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The International Pharmacopoeia + International Chemical Reference Standards -

Dr Sabine Kopp – Caroline Mendy

Quality Assurance and Safety: Medicines

World Health Organization

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The International Pharmacopoeia –Ph. Int.

Introduction

Ph. Int. - scope

WHO consultative procedure

What's new

Link with other programmes and organisations

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International PharmacopoeiaHistorical overview

1874 Discussion on Unification of terminology and

composition of drugs 1902 First Conference organized by the

Government of Belgium 1906 Agreement on Unification of the Formulae of

Potent Drugs ratified by 19 states 1925 Brussels agreement (signed 1929)

League of Nations: “international pharmacopoeia”

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International PharmacopoeiaHistorical overview - 2 -

1937 First meeting (experts from B, CH, DK, F, NL,

UK, USA) - League of Nations

1947 Interim Commission of WHO takes up health

related work of League of Nations

1948 First World Health Assembly established

Expert Committee on Unification of

Pharmacopoeia

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International PharmacopoeiaHistorical overview - 3 -

1950 WHA approved publication of Pharmacopoeia

Internationalis

WHO Expert Committee: 1951 named: Expert Committee on International

Pharmacopoeia 1959 named: Expert Committee on Specifications

for Pharmaceutical Preparations --> to date

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International Pharmacopoeia

A collection of monographs and requirements for:

Drug substances

Excipients

Finished dosage forms

General methods and requirements:

dosage forms, e.g. tablets, liquid preparation for oral use

dissolution testing

Supplementary information, e.g. General Guidelines for Chemical Reference Substances

Infrared reference spectra

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International Pharmacopoeia

Scope since 1975

Model List of Essential Medicines and

Medicines recommended and specifications needed by WHO Programmes, e.g. to treat Malaria, TB, HIV/AIDS and for children!

implementation: “ready for use” by Member States

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WHO Procedure for the preparation of drug Quality Control specifications (1)

…..or why it takes so long….

Step 1: Identification of specific pharmaceutical products for which Quality Control (QC) specifications need to be developed, confirmation by all WHO parties concerned (Expert Committee, Specific disease programme, pre-qualification project team, etc.)

Step 2: Provision of contact details from manufacturers of the above products in collaboration with all parties concerned

Step 3: Contact manufacturers for provision of QC specifications and samples

Step 4: Identify and contact QC laboratories for collaboration in the project (2-3 laboratories depending on how many pharmaceutical products have been identified in step 1), Contract for laboratory work

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WHO Procedure for the preparation of drug Quality Control specifications (1)

…..or why it takes so long….

Step 5: Prepare the contract for drafting the specifications and undertaking the necessary laboratory work

Step 6: Search for information on QC specifications available in the public domain

Step 7: Laboratory testing, development and validation of Quality Control Specifications

Step 8: Support WHO Collaborating Centre in the establishment of International Chemical Reference Substances

Step 9: Follow the consultative process, mailing of draft specifications to Expert Panel and specialists

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WHO Procedure for the preparation of drug Quality Control specifications (2)

…..or why it takes so long….

Step 10: Discussion of comments with contract laboratories, WHO Collaborating Centres, additional laboratory testing to verify and/or validate specifications

Step 11: Consultation to discuss the comments and test results received as feed-back

Step 12: recirculation for comments

Step 13: as step 10

Step 14: Present the drafts to the WHO Expert Committee on Specifications for Pharmaceutical Preparations for possible formal adoption,

…if not adopted repetition of steps 11 to 13 as often as necessary

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WHO does the work … with Partners

National and regional authorities

International organizations (UNAIDS, UNICEF, World Bank, etc.)

International professional and other associations, NGOs (including consumer associations, MSF, industry: IFPMA-IGPA-WSMI, FIP, WMA, etc.)

WHO Expert Panel on The International Pharmacopoeia and Pharmaceutical Preparations (official nomination process)

Specialists from all areas, regulatory, university, industry

WHO Collaborating Centres (official nomination process)

Pharmacopoeia Commissions and Secretariats, national institutions and institutes

Regional and interregional regulatory groups (ASEAN, ICH, etc)

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International Pharmacopoeia

current: 4th Edition + 1st Supplement Consolidated in :

2 Volumes - Vol. 1: pharmaceutical substances (A-O)

- Vol. 2: pharmaceutical substances (P-X) + dosage forms + radiopharmaceuticals + methods of analysis + reagents

1st Supplement - new requirements and revisions

Available in Publication, CD-ROM and Online

http://www.who.int/medicines/publications/pharmacopoeia/overview/

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4th Edition – new (1)

4th Edition

Monographs on antiretrovials (ARVs)Revision of existing monographsImproved presentationImproved cross-referencing to general methodsImproved search functions for CD-ROM and online versionNew notice on "manufacture"New notice on impuritiesNew list of impurities shown to be controlled by tests

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4th Edition – new (2)

First Supplement

New monographs for ARVs, TB and Malaria medicines, medicines for children

Revisions, 125 IR reference spectra, supplementary info

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New Ph. Int. monographs - adopted by 42nd WHO Expert Committee

– Lumefantrine– Artemether and lumefantrine tablets

– Rifampicin, isoniazid and ethambutol tablets– Rifampicin and isoniazid dispersible tablets– Rifampicin, isoniazid and pyrazinamide dispersible tablets

– Zinc sulfate– Zinc sulfate tablets, paediatric– Zinc sulfate oral solution, paediatric

– Magnesium sulfate injection

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New Ph. Int. monographs - adopted by 43rd WHO Expert Committee

– Efavirenz capsules– Efavirenz oral solution– Emtricitabine– Nevirapine– Nevirapine oral suspension – Nevirapine tablets – Zidovudine, Lamivudine and Nevirapine tablets

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New Ph. Int. monographs - adopted by 43rd WHO Expert Committee

– Artemether and Lumefantrine oral suspension– Chloroquine sulfate oral solution– Quinine sulfate tablets

– Cycloserine– Cycloserine capsules– Ethambutol hydrochloride tablet

– Mebendazole– Oseltamivir phosphate – Chewable Mebendazole tablets

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New Ph. Int. monographs - adopted by 43rd WHO Expert Committee

The following monographs adopted subject to minor modifications:

Fludeoxyglucose (18F) injection

Gallium citrate (67Ga) injection

Technetium (99mTc) pentetate complex injection

Sodium pertechnetate (99mTc) injection (fission)

The following monographs adopted subject to minor modifications and final confirmation by IAEA:

Iobenguane (123I) injection

Sodium iodide (131I) injection

Sodium iodide (131I) solution

Sodium pertechnetate (99mTc) injection (non-fission)

Thallous chloride (201Tl) injection

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New Ph. Int. Work Programme –adopted by WHO Expert Committee

Medicines for HIV/AIDS-related conditions– Antibacterials– Antifungal, antiprotozoal and antimycobacterial agents

Anti-epilectics – paediatric formulations (oral liquids and chewable tablets)

Anthelmintics

Palliative care

Reproductive health

Insulins

Large volume parenterals (eg glucose IV infusion)

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International Chemical Reference Substances (ICRS)

207 ICRS + 12 melting point reference substances Established by WHO COLLABORATING CENTRE FOR CHEMICAL

REFERENCE SUBSTANCES in Sweden Primary reference standard Linked to Ph.Int. Price for ICRS US$ 70 Includes: - Directions for use - Certificate of analysis Monitoring and on-going stability testing Can be used for tests and analysis not included in Ph.Int.

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International Infrared Reference Spectra

Established by WHO COLLABORATING CENTRE FOR CHEMICAL REFERENCE SUBSTANCES in Sweden

155 International Infrared Reference Spectra

(125 published in

Ph.Int. 4th Ed. Suppl. 1)

4000,0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400,0

0,0

10

20

30

40

50

60

70

80

90

100,0

cm-1

%T

W105232T

IR-spectrum of lamivudineIR-spectrum of lamivudine

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Int. Ph. and links with other programmes and organizations

Collaboration with national and regional pharmacopoeias, incl. Brazilian Pharmacopoeia, Chinese Pharmacopoeia, JP, IP, Ph.Eur., USP, and PDG

Collaboration with national/regional regulatory authorities and quality control laboratories

Collaboration with international organizations (e.g. UNICEF, IAEA)

Links with Prequalification Programme - A United Nations Programme managed by WHO

Collaboration with manufacturers worldwide

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Int. Ph. and links with other programmes and organizations

Monographs for antimalarials, anti-TB drugs, etc. (different clusters in WHO)

General requirements for products derived from plant materials (WHO Traditional Medicines Programme)

Monographs for radiopharmaceuticals (with International Atomic Energy Agency - IAEA)

Monographs for excipients (with Pharmacopoeial Discussion Group – PDG, IPEC)

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UN Prequalification of Medicines ProgrammeUN Prequalification of Medicines Programme

International Pharmacopoeia (Ph.Int.) and its international chemical reference standards (ICRS) are essential tool for PQ activities

The Ph.Int. enjoys priority in the PQ Programme

BP, Ph.Eur. and USP methods should only be applied, where an Applicant has made specific commitments to do so in the dossier

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UN Prequalification of Medicines ProgrammeUN Prequalification of Medicines Programme

The International Pharmacopoeia is the only reference source for many of the priority medicines dealing in the PQ programme, such as:

artemisinin-related Antimalarial products (e.g. artemether, artesunate, artenimol);

Antiretrovirals products (e.g. abacavir, efavirenz, nelfinavir mesilate, ritonavir);

Fixed-dose combinations (e.g. artemether/lumefantrine tablets, lamivudine/nevirapine/zidovudine tablets);

Paediatric formulations (e.g. artemether and lumefantrine oral suspension, paediatric didanosine liquid for oral use)

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The International Pharmacopoeia's advantages (1)

The International Pharmacopoeia's advantages (1)

1. Specifications validated internationally, through an independent scientific process

2. Input from WHO Collaborating Centres, national Drug Quality Control laboratories

3. Collaboration with manufacturers around the world, especially for new projects

4. Development considering the costs of analysis, i.e. using as few ICRS as possible

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The International Pharmacopoeia's advantages (2)

The International Pharmacopoeia's advantages (2)

5. Collaboration with standard-setting organizations and parties, including regional and national pharmacopoeias

6. Networking and close collaboration with WHO Member States, Drug Regulatory Authorities

7. Links with other WHO activities

8. FREE FOR USE by all Member States

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Further questions ??????http:www.who.int/medicines

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Safe quality medicines