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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Prequalification of Medicines
Dr Lembit Rägo, CoordinatorQuality Assurance and Safety: Medicines (QSM)Department of Essential Medicines and Pharmaceutical Policies (EMP) Health Systems and Services (HSS)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Web site updated constantly – www.who.int/prequal
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Prequalification of Medicines ProgrammePrequalification of Medicines Programme
� The UN Prequalification Programme is ensuring that medicines procured with international funds are of assessed and inspected quality, efficacy and safety.
� The Prequalification Programme is an action plan for expanding access to priority essential medicines in the following areas:
- HIV/AIDS
- Tuberculosis- Malaria- Reproductive Health- Selected individual products for other diseases such as oseltamivir and Zinc sulphate
� A UN Prequalification Program of Quality Control Laboratoriesexists to facilitate the quality control of the prequalified products.
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Prequalification of Medicinal Products: ObjectivesPrequalification of Medicinal Products: Objectives
- Propose a list of prequalified products and manufacturers
meeting international norms and standards of which the quality, efficacy and safety has been assessed, inspected and controlled
- Ensure that international norms and standards are applied at all the steps of the Prequalification Programme.
- Make sure re-evaluation and maintenance of the list are performed and that variations and changes are correctly controlled.
- Help the national drug regulatory authorities to build up capacity in assessment, inspection and control meeting
international norms and standards.
- Develop the local possibilities of production and clinical studies by offering customized technical assistance.
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Expression
of Interest
Compliance
Additional information
and data
Corrective
actions
Compliance
Assessment Inspections
Medicines Prequalification ProcessMedicines Prequalification Process
Prequalification
Monitoring
Product dossier
SMF
Dossier maintenance
(variations)Handling of
complaints
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Assessment of the product dossier i.e. quality specifications, pharmaceutical development, stability, bioequivalence…
� Copenhagen assessment week- 15 to 20 assessors during one week at least every two months - Every dossier is assessed by four assessors including one senior assessor for the second assessment- An assessment report is issued- Letter summarizing the findings and asking for clarification and additional data if necessary; sent first by e-mail to the applicant followed by surface mail
� Handling of variations of already prequalified products
- Done in house on a continuous basis
Prequalification of Priority Essential Medicines (1) Prequalification of Priority Essential Medicines (1)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
� Inspections of manufacturers of 1. - Finished Products (FPP)� - Selected Active Pharmaceutical Ingredient (API) and also � - Selected Contract Research Organizations (CRO, which
carry out clinical/bioequivalence studies)
Team of inspectors - - WHO representative (qualified GMP inspector)- - Inspector from well-established inspectorate- - National inspectors invited to be part of the team as
observers but have no decision making power (different GMP standards, potential conflict of interest)
- -Inspector of potential target countries (and other countries in need) as observer, for capacity building purposes.
Prequalification of Priority Essential Medicines (2)Prequalification of Priority Essential Medicines (2)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
In June 2007 the 7th Invitation to manufacturers of antituberculosis
medicines was launched, specifying the recommended dosage
forms and strengths:1. Single ingredient first-line antituberculosis medicines
� Ethambutol, tablet 400 mg
� Isoniazid, tablet 300 mg
� Pyrazinamide, tablet 400 mg
� Rifampicin, capsule 150 mg; 300 mg
� Streptomycin, powder for injection 1g (vial)
2. Fixed dose combination products of first-line anti-TB medicines
� Isoniazid + Rifampicin, tablet 75 mg + 150 mg; tablet 150 mg + 150 mg
� Ethambutol + Isoniazid, tablet 400 mg + 150 mg
� Ethambutol + Isoniazid + Rifampicin, tablet 275 mg + 75 mg + 150 mg
� Ethambutol + Isoniazid + Pyrazinamide + Rifampicin, tablet 275 mg +
75 mg + 400 mg + 150 mg
Example of invitations to manufacturers to submit Expression of Interest (EOI) (1)
Example of invitations to manufacturers to submit Expression of Interest (EOI) (1)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
3. Single ingredient second-line antituberculosis medicines� Amikacin, 250 mg/ml (vial 2 ml, 4 ml); powder for injection 1g
(vial)
� Capreomycin, powder for injection 1g (vial)
� Cycloserine, capsule 250 mg
� Ethionamide, coated tablet 125 mg; 250 mg
� Kanamycin, powder for injection 1g (vial)
� Levofloxacin, tablet 250 mg
� Moxifloxacin, tablet 400 mg
� Ofloxacin, tablet 200 mg; 400 mg
� Prothionamide, coated tablet 250 mg
� P-aminosalicylic acid, granules 4g
� P-aminosalicylic sodium, granules 100 g
4. Scored solid dosage formulations for children, dispersible� Paediatric formulations are currently under review with new
recommendations on strengths and combinations due by April 2009.
Invitations to manufacturers to submit EOI (2)Invitations to manufacturers to submit EOI (2)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Assessment & Inspections
� Key numbers for 2008
• 40 products prequalified (21 in 2007),
• 92 dossiers submitted (90 in 2007)
• 732 assessment reports (463 in 2007)
• 52 inspections (45 in 2007)
� For each prequalified product there were:
� 5-15 assessment reports
� At least 1 inspection (may be more for API, FPP, CRO)
� 2 years total time on average to get prequalified
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
� Currently prequalifed products (31 January 2009):
� 164 for treatment of HIV/AIDS and related diseases
� 18 for treatment of tuberculosis (10 prequalified in 2007-08)
� 14 for treatment of malaria (9 prequalified in 2007-08)
� Total 196
List of WHO Prequalified Medicinal ProductsList of WHO Prequalified Medicinal Products
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
2005 2006 2007 2008
HIV 67 42 25 42
TB 17 9 17 12
Malaria 3 5 7 9
Repr Health - - 10 4
Product dossiers accepted for evaluation
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
As of 3 February 2009 :
� 55 products for treatment of HIV/AIDS and related diseases
� 36 products for treatment of tuberculosis
� 20 products for treatment of malaria
� 14 reproductive health products
� Total 125
Currently under evaluation in WHO Prequalification Programme
Currently under evaluation in WHO Prequalification Programme
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Transparency – dossier status informationon the web
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Inspections - statistics in 2008 vs 2007
� A total of 62 (2007 – 46) inspections were carried out in 2008:
• 27 (26) inspections of the manufacturing sites offinished product manufacturers
• 11 (6) inspections of the manufacturing sites ofactive pharmaceutical ingredients (APIs)
• 14 (13) inspections of contract research organizations (CROs)
• 10 (1) Quality control laboratories
� In 2008 three/four inspectors in-house
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Prequalification Programme:Transparency – WHOPARs, WHOPIRs and NOCs
Prequalification Programme:Transparency – WHOPARs, WHOPIRs and NOCs
� These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO:
"3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;"
� A WHO Public Assessment Report (WHOPAR) is a summary of the quality and efficacy/safety assessments for a product prior to its prequalification and includes the Summary of Product Characteristics (SPC)
� A WHO Public Inspection Report (WHOPIR) provides a summary of the inspection where found to be GMP compliant
� A Notice of Concern (NOC) is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or research organization.
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Transparency – Inspection outcomes on the web
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Training activities in 2008
� In total 11 training courses organized and 4 co-organized
� In Brazil, China, Ghana, India, Indonesia, Iran, Jordan, Morocco, Nicaragua, Pakistan, Tanzania …
� More than 500 participants - staff of regulatory authorities and pharmaceutical manufacturers
� Topics:
• Development of dossiers for submission
• Assessment of bioequivalence (interchangeability) of medicines
• Pharmaceutical Development of Paediatric Formulations
• GMP, Quality and Bioequivalence of malaria ATC products
• GMP, Quality and Bioequivalence of Reproductive Health products
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
4
9
4
11
4
0
2
4
6
8
10
12
14
16
2006 2007 2008
Trainings organized or supported by PQP
PQP supported
PQP organized
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Training workshops focusing on specific categories of medicines2006-2008
1
1
1
4
3
HIV/AIDS medicines Antimalarials
TB medicines RH products
Pediatric formulations
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Topics of training workshops2006-2008
8
10
53
3
4
42
Prequalification advocacyPrequalification requirementsGood manufacturing practiceQuality controlBioequivalence/BCS and GCPAssessment of medicinesPharmaceutical developmentPQ general
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Capacity building
� Part of the programme from its start
� Let us listen the view point of a country representative…
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
23
WHO Prequalification Programme for Medicines: the Experience of Tanzania in Regulatory Capacity Building
Mr Hiiti SilloActing Director, Medicines and CosmeticsTanzania Food and Drugs Authority
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
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Outline
1. Background
2. Capacity building activities for NMRAs
3. Benefits from PQP
4. Conclusion
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Background
� PQ was first introduced to African Regulators in 2001
• Medicines Control Authority of Zimbabwe
• Tanzania and Uganda followed later in 2003 & 2004 respectively
� Objectives of PQ to capacity building of NMRAs
• Strengthen national regulatory capacity by provision of training and personal development to experts from NMRAs
• Strengthen the Member States confidence in the PQP and evaluation of prequalified products by providing extensive exposure into prequalification processes and expertise
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Background (2)
� Objectives ...
• Disseminate understanding of PQP and strengthen PQP network by training of local and regional resource persons to be involved in Prequalification networking and trainings
• Motivate and stimulate NMRAs to commit to future co-operation with PQP following involvement of its staff in PQP activities
• To create networks among individual experts participating in assessment sessions and inspections
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
PQP capacity building activities for NMRAs
� Training programmes on assessment of dossiers and GMP inspection
• East Africa regulatory & industry experts in 2006, 2007 and 2008
• West Africa in 2007 & 2008
• Assessment sessions in Copenhagen
• Ethiopia, Ghana, Kenya, South Africa, Tanzania, Uganda Zambia, Zimbabwe
� Inspection of manufacturing sites
� Tanzania
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Benefits - assessment sessions
� Guidelines for submission of documentation for registration have been reviewed
• Active Pharmaceutical Ingredient (API), Pharmaceutical Development, Efficacy (Clinical trials and Bioequivalence) e.g. Zimbabwe, Tanzania
� Assessment procedures including assessment templates, details in reports and quality assurance measures (second/peer review) have introduced.
� Variation guidelines to facilitate approval of variations/amendments of approved products e.g. Tanzania, Uganda and Zimbabwe.
� Abbreviated assessment procedure for products already Prequalified and/or registered in ICH regions
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
� Since November 2006 – present
� 6 fellows – from Zimbabwe, Uganda, Tanzania and Ethiopia
• More fellows to join in 2009 including GMP inspectors
� 3-months hands-on experience in everyday work of the PQ Program team
� Optional participation as observer in inspections
� Follow-up plan for implementation at home NMRA upon return
Benefits - Rotational Position at WHO HQ
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Benefits - Rotational Position at WHO HQ (2)
� Hands on training by peer reviewed assignments � Group and one-to-one discussions� Preparation and review of guidelines, SOPs,
Templates and Forms� Participation in internal and external meetings� Participation in and/or making presentation at
seminars, workshops and expert committee meetings
� Preparation of responses to and correspondences with countries, companies, organizations and individuals
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Benefits - Prequalification of labs and Quality Monitoring Project
� Skills in sampling and testing of marketed products
� Evaluation of QC lab results to determine market status
� Development of laboratory quality systems
� Training of laboratory staff under the scheme –Increased competence of analysts
� Networking among laboratory analysts in the region
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
� Platform for mutual recognition and networking• Between regulators in Africa with those from ICH or
PIC/S countries• WHO-PQ reference for NMRA assessments in
developing countries• Among NMRAs using same guidelines adopted from
WHO-PQ and have undergone similar training
� Enhance reputation and public image of NMRAs• WHO-PQ list can be used to offer any exemptions by
NMRAs when called for• WHOPARs and WHOPIRs used in expedited evaluation
� Utilisation of reliable regulatory decisions• other agencies, institutions and experts without
compromising independency and capacity building objectives e.g. EMEA, EDQM, Health Canada, USFDA Tentative Approvals
Other Benefits (2)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
� Stimulates harmonization among• NMRAs
� group assessments pass on skills� readily available, user friendly guidelines - easy to
adopt/adapt� Building trust among regulatory staff from same
region e.g. Tanzania, Uganda and Kenya in East Africa
• Manufacturers� Improve dossiers by use of WHO guidelines for
markets that do not have own guidelines� Experience in submitting PQ dossiers improves
appreciation of regulatory requirements in other regions
� Reduced cost – same dossiers to PQP and to NMRAs
Other Benefits (3)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Prequalification of Quality Control Laboratories(QCL)
� So far mainly for AFRO region, now wider scope
� 6 QCL prequalified in 2008
• Adcock, South Africa – 01/2008
• National QCL, Kenya – 07/2008
• National QCL, Morocco – 07/2008
• Vimta Labs, India – 07/2008
• CHMP, France – 10/2008
• National institute of Drug Quality Control - NIDQC (Vietnam) -11/2008
� 10 inspection and pre-audits of QCLs performed
• In cooperation with inspectors from South Africa, Austria, France, Poland, Singapore and Estonia
� 8 QC Labs expressed interest, 2 of them already prequalified
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
QCL Prequalification trendsQCL Prequalification trends
83
10
3
16
3
22
8
24
0
5
10
15
20
25
30
35
2004 2005 2006 2007 2008
QCLs Prequalified QCLs Interested
Prequalified QCLs:
• South Africa, RIIP+CENQAM (2005)
• Algeria, LNCPP (2005)
• South Africa, Adcock Ingram (2008)
• Morocco, LNCM (2008)
• Kenya, NQCL (2008)
• India, Vimta Labs (2008)
• France, CHMP (2008)
• Vietnam, NIDQC (2008)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Sampling and testing projects in 2008Sampling and testing projects in 2008Sampling and testing projects in 2008
� Quality survey of antimalarials (ACTs and sulfadoxine-pyrimethamine)• Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya,
Madagascar, Nigeria, Senegal, Tanzania, Uganda
• 936 samples collected and screened by Minilab, 299 selected for full testing in laboratory (testing ongoing)
• Assessment of quality of product information (Labelling and PIL)
� Quality monitoring of products funded by UNITAID • Pilot phase (paediatric and second-line antiretrovirals) in cooperation
with NDRAs in Kenya, Tanzania, Uganda, Zambia
• 378 samples collected and tested in laboratory (testing ongoing)
• Assessment of quality of product information (Labelling and PIL)
� Quality survey of anti-TB medicines in Eastern Europe• Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan,
Ukraine, Uzbekistan; Focused on Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin (360 samples planned)
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Technical Assistance - Policy
Criteria for the products in relation to which technical assistance is considered:
� Inclusion in the list of expression of interest
� High value for Public Health purposes
� Poor representation on the Prequalification list
� Manufacturer has applied for PQ (exemptions can be made upon justified requests)
Criteria for the experts:
� Excellent qualifications and long standing experience in the area where expertise is required
� Absence of conflict of interest
� Independence from inspection and assessment of prequalified products
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Experts participating in TAs
2
6 10
5
11
12
0
5
10
15
20
25
2006 2007 2008
Involvement ofother experts inmissions
Involvement ofOTECI experts
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Revision of PQ procedure in 2008
Reasons for revision
• 5 years experience from implementation
• Differences between procedure and actual activity practices
• Unclear responsibilities of parties
Aims of revision
• increase transparency of PQ activities
• publish more details of prequalified products
• harmonize terminology and clarify procedures
• better define responsibilities
• confidentiality agreement with applicants
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
New PQ procedure for APIs in 2009
� Until now the qualification of API source and manufacturer is primarily the responsibility of the finished product manufacturer => API manufacturer seldom inspected and API dossier may not be evaluated in depth
� API source considered "confidential" information
� Oct 2008 WHO Expert Committee on Specifications for Pharmaceutical Preparations will discuss
• Procedure for API Master File in Prequalification Programme
• PQ procedure for active pharmaceutical ingredients (APIs) – new "regulatory" approach
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Problems
� Anti-malarials and anti-tuberculosis products – old problems but few new solutions
• Immature submissions – takes time to get to the maturity needed
• Relative lack of motivation from applicants
• Relative lack of new innovator products
• Generic products with no innovator
• …or problem "new" products
• GMP non-compliance (both for finished dosage form and API)
• Quality part of the dossier – specifications, stability data etc incomplete
Safety and efficacy – poor clinical and safety data, poor quality information, poor information for users
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Challenges
� Availability of national experts (qualified assessors and inspectors) in forthcoming years
� Increasing demand for capacity building – shift from general to more specific and technical
� Increasing demand for prequalified products for medicines of high public health value (new product groups, individual products, NTD products)
� Increasing demand of ad hoc services regarding quality
� Trust building and information exchange to avoid duplications
� Constant need to improve communication (resource demands for this purpose remain underestimated)
� Meeting the needs with the permanent staff available under the conditions prescribed by the environment
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Summary remarks (1)
� The purpose of the prequalification programme is to list good quality, safe and effective medicinal products in the interest of public health in resource-limited countries.
� The products should be submitted with technical data proving the quality of API and finished product together with necessary data on safety and efficacy (quality submissions in demand)
� Manufacturing sites of API s and finished products should operate according to GMP principles in order to deliver consistent quality products
� CROs should conduct studies in compliance with GCP / GLP as appropriate
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
Summary remarks (2)
� Technical assistance for promising manufacturers/products can be made available to achieve the goal and speed up the prequalification process.
� Close cooperation with international procurement and financial institutions
• quality as prerequisite for procurement decision
• instruments to support quality production
� Encourage manufacturers to invest into quality, and to apply for independent evaluation
� Main aim of PQ – to increase choice and access to quality products without compromising requirements for quality, safety and efficacy should remain unchanged
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UN Prequalification of Diagnostics, Medicines and Vaccines 4th Consultative Stakeholders Meeting, 3 February 2009
A BIG THANK YOU!
� WHO wishes to gratefully acknowledge the assistance and help provided in 2008 by our many partners in and outside WHO, donors and many other individuals and organizations
� Especially we are grateful to the staff from National Drug Regulatory Authorities of:
� Australia, Austria, Brazil, Canada, China, Estonia, Ethiopia, France, Germany, Ghana, Hungary, Italy, Kenya, Netherlands, Poland, Singapore, South Africa, Spain, Sweden, Switzerland, Tanzania, Uganda, Ukraine, United Kingdom, and Zimbabwe …