Quality of RH Medicines:
Update from WHO Prequalification of Medicines
Programme and beyond.
4 October 2012, Paris
Dr Lembit Rägo
Coordinator
Quality Assurance and Safety: Medicines
Essential Medicines and Pharmaceutical Policies
World Health Organization
Geneva
ragol@who.int
1
Content
•
•
•
•
Context and links with other WHO activities
What is prequalification programme (PQP):
Overview of the programme activities
Specifics of RH medicines
- Challenges and a way forward
• What it can offer to the regulators and industries?
• Conclusions
2
• The Millennium
Development Goals
(MDGs):
• Eight international
development goals that
192 United Nations
member states and at
least 23 international
organizations have agreed
to achieve by the year
2015
3
Medicines work in WHO HQ
• Department of Essential Medicines and Health Products (EMP)
– Three teams for medicines work
• Quality Assurance and Safety: Medicines (QSM)
• Medicines Access and Rational Use (MAR)
• Medicine Programme Coordination (MPC)
• Collaboration with other clusters/departments/programmes/units in HQ
– Vaccines and biologicals (IVB/QSS) – Vaccines prequalification
programme
– EMP – Diagnostics prequalification programme
– Disease oriented programs (HIV/AIDS, malaria, TB, neglected
diseases)
• Collaboration with WHO regional and country offices
4
QSM Technical Programmes
•
•
•
•
•
•
International Nonproprietary Names (INNs)
Quality Assurance
Safety/Pharmacovigilance
Regulatory support
Prequalification Programme for Medicines
Quality Assurance and Safety of Blood Products and
Related Biologicals
• Anti SFFC (anticounterfeiting)
5
Active collaboration with other international,
regional and national organizations
• UN family, international organizations and donors:
–
–
–
–
UNICEF, UNFPA, UNIDO etc.
BMGF, Global Fund, UNITAID
Manufacturers associations
MSF
• Regional
– EMA/EU
– Council of Europe/EDQM
– NEPAD
• Professional and scientific
– FIP, CIOMS, IUPHAR, ISPE
• National level
– National Medicines Regulatory Authorities (from all WHO Member
States)
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Prequalification of Medicines Programme
 The UN Prequalification Programme managed by WHO is ensuring that
medicines procured with international funds are of assessed and
inspected for quality, efficacy and safety, involves
Prequalification programme for medicines (finished dosage forms)
Prequalification of active pharmaceutical ingredients (APIs)
Prequalification of quality control (QC) laboratories
 The Prequalification Programme is an action plan for expanding access
to priority essential medicines in the following four areas:
- HIV/AIDS
- Tuberculosis
- Malaria
- Reproductive Health
- Selected individual products for other diseases (Flu, Zinc sulphate)
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Extensive collaboration with regulators
• Not duplicating work done be stringent regulatory
authorities
– SRA approval of new and generic products – abridged procedure
– US FDA tentative approvals – based on confidentiality agreement
including in the PQ products list
– European Medicines Agency (EMA) – Art 58 … and beyond
– Collaboration with EDQM, in particular in the area of APIs
(confidentiality agreements with US FDA, EDQM, EMA …)
• Active participation and involvement of
– SRA experts
– Regulatory authority experts from less resourced settings
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http://www.who.int/medicines/areas/quality_safety/en/ or
http://apps.who.int/prequal/
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Steps in the process
10
Medicines Prequalification Process
Expression
of Interest
Assessment
Product dossier
SMF
Inspections
Corrective
actions
Additional information
and data
Compliance
Compliance
Prequalification
Handling of
complaints
Monitoring
Dossier maintenance
(variations)
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Transparency
• Very comprehensive web site
• Guidance for applicants
– Technical guidelines
– Guidance on specific issues (comparator products etc.)
•
•
•
•
•
List of products prequalified and in pipeline
WHO Public Assessment Reports (WHO-PARs)
WHO Public Inspection Reports (WHO-PIRs)
Notice of Concern (NOC) documents
News, announcements for public meetings etc.
12
Transparency – dossiers and their status
information on the web
13
Transparency – WHO Public Assessment Reports
(WHOPARs): a lot of information
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Transparency - WHOPIRs and NOCs
• These are published in response to the WHA Resolution WHA57.14
of 22 May 2004, which requested WHO, among other actions:
– "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 Inspection Report (WHOPIR) provides a summary
of the inspection (where found to be GMP complaint)
• 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 contract research organization.
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API prequalification developing
Note: as per today 12 different Chinese API manufacturers with 14 applications
for individual API Prequalification received. None yet prequalified as
applications relatively recent
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Service Delivery: Assessors
7.0
Reliability
5.6
Average Rating
6.2
6.1*
6.0
5.0
Responsive
Assurance
Empathy
6.3
6.0
5.9*
5.6
5.0*
Tangibles
5.3*
5.7
5.5
5.3
5.0
4.7*
4.4*
4.0
3.0
Desired and
minimum level
of service
Actual
score
2.0
1.0
Reliability: ability to
Responsiveness:
Assurance: knowledge,
Empathy: caring,
Tangibles: appearance
perform the promised
willingness to help
courtesy and ability to individualized attention of physical facilities,
service dependably applicants and provide
convey trust and
provided to applicants equipment, personnel,
and accurately
prompt service
confidence
and communications
materials
Base: Manufacturers (Regulatory Affairs), n=18
[Q10-Q14]
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Why products do not get prequalified?
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Common deficiencies: quality
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Common deficiencies: Safety/Efficacy – bioequivalence
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Prequalification programme in 2011
• During 2011 35 products (finished dosage forms)
prequalified
• At the end of 2011, the WHO list of prequalified medicines 269 products manufactured in 25 countries
• By the end of the year 8 active pharmaceutical ingredients
(APIs) (6 for antimalarials and 2 for anti-TB medicines)
prequalified
• 6 more medicines Quality Control Laboratories (QCL)
prequalified (Belgium, Brazil, India, the Netherlands,
Portugal and Tanzania). At the end of 2011, a total of 23
QCLs had been prequalified, covering all WHO 6 regions
(further 32 were working towards becoming prequalified).
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Training activities as a core
• PQP also organized, co-organized or supported 32
training courses, for nearly 1400 participants.
• Training on general or specific technical issues was given
to manufacturers, and to NMRA and QCL staff.
• Courses generally also include an introduction or update
on PQP requirements and services.
• PQP has a 3 months rotational post for developing
country assessors – many regulators from China, Ghana,
Tanzania, Kenya, Uganda, Botswana, Zambia,
Zimbabwe, Ukraine etc. have been in this post – current
fellow on post is from Kenya
Drug Information Association
www.diahome.org
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23
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Technical assistance
• In 2011, PQP organized 17 technical assistance
missions to 13 pharmaceutical manufacturers in 5
countries (Bangladesh, China, Kenya, Nigeria and
Pakistan),
• Technical assistance for 5 CROs in China,
• Technical assistance for 2 QCLs in China, and 1 QCL
each in Benin, Cameroon, Madagascar and Thailand.
• Assistance took the form of an audit, followed by
development of an improvement plan. Training in specific
technical regulatory areas was made available where
needed.
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Technical assistances organized by PQP in
individual countries
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Quality monitoring projects
(1)
• Quality survey of antimalarials Africa
– Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania
– ACTs and sulfadoxine-pyrimethamine
– 935 samples collected and screened by Minilab, 306 tested in laboratory
SPs
ACTs
70
63
67
Non-compliant
56
60
50
Compliant
100%
90%
44
7
80%
40
%
32
27
30
60%
17
20
50%
80
12
68
40%
8
10
17
30%
0
0
0
0
0
n
ro o
e
m
Ca
12
111
70%
i
Eth
ia
op
a
an
Gh
a
ny
Ke
a
eri
Nig
a
nz
Ta
ni a
12
73
20%
10%
3
2
1
0%
PQ total
Non-PQ
total
AL PQ
AL non-PQ A&A co-p
PQ
A&A co-p
non-PQ
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Quality monitoring projects
(2)
• Quality survey of anti-TB medicines in NIS
– Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan
– Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin
– 291 samples collected and tested
25
23
20
13
15
%
10
10
5
10
7
4
• None of 38 samples of WHOprequalified products failed
0
n i a a i ja n l a ru s
t an r ai n e i s t an
e
s
m
b
Be
Uk z b e k
ak h
Ar Az er
z
a
U
K
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WHO Projects Organized in Cooperation with
SFDA in China
Focus on quality and safety of medicines, sponsored by
• Bill and Melinda Gates Foundation (BMGF)
– To improve TB control in China by increasing national
capacity to produce fixed-dose combination (FDC) antiTB medicines of assured quality and to regulate TB
FDC drugs
• Global Fund to Fight HIV/AIDS, TB and Malaria (GFATM)
– To improve the quality of anti-TB, HIV/AIDS and malaria
medicine produced in China to ensure improved
accessibility and patient outcomes
TBS, Nov 3, 2011
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Status of RH: PQ and ERP
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Why RH manufacturers do not apply for PQ?
And when they apply why slow progress?
 No "market" for international standard quality products, enough
market for products "as it is"
 The need to make human and financial investments
 A lack of technical and regulatory skills
 Not yet ready to participate internationally/globally –
national/subregional markets unsaturated
 Differences between PQP and national regulatory requirements and
their implementation
 Varying requirements and standards of procurers
 Risk of losing traditional markets once defined as sub-standard –
PQ programme NOCs etc.
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What PQ can offer to the regulators and
industries in the regions?
• Regulators
– Capacity building/training – improved technical knowledge and
skills
– Practice and experience for collaboration and cooperation
– Offers a lot of practical tools and guidelines
– Helps to build more credible regulatory systems
– Save resources
• Industries
– Free of charge capacity building
– Better quality production/products/regulatory knowledge – better
access to markets
– Access to international funds
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Conclusions
• PQP is a powerful and effective mechanism to promote
access to quality medicines
• PQP has saved lives
• PQP is not a replacement for national regulatory systems
but a (time limited) mechanism to promote access to
quality medicines
• Major proactive contributor to capacity building
• Promotes collaboration and cooperation among
regulators, including relying on each others work and
reducing duplications
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Selection of articles and publications about PQP
•
•
The biowaiver procedure: its application to antituberculosis products in the WHO
prequalification programme. Strauch S, Jantratid E, Stahl M, Rägo L, Dressman JB. In J
Pharm Sci. 2011 Mar;100(3):822-30. Epub 2010 Oct 6.
Ensuring quality medicines: a decade of prequalification”. In WHO Drug Information,
25(3):231−239. Available at:
http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2011_Vol25-/en/index.html
•
“WHO Prequalification of Medicines Programme: facts and figures for 2010.” In WHO Drug
Information, 25(2):101−103. Available at:
http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2011_Vol25-2/en/index.html
•
“Inspection of API manufacturing sites.” In: WHO Drug Information, 25(1):24−27 and in
WHO Pharmaceuticals Newsletter, No. 1, 2011, pp. 12−18. Available at:
http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2011_Vol25-1/en/index.html
http://www.who.int/medicines/publications/PharmNewsletter1_11/en/index.html
•
Survey of the quality of anti-tuberculosis medicines circulating in selected newly
independent states of the former Soviet Union. Available at:
http://www.who.int/prequal/info_applicants/qclabs/quality_monitoring.htm
•
“Best medicines. Good-quality active pharmaceutical ingredients are vital to the product of
good-quality medicines.” In: World Pharmaceutical Frontiers, September 2011. Available at:
http://edition.pagesuiteprofessional.co.uk/launch.aspx?referral=other&pnum=77&refresh=5Wp1z0E20B4c&EID
=daba9217-c7a4-4529-a687-a6fb6437e4c5&skip=&p=77
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www.diahome.org