Prequalification Programme: Priority
Essential Medicines
QUALITY,
GOOD MANUFACTURING PRACTICE AND
BIOEQUIVALENCE
WITH A FOCUS ON ANTITUBERCULOTICS
5-9 November 2007
Jiaxing, China
1
Prequalification Programme: Priority Essential Medicines
Presented by:
Dr A J van Zyl
安德李
Technical Officer
WHO
HTP/PSM/QSM
vanzyla@who.int
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
2
In this presentation…
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Why prequalification? What is prequalification? How does
it work?
Steps in prequalification
Norms and standards used
Evaluations (dossiers and site inspections)
Outcome of assessment
Capacity building and improvements
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Quality of medicines remains a problem in many
countries

Oct 2006. Panama: More than 30 died
- cough syrup containing diethylene
glycol – industrial solvent (in
antifreeze) – kidney failure

1999. Belgium: Two babies died.
Injected KCl (supposed to be glucose)

2000. USA: 17 children died. No active
ingredient in inhalers


Picture. New York Times 2007
Death by GMP: MH Anisfeld. GMP Review. Vol 4 No 4 2006
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What is WHO doing to help the countries?

Normative functions – setting norms and standards
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Including GMP

Capacity building

Prequalification Programme: Priority Essential Medicines

"Three in one" – more tuned to real public health problems,
immediate feedback, better quality, higher efficiency
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Prequalification of essential medicines
The UN prequalification program:

Is an action plan for expanding access to medicines for patients
with:

HIV/AIDS

Tuberculosis

Malaria
And access to Reproductive Health Products

Ensures quality, efficacy and safety of medicines procured using
international funds (e.g. GFTAM)
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How is prequalification organized?
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Role of WHO:
Managing and organizing the project on behalf of the United Nations.
• Provides technical and scientific support
• Ensures that international norms and standards are applied all
through the process including assessment, inspection (GMP, GCP,
GLP) and quality control
Partners:
• 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); HIV/AIDS Department
Actors:
Mainly qualified assessors and inspectors from National DRAs (also
from National Quality Control Laboratories) of ICH and associated
countries, and inspectorates belonging to PIC/S
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Department of Medicines Policy and Standards,
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Steps in prequalification
I
Expression of Interest
Product dossier
SMF
Assessment
Inspections
Additional information
and data
Corrective actions
Compliance
Compliance
Prequalification
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Monitoring
Quality Assurance (QA) of WHO prequalification
process
PQ team has its own Quality Assurance system:
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Quality Assurance and Safety: Medicines (QSM)
Standard Operating Procedures (SOPs)
Manuals and guidelines
General Procedure for Prequalification
Norms and standards (product dossiers,
manufacturers etc)
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
Product dossier assessment
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Anti-Tuberculosis Products
7th Invitation
to manufacturers of antituberculosis medicines
to submit an Expression of Interest (EOI) for product evaluation to the
WHO Prequalification Programme
(June 2007)
Interested manufacturers are encouraged to submit documentation for recommended dosage
forms and strengths, as specified below, of medicinal products in the following categories.
1. Single ingredient first-line antituberculosis medicines
- Ethambutol, tablet 400 mg
- Isoniazid, tablet 300 mg
- Pyrazinamide, tablet 400 mg
- Rifampicin, capsule 150 mg; 300 mg
- Streptomycin, powder for injection 1g (vial)
2. Fixed dose combination products of first-line antituberculosis medicines
- Isoniazid + Rifampicin, tablet 75 mg + 150 mg; tablet 150 mg + 150 mg
- Ethambutol + Isoniazid, tablet 400 mg + 150 mg
- Ethambutol + Isoniazid + Rifampicin, tablet 275 mg + 75 mg + 150 mg
- Ethambutol + Isoniazid + Pyrazinamide + Rifampicin,
tablet 275 mg + 75 mg + 400 mg + 150 mg
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Anti-Tuberculosis Products
3. Single ingredient second-line antituberculosis medicines
- Amikacin, 250 mg/ml (vial 2 ml, 4 ml); powder for injection 1g (vial)
- Capreomycin, powder for injection 1g (vial)
- Cycloserine, capsule 250 mg
- Ethionamide, coated tablet 125 mg; 250 mg
- Kanamycin, powder for injection 1g (vial)
- Levofloxacin, tablet 250 mg
- Moxifloxacin, tablet 400 mg
- Ofloxacin, tablet 200 mg; 400 mg
- Prothionamide, coated tablet 250 mg
- P-aminosalicylic acid, granules 4g
- P-aminosalicylic sodium, granules 100 g
4. Scored solid dosage formulations for children, preferably dispersible
- Ethambutol, tablet 100 mg
- Isoniazid, tablet 50 mg; 100 mg
- Isoniazid + Rifampicin, tablet 60 mg + 60 mg; tablet 30 mg + 60 mg
- Isoniazid + Pyrazinamide + Rifampicin, tablet 30 mg + 150 mg + 60 mg
- Pyrazinamide, tablet 150 mg
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Evaluation 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
Letter is sent first by e-mail to the applicant followed by surface mail
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Assessment procedure- Product dossiers
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Innovator products
•
•
•
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Multisource (generic) products
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•
•
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Abridged procedure if approved by stringent authorities like EMEA and US FDA
Assessment reports from Drug Regulatory Authorities (DRSs), WHO Certificate of
Pharmaceutical Product (CPP), batch certificate, update on changes
Trusting scientific expertise of well-established DRAs
Full dossier with all the data and information requested
Quality:
• Information on starting materials and finished product, including API details, specifications,
stability data, formulation, manufacturing method, packaging, labelling etc
Efficacy and safety:
• Bio-equivalence study or clinical study report
Commercial sample

Requested, but not always analysed before prequalification.
US FDA tentative approvals for ARVs – recognition scientific assessment based on information
exchange (Confidentiality agreement between US FDA and WHO); the same approach will
soon apply for EU Art58 and Canadian JCPA procedure)
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Prequalification: generics and not generics

Generic medicines:
1. To contain the same active ingredients as the innovator drugs as the innovator drug
2. To be identical in strength, dosage form, and route of administration
3. To have the same indications for use
4. To meet the same batch requirements for identity, strength, purity and quality
5. To be manufactured under the same strict standards of GMP required for innovator products.
6. To be bio-equivalent
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Prequalification requirements for generics
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What if not generics
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Fully in line with major regulatory agencies
Full data to prove safety (including preclinical toxicology) and efficacy has to
be presented
Not all non-innovator products in prequalification pipeline can be
defined as generics – no innovator may be available

See also FDA requirements for generic drugs (www.fda.gov/cder/ogd)
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
Norms and standards used
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Prequalification: where
the technical documents
come from?

International consultation
process

The WHO Expert
Committee – review and
adopts

Executive Board

World Health Assembly

Printed in respective TRS
and WHO web site
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Department of Medicines Policy and Standards,
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Publications 2005/2006
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New, user friendly prequalification web site launched in November
2006: http://who.int/prequal/
Articles:
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1. Prequalifi cation of medicines. WHO Drug Information, 2005, 19:1.
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2. WHO and its Prequalification Programme: an Overview. WHO
Pharmaceuticals Newsletter, 2005, No. 2.
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3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans
ML, Rägo L. Ongoing monitoring of antiretroviral products as part of
WHO’s Prequalifi cation Programme. Journal of Generic Medicines,
2006, 3(2):96–105.
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Problems encountered with product dossiers
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General
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HIV/AIDS: Initially – few monographs (Official Pharmacopoeia)
Malaria - very few innovator products, many not typical generics as well
 Very few antimalarials approved in ICH and associated countries
Limited DRAs and regulatory experts having experience
Fixed dose combinations more complicated than single component products
TB: Old products, low profits – lack of data meeting current requirements
General Quality related issues
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Manufacturers do not comply with GMP
Products not controlled - registered and produced only for export
Lack of specifications or poorly defined manufacturers specifications
Stability data missing or not meeting requirements
No method validation etc.

Mostly manufacturers can overcome these problems if motivated.
However, it may take a lot of time
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Problems encountered with product dossiers
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Lack of reference products for bioequivalence studies
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For generic products: Bioequivalence studies to show the same blood
concentrations (assume same safety and efficacy profile)
Often unclear which comparator product to be used
BE not a requirement in all countries
Safety and efficacy related issues
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Insufficient data submitted
 Incomplete protocols and trial reports
 Incomplete evaluation of published literature
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No characterisation of pharmacokinetic properties of the product
General statements made: No interaction known (clearly not true); No (or minimal)
adverse events (literature survey if no original data)
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Too broad efficacy claims
Galenical development history not provided
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Inspection of sites
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Inspections:
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Team of inspectors for each inspection
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WHO PQ inspector plus PIC/S member country plus local
country inspector (observer)
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Some cases – capacity building (recipient country)
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Preparation includes SMF, product information,
inspection reports, complaints etc
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APIs, Finished products
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Clinical studies: Mostly Bioequivalence studies (generic
products
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Inspections:
Assess compliance with
WHO norms and standards:

GMP
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GCP
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GLP
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GSP
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GDP…
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Organizations conducting clinical trials
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WHO training materials
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Where are the inspections performed?
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India, Bangladesh, Pakistan
China
Belgium
Canada
Malaysia
France
South Africa
Switzerland
United States
Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda
…
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Inspections:
Production and control activities:
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Normally over 3 days
Covers all aspects of GMP
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Quality management, Quality assurance, Premises, Equipment,
Documentation, Validation, Materials, Personnel, Utilities (e.g.
HVAC, water) . . .
Also data verification (dossier) including stability data,
validation (process), development batches and bio batches
Quality control laboratory – specifications, reference
standards, methods of analysis, validation and qualification
...
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Inspections:
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Bio-equivalence studies
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GCP and GLP
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About 2 days per study including
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Clinical part
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Bio-analytical part
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Clinic, Pharmacy and related areas, data verification
Laboratory and data verification
Statistical analysis
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Problems identified in GMP inspections:
Various including validation, ventilation, equipment,
quality risk management…
 Validation and qualification work was often
incomplete
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Validation Master Plans (VMP) lacked details
Validation policies as defined in the VMPs were
not implemented
Process validation was lacking
Validated procedures (e.g. environmental
monitoring) were lacking
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Problems identified in GMP inspections:
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No URS for HVAC, water and computer systems
Incomplete (not detailed) or "no" qualification of HVAC / water /
computers
Insufficient filtration of air to production areas
No prevention of possible cross-contamination and contamination.
No authorized schematic drawings
"As built" AHUs lacked components reflected in the schematic
drawings, including filters
Temperature and RH mapping studies incomplete, or results not
applied
HVAC systems not controlled or monitored
Filters:
 not planned, classified, tested (including installed filter leakage test),
monitored
Pressure differential gauges not controlled, including calibration
and zero checks
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Problems identified in GMP inspections:

Wrong sequence of
components (e.g. after
filtration)
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Inappropriate AHU for
equipment
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e.g. coaters, FBD
Claim "wet scrubbers" – but not
functional
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Inappropriate change control
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No quality risk management
documented
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Problems identified in GCP inspections:
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Volunteers
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Ethics committee
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Independence
Supportive documentation
Clinic
Archives
Pharmacy
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Number of volunteers in a study
No control for participating in several studies in a short period
Supportive documentation – DOB, identification, ECGs
Screening
ICF
Documentation, randomization, dispensing
CRFs
Analytical method validation
Stability (stock solutions, samples)
Source data including chromatograms
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Outcome
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Transparency:
WHO Public
Inspection
Reports
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Increased transparency about the "pipeline"
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Outcome
 List of prequalified products
New and revised guidelines, norms and standards
Monographs
International Chemical Reference standards
Sampling and testing of products on the market
Training
Capacity building
...
See also Annual Report
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List of prequalified products
Disease 2001
HIV/
AIDS
TB
Malaria
…
2002
2003
2004
2005
2006
2007
…
…
…
…
25
19
(excluding US
FDA, Canada)
(excluding US
FDA)
…
(5)
2
1
0
4
0
2
3
0
3
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Monitoring…
 Ongoing assessments and follow-up
•
•
•
•
Products
Manufacturing sites (both for APIs and finished dosage forms)
CROs
Sampling and testing
• Data verification inspections
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Since 2005: PQ Annual report
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
Capacity building and improvement
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Capacity building of DRAs and Manufacturers

Both remain important components and need
strengthening
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Both need improvement and new approaches

From 2006 - in addition - provide (to selected
manufacturers):
Technical Assistance
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Measures taken to get more products
prequalified
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Action taken. . .
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Formerly very limited resources vs huge obligations and scope
 Initially only ONE professional - today at least 15 (including 4
secondments from Governments such as France and China)
Business plan and funding proposals – now funds received (Gates)
and (UNITAID)
Internal SOPs and work procedures
"Note for Applicants" (anti-malaria products)
New regulatory guidance documents created and started
Specific guidance on comparator products
More direct discussions with manufacturers started
Regulatory advice on complicated cases including BE
Pharmaceutical development, technology transfer, paediatric
formulations "Notes to consider"
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Measures taken to get more products
prequalified
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Action taken (2) . . .
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Additional funding (e.g. Gates, UNITAID)
Additional training workshops
Additional staff to be recruited
Communication to be improved
 Regulators
 Manufacturers
 Donors and partners
More proactive approach towards potential suppliers – new elements
 Regulatory advice
 Technical assistance
Strengthening links with WHO regions
Taylor made approach to different regions
Building capacity in countries
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Alternative regulatory pathways

USA FDA tentative approvals linked to PEPFAR
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EU Article 58
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
Included in WHO PQ List
Confidentiality agreement with US FDA in place
For products exclusively to be used outside EU
Canadian Access to medicines scheme

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WHO cooperation with the above mentioned
Confidentiality agreement in preparation
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谢谢
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