9 Pre Qualification

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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



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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



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WHO - EDM


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



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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)



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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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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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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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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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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


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



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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



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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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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)



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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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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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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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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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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



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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)



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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 ...



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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



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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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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

Documents

9 Pre Qualification