the international pharmacopoeia overview caroline mendy technical officer - quality assurance and...

The International Pharmacopoeia

Overview

Caroline MendyTechnical Officer - Quality Assurance and Safety: Medicines

Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009


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The International Pharmacopoeia – Ph. Int The International Pharmacopoeia – Ph. Int

Scope

WHO Consultative procedure

4th Edition

APIs monographs features

What's new


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Pharmacopoeias Pharmacopoeias

Pharmacopoeias may be:

National e.g. Brazilian, British, Chinese, Indian, Japanese, Mexican, Spanish, United States

Regional e.g. European

International The International Pharmacopoeia


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Pharmacopoeias Pharmacopoeias

National and regional pharmacopoeias

Cover medicines used in the relevant country or region

Are legally binding "official" in the relevant country or region

Are prepared by a national or regional authority


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The International PharmacopoeiaA few dates…

The International PharmacopoeiaA few dates…

The history of the International Pharmacopoeia dates back 1874…

1948 First World Health Assembly established Expert Committee on Unification of Pharmacopoeia

1950 WHA approved publication of Pharmacopoeia Internationalis (Ph.Int)


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The International PharmacopoeiaThe 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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The International Pharmacopoeia The International Pharmacopoeia

Scope since 1975

Model Lists of Essential MedicinesEssential medicines are selected with due regard to disease prevalence, evidence on efficacy and safety, and comparative cost-effectiveness.

Medicines recommended and specifications needed by WHO Programmese.g. treatment guidelines for Malaria, TB, HIV/AIDS and for children!


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implementation: “ready for use” by Member States

"The Ph.Int [… ] is intended to serve as source material for reference or adaptation by any WHO Member State wishing to establish pharmaceutical requirements. The pharmacopoeia, or any part of it, shall have legal status, whenever a national or regional authority expressly introduces it into appropriate legislation."

[Reference to World Health Assembly resolution WHA3.10, WHO Handbook of Resolutions and Decisions, Vol. 1, 1977, p. 127]


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How does the Ph.Int function?How does the Ph.Int function?

The Ph.Int is based on the work and decisions of the WHO Expert Committee on Specifications for Pharmaceutical Preparations

Aim over the last 60 years:

"to promote quality assurance and quality control of pharmaceuticals"


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What is the WHO Expert Committee?What is the WHO Expert Committee?

Official Advisory Body to Director-General of WHO

Governed through rules and procedures (Ref. WHO Manual)

Participation to Expert Committee (EC) meetings:

– Voting members ("Experts") selected from WHO Panel of Experts

– Technical advisers– Observers: - international organizations,

- NGOs, - professional associations…


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Outcome of the WHO Expert Committee?Outcome of the WHO Expert Committee?

Report of this WHO Expert Committee

• Summarizes discussion

• Gives recommendations to WHO + Member States

• Includes newly adopted guidelines;

• Is presented to WHO Governing Bodies for final comments, endorsement and implementation by Member States

constitutes WHO technical guidance


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WHO does the work … with Partners (1)WHO does the work … with Partners (1)

National/Regional regulatory authorities and quality control laboratories

Regional/Interregional regulatory groups (ASEAN, ICH...)

International organizations (UNAIDS, UNICEF, World Bank…)

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


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WHO does the work … with Partners (2)WHO does the work … with Partners (2)

Pharmacopoeia Commissions and Secretariats (e.g. Brazilian, BP, IP, JP, Ph.Eur, Ch.P, USP, and PDG )

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

WHO Collaborating Centres (official nomination process)

Specialists from all areas (regulatory, university, industry…)


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WHO Consultative procedureWHO Consultative procedure

This process is designed to ensure wide consultation and transparency during monograph development and to make the adopted texts available in a timely manner.


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

…..or why it takes so long….


…..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 (including Department of Essential Medicines and Pharmaceutical Policies (EMP) specific disease programmes and the Prequalification Programme)

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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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 QC 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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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 feedback

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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… If adopted proceed to step 15

Step 15: Incorporate all changes agreed during the discussion leading to adoption together with any editorial points. Where necessary, also take account of any further comments that may still be received due to comment deadlines for recirculated texts (Step 12 and beyond) falling shortly after the meeting.

Step 16: In all cases, confirm the amended text by correspondence with the relevant experts and/or contract laboratory before making it available on the WHO Medicines website.

Step 17: Make "final texts" available on the Medicines website to provide users such as PQ assessors and manufacturers with the approved specifications in advance of the next publication date.






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Manufacturer's involvementManufacturer's involvement

Dialogue from the early stages of development of the draft monograph to the final text…

Samples, Reference material

Documentation

Discussion on analytical issues when relevant

Comments on draft(s)


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Requirements for samplesRequirements for samples

200 units: tablets, capsules

300 ml for: oral solution/suspension, injection

2 x 40 g for: API

5 g for: unpurified API

5 g for: intermediates

some mg for: individual impurities


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Requirements for specifications (1)Requirements for specifications (1)

Manufacturer's documentation is kept confidential

Description, Chemistry, Solubility, Storage, Labelling

Definition, with information on polymorphism if relevant

Identification

Assay

Specific tests (sulfated ash, optical rotation, loss on drying…)

Related substances


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Requirements for specifications (2)Requirements for specifications (2)

Precise description of analytical methods

Impurities (chemical names, structures, origin)

Any relevant information on

Performance testing (e.g. dissolution)

Stability

Validation of analytical methods


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Comments on draftsComments on drafts

Different possible channels to communicate with the Secretariat as comments may be received

directly from the manufacturers

via the international manufacturers associations (opportunity is then given to other manufacturers to comment on drafts)

ex: list of impurities, Manufacture section…


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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 – (1)4th Edition – (1)

4th Edition

Monographs on antiretrovirals (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 (2)4th Edition (2)

First Supplement

About 30 new monographs for medicines for HIV/AIDS, TB and Malaria, including some for children

Revisions, 125 IR reference spectra, supplementary info


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CAS numberCAS number

Cross-reference to

a general method

Cross-reference to

a general method

Alternative testsAlternative tests

Chemical name in accordance with IUPAC nomenclature rules

Chemical name in accordance with IUPAC nomenclature rules

International chemical reference substance (ICRS)International chemical reference substance (ICRS)ReagentsReagents


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List of known and potential impurities that have been shown to be controlled by this

monograph

List of known and potential impurities that have been shown to be controlled by this

monograph


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Monographs – Methods of analysisMonographs – Methods of analysis

Special features

….when complex, technically demanding methods are described (e.g. HPLC),

--> a less technically demanding analytical method (e.g. TLC) proposed as alternative (if possible).


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APIs Monographs – Methods of analysisAPIs Monographs – Methods of analysis

General methods

Physical and physicochemicale.g. UV and IR spectrophotometry,

pH, chromatography

Chemicale.g. general identification, limit tests,

sulfated ash, water

Biologicale.g. sterility, bacterial endotoxins

Materials of plant origine.g. ash, iodine value

Monographs tests

Where use general method• Provide specific details or• Modify

Where no general method • Provide full details


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APIs Monographs – IdentificationAPIs Monographs – Identification

Whenever possible, includes

• infrared

• specific optical rotation, where relevant

• 2 or 3 other tests – TLC, UV, colour/other simple test

Whenever applicable, includes

• a test for counter-ion

Allows choice between

• infrared (+ counter-ion)

• other tests (+ counter-ion)


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APIs Monographs – ManufactureAPIs Monographs – Manufacture

Statements under the heading "Manufacture"

serve to alert users and may include

• requirements/mandatory instructions to manufacturers• guidance – when clear from wording

deal with aspects of quality not controlled within the body of the monograph

enantiomeric purity Lamivudine

contamination Heparin sodium

alkyl mesilates Nelfinavir mesilate

histamine-like substances Streptomycin sulfate


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APIs Monographs – AssayAPIs Monographs – Assay

Purpose (+ impurity tests) is to determine purity of substance

Method – usually robust and precise (e.g. titration) rather than specific

Limits given under Definition

Limits calculated with reference to • anhydrous substance – if test for Water• dried substance – if test for Loss on drying


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APIs Monographs – Impurity controlAPIs Monographs – Impurity control

Related substances tests

General chemical tests

• heavy metals

• sulfated ash

• loss on drying

Physical tests

• absorbance, specific optical rotation solid APIs

• relative density, clarity of solution liquid APIs


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APIs Monographs – Related substancesAPIs Monographs – Related substances

General considerations

Test methods - usually HPLC or TLC

Acceptance criteria - comparison of peak areas or spot intensities

A test may control known and unknown impurities

Known impurities may be named or unnamed within the test


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APIs Monographs – Related substancesAPIs Monographs – Related substances

General considerations

Any list of impurities provided at the end of monograph

• is not part of the requirements

• is given for information

• includes likely and potential impurities that have been shown to be controlled by the requirements of the monograph

Other impurities may also be controlled

• list may be extended


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International Chemical Reference Substances (ICRS)

International Chemical Reference Substances (ICRS)

More than 200 ICRS + melting point reference substances

Established by WHO COLLABORATING CENTRE FOR CHEMICAL REFERENCE SUBSTANCES

Primary reference standard

Linked to Ph.Int

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 International Infrared Reference Spectra

Established by WHO COLLABORATING CENTRE FOR CHEMICAL REFERENCE SUBSTANCES

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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Newly adopted monographs - 42nd WHO Expert Committee

Newly adopted monographs - 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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Newly adopted monographs - 43rd WHO Expert Committee (1)Newly adopted monographs - 43rd WHO Expert Committee (1)

• Artemether and Lumefantrine oral suspension

• Chloroquine sulfate oral solution• Quinine sulfate tablets

• Cycloserine• Cycloserine capsules• Ethambutol hydrochloride tablets

• Mebendazole• Oseltamivir phosphate • Chewable Mebendazole tablets

• Efavirenz capsules• Efavirenz oral solution• Emtricitabine• Nevirapine• Nevirapine oral

suspension • Nevirapine tablets • Zidovudine, Lamivudine

and Nevirapine tablets


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Newly adopted monographs - 43rd WHO Expert Committee (2)Newly adopted monographs - 43rd WHO Expert Committee (2)

• Fludeoxyglucose (18F) injection

• Gallium citrate (67Ga) injection

• Thallous chloride (201Tl) injection

• Iobenguane (123I) injection• Technetium (99mTc)

pentetate complex injection

• Sodium iodide (131I) injection• Sodium iodide (131I) solution• Sodium pertechnetate

(99mTc) injection (fission)• Sodium pertechnetate

(99mTc) injection (non-fission)


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Work programmeWork programme

Entire Work Plan 2009 accessible on The Ph.Int website

http://www.who.int/medicines/publications/pharmacopoeia/Workplan2009.pdf

Updated after Expert Committee Meetings (e.g. new focus on anti-infectives)

Adopted monographs available on specific pages + drafts texts in future


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WHO’s strategy for quality controlWHO’s strategy for quality control

Step-wise approach:

Basic tests (identification) Screening tests (TLC) The International Pharmacopoeia International reference materials

(ICRS and IR reference spectra)


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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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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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Thank you !

the international pharmacopoeia overview caroline mendy technical officer - quality assurance and...

Documents

pharmaceutical requirements

pharmaceutical preparationsaim

unification of pharmacopoeia

pharmacopoeias national

expert committee

pharmacopoeias pharmacopoeias

int function

member statesthe ph