Transcript Product - World Health Organization

QA /QC including issues
related to GF policies and
prequalification :general
principles
Truls Eriksen
Technical Officer
HIV/AIDS and STI
WHO Western Pacific Regional Office
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Overview of presentation
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Introduction
Determinants of quality/QA
GFATM policy on QA
WHO prequalification project
QC
Conclusion
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What is quality?
• Fitness for purpose
• Fulfilling of needs
• Compliance with specifications
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What is quality assurance?
• QA is the sum total of the organized
arrangements made with the object of
ensuring that medicinal products are of
the quality required for their intended
use;
• “Quality assurance is about getting it
right “
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Determinants of Product Quality
• Product manufacture
• Active ingredients
• Equipment and
maintenance
• Inactive ingredients
• Plant environment
• Packagingimmediate and
external
• Manufacturing process
• Labeling./packet inserts/
• Quality control program
• Product formulation
Product information
• Handling and storage
conditions
Product=specific medicine manufactures at a specific site
Product=medicine in container with label, packaging insert
and information
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GMP, inspection and licensing
Evaluation of product dossier
Product Selection
Use
Storage/handling
QA
Procurement
Prod.Specs.
Prequalification
Tender contract
Storage/distribution
GSP,GDP
Monitoring of
supplier performance
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Inspections/licensing
Critical Elements in QA for Procurement
• Product selection
• Inspection of shipments
• Supplier prequalification
• Laboratory testing
• Product certification
• Appropriate storage,
transport, dispensing, and
use procedures
• Contract specifications
• Product monitoring/
reporting system
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Building on:
Interagency Guidelines: Operational Principles for
Good Pharmaceutical Procurement. WHO, Geneva, 1999.
WHO/EDM/PAR/99.5.
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Before May 2005:
Products bought using GF must be:
WHO prequalified; or
Approved by Stringent Regulatory Authority; or
Approved by National Regulatory Authority
After May 2005:
WHO prequalified; or
Approved by Stringent Regulatory Authority
Quality standard has been raised !!
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Quality assurance refers to the management activities
required to ensure that the medicines (or other health
products) that reach patients are safe, effective and
acceptable to the patient.
These activities may include, but are not limited to, (drug)
registration, pre-qualification and quality control.
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Pharmaceuticals procured with Global Fund
resources are subject to authorization by the
National Drug Regulatory Authority (NDRA) in the
country in which they are used, following its
standard practices for drug registration (or other
forms of authorization, such as authorizations for
special use) for pharmaceutical products.
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Multi-source pharmaceutical products
Multi-source pharmaceutical products are off-patent
products that have a prior history of safe and
efficacious use.
Multi-source pharmaceutical products tend to be
available from a wide range of manufacturers around
the world.
For such multi-source products, there are no additional
requirements other than verification of compliance with
quality standards must be conducted in accordance
with relevant requirements of the NDRA in the
recipient’s country.
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Single and limited-source pharmaceutical products
Products that are available only from a single supplier,
normally the originator company, are referred to as single
source products.
If in addition to the single supplier there are a limited
number of other suppliers, the product is referred to as a
limited-source product.
Many of the antiretrovirals and antimalarials belong to the
latter category.
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Single and limited-source pharmaceutical products
Grant funds may be used to procure a single- or limitedsource pharmaceutical product provided that such
product meets one of the following standards:
a) Have been found to be acceptable by the UN
Procurement Quality and Sourcing Project (also known
as the WHO Prequalification Project ); or
b) Have been authorized for consumption in their
country by a stringent regulatory authority
c) Have been authorized by the NDRA in the recipient’s
country, provided that this clause shall only apply until April
30, 2005.
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Countries with stringent regulatory
authorities
Pharmaceutical Inspection Cooperation Scheme (PIC/S) participating regulatory authorities
Australia
Austria
Belgium
Canada
Czech Republic
Denmark
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Malaysia
Netherlands
Norway
Portugal
Romania
Singapore
Slovak Republic
Spain
Sweden
Switzerland
United Kingdom
European Union Member States, Japan and United States
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Single and limited-source pharmaceutical products
After April 30, 2005, Grant funds may only be used to procure
single- or limited-source pharmaceutical products that
meet the requirements of the two standards set out in
a) and b), provided that:.
(1) Contracts entered into by the Principal Recipient on or
before April 30, 2005 with suppliers for products that
qualified for purchase under clause c) may be honoured
until such contracts expire or otherwise terminate.
(2) After April 30, 2005, the Principal Recipient may not enter
into any new contracts, nor extend any existing contracts,
for the supply of products that would have qualified for
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purchase under clause c) prior to April 30, 2005.
NDRA marketing authorization (registration) for new products
For products that have
•passed the WHO Prequalification Project review, or
•have been authorized by stringent regulatory authority
DRA’s are encourages to expedite registration by
accepting the above
•Fast track registration
•Provisional registration
•Waive registration
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Guide to the Global Fund’s Policies on
Procurement and Supply Management
Single and limited-source pharmaceutical products
Recommendation
Number of
equivalent
products under
option (a) or (b)
 2 Equivalent
products
 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.
The PR is required to notify GF if procuring under (i) or (ii)
which should be time-limited until products under option a)
and b) are available
(a), (b)
End Option (c) on
30 April 2005
(i) In pipeline of
Option (a) or (b) +
Manufactured in a
facility compliant
with GMP following
inspection by WHO
or stringent
regulatory authority
If products
unavailable,
PR informs
Secretariat
and then:
Evidence of
application
submitted
and GMP
compliance
IF NOT, THEN
(ii) Manufactured in
a GMP-compliant
manufacturing
facility
Evidence of
GMP
compliance
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Use of option i) or ii)
QC of samples is required and GF will contract an
independent third-part to conduct random quality analysis
In general QC should be carried out for quality monitoring
Laboratories used must meet the following criteria
1. Be “prequalified”
2. ISO17025 or EN45002 Accreditation
3. Acceptance by stringent regulatory authority
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WHO Prequalification Project
• I. Assessment of products dossiers i.e. quality specifications, pharmaceutical
development, bioequivalence etc. : teams of professionals from national drug
regulatory authorities: Brazil, Canada, Denmark, Estonia, Finland, France,
Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa,
Sweden, Switzerland, Tanzania, Zimbabwe ...
• II. Manufacturing site inspections: teamwork of inspectors: WHO
representative (qualified GMP inspector), inspector from well-established
inspectorate (Pharmaceutical Inspection Convention Scheme countries)
and national inspector(s): Canada, France, Italy, Switzerland, The
Netherlands …
• Quality control analysis - upon need but not always necessarily before
prequalification and supply, increasingly as part of follow-up
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http://mednet3.who.int/prequal
WHO Prequalification Project
HIV/AIDS
As of June 2005:
88 HIV/AIDS products
53 ARVs
34 originator products (30single, 4FDCs)
19 generic products (15 single, 4 FDCs)
14 2nd line ARVs
8 paediatric formulations
35 other products for HIV-care (non-ARV)
6 originator products
29 generics hiv_suppliersJune05.pdf
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WHO Prequalification Project
Malaria
As of 2005:
Malaria products:
2 products only:
Artesunate 50 mg tablets
Arthemeter/Lumefantrine 20/120mg tablets
mal_suppliers.pdf
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WHO Prequalification Project
Malaria
However, 25 products are currently being evaluated
4 artemether capsules/tablets
7 artemether inj.
5 artesunate tablets
3 artesunate rectal
3 artesunate+ amodiaquine tablets
3 artesunate+sulfadoxine+pyrimethamine tablets
1 Dihydroartemesinine/piperaquine phosphate tablets
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WHO Prequalification Project
TB
As of 2005:
TB products:
7 products only:
tub_suppliers.pdf
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WHO Prequalification Projectwithdrawals
Withdrawals from of products because of :
non-compliant with international standards of
Good Clinical Practice and Good Laboratory
Practice
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WHO Prequalification Projectwithdrawals
WHO's advice to countries is that, in principle, patients
should suspend the use of de-listed medicines and switch
to other prequalified products.
The risk of withholding treatment is higher than that of
providing medicines whose bioequivalence is not proven
but which have demonstrated quality and safety. A switch
to non-prequalified products is not recommended, as their
quality has not been documented by WHO.
However, if it is difficult to obtain alternative prequalified
products immediately, it is recommended that patients
continue the use of de-listed products.
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Quality Control (QC)
• Part of quality assurance
• Testing to confirm compliance with
specification
• QC useful in monitoring product quality during
storage/distribution/use
• Screening for Counterfeit medicines
• Quality needs to be built into a product during
design, formulation and manufacture
• Can not “test quality into a product”
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GMP, licensing
Evaluation of product
dossier
Product Selection
QC
Use
Storage/handling
Inspections/licensing
QA
Procurement
Prod.Specs.
Prequalification
Tender contract
QC
Storage/distribution
QC
GSP,GDP
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Inspections/licensing
QC of “new” ARVs
WHO Monographs:
WHO Draft monographs for comment:
•Didanosine
•Stavudine
•Indinavir sulfate
•Lamuvidine
•Nelfinavir mesilate
•Nelfinavir mesilate tablets
•Nevirapinhe
•Nelfinavir mesilate oral; powder
•Ritonavir
• Saquinavir mesilate capsules
•Saquinavir
•Saquinavir mesilate
The Int. Chem. Ref substances required for the monograph for
Didanosine and Nevirapine are available. Those required for the other
monographs are in preparation and notification will be given (on this
website) when they are available
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Counterfeit ARVs
• Information Exchange System
• Alert No. 110
• Counterfeit triple antiretroviral
combination product (Ginovir 3D)
• zidovudine (200 mg), lamivudine (150 mg)
and indinavir (40 mg).
• detected in Côte d’Ivoire
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WHO Definition of a counterfeit
medicine
• A product that is deliberately and fraudulently
mislabeled with respect to source and/or
identity. Counterfeiting can apply to both
generic and branded products. Counterfeit
products may include:
–
–
–
–
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products with the correct ingredients
with wrong ingredients
without ingredients
with incorrect quantities of active ingredients
with fake packaging
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Counterfeit malaria medicines
• Recent reports of counterfeit antimalarials :
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–
–
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Chloroquine
Quinine
Sulphadoxine-pyrimethamine (Fansidar TM)
Metakelfin TM
Mefloquine
Halofantrine
Primaquine
Artesunate
Intramuscular artemether
Dihydroartemisinin ?
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Fake artesunate in mainland SE
Asia 2000-1
• 38 % of shop bought
artesunate counterfeit,
containing no active
drug
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Paul Newton, Welcome Foundation
Repeat artesunate survey 2002-3
• In the same areas, by Dondorp et al.
• 188 artesunate samples
• 58 % ‘artesunate’ blisterpacks contained no
artesunate. All labelled as made by ‘Guilin
Pharma’
• 9 % of mefloquine was substandard and
probably fake
• No counterfeit artesunate injection or oral
artemether, dihydroartemisinin were found
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Paul Newton, Welcome Foundation
Genuine Hologram Fake Artesunate Type 2
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Genuine Hologram Fake Artesunate Type 3
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Genuine Hologram Fake Artesunate Type 4
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Genuine Hologram Fake Artesunate Type 5
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Genuine Hologram Fake Artesunate Type 6
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Genuine Hologram
Fake Artesunate Type 7
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Rapid Alert System on combating
counterfeit drugs
http://218.111.249.28/ras
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Rapid Alert System
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Information System for reported cases
Repository of reports and response data
Alert mechanism enhancing process flow
Platform for communication & collaboration
Objectives:
• To transmit alerts on counterfeit medicines
• Support professional assessment
• Improve national & international smart partnership
& networking
• Reduce the incidence of counterfeit medicines
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• Increase awareness of the problems
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Conclusion - Quality can be assured
through:
Prequalification of products/manufacturers
WHO Prequalification Project
Prior registration in countries with stringent regulatory
authority
National Registration by DRA (fast track)
Maintaining product quality through:
Proper storage (GSP)
Proper distribution (GDP), dispensing and use
Monitoring of quality through out the distribution
chain
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