PREQUALIFICATION
General overview and procedures
and practical implications of WHO PQ, FDA registration, registration with
PICs member countries for procurement agencies involved in procurement
Technical Briefing Seminar for Consultants on Procurement and
Supply Management
for HIV/AIDS, TB and Malaria
Organized by WHO and AMDS Network
Copenhagen, Denmark
31 January 2006
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: +41.22.791.4730
World Health Organization
E-mail: [email protected]
Prequalification of essential medicines
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The UN prequalification program is an action plan for expanding
access for the hardest hit by
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HIV/AIDS
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Tuberculosis
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Malaria
for ensuring quality, efficacy and safety of medicines all the way
through the medicines supply chain.
Department of Medicines Policy and Standards
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WHO - PSM
Why the prequalification is needed
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Problems
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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
Department of Medicines Policy and Standards
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WHO - PSM
Challenges of prequalification
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Demand for affordable antiretrovirals, anti-malaria drugs
and anti-tuberculosis drugs is increasing
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Numerous generic manufacturers offering products
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Challenges for UN family and procurement
agencies/organizations
Department of Medicines Policy and Standards
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WHO - PSM
Is quality of pharmaceuticals a problem?
Substandard drugs is a big problem - antibiotics, antimalarials,
antituberculosis antiretrovirals drugs included
Incorrect
ingredient
16%
Percentage breakdown of
data on 325 cases of
substandard drugs reported from around the
world to WHO database
Incorrect
amount
17%
Other errors
7%
Department of Medicines Policy and Standards
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No active
ingredient
60%
WHO - PSM
Prequalification basic principles
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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
Department of Medicines Policy and Standards
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WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
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.
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Gives assurance that international norms and standards are
applied at all the steps of the prequalification and at the process
itself.
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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.
Department of Medicines Policy and Standards
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WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
How prequalification is organized
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Role of WHO: Managing and organizing the project on behalf of the
United Nations.
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Partners:
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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
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
Department of Medicines Policy and Standards
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WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
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
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Every dossier is assessed by at least two assessors.
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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
mail
Department of Medicines Policy and Standards
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WHO - PSM
Assessment procedure-Product dossiers
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Innovator products
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Multisource products (generics)
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Assessment report from DRAs
WHO Certificate of Pharmaceutical Product (CPP)
Batch certificate
Update on changes.
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
Department of Medicines Policy and Standards
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WHO - PSM
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)
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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 before
prequalification and supply; increasingly as part of follow-up
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Department of Medicines Policy and Standards
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WHO - PSM
Prequalification of quality control laboratories
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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
Department of Medicines Policy and Standards
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WHO - PSM
Training activities
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In 2005 three comprehensive 5-day training courses on quality, GMP
and BE for TB drugs and ARVs (Malaysia, China, Ukraine)
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Course on quality, GMP and BE planned for Jan-06 (China)
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Two GMP training courses for NDRA inspectors (South-Africa, China)
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Recent GMP training course in Tanzania (with PQ participation)
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Training of QC lab officials
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Training of PQ staff and inspectors working for WHO in BE study
inspections (January-February -06)
Department of Medicines Policy and Standards
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WHO - PSM
Current status – December 2005
 Started with HIV/AIDS products in 2001 – malaria and TB products joined
later
 Prequalified products (Dec 2005)
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105
8
2
115
HIV related medicines
anti-tuberculosis medicines
anti-malarial medicines
Dossiers arrived
- 316 (Aug-05)
- 156
- 48
520
343 (Dec -05)
165
49
557
 Ongoing assessments and follow-up
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Products
Manufacturing sites
CROs
Department of Medicines Policy and Standards
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WHO - PSM
Current status – Manufacturers of finished products
 In the prequalification list: 15 sites of generics
 Asia:
9 sites
 Europe: 4 sites
 Africa: 2 sites
Department of Medicines Policy and Standards
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WHO - PSM
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
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•
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)
Department of Medicines Policy and Standards
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WHO - PSM
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)
Department of Medicines Policy and Standards
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WHO - PSM
Global Fund Quality assurance policy related to procurement
Practical implications of FDA registration, registration with PICs
member countries for procurement
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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
Department of Medicines Policy and Standards
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WHO - PSM
New Policy, Global Fund
 2 Equivalent
products
Number of
equivalent
products under
option (a) or (b)
 2 Equivalent
products
* 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.
Recommendation
End Option (c) on
30 April 2005
If products
unavailable,
PR informs
Secretariat
and then:
(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
The PR is required to notify GF if procuring under (i) or (ii)
Department of Medicines Policy and Standards
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WHO - PSM
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_Cou
ntries_ICH_PICS.pdf
Department of Medicines Policy and Standards
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WHO - PSM
Countries with "stringent" regulatory
authorities
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PIC/S= Pharmaceutical Inspection
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Convention and Pharmaceutical Inspection
Cooperation Scheme participating
regulatory authorities
(www.picscheme.org)
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Australia
Austria
Belgium
Canada
Czech Republic
Denmark
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Malaysia
Netherlands
Norway
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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 )
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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
WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
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…..
Department of Medicines Policy and Standards
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WHO - PSM
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
Dossier
assessment
Inspections
GMP/GCP
Sometimes "GMP compliance" alone does not tell the whole truth!!
Department of Medicines Policy and Standards
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WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!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
Department of Medicines Policy and Standards
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WHO - PSM
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
Department of Medicines Policy and Standards
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WHO - PSM
Summary and conclusion
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Good news; quality of generics exists
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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
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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
Department of Medicines Policy and Standards
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WHO - PSM
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!!
Department of Medicines Policy and Standards
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WHO - PSM
Summary and conclusion
CONT…
No more poor quality medicines for
poor people!
Equitable access to good quality,
safe and effective medicines for all!
Department of Medicines Policy and Standards
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WHO - PSM
http://mednet3.who.int/prequal/
Department of Medicines Policy and Standards
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WHO - PSM
THANK YOU VERY MUCH
FOR
YOUR ATTENTION!!
Department of Medicines Policy and Standards
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WHO - PSM