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PQP-overview & update January 20111
Prequalification of Medicines Overview & update
Wondiyfraw Z. Worku
WHO Prequalification of Medicines Programme
Assessors training, Copenhagen
January 2011
PQP-overview & update January 20112
Agenda
• PQP and its activities• Paths towards prequalification• PQ process flow • Some numbers and achievements• Our future and challenges• Summary
PQP-overview & update January 20113
UN Prequalification Programme for Priority Essential Medicines
• A UN action plan since 2001 to expand access to priority essential medicines for– HIV, Malaria, TB, – RH, selected Influenza products and Zinc products for Acute
diarrhoea
• To ensure quality, safety and efficacy of medicines procured using international funds– Propose a list of prequalified products and manufacturers
meeting international norms and standards
PQP-overview & update January 20114
UN Prequalification Programme for Priority Essential Medicines
– Also since recently, to propose list of prequalified APIs and their manufacturers
– Ensure that international norms and standards are applied at all the steps of the Prequalification Programme.
• Help the national medicine regulatory authorities to build up capacity in assessment, inspection and quality control meeting international norms and standards.
• Develop local possibilities of manufacturing and clinical studies by offering customized technical assistance.
PQP-overview & update January 20115
UN Prequalification Programme for Priority Essential Medicines
• Principally for generic products • Similar programmes run by WHO:
– Prequalification of Vaccines• http://www.who.int/immunization_standards/vaccine_quality/pq_system/en/index.html
– Prequalification of diagnostic products• http://www.who.int/diagnostics_laboratory/evaluations/en/
PQP-overview & update January 20116
Why PQ?
• Many of the UN and other procurement agencies lack sufficient means to ensure safety, efficacy and quality of procured medicines and other medical items.
• Many of the receiving and exporting countries do not have/did not have well established regulatory system.
• Increasing demand for generic medicines-several players- substandard products– A number of reports on sub standard Anti Tb and Malaria
products
• Need for common-international standard.
PQP-overview & update January 20117
Similarities with NMRAs
• Like NMRAs, the prequalification programme performs
- Dossier assessments
- Inspections
- Quality control testing (mostly through post approval sampling)
- Also post approval pharmacovigilance activities (through sister units within EMP/QSM)
PQP-overview & update January 20118
Differences from NMRAs
• Priority therapeutic areas• Assessments and inspections by international experts• Marketing authorization is not issued.• Prequalification of APIs• Prequalification of quality control laboratories• Provides technical assistance to applicants• No fees
PQP-overview & update January 20119
Prequalification activities• Prequalification of medicinal products and APIs
– Review of quality and safety/efficacy documentation– Inspection of manufacturing sites and CROs
• Prequalification of quality control laboratories– To identify suitable laboratories for quality testing of products
procured using international funds– Also for quality survey of products
• Technical assistance and capacity building– Help manufacturers to meet dossier and GMP requirements– To build capacity of national medicine regulatory authorities
PQP-overview & update January 201110
Organogram
Program Manager
Head :Inspections
Head: Dossier assessments
LiaisonQuality Control
Technical Assistance
Inspector AssessorInspector Assessor
Admin Support
PQP-overview & update January 201111
Paths for inclusion of a product in the list of prequalified products
• Prequalification of multisource generic products – Full review and inspection by PQP
• Prequalification of innovators– Approval based on marketing authorization issued by an NMRA in
ICH region and associated countries
• Prequalification of generic products approved by SRA– Approval based on SRA marketing authorization– For established generic products
• Recognition of temporary approvals / scientific opinions – USFDA PEPFAR approval/tentative approval– EMA article 58– Hcnda Access programme
PQP-overview & update January 201112
The assessment process• Coordinated by Dr. Matthias Stahl,
– Quality assessors
– BE assessors
– Clinical assessors
– Support staff
• Six full time in-house and one rotational assessor. • More than 50 temporary advisors (pool of external
assessors)• Six sessions per annum (every other month) here in
CPH. • More than 30 assessors per session.
PQP-overview & update January 201113
International standards for prequalification
• Primarily WHO guidance documents and standards – PQ main generic and variation guidelines– The WHO Bioequivalence and bio waiver guidelines– The WHO Stability guideline– International Pharmacopoeia– WHO GMP and GCP Guidelines
• ICH guidelines • Other guides issued by SRAs such as USFDA and EMA• Other recognized pharmacopoeias
– BP, EP, JP, USP
PQP-overview & update January 201114
Process flowApplication for prequalificationDossier, Samples & SMF
ScreeningApplicant
GMP
Review of GMP Certification,
Inspection reports, Site Master Files (SMF).
Informationrequested
Application accepted for assessment
Assessment
Accepted Accepted
Applicant
ManufacturerInspection
Corrective and preventative actions
Final decision on prequalification
Listing on WHO website
VariationsComplaints
Random samplingRequalification
Informationrequested
Informationrequested
Expression of interest (EOI)
WHOPIR
WHOPAR
PQP-overview & update January 201115
Invitation for Expression of interest (EOI)
• A list of medicines invited for prequalification– Priority public health medicines – We can only accept product dossiers for medicines included in
this list
• List prepared by WHO clinical experts (HIV, TB, Malaria, RH, Influenza, Zinc) – Based on inclusion in treatment guidelines and/or WHO model
list of essential medicines
• Revised as needed to capture new developments
PQP-overview & update January 201116
WHOPAR and WHOPIR
• PQ transparency – As per WHA Resolution WHA57.14, dated 22 May 2004 – Also the pipeline (dossier status sheet)
• WHOPAR– Assessment history– Discussion on the review outcomes– Approved SmPC, PIL and labels– Prepared by team of experts (Clinical, BE and Quality assessors)
• WHOPIR– For FPP, API, CRO and QC lab inspections – Scope and dates of inspection– Summary of observations and findings– Conclusion
PQP-overview & update January 201117
Variations
• Part of the prequalification status maintenance activity• To ensure that changes will not negatively impact the
product in terms of quality, safety and efficacy• Guideline primary based on the EU guide
– Discussions ongoing on possible revision
• Mostly handled by in-house assessors– Growing activity as the number of prequalified products has
increased– Time lines shortened
PQP-overview & update January 201118
Requalification
• Every 5 years or when requested, as per PQ procedure• Guideline adopted by the WHO Expert Committee in
2009• Verification of acceptability of the product in terms of
– current norms and standards– consistency of the product quality
• First set of products have been identified and applicants are requested to submit the necessary data
PQP-overview & update January 201119
Prequalification of APIs• Procedure approved by the WHO Expert Committee in 2009
– Separate from the APIMF procedure• GMP compliance is mandatory• Does not require submission of the corresponding FPP dossier• A separate list of prequalified APIs and their manufacturers will be posted on our
website– Same guideline- PQ Generic guide
• Launched in October 2010 (as pilot programme)– Initially for those APIs for which we already have approved APIMFs– Will soon be expanded to invite other APIs included in our EOI
• Expected to be of importance to NMRAs and procurement agencies
PQP-overview & update January 201120
Major achievements in 2010
• Revision of our main guideline for multi source generic products– To harmonize requirements and formats with other regulators
(adoption of CTD)– To provide further details to requirements– Revision of development, process validation and stability
requirements for prequalification
• Growing number of PhInt monographs • Improvement in internal handling of variations• High number of prequalified products despite declining
submission
PQP-overview & update January 201121
Major Achievements 2010, contd• Undertook manufacturer survey • First manufacturers meeting took place in July 2010 • Studies to determine the value of PQ to manufacturers (ongoing)• Joint assessment of one HIV and one second line TB product
dossiers with EAC countries – Capacity building and promotion of regional harmonization– Facilitating national registration– No duplication of efforts– Incentive for manufacturers
• Two products manufactured by Varichem were prequalified
PQP-overview & update January 201122
List of products included in WHO prequalified products list
Prequalified products
75%
12%
7% 3% 3%HIV
TBMalaria
RHInfleunza
• Prequalified generics and innovators as of December 31st 2010: 252 products (assessed and inspected by PQ)• Total listed as of December 31st 2010 (including those listed based on USFDA/EMA/HCnda approvals): 350 products
0
5
10
15
20
25
30
35
40
45
50
2007 2008 2009 2010
HIV TB Malaria RH Influenza USFDA
PQP-overview & update January 201123
Inspections
0
5
10
15
20
25
30
35
2005 2006 2007 2008 2009 2010
FPP
API
CRO
QCL
PQP-overview & update January 201124
Prequalified / interested quality control laboratories
83
10
3
16
3
22
8
24
11
29
17
30
0
5
10
15
20
25
30
35
40
45
50
2004 2005 2006 2007 2008 2009 2010
QCLs Prequalified QCLs Interested
Prequalified QCLs: South Africa,
RIIP+CENQAM (2005) Algeria, LNCPP (2005) South Africa, Adcock
Ingram (2007) Morocco, LNCM (2008) Kenya, NQCL (2008) India, Vimta Labs (2008) France, CHMP (2008) Vietnam, NIDQC (2008) Kenya, MEDS (2009) Singapore, HSA (2009) Singapore, TÜV (2009) Canada, K.A.B.S.
Laboratories (2010) Ukraine, CLQCM (2010) Ukraine, LPA (2010) Peru, CNCC (2010) Uruguay, CCCM (2010) Bolivia, CONCAMYT
(2010)
PQP-overview & update January 201125
Quality survey of Antimalarial medicines in Sub-Saharan Africa
2010
• To evaluate quality of ACTs and Sulfadoxine/Pyrimethamine
• Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania
• To estimate quality at different points of the distribution system
• To identify possible causes for any findings
• To propose possible strategies and implementation plans to address the problems identified by the study
PQP-overview & update January 201126
Collected samples by products935 samples
516
26
1 1185
327
362
30Artemether/LumefantrineArtesunate/AmodiaquineDihydroartemisinin/Piperaquine PhArtemisinin/Piperaquine PhArtemisinin/Naphthoquine PhArtesunate/MefloquineArtesunate+SPP
Artesunate+SP
Sulfadoxine/PyrimethamineSulfamethoxypyrazine/ Pyrimethamine
PQP-overview & update January 201127
Results
3
80
73
111
2
68
12
12
1
12
17
7
0%
20%
40%
60%
80%
100%
PQ total Non-PQtotal
AL PQ AL non-PQ
A&A co-pPQ
A&A co-pnon-PQ
Non-compliant Compliant
83 samples of PQ products
– AL (Novartis, Ajanta, Ipca)
– A&A co-pack (Cipla, Guilin, Ipca)
PQP-overview & update January 201128
Quality survey of anti TB medicines
• Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan– Countries with high multidrug-resistant and extensively drug-
resistant TB
• Rifampicin caps, Isoniazid tabl/inj, Rifampicin/Isoniazid tablets, Kanamycin inj powder, Ofloxacin tabl/infusion
PQP-overview & update January 201129
9
45
15
17
43
1
41 67
6
32
2 12
0%
20%
40%
60%
80%
100%
Non-compliant Compliant
Results
291 samples from 33 manufacturers and 90 sampling sites
PQP-overview & update January 201130
Results continued
• 38 samples of WHO-prequalified products
• Isoniazid/Rifampicin tablets– 75/150mg, Lupin India (18), Sandoz Private India (17)– 30/60mg (2) and 60/60mg (1) Macleods Pharmaceuticals India
• None of WHO-prequalified products failed to comply with specifications
PQP-overview & update January 201131
Technical assistance to applicants
• More than 60 technical assistance missions have been organized and delivered
213
210
3
8 7
21
14
4
8
0
5
10
15
20
25
30
2006 2007 2008 2009 2010
Technical assistances organized by PQP
REG
GPCL
GCP
GMP
PQP-overview & update January 201132
Trainings
• More than 65 trainings have been delivered
4
9
4
11
4
12
5
16
4
0
2
4
6
8
10
12
14
16
18
20
2006 2007 2008 2009 2010
Trainings organized or supported by PQP
PQP supported
PQP organized
PQP-overview & update January 201133
Trainings (contd)
• More than 3130 assessors, inspectors and manufacturers have been trained
165
198
10357
263
301
568
396
282
4944
793
203
130
73
0
200
400
600
800
1000
1200
2007 2008 2009 2010
Participants in trainings organized or co-organized/supported by PQP
Others
QCL staff
Regulators
Manufacturers
PQP-overview & update January 201134
Rotational post within WHO PQP team
• A full time P3 position, on rotational basis (one participant every three months)
• A unique arrangement for assessors from national medicine regulatory authorities (developing countries)
• Opportunity for further development in regulatory skills and exposure to the WHO Medicines area of work
• Several assessors from Ethiopia, Kenya, Tanzania, Uganda, Zimbabwe, Zambia and Ukraine have participated.
PQP-overview & update January 201135
The future
• Additional therapeutic areas may be included• Prequalification of API continued• Requalification continued• Revision of our variation guide• Continue with capacity building and harmonization
activities including joint assessments• Continue with our technical assistance missions
PQP-overview & update January 201136
Challenges• Declining number of submissions• Slow progress with respect to RH, TB and Malaria
dossiers• Increasing demand vs limited capacities
– Additional therapeutic areas– Prequalification of APIs– Additional support to procurement agencies (risk assessment for interim
procurement decisions)
• Increasing demand for technical assistance– From initial dossier compilation to prequalification– GMP compliance
PQP-overview & update January 201137
Info rich & user friendly website
• Notice of concerns & related info
• Prequalification lists
• Procedures & Guidelines
• Prequalification of APIs
• Inspection info • Trainings and
meetings• Public
assessment and inspection reports
www.who.int/prequal
PQP-overview & update January 201138
Summary• Prequalification of priority essential medicines
– Promoting access to safe, effective and quality medicines– Prequalification of APIs and – Prequalification of quality control laboratories– Provides technical assistance to applicants– NMRAs capacity building
• International standards are applied• Assessment and inspections by international experts• Mainly for multisource generics and innovator products approved
in ICH region • Has issued a revised CTD based guideline for multisource
pharmaceutical products– Can serve as resource document for NMRAs
• Active participation in regional regulatory harmonization efforts – Joint assessments
• Complete information on the web, transparent– www.who.int/prequal
PQP-overview & update January 201139
Thank you