un / who prequalification programme for priority medicines milan smid, md, phd training workshop:...
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UN / WHO Prequalification Programme for Priority
MedicinesMilan Smid, MD, PhD
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.2 |
UN Prequalification Programme for Priority Essential MedicinesUN Prequalification Programme for Priority Essential Medicines
Action plan of UN from 2001 for expanding access of priority medicines to patients with
– HIV/AIDS
– Malaria
– Tuberculosis
– Reproductive health
– Influenza
– Acute diarrhoea
– Potentially other categories of products, if there is the need
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.3 |
Elements of Prequalification ProgrammeElements of Prequalification Programme
Objective: To ensure quality, efficacy and safety of medicines procured
using international funds (e.g. GFTAM, UNITAID)
Components: Evaluation of Quality, Safety and Efficacy of prioritised Essential
medicines, inspections of manufacturers and monitoring of the products after their prequalification.
Prequalification of quality control laboratories. Building capacity of regulators, manufacturers and quality control
laboratories.
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.4 |
How prequalification is organized?How prequalification is organized?
WHO manages and organizes the programme on behalf of the United Nations:
• provides technical and scientific support to assessment, inspections (GMP, GCP, GLP) and quality control (GPCL)
• involvement of qualified assessors and inspectors mostly from NRAs of ICH and associated countries and PIC/S inspectorates
• guarantees that international norms and standards are applied all through the process
• supports capacity of NRA in developing countries to evaluate, inspect and control the quality of medicines
• involvement of qualified assessors and inspectors from NRAs in developing countries
• by involvement of manufacturers from development countries into the project supports their capacity to produce according to international norms and standards
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.5 |
How prequalification is organized?How prequalification is organized?
WHO PQT working in co-operation with partners
• UNICEF• The Global Fund to Fight AIDS, Tuberculosis and Malaria• UN Population Fund (UNFPA)• UNAIDS• World Bank
• Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.6 |
Essential steps of PQ evaluation procedureEssential steps of PQ evaluation procedure
Need is specified and agreed by WHO treatment programmes Invitation for Expression of interest (EOI) is published Interested parties submit dossiersDossiers receive initial screeningFull dossiers are assessed Inspections are conducted at manufacturing sites and at CROsSamples are tested, if needed If outcome is positive, pharmaceutical product is listed on the
website, including product information (SPC, PIL), assessment report (WHOPAR) and inspection report (WHOPIR)
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.7 |
Essential steps of monitoring of PQ productEssential steps of monitoring of PQ product
Variations to the dossier of prequalified product
Sampling and Testing
Reinspections
Reevaluation
De-listing or suspension (if and when appropriate)
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.8 |
StandardsStandards
WHO standards as defined in WHO guidelines and International Pharmacopoeia are applied in prequalification process
If these not exist, ICH guidelines are applied
In case of need, guidelines of stringent regulatory authorities, which are involved in ICH process
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.9 |
IExpression
of Interest
Compliance
Additional informationand data
Corrective actions
Compliance
Assessment Inspections
Steps in prequalification
Prequalification
Maintenance and monitoring
Product dossierSMF
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.10 |
Evaluation procedureEvaluation procedure Assessment of product dossiers
(Quality specifications, pharmaceutical development, production, control, stability, bioequivalence etc).
Teams of professionals from national Drug Regulatory Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ...
Copenhagen assessment week
• 8 to 20 assessors together during one week at least every two months at UNICEF in Denmark
• Every dossier is assessed by at least four assessors. • An assessment report is issued - signed by assessors• Letter summarizing the findings and asking for clarification and
additional data if necessary is sent first by e-mail to the applicant followed by surface mail
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.11 |
Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions)
Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions)
34196
151
12
1
0 EURO
AMRO
AFRO
WPRO
SEARO
EMRO
In total 603 participations
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Assessors participating in PQ assessment (all visits in 2001-2008, AFRO countries)
Assessors participating in PQ assessment (all visits in 2001-2008, AFRO countries)
13
2
3
1
33
18
39
42
Ethiopia
Ghana
Kenya
Nigeria
South Africa
Tanzania
Uganda
Zimbabwe
151 AFRO participations
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.13 |
Inspections:Inspections:
Team of inspectors for each inspectionWHO PQ inspector plus PIC/S member country plus local
country inspector (observer)Some cases – capacity building (recipient country)Preparation includes SMF, product information, inspection
reports, complaints etcAPIs, Finished products Clinical studies: Mostly Bioequivalence studies (generic
products
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Co-inspectors to WHO PQ inspections(plan I-VIII 2009)
Co-inspectors to WHO PQ inspections(plan I-VIII 2009)
3
2
12
4
1Ethiopia
Ghana
Lesotho
Tanzania
Uganda
Zimbabwe
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.15 |
Prequalification assessmentPrequalification assessment
Innovator products• Accepted, if approved by stringent authorities like US FDA and
EMEA • Based on availability of assessment reports, WHO Certificate of
Pharmaceutical Product (CPP), batch certificate• Continuous update on product changes after prequalification
• Confidence in scientific expertise of well-established RAs
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.16 |
Alternative regulatory pathways
USA FDA tentative approvals linked to PEPFAR– Included in WHO PQ List – Confidentiality agreement with US FDA in place
EU Article 58– For products exclusively to be used outside EU
Canadian Access to medicines scheme– WHO cooperation with the above mentioned– Confidentiality agreement in preparation
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.17 |
Prequalification assessmentPrequalification assessment
Multisource products Assessment • Quality: information on starting materials and finished product,
(API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc.)
• Interchangeability with reference product (efficacy and safety): Report of bio-equivalence, biovaiwer or clinical study demonstrating interchangeability with reference product
• Inspection of manufacturers and CROs• Laboratory analysis in case of need
Monitoring after prequalification
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.18 |
Prequalification assessmentPrequalification assessment
Combined products, new dosage forms, new indications
Assessment • May require safety and efficacy data
Monitoring after prequalification
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.19 |
Outcomes of PQ procedureOutcomes of PQ procedure
Information in public domain (homepage)
Lists of PQ medicinal products WHOPAR (SPC, PIL, labelling) WHOPIR (both FPP and API) Information on progress of assessment procedure and
inspections Supportive documents: WHO guidelines, description of PQ
procedure
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.20 |
Same principals applied in prequalification as valid for national regulatory approvals by stringent authorities
Same principals applied in prequalification as valid for national regulatory approvals by stringent authorities
Benefits prevail the risks at a time of regulatory approval and nothing indicates that benefits will not prevail also during use of product in normal medical practice
– Available data about quality (Dossier)– Available data about efficacy and safety or interchangeability (Dossier)– Available data are credible and were eticaly obtained
• Good practices (GLP, GCP, GPhVP, …)– Existing reassurance about production in stable quality and quality assurance
mechanisms• GMP
– Way of use of medicine characterized for physicians and patients • Data sheets, SPCs, PILs, package labeling
– Lack of knowledge is be properly manged• Pharmacovigilance, risk management programmes
– Evaluations and inspections follow WHO and/or ICH standards
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.21 |
Difference between PQP and national approval procedures
Difference between PQP and national approval procedures
Only certain categories of products are accepted
Voluntary - no direct legal implications
Free of charge (yet)
Assessment and inspections done by multinational teams
Assessment and inspection outcomes are publicly available, no negative conclusions and findings published (yet)
Issues of IPP fully in responsibility of applicant / manufacturer
Definitive negative conclusions exceptional
Technical assistance and regulatory support possible
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.22 |
http://who.int/prequal/http://who.int/prequal/
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.23 |
Prequalified Priority Products(November 2008)
Prequalified Priority Products(November 2008)
0
50
100
150
200
250
HIV/AIDS Tuberculosis Malaria
FDC
Monocomponent
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0
50
100
150
200
250
HIV/AIDS Tuberculosis Malaria
Prequalification procedures
HC assessment
FDA assessment
Innovators
Multisourceproducts
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.25 |
Countries, in which PQ products are manufactured (August 2008)
Countries, in which PQ products are manufactured (August 2008)
145
1611
10
9
9 99 8 8 6
3
1India
France
South Africa
UK
Canada
Germany
Spain
Switzerland
Netherlands
USA
China
Australia
Pakistan
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.26 |
In August 2008 the 6st Invitation for submissions of
antimalarial medicines was launched:
1.Artemisinin-based fixed dose oral combination formulations
- Artemether + Lumefantrine, – tablet 20 mg + 120 mg;
– tablet 40 mg + 240 mg
– tablet 60 mg + 360 mg;
– tablet 80 mg + 480 mg
Invitations to manufacturers to submit EOIs /1Invitations to manufacturers to submit EOIs /1
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.27 |
Invitations to manufacturers to submit EOIs /2Invitations to manufacturers to submit EOIs /2
2. Artemisinin-based fixed dose combination or co-blistered oral formulations
- Artesunate + Amodiaquine, – tablet 25mg + 76.5mg; – tablet 50mg + 153mg– tablet 100mg + 306mg
- Artesunate + Mefloquine, – tablet 25mg + 250mg; – tablet 50mg + 250mg– tablet 100mg + 250mg
- Artesunate + Sulfadoxine + Pyrimethamine, – tablet 25mg + 500mg + 25mg – tablet 50mg + 500mg + 25mg; – tablet 100mg + 500mg + 25mg
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.28 |
Invitations to manufacturers to submit EOIs /3Invitations to manufacturers to submit EOIs /3
3. Artemisinin-based fixed dose combination or co-blistered oral paediatric formulations, preferably dispersible
- Artemether + Lumefantrine
- Artesunate + Amodiaquine
- Artesunate + Mefloquine
- Artesunate + Sulfadoxine + Pyrimethamine
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.29 |
Invitations to manufacturers to submit EOIs /4Invitations to manufacturers to submit EOIs /4
4. Artemisinin-based single-ingredient formulations
- Artemether, oily injection 20 mg/ml; 40 mg/ml; 80 mg/ml
- Artesunate, powder for injection 60 mg (vial)
- Artesunate, suppositories 50 mg; 100 mg; 200 mg; 400 mg
- Artesunate, tablet* 25 mg; 50 mg; 100 mg
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.30 |
Invitations to manufacturers to submit EOIs /5Invitations to manufacturers to submit EOIs /5
5. Other antimalarial medicines
- Amodiaquine, tablet 153 mg (or 200 mg as hydrochloride)
- Mefloquine, tablet 250 mg
- Sulfadoxine + Pyrimethamine, tablet 500 mg + 25 mg
____________
* Artesunate tablets to be used only in combination with either Amodiaquine, Mefloquine or Sulphadoxine + Pyrimethamine
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.33 |
Prequalification of Quality Control Laboratories
Prequalification of Quality Control Laboratories
Invitation for expression of interest issued by WHO
Laboratory Information File submitted by interested QCLs
If needed, technical assistance is provided
Inspection is organised
Currently 7 QCLs prequalified, 18 in process of prequalification (mostly from Africa)
More information PQP website
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.34 |
Quality control laboratories participating in WHO PQP(January 2009)
Quality control laboratories participating in WHO PQP(January 2009)
41 1 1 1
15
41 2 2
0
2
4
6
8
10
12
14
16
18
20
AFRO EMRO SEARO WPRO EURO
Prequalified Interested
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.35 |
Contribution of PQ to capacity buildingContribution of PQ to capacity building
Organization of trainings– general and problem specific (HIV/AIDS, TB and antimalarial
products, pediatric dosage forms, BE, BE/BCS, GMP)
– Trainings of NRA staff and manufacturers frequently combined
Involvement of assessors from NRAs into PQ assessment
Involvement of inspectors from NRAs into PQ inspections
3 months rotations of experts from NRAs in WHO HQ – PQT
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.36 |
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
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.37 |
Topics of training workshops2006-2008
Topics of training workshops2006-2008
8
10
53
3
4
42
Prequalification advocacyPrequalification requirementsGood manufacturing practiceQuality controlBioequivalence/BCS and GCPAssessment of medicinesPharmaceutical developmentPQ general
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.38 |
165
198
103
57
263
301
568
0
100
200
300
400
500
600
700
2007 2008
Participants in trainings organized or supported by PQP
Others
QCL staff
Regulators
Manufacturers
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.39 |
Rotation positions at WHO PQPRotation positions at WHO PQP
Zimbabwe 2
Uganda 2
Tanzania 2
Ethiopia 1
Kenya expected
3 4
EAC Others
2006-January 2009 (including ongoing stays)
EAC: 57,1%
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.40 |
Technical AssistanceTechnical Assistance
Provision of expert consultants to– Manufacturers – Quality control laboratories– Regulators
Assistance focuses on – GMP, GCP or GLP compliance– Regulatory guidance
Assistance is separated from the assessment / inspections and may be followed by specific trainings
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.41 |
Technical assistances organized by WHO PQP 2006-2008Technical assistances organized by WHO PQP 2006-2008
2
1
3
2
10
3
8
0
2
4
6
8
10
12
14
2006 2007 2008
REG
GPCL
GCP
GMP
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.42 |
Conditions for provision of technical assistance
Conditions for provision of technical assistance
Manufacturers:Participation in the prequalification programme,Found to be capable and willing to improveLocation in a developing country
Products: Inclusion in the list of expression of interestHigh value for Public Health purpose Poor representation on the Prequalification list.
Artemisinin based combined medicines,February 23-27, 2009, Kampala, Uganda.43 |
Thank you for attention