prequalification general overview and procedures and practical implications of who pq, fda...
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PREQUALIFICATIONGeneral overview and procedures
and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement agencies
involved in procurement
Maija Hietava M.Sci.Pharm
Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster
Tel: +41.22.791.3598 Fax: +41.22.791.4730World Health Organization
E-mail: [email protected]
Technical Briefing Seminar for Consultants on Procurement and Supply Management
for HIV/AIDS, TB and MalariaOrganized by WHO and AMDS Network
Copenhagen, Denmark 31 January 2006
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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.
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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
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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
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Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis antiretrovirals drugs included
Incorrect amount
17%
No active ingredient
60%Other errors7%
Incorrect ingredient
16%Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database
Is quality of pharmaceuticals a problem?
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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
http://mednet3.who.int/prequal/ ) Open to both innovators and multisource/generic manufacturers No cost for applicants during pilot phase
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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
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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.
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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
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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
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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
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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
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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 e-mail to the applicant followed by surface
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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
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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 beforeprequalification and supply; increasingly as part of follow-up
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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
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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)
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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 - 316 (Aug-05) 343 (Dec -05)• 8 anti-tuberculosis medicines - 156 165• 2 anti-malarial medicines - 48 49• 115 520 557
Ongoing assessments and follow-up• Products• Manufacturing sites • CROs
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Current status – Manufacturers of finished products
In the prequalification list: 15 sites of generics
Asia: 9 sites Europe: 4 sites Africa: 2 sites
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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)
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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)
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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
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New Policy, Global Fund
2 Equivalent products
Number of equivalent
products under option (a) or (b)
Recommendation
End Option (c) on 30 April 2005
(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
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)
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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:
http://www.theglobalfund.org/pdf/guidelines/List_of_Countries_ICH_PICS.pdf
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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
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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
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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…..
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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
InspectionsGMP/GCP
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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
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!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!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
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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
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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
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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!!
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Summary and conclusion CONT…
No more poor quality medicines for poor people!
Equitable access to good quality, safe and effective medicines for all!
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http://mednet3.who.int/prequal/
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THANK YOU VERY MUCH FOR
YOUR ATTENTION!!