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PREQUALIFICATION General overview and procedures

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1 PREQUALIFICATION General overview and procedures
and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement agencies involved in procurement Technical Briefing Seminar for Consultants on Procurement and Supply Management for HIV/AIDS, TB and Malaria Organized by WHO and AMDS Network Copenhagen, Denmark 31 January 2006 Maija Hietava M.Sci.Pharm Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster Tel: Fax: World Health Organization

2 Prequalification of essential medicines
The UN prequalification program is an action plan for expanding access for the hardest hit by HIV/AIDS Tuberculosis Malaria for 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 PQ This presentation focuses on prequalification of medicinal products

3 Why the prequalification is needed
Problems Millions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatment Procurement and supply of substandard and counterfeit products in different countries Weak/absent QA systems of medicines supply chain Lot of money invested in procurement no harmonized quality assurance system available for procurement organizations Risks Sourcing of poor quality products or even counterfeit medicines  risk to patients, treatment failure, resistance Risks 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 increasing Numerous generic manufacturers offering products Challenges for UN family and procurement agencies/organizations The 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 included Incorrect amount 17% No active ingredient 60% Other errors 7% 16% Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database Study 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 manufacturers Legitimate - General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodies Widely discussed FIP Congress, Nice 2002 Supported by ICDRA in 2002 and 2004, representing more than 100 national drug regulatory authorities Transparent (all significant information available on the web site ) Open to both innovators and multisource/generic manufacturers No cost for applicants during pilot phase We cannot oblige manufacturers to attend Widely 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 EOI Please 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/CROs Meeting international norms and standards on quality, safety, and efficacy (Q, S & E) Harmonization Co-operation, training, capacity building – NDRAs, WHO, NGOs Facilitate access to treatment Procurement mechanisms (e.g. tender, competition) Ongoing monitoring of Quality, Safety & Efficacy WHO commitment to developing We 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/NDRAs WHO treatment programs: Determine drugs on EOIs Procurement organizations: Develop harmonized QA system Ongoing monitoring – we keep monitoring even after listing of the product

8 Objectives Propose 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 products Ensure re-qualification and update of the list of prequalified products and manufacturers as new products and manufacturers meet the standards Ensure the appropriate control of variations and changes Develop the local capacity for quality production and clinical studies. National regulatory authorities (DRA) are involved in dossier assessment and inspections Producers receive invaluable specific technical feedback Help 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 intervals Supplier to communicate any changes Re-inspection at least every 3 years Change to key personnel or the manuf site could also result in re-insp Re-evaluat of dossier every 3 years or sooner if change of formula, manuf method/site Requal 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 if fraud/omission (post-PQ) batch not in compliance with agreed spec's serious complaints if suspension of supply ≥ 1 year if 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 and guarantee 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) 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 inspection 4. Assessment of the dossier and writing of the assessment report and assessment letter. 5. Outcome of the evaluation communicated to supplier EOI =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 manufacturers 7.Inspection of the Research Laboratory or Contract Research Laboratory (CRO) where the bioequivalence study has been performed  GCP compliant list of CROs 8.Conclusion and listing of the product in the prequalification list 9.Publication of the Public Assessment (WHOPAR) and Inspection (WHOPIR) Reports 10.Assessment of the variation when submitted, market survey, de-listing if necessary 11.Re-qualification after 3 years

13 Assessment procedure Assessment 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 week 8 to 12 assessors together during one week at least every two months at UNICEF in Copenhagen Every dossier is assessed by at least two assessors. An assessment report is issued; signed by two assessors Letter summarizing the findings and asking for clarification and additional data if necessary. Letter is sent first by to the applicant followed by surface mail Nigeria, UK and Norway coming… UNICEF – facilities for storage, rooms for assessors Security 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 products Assessment report from DRAs WHO Certificate of Pharmaceutical Product (CPP) Batch certificate Update on changes. Multisource products (generics) Full dossier with data and information Quality : information on starting materials and finished product including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc Efficacy: Bio-equivalence study or clinical study report US FDA tentative approvals – recognition based on information exchange (Confidentiality agreement) Commercial sample CPP=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 CPP Assessment report or EPAR – if not available then full doc If 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 possible Simplified 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 different Sample (CoA). Stringent=ICH (EU/EMEA, FDA, Japan PMDA; Pharmaceuticals and Medical Devices Agency) + PIC/S (Canada, Australia, Malaysia, Singapore, Norway, Switzerland) FDA Only 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 inspectors WHO 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 before prequalification and supply; increasingly as part of follow-up QC routinely before procurement

16 Prequalification of quality control laboratories
To increase the local capacity to control the quality of pharmaceutical products Quality Control Laboratories in sub Saharan Africa as priority WHO norms and standards for QC laboratories Prequalification process Expression of Interest (EOI) Laboratory Information File (LIF), evaluation Inventory Audit – help/evaluate Inspection with the team of inspectors Prequalified laboratories list public in WHO web site (2 listed) Reassessment system The 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 activities In 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 officials Training 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 later Prequalified products (Dec 2005) Dossiers arrived 105 HIV related medicines (Aug-05) 343 (Dec -05) 8 anti-tuberculosis medicines 2 anti-malarial medicines Ongoing assessments and follow-up Products Manufacturing sites CROs For 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/AIDS HIV=103 68 ARVs (34 from innovators, 34 from generic manufacturers) – singles 54, 2-FDC 8, 3-FDC 6. 35 others TB=8 4 from Sandoz, Wyeth, 4 from generic manufacturers – 6 FDCs MA=2 Total 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/AIDS Procurement policy of GF motivates manufacturers to seek PQ status. TB Procurement 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. MA Most 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 generics Asia: sites Europe: 4 sites Africa: 2 sites

20 Ongoing monitoring and requalification
Samples taken after supply Routine inspections and additional inspections Changes and variations controlled Products and manufacturers Requalification (re-assessment) every 3 years World Health Assembly resolution: WHA57.14 of May 2004 Public reports requested WHOPIRs (WHO Public inspection report) and WHOPARs (WHO Public Assessment Report) are now on the prequalification web site Increasing 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 intervals Supplier to communicate any changes (safety, efficacy, quality) Re-inspection at least every 3 years Change to key personnel or the manuf site could also result in re-insp Re-evaluat of dossier every 3 years or sooner if change of formula, manuf method/site Requal 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 if fraud/omission (post-PQ) batch not in compliance with agreed spec's serious complaints if suspension of supply ≥ 1 year if changes to API, formulation, manuf method/facility or other production aspects require re-assessment.

21 PQ web site information for procurement
List of prequalified products List of manufacturers of manufacturers for APIs (Active Pharmaceutical Ingredient) and FFPs (Finished Pharmaceutical Product), which are GMP compliant List of GCP compliant Contract Research Organisations (CROs), bio-equivalence centers and research laboratories, which are GCP/GLP compliant WHOPIRs (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 procurement Grant 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; or Product 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 slide A 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 products Number of equivalent products under option (a) or (b) Recommendation End Option (c) on 30 April 2005 New Policy, Global Fund  2 Equivalent products If 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 of Option (a) or (b) + Manufactured in a facility compliant with GMP following inspection by WHO or stringent regulatory authority IF 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 procurement Access 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 (www.picscheme.org) Australia Austria Belgium Canada Czech Republic Denmark Finland France Germany Greece Hungary Iceland Ireland Italy Latvia Liechtenstein Malaysia Netherlands Norway Poland Portugal Romania Singapore Slovak Republic Spain Sweden Switzerland United Kingdom ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use participating regulatory authorities (www.ich.org ) European Union* Japan United 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 quality Starts 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 side GFTAM = Global Fund TB, Aids and Malaria

27 Important in the regulatory assessment of GENERIC pharmaceuticals
There are requirements especially for Generics (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 requirements Bioequivalence 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 process Sometimes "GMP compliance" alone does not tell the whole truth!! Dossier assessment Inspections GMP/GCP

29 This is misleading and/or misunderstood
WHO type certificate (by WHO Certification Scheme) is used worldwide  But it is not WHO certificate GMP compliance?? National GMP requirements are not always those of WHO or stringent authority requirements Does 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 site WHO GMP/GCP CERTIFICATE WHO PQ is using FDA based requirements Bioequivalence 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 prequalification Confidentiality Agreement with the US FDA Recognition of US FDA tentative approval process for ARVs based on the scientific assessment done by FDA Additional 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 2005 Constant upgrading guidelines and guidance documents increasing workload Building of the Quality system Resources for 2006/2007 GFTAM = Global Fund TB, Aids and Malaria

32 Summary and conclusion
Good news; quality of generics exists Relatively large number of products and suppliers comply with the standards Many potential suppliers appreciating feedback and willing to improve Unique technical knowledge obtained of products, especially generic antiretrovirals and antimalarials Bad news: quality assurance has the price Only limited number of products have met the required standards Takes time to get into compliance Data to be generated, tests carried out GMP upgrade needed Bad quality generics may undermine the public confidence in generics

33 Summary and conclusion CONT…
However… REMEMBER Quality can not be assessed, tested or inspected into the product, BUT has to be built into the product in 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!

35

36 THANK YOU VERY MUCH FOR YOUR ATTENTION!!


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