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Ensuring access to drug products thatare of acceptable quality
WHO Pilot Procurement, Quality andSourcing (pre-qualification) project
Dr Lembit Rgo
Quality Assurance and Safety: MedicinesEssential Drugs and Medicines PolicyHealth Technology and Pharmaceuticals Cluster,
World Health OrganizationTel: +41.22.791. Fax: +41.22.791.4730
E-mail: [email protected]
WHO/EDM Technical briefing seminar
2 October 2002
Geneva
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Quality of Anti-retroviral Drugs
Presentation outline
s Is quality of pharmaceuticals a problem?
s What WHO is doing to help countries to ensure quality of
pharmaceuticals?
s Why quality problems of ARVs are not easy to solve?
s WHO Pilot Procurement, Quality and Sourcing Project Why and how? Expected outcomes Problems encountered
First results
s Future challenges
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Substandard drugs is a big problem - antibiotics,antimalarials, antituberculosis drugs included.
Incorrect
amount
17%
No active
ingredient
60%
Other errors
7%
Incorrect
ingredient
16%
breakdown of data on 325
cases of substandard drugs -
including antibiotics, the world
to WHO database
Percentage breakdown ofPercentage breakdown of
data on 325 cases ofdata on 325 cases of
substandard drugs -substandard drugs -
including antibiotics,including antibiotics,
antimalarials andantimalarials and
antituberculosis drugs -antituberculosis drugs -reported from around thereported from around the
world to WHO databaseworld to WHO database
Is quality of pharmaceuticals a problem?
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The quality of anti-malarial products - bothcontent and dissolution are problems
0
20
40
60
80
100
Gabon
Ghana
Kenya
Mali
Mozambi
q
Sudan
Zimbab
Chloroquine tablets- %failure*
Content Dissolution
Is quality of pharmaceuticals a problem?
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The quality of anti-malarial products - bothcontent and dissolution are problems
020
40
60
80
100
Gabon
Ghana
Kenya
Mali
Mozambi
qu
Sudan
Zimbabw
Sulphadoxine/pyrimethamine - %failure*
Content Dissolution
Is quality of pharmaceuticals a problem?
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WHO - EDM
Is quality of pharmaceuticals a problem?
Why is Quality of Pharmaceuticals So Different?
s
Huge regulatory capacity gaps - if no proper requirements or nocapacity for implementation of requirements the quality may vary
s No global standards for generics - WHO has a comprehensive
set of guidelines but implementation varies
s No requirements, or no equal quality requirements for export -
very few countries effectively control quality of pharmaceuticals forexport; certificates for export are issued more easily than for
domestic markets
s Know-how gap - if no properly educated people available no good
results can be expected
s Financial incentives - quality has its price and generic
manufacturers work for profit as any other business
s Other reasons ...
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WHO - EDM
Four objectives of WHO Medicines Strategy: 2002-2003
1. Policy 3. Quality and safety2. Access 4. Rational Use
1. Rationalselection
4. Reliable health &supply systems
2. Affordableprices
3. Sustainablefinancing
ACCESS
What is WHO doing to help countries to ensure quality?
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bearing in mind the previous report on the subject, that highlight challengesrelated to the international trade agreements, access to essential drugs,
drug quality and rational use of medicines, together with the urgent need
to improve access to treating priority health problems such as malaria,
childhood illnesses, HIV/AIDS and tuberculosis, among others;
REQUESTS Director-General:
(3) to provide support for implementation of drug monitoring systems in order
better to identify developing resistance, adverse reactions and misuse of
drugs within health systems, thus promoting rational use of drugs;
(6)to provide support to Member States to set up efficient nationalregulatory mechanismsfor quality assurance that will help ensure
compliance with good manufacturing practices, bioavailability and
bioequivalence
World Health Assembly resolution 54.11, 21 May2001: WHO Medicines Strategy
What is WHO doing to help countries to ensure quality?
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Quality and safety: global norms, standards, guidelines,nomenclature (http://www.who.int/medicines)
s Global norms and standards in production and inspection, quality control (incl. International
Pharmacopoeia), model certificates
q TRS publications, Quality Assurance, vol. 1 and 2 ...
s Guidelines for generic drug registration and model legislation
stability testing, bioequivalence, QA in pharmaceutical supplysystems ...
classification and self-medication products, internet &
pharmaceuticals etc.
q but limited guidance in efficacy and safety area
s Nomenclatures, classifications INNs (International Nonproprietary Names)
ATC classification and Daily Defined Doses (DDDs)
What is WHO doing to help countries to ensure quality?
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What is WHO doing to help countries to ensure quality?
What is WHO doing in order to reduce quality andregulatory gaps? (http://www.who.int/medicines/)
s Supporting capacity building and training of regulators Based on norms and standards and guidance materials
Preparing training tools, organizing training seminars and
workshopsq Validated GMP training modules on CD-rom, GMP training courses
q Workshops on quality assurance, drug registration Facilitating information exchange
q WHO Drug Information, WHO Pharmaceutical Newsletter, Rapid Alerts
q Increasing information on the web site - guidelines, INNs database etc.
q Biennial International Conferences of Drag Regulatory Authorities
(ICDRAs)
s Supporting regional harmonization initiatives Favoring networking, providing technical assistance
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Pilot Procurement, Quality and Sourcing Project
WHO Pilot Procurement, Quality and Sourcing (pre-qualification) project: Access to HIV/AIDS Drugs
and Diagnostics of Assured Qualitys Why the project was launched?
Requests from countries and other organizations to help in
terms of assuring quality of HIV/AIDS drugs
Other UN agencies lacking technical knowledge and seeking
technical help from WHO
Technically complicated group of drugs
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics ofAssured Qualitys
Partners* UNAIDS UNICEF WHO
UNFPA With the support of World Bank
q *All organisations are also members of the InternationalPharmaceutical Co-ordination Group (IPC)m:
s Starting - Expression of Interest Launched by partners in 2001
Offers from manufacturers of HIV/AIDS drugs and diagnosticsreceived in the 3rd quarter of 2001 ...
s WHO role Provide technical assistance in quality related issues
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Pilot Procurement, Quality and Sourcing Project
The drugs involved in the pilot project* (I)
s Antiretroviral agents Non-Nucleoside Reverse Transcriptase Inhibitors such as
Nevirapine; Efavirenz; Delavirdine
Nucleoside Reverse Transcriptase Inhibitors such as Zidovudine,
Didanosine; Zalcitabine; Stavudine; Lamivudine; Abacavir;
Lamivudine + Zidovudine.
Protease Inhibitors such as Saquinavir, Ritonavir, Indinavir;
Nelfinavir; Amprenavir; Lopinavir + Ritonavir;
Anti-infective drugs listed below:
s Antibacterial and antimycobacterial agents, including Azithromycin; Clarithromycin; Clindamycin; Ceftriaxone; Cefixime;
Ciprofloxacin; Rifabutin
* Based on the first Expression of Interest
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Pilot Procurement, Quality and Sourcing Project
The drugs involved in the pilot project (II)
s Antiprotozoal agents, including Trimethoprim/Sulphamethoxazole(IV); Pentamidine; Pyrimethamine;
Sulfadiazine; Folinic acid
s Antiviral agents, including
Acyclovir; Cidofovir; Ganciclovir; Forscarnet
s Antifungal agents, including Amphotericin B; Fluconazole; Itraconazole; Ketoconazole;
s Anti-cancer drugs Vinblastine; Etoposide; Bleomycin; Vincristine
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
s
Key question: what standards to apply? (EOI covered bothoriginator and generic products) Small group of regulators was asked this question, answers were
collected and summarized, outcome discussed and agreed with
partners Conclusions:
q 1. Originator products: abridged procedure relying on
scientific expertise of well established regulatory authorities
q 2. Generic drugs: WHO standards used for multisource
(generic) drugs both for dossier assessment and GMP
inspections - as pharmacopoeial standards not available full
assessment necessaryq Separate guides cover both 1 and 2 were composed - both
available on website:http://www.who.int/medicines/
WHO B i R i t f G i D
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WHO Basic Requirements for Generic Drugs
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
s
What is required (1) ? 1. Details of the product 2. Regulatory situation in other countries 3. Active pharmaceutical ingredient (s) (API) 3.1 Properties of the active pharmaceutical ingredient(s)
3.2 Sites of manufacture 3.3 Route(s) of synthesis 3.4 Specifications
API described in a pharmacopoeia:
API not described in a pharmacopoeia:
3.5 Stability testing
WHO Expert Committee on Specifications for Pharmaceutical
Preparations, Thirty-fourth report. Geneva, World Health Organization,
1996: 65-79(WHO TRS, No 863)
http://www.ifpma.org/ich5q.html#stability
WHO B i R i t f G i D
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WHO Basic Requirements for Generic Drugs
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
s What is required (2)? 4. Finished product 4.1. Formulation
4.2. Sites of manufacture
4.4. Manufacturing procedure 4.5 Specifications for excipients 4.6 Specifications for the finished product
4.7 Container/closure system(s) and other packaging
4.8 Stability testing
WHO B i R i t f G i D
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WHO Basic Requirements for Generic Drugs
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
s
What is required (3)? 4.9 Container labelling 4.10 Product information 4.11 Patient information and package inserts 4.12 Justification for any differences to the product in the
country or countries issuing the submitted WHO-type
certificate(s) 4.13 Interchangeability (bioequivalence studies, or
justificaton, if not provided) 4.14 Summary of pharmacology, toxicology and efficacy of
the product
q Based on "Marketing Authorization of Pharmaceutical Productswith special Reference to Multisource (Generic) Products: a
Manual for a Drug Regulatory Authority, WHO/DMP/RGS/98.5)
and other relevant WHO documents
Pilot Procurement Quality and Sourcing Project
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
s Project has two major objectives
Assessment of HIV/AIDS related drugs quality (pre-
qualification)
Creating WHO Model Quality Assurance System for
Procurement (MQAS-P)
Pilot Procurement Quality and Sourcing Project
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality - products I
s Invisible products for running quality assessment (pre-qualification) project:
First, internal WHO/QSM Quality Assurance System
created and implemented Operations Manual drafted, Standard Operating
Procedures and records created and implemented
General Procedure for assessment (pre-qualification) of
drugs drafted, circulated for comments and approved
by WHO Expert Committee for Pharmaceutical
Specifications in Oct 2001 Quality Manual created (as per ISO)
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics of AssuredQuality - products II
s
Invisible products done for running quality assessment(pre-qualification):
Code of Conduct for assessors and inspectors created
and implemented More than 180 product dossiers (not only ARVs but
also drugs for HIV care) assessed and communicated(to manufacturers)
upon need re-assessment of dossiers
GMP inspections carried out and results
communicated, inspections ongoingq What is the value of feedback to manufacturers? (money?knowledge?)
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality - products III
s Visible products of running quality assessment (pre-qualification): outcome
Products
q First set of products and suppliers published 20 March
2002 - all information on web site
http://www.who.int/medicines/q Draft Model Quality Assurance System for Procurement
(MQAS-P) created
Pro-active communication and feedback to regulators
q Workshops, training courses: Washington DC (PAHO)
April 2002, Pretoria (AFRO) June 2002, SEARO (Sept
2002) ...
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Pilot Procurement, Quality and Sourcing Project
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
s Assessment of dossiers
Carried out by teams of professionals from national DRAs
(mix of developed and developing countries)
s
Manufacturing sites inspections Carried out by teams of three: WHO representative
(qualified GMP inspector), inspector from well established
inspectorate (PIC/S countries) and national inspector(s)q Qualified inspectors pool limited, no additional capacities
Problems encountered
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Problems encountered
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality: Quality problems I
s General problems and deficiencies identified:
q Several substances and products not in pharmacopoeia
q Lack of established reference standards
q Active pharmaceutical ingredients e.g. route of synthesis
unknown, supplier unknownq Unacceptable impurities
q No analytical methods and method validation
q In vitro dissolution tests of solid dosage forms have not
been carried out
q Regulatory approval not based on thorough evaluation
Problems encountered
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Problems encountered
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality: Quality problems II
s Specific problems : Unacceptable chiral activity, stereo-
isomerism of active pharmaceutical ingredient (API) - potentially
inactive API
s CHIRALITY / ENANTIOMERIC PURITYCHIRALITY / ENANTIOMERIC PURITY Stavudine
Lamivudine Indinavir (1/ 32 possible stereoisomers) Saquinavir mesylate (1/64 possible) Ritonavir
Only one enantiomer registered and claimed in the innovators
dossierEMEA/CPMP/375/96 EPAR : (-) Lamivudine selected because less
cytotoxic than (+) Lamivudine and the racemate (50:50 mixture)
Problems encountered
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Problems encountered
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality: Quality problems III
s CHIRALITY / ENANTIOMERIC PURITY:CHIRALITY / ENANTIOMERIC PURITY: Lamivudine example (1):
s No information on the stereochemical configuration
s No information on how the synthesis can lead to the correct
enantiomer evidence of structure / right enantiomer?
s
No validation on manufacturing process of the API: only 2batches with batch size unknown batch-to-batch consistency
not demonstrated/ is the same enantiomer obtained each time? Is
it contaminated with the same amount of the undesirable
stereoisomer each time?
s Absence of control of the undesirable enantiomer in the finishedpharmaceutical product including biobatch
s ...
Problems encountered
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Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality: Quality problems IV
s No, or incomplete data and information on:
Validation of analytical methods
Stability data (both active pharmaceutical ingredient
and finished product) Process validation
Development pharmaceutics
Bio-equivalence
Problems encountered
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Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality: Quality problems V
s BIOEQUIVALENCE
s Lamivudine examples
1 file for oral solution no BE study required
6 files for tablets from 4 manufacturers
s 2 manufacturers: no BE study
s 2 manufacturers: BE study included for at least one
formulation strength Major deficiencies identified in BE studies from both
manufacturers (assay validation, relevant test product?)
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y g j
Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality: Quality problems III
s GMP deficiencies:
Hormones, cytotoxics and ARVs in same area
Qualification and validation lacking (premises, systems,
equipment, processes)
Cleaning validation No verification of air classification of areas for sterile
product manufacturing Sampling and testing of APIs
Loss in traceability of materials used in production
Fraudulent data ...
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Why compliance with WHO standars is needed?
All literature about drugs based on originator products:
s Thus, the generic products have to be interchangeable
with originator products! Pharmaceutical interchangeability- the same active ingredient (with
the same route of synthesis), the same dosage form the same
quality
Therapeutic interchangeability- bioequivalence studies in vivo amust for this group to prove the same efficacy and safety
s If not interchangeable, then documentation to support
new drug application must be prepared New toxicological studies
New clinical studies q Not realistic approach
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Access to HIV/AIDS Drugs and Diagnostics ofAssured Quality
Current status:
s Good news Relatively large number of products and suppliers indicated
First pre-qualified suppliers list published Potential suppliers appreciating feedback and willing to improve Unique knowledge obtained about generic ARVs
Good quality generic ARV products do exist
s Bad news Only limited number of products have met the required standards Takes time to get into compliance
q
Data to be generatedq GMP upgrade needed
Quality Assurance at a price!
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Future challenges beyond the HIV/AIDS related drugs
Applying the same approach to other priority diseases like TB andmalaria (pre-qualification of these products has started already)
Strengthening procurement quality assurance Globally
q Creating WHO Model Quality Assurance System for
Procurement through WHO normative procedures
q Step-by-step harmonization of Quality Assurance Systems in
procurement organizations - long-term commitment needed
q Mutual trust between those who start using MQS - exchange of
inspection results and other information, less duplication,common pool of pre-qualified products as public good
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