHO and AMDS NetworkCopenhagen, Denmark31 January 2006Maija HietavaM.Sci.PharmQuality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals ClusterTel: Fax:World Health Organization
2 Prequalification of essential medicines The UN prequalification program is an action plan for expanding access for the hardest hit byHIV/AIDSTuberculosisMalariafor ensuring quality, efficacy and safety of medicines all the way through the medicines supply chain.Approval of products (PQ of medicinal products) ---- Procurement, supply, distribution (MQAS – PQ of procurement organizations) ---- Post-approval quality control (PQ of QC labs). Each of these 3 links in the medicines supply chain is subject to PQThis presentation focuses on prequalification of medicinal products
3 Why the prequalification is needed ProblemsMillions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatmentProcurement and supply of substandard and counterfeit products in different countriesWeak/absent QA systems of medicines supply chainLot of money invested in procurement no harmonized quality assurance system available for procurement organizationsRisksSourcing of poor quality products or even counterfeit medicines risk to patients, treatment failure, resistanceRisks to patients: too high doses – AEs, too low doses – treatment failure and/or development of resistance
4 Challenges of prequalification Demand for affordable antiretrovirals, anti-malaria drugs and anti-tuberculosis drugs is increasingNumerous generic manufacturers offering productsChallenges for UN family and procurement agencies/organizationsThe above of course increase the pressure on all the links in the supply chain
5 Is quality of pharmaceuticals a problem? Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis antiretrovirals drugs includedIncorrectamount17%No activeingredient60%Other errors7%16%Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO databaseStudy shows procurement of substandard drugs is a reality. Drugs may not contain API at all or may contain different API (paracetamol instead of antibiotic, for example).
6 Prequalification basic principles Voluntary for participating manufacturersLegitimate - General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodiesWidely discussedFIP Congress, Nice 2002Supported by ICDRA in 2002 and 2004, representing more than 100 national drug regulatory authoritiesTransparent (all significant information available on the web site )Open to both innovators and multisource/generic manufacturersNo cost for applicants during pilot phaseWe cannot oblige manufacturers to attendWidely discussed AND SUPPORTED (FIP= International Pharmaceutical Federation - in French). ICDRA made a formal recommendation that "WHO should continue the Pre-qualification Project of medicines for priority disease programmes, particularly for HIV/AIDS, malaria and Tb".Website contains everything except pipeline info, however GMP and GCP/GLP compliant site mentioned in their own right (even though product may not be fully prequalified). WHOPARs and WHOPIRs.Impartial – PQ team not involved in procurement, supply, policy making, WHO treatment programs or in selecting drugs for EOIPlease note "Procedure for assessing…" (2.12 Cost Recovery) – "WHO reserves the right to charge for the quality assessment procedure on a cost recovery basis"!!
7 Expected outcome of prequalification List of products and manufacturers/CROsMeeting international norms and standards on quality, safety, and efficacy (Q, S & E)HarmonizationCo-operation, training, capacity building – NDRAs, WHO, NGOsFacilitate access to treatmentProcurement mechanisms (e.g. tender, competition)Ongoing monitoring of Quality, Safety & EfficacyWHO commitment to developingWe prequalify products, not manufacturers.UNFPA and UNICEF have QA systems in place, but they are quite different from one another, not harmonized, extent and quality of inspections may vary, and mutual recognition and coordination of such inspections is an exception rather than the rule.Harmonization on all levels:Assessments: Sitting together, minimum 2 assessors/dossier, guidances, assessment templates).NDRAs: Capacity building - assessors/inspectors from dev countries attend, training workshops for local manufacturers/NDRAsWHO treatment programs: Determine drugs on EOIsProcurement organizations: Develop harmonized QA systemOngoing monitoring – we keep monitoring even after listing of the product
8 ObjectivesPropose a list of prequalified manufacturers and products of which the quality, efficacy and safety have been assessed, inspected and controlled to meet international norms and standards.Gives assurance that international norms and standards are applied at all the steps of the prequalification and at the process itself.Make possible and speed up access to good quality of medicines. Fast track process for listing can take as little as two months from the date of application.The various steps are compliant with international norms and standards, the process itself is also QA'd (=internal QA system).
9 Objectives cont…Follow-up and regular monitoring of the quality of manufacturers and productsEnsure re-qualification and update of the list of prequalified products and manufacturers as new products and manufacturers meet the standardsEnsure the appropriate control of variations and changesDevelop the local capacity for quality production and clinical studies.National regulatory authorities (DRA) are involved in dossier assessment and inspectionsProducers receive invaluable specific technical feedbackHelp the national DRA to build up capacity in assessment, inspection and control meeting international norms and standards"The Procedure for Assessing the Acceptability, in Principle, of Pharmaceutical Products for Purchase by United Nations Agencies" speaks of RE-EVALUATION:At regular intervalsSupplier to communicate any changesRe-inspection at least every 3 yearsChange to key personnel or the manuf site could also result in re-inspRe-evaluat of dossier every 3 years or sooner if change of formula, manuf method/siteRequal generic: Updated dossier, incl any changes that may impact…, letter of invitation for an inspection of manuf site/CRO, sample of all commercial present's.Requal innovator: Updated dossier, incl any changes that may impact…, if no changes – only a letter confirming this is ok, WHO may request copies of latest inspection reports by DRAs, in some cases WHO may decide to do insp's.RE-EVALUATION also iffraud/omission (post-PQ)batch not in compliance with agreed spec'sserious complaintsif suspension of supply ≥ 1 yearif changes to API, formulation, manuf method/facility or other production aspects.Some dossiers very poor quality, failed inspections or postponed scheduled inspections at the last minute. Quality of dossiers has improved, increased willingness to upgrade manufacturing sites. WHO cannot take responsibility for the time taken to submit additional data requested or time taken to take corrective action…Some NDRAS have adopted procedures from PQ and may fast-track PQ'd dossiers.
10 How prequalification is organized Role of WHO: Managing and organizing the project on behalf of the United Nations.provide technical and scientific support andguarantee that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP/GLP) and quality controlPartners:UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World BankAnti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility)US FDA tentative approvals – recognition based on information exchange (Confidentiality agreement)Actors: Mainly assessors and inspectors of National DRAs as well as National Quality Control Laboratories of PIC/S and ICH member countries…guarantee – through our manuals and guidelines
11 Steps of prequalification 1. Expression of interest (EOI) from a prospective supplier interested in a voluntary participation in the program.2. Receipt of the dossier at UNICEF in Copenhagen and the Site Master File in WHO Geneva.Explicative notes and guidelines are published on the WEB in order to explain how to bring together a product dossier meeting the requirements for prequalification.3. Screening of the dossier, "Quality" part, "Clinical" part and samples. possible inspection4. Assessment of the dossier and writing of the assessment report and assessment letter.5. Outcome of the evaluation communicated to supplierEOI =public, selection determined by WHO clinical departments, UNAIDS, WHO disease orientated programmes, based on WHO guidelines, position statements AND EML and a WHO survey of the most frequently occurring HIV related morbidity.Can return dossiers that do not contain all the necessary bits and pieces. BUT cannot refuse assessing poor dossiers – also need to capacity build these, otherwise favourism…Usually several rounds of review (AD etc) before final approval.
12 Steps of prequalification cont… 6.Inspection of the site (s) of manufacturing and follow-up inspection when necessary GMP compliant list of manufacturers7.Inspection of the Research Laboratory or Contract Research Laboratory (CRO) where the bioequivalence study has been performed GCP compliant list of CROs8.Conclusion and listing of the product in the prequalification list9.Publication of the Public Assessment (WHOPAR) and Inspection (WHOPIR) Reports10.Assessment of the variation when submitted, market survey, de-listing if necessary11.Re-qualification after 3 years
13 Assessment procedureAssessment of products dossiers i.e. quality, specifications, pharmaceutical development, bioequivalence etc.teams of professionals from national drug regulatory authorities (DRA): Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe ...Copenhagen assessment week8 to 12 assessors together during one week at least every two months at UNICEF in CopenhagenEvery dossier is assessed by at least two assessors.An assessment report is issued; signed by two assessorsLetter summarizing the findings and asking for clarification and additional data if necessary.Letter is sent first by to the applicant followed by surface mailNigeria, UK and Norway coming…UNICEF – facilities for storage, rooms for assessorsSecurity at UNICEF better than at WHO. However running out of storage space!!!Does not mean UNICEF in any way participates in or influences the scientific assessments!
14 Assessment procedure-Product dossiers Innovator productsAssessment report from DRAsWHO Certificate of Pharmaceutical Product (CPP)Batch certificateUpdate on changes.Multisource products (generics)Full dossier with data and informationQuality : information on starting materials and finished product including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etcEfficacy: Bio-equivalence study or clinical study reportUS FDA tentative approvals – recognition based on information exchange (Confidentiality agreement)Commercial sampleCPP=establishes the status of the pharmaceutical product and of the applicant for the certificate in the exporting country. It is for a single product only since manufacturing arrangements and approved information for different dosage forms and different strengths can vary.INNOVATOR GUIDANCE (ON THE WEB)WHO CPPAssessment report or EPAR – if not available then full docIf composition/formulation, strength, specifications different – arguments/data (pharmaceut equivalence/BE)Stab data if primary packaging different.5. Sample (CoA)GENERICS GUIDANCE (ON WEB)Full dossier needed because not scrutinized by reg authority before.ICH-GENERICS GUIDANCE (NOT ON WEB)Assessment report (or full doc); for old products bibliographic submission possibleSimplified procedure if ≥ years of documented experience of the API in ICH (EU regulation states 10 years). For FDC FPPs BE also has to be demonstrated – In a bibliographic registration efficacy and safety are documented from literature and no BE necessary for single-APIs. For FDC FPPs BE should be demonstrated against the individual API components.WHO type batch certificate (Annex 3)If formulation, strength, spec's different – arguments/data (pharmaceut equivalence/BE)Stab data if primary packaging differentSample (CoA).Stringent=ICH (EU/EMEA, FDA, Japan PMDA; Pharmaceuticals and Medical Devices Agency) + PIC/S (Canada, Australia, Malaysia, Singapore, Norway, Switzerland)FDAOnly difference is the WHO Prequalification process is voluntary for manufacturers, and there is no legally binding marketing authorization.Patent issues are not taken into account, each country has its own patent laws – a product may be patented in one country but not in another - that need to be considered, also NDRA approval is required before marketing in a specific country. Suffices that a company is duly authorized for pharmaceutical manufacture in its own country (= compliant with GMP, as certified by the NDRA and/or certified GMP inspector) and that the final product meets the stringent standards of quality, safety and efficacy. Procurement organizations must consider patent status in countries from which they procure and to which they intend to supply.PQ does not mean exemption from national reg approval BUT in certain countries legislation may allow Governmental and/or emergency supplies to be exempted.
15 Inspection procedure Inspections Manufacturing site (FPP, packaging) Active pharmaceutical ingredient (API)Research laboratory/Contract Research Organization (CRO)Teamwork of inspectorsWHO representative (qualified GMP inspector)Inspector from well-established inspectorate (Pharmaceutical Inspection Convention Scheme PIC/S countries)National inspector(s): Canada, India, China, France, Italy, Switzerland, South-Africa, Thailand…Quality control analysis - upon need but not always necessarily beforeprequalification and supply; increasingly as part of follow-upQC routinely before procurement
16 Prequalification of quality control laboratories To increase the local capacity to control the quality of pharmaceutical productsQuality Control Laboratories in sub Saharan Africa as priorityWHO norms and standards for QC laboratoriesPrequalification processExpression of Interest (EOI)Laboratory Information File (LIF), evaluationInventory Audit – help/evaluateInspection with the team of inspectorsPrequalified laboratories list public in WHO web site (2 listed)Reassessment systemThe official inspection means SH + PIC lab personnel with inspection auditing training (from National QC labs of PIC/S countries). GMP inspectors not normally familiar with lab inspections.
17 Training activitiesIn 2005 three comprehensive 5-day training courses on quality, GMP and BE for TB drugs and ARVs (Malaysia, China, Ukraine)Course on quality, GMP and BE planned for Jan-06 (China)Two GMP training courses for NDRA inspectors (South-Africa, China)Recent GMP training course in Tanzania (with PQ participation)Training of QC lab officialsTraining of PQ staff and inspectors working for WHO in BE study inspections (January-February -06)TSH: We have sent dev country officials to EDQM training in Strasbourg. EDQM = European Directorate for the Quality of Medicines (part of this is OMCL= European Network of Official Medicines Control labs)
18 Current status – December 2005 Started with HIV/AIDS products in 2001 – malaria and TB products joined laterPrequalified products (Dec 2005) Dossiers arrived105 HIV related medicines (Aug-05) 343 (Dec -05)8 anti-tuberculosis medicines2 anti-malarial medicinesOngoing assessments and follow-upProductsManufacturing sitesCROsFor ARVs limited therapeutic experience and no well established quality standards, like pharmacopoeial monographs. Also particular properties of some of these substances (eg chiral activity, isomerism, sensitivity to rel humidity etc), requiring expert assessment. And these drugs were largely in accessible in the countries most affected by HIV/AIDSHIV=10368 ARVs (34 from innovators, 34 from generic manufacturers) – singles 54, 2-FDC 8, 3-FDC 6.35 othersTB=84 from Sandoz, Wyeth, 4 from generic manufacturers – 6 FDCsMA=2Total number of submitted dossiers (24 Oct): 338 (HIV/AIDS), 157 (TB), 49 (MA) = 544 (=PQ'd + cancelled +active)ACTIVE (IN PIPELINE) – 94 (HIV/AIDS), 55 (TB), 44 (MA)HIV/AIDSProcurement policy of GF motivates manufacturers to seek PQ status.TBProcurement of TB prod's not yet strictly monitored. AND GDF subsidizes manufacturers which discourages investments to improve quality. They are not motivated to improve quality, since they do not need to do that to sell them (happy to meet local standards only). Some manufacturers have not even performed stability studies.MAMost artemisinines are not approved in ICH. Defining the documentation needed poses challenges. Most cannot be evaluated based on guidance for generics or innovators. Very few agreed standards. Therefore different approach:1. BE or 2. E/S (bibliographic +clin studies). The Malaria Medicines and Supplies Service encourages manufacturers to apply for PQ and organizes technical assistance in assembling dossiers.
19 Current status – Manufacturers of finished products In the prequalification list: 15 sites of genericsAsia: sitesEurope: 4 sitesAfrica: 2 sites
20 Ongoing monitoring and requalification Samples taken after supplyRoutine inspections and additional inspectionsChanges and variations controlledProducts and manufacturersRequalification (re-assessment) every 3 yearsWorld Health Assembly resolution: WHA57.14 of May 2004Public reports requestedWHOPIRs (WHO Public inspection report) and WHOPARs (WHO Public Assessment Report) are now on the prequalification web siteIncreasing interest in WHO Public Inspection Reports (WHOPIR)APART FROM THE BELOW, FOLLOWING PQ THE FURTHER LIFE CYCLE OF THE PRODUCT IS LARGELY THE LEGAL RESPONSIBILITY OF THE RESPECTIVE COUNTRIES (THIS WOULD INCLUDE PMS ACTIVITIES ETC)."The Procedure for Assessing the Acceptability, in Principle, of Pharmaceutical Products for Purchase by United Nations Agencies" speaks of RE-EVALUATION:At regular intervalsSupplier to communicate any changes (safety, efficacy, quality)Re-inspection at least every 3 yearsChange to key personnel or the manuf site could also result in re-inspRe-evaluat of dossier every 3 years or sooner if change of formula, manuf method/siteRequal generic: Updated dossier, incl any changes that may impact…, letter of invitation for an inspection of manuf site/CRO, sample of all commercial present's. Things may change over time (limits of impurities, solvents in purification process).Requal innovator: Updated dossier, incl any changes that may impact…, if no changes – only a letter confirming this is ok, WHO may request copies of latest inspection reports by DRAs, in some cases WHO may decide to do insp's.RE-EVALUATION also iffraud/omission (post-PQ)batch not in compliance with agreed spec'sserious complaintsif suspension of supply ≥ 1 yearif changes to API, formulation, manuf method/facility or other production aspects require re-assessment.
21 PQ web site information for procurement List of prequalified productsList of manufacturers of manufacturers for APIs (Active Pharmaceutical Ingredient) and FFPs (Finished Pharmaceutical Product), which are GMP compliantList of GCP compliant Contract Research Organisations (CROs), bio-equivalence centers and research laboratories, which are GCP/GLP compliantWHOPIRs (WHO Public Inspection Report)WHOPARs (WHO Public Assessment Report)
22 Global Fund Quality assurance policy related to procurement Practical implications of FDA registration, registration with PICs member countries for procurementGrant funds to procure products meeting following standards(A) such product is acceptable under the WHO Prequalification Program; or(B) such product has been authorized for use by a stringent regulatory authority, FDA tentative approvals;> 2 manufacturers option A or B applies AND the product is available (conditions defined)(C)* If the Principal Recipient determines that there is only one or no (< 2) equivalent pharmaceutical product that meets the standards of either (A) or (B) or if the Principal Recipient determines that the products that meet these standards are unavailable (Defined as inability of the manufacturer to supply a sufficient quantity of finished product within 90 days from date of order), then Grant funds may be used to procure another equivalent pharmaceutical product, provided that such product is selected in accordance with the following, in order of priority:Application submitted to the WHO Prequalification Program or to a stringent regulatory authority and product manufactured at a GMP compliant site; orProduct manufactured at the GMP compliant site (WHO or ICH or PIC/S**)(Random quality analysis of products being procured according to these criteria)*(C) UNTIL 30 APRIL 2005: approval by the NDRA of the recipient country.** ICH or PIC/S countries: see next slideA stringent regulatory authority is defined as a national drug regulatory authority (NDRA) participating in The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) or the Pharmaceutical Inspection Co-operation Scheme (PIC/S)- If there are two or more manufacturers for which Option A or B applies AND the product is available from these manufacturers (defined as the ability to supply a sufficient quantity to the country within 90 days of the date of order), then the product must be procured from this set of manufacturers.
23 2 Equivalent productsNumber of equivalent products under option (a) or (b)RecommendationEnd Option (c) on 30 April 2005New Policy, Global Fund 2 Equivalent productsIf products unavailable, PR informs Secretariat and then:* Product defined as: chemical + strength + formulation** Unavailability defined as: inability of the manufacturer to supply a sufficient quantity of finished product within 90 days from date of order.The PR is required to notify GF if procuring under (i) or (ii)(i) In pipeline ofOption (a) or (b) +Manufactured in a facility compliant with GMP following inspection by WHO or stringent regulatory authorityIF NOT, THEN(ii) Manufactured in a GMP-compliant manufacturing facility
24 Access to a list of countries that belong to ICH or PIC/S: Global Fund Quality assurance policy related to procurement Practical implications of FDA registration, registration with PICs member countries for procurementAccess to a list of countries that belong to ICH or PIC/S:
25 Countries with "stringent" regulatory authorities PIC/S= Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme participating regulatory authorities (AustraliaAustriaBelgiumCanadaCzech RepublicDenmarkFinlandFranceGermanyGreeceHungaryIcelandIrelandItalyLatviaLiechtensteinMalaysiaNetherlandsNorwayPolandPortugalRomaniaSingaporeSlovak RepublicSpainSwedenSwitzerlandUnited KingdomICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use participating regulatory authorities ( )European Union*JapanUnited States* Members include: Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Poland, Slovakia, Slovenia, Spain, Sweden, The Netherlands, United Kingdom
26 Important about Quality of Pharmaceutical Products Building in the qualityStarts during development phase documented evidence during the product life cycle that product used in bioequivalence studies (sometimes pilot batches) is the same as the marketed product (big production batches)Reliable regulatory system and control for stability studies and product variations during the life cycle of a product (if changes are not controlled systematically, there could be a significant change during the product life cycle); capacity problems at the regulatory sideGFTAM = Global Fund TB, Aids and Malaria
27 Important in the regulatory assessment of GENERIC pharmaceuticals There are requirements especially forGenerics (requirements have not been harmonised yet)Bioequivalence studies (not always a requirement as such)Bioequivalence (guidance not harmonised yet)Variations = changes in the product that may have effect on quality (not always strictly followed or controlled)Stability studies (not always strictly followed or controlled)Requirements are controlled by the authorities (capacity problems!)And…..WHO PQ is using FDA based requirementsBioequivalence studies are not always a requirement in the national legislation. Could be sometimes replaced by in vitro comparative dissolution studies
28 Important in the PQ process related to Quality and Efficacy Dossier evaluation and Inspections (GMP = manufacturing and GCP for bioequivalence studies)Go hand in hand in the PQ processSometimes "GMP compliance" alone does not tell the whole truth!!Dossier assessmentInspectionsGMP/GCP
29 This is misleading and/or misunderstood WHO type certificate (by WHO Certification Scheme) is used worldwide But it is not WHO certificateGMP compliance??National GMP requirements are not always those of WHO or stringent authority requirementsDoes not tell everything about the product
30 WHO GMP/GCP CERTIFICATE !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!This is correct!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!WHO Prequalification does not give GMP/GCP certificates, but the GMP/GCP compliant companies are listed in our web siteWHOGMP/GCPCERTIFICATEWHO PQ is using FDA based requirementsBioequivalence studies are not always a requirement in the national legislation. Could be sometimes replaced by in vitro comparative dissolution studies
31 Recent news and new challenges 2005 changes in GFTAM procurement policy – challenges for prequalificationConfidentiality Agreement with the US FDARecognition of US FDA tentative approval process for ARVs based on the scientific assessment done by FDAAdditional fields of cooperation with European Directorate of the Quality Medicines (responsible for European Pharmacopoeia)Jointly funded post established with UNICEF to help managing the assessment weeks in Copenhagen from Sept 2005Constant upgrading guidelines and guidance documents increasing workloadBuilding of the Quality systemResources for 2006/2007GFTAM = Global Fund TB, Aids and Malaria
32 Summary and conclusion Good news; quality of generics existsRelatively large number of products and suppliers comply with the standardsMany potential suppliers appreciating feedback and willing to improveUnique technical knowledge obtained of products, especially generic antiretrovirals and antimalarialsBad news: quality assurance has the priceOnly limited number of products have met the required standardsTakes time to get into complianceData to be generated, tests carried outGMP upgrade neededBad quality generics may undermine the public confidence in generics
33 Summary and conclusion CONT… However… REMEMBERQualitycan not be assessed, tested or inspected into the product, BUThas to be builtinto the productin all the steps …development phase, production, QC, BE study etc.with the help of guidelines, regulatory requirements etc.!!More technical help to manufacturers in developing countries is needed!!
34 Summary and conclusion CONT… No more poor quality medicines for poor people!Equitable access to good quality,safe and effective medicines for all!