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The International Pharmacopoeia Overview. Caroline Mendy Technical Officer - Quality Assurance and Safety: Medicines. Quality of Active Pharmaceutical Ingredients, Beijing, March 2010. The International Pharmacopoeia – Ph. Int . Scope

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The International Pharmacopoeia


Caroline Mendy

Technical Officer - Quality Assurance and Safety: Medicines

Quality of Active Pharmaceutical Ingredients, Beijing, March 2010

the international pharmacopoeia ph int
The International Pharmacopoeia – Ph. Int
  • Scope
  • WHO Expert Committee on Specifications for Pharmaceutical Preparations
  • WHO consultative procedure
  • 4th Edition - APIs monographs features
  • What's new
national regional pharmacopoeias
National/Regional Pharmacopoeias
  • Medicines for a specific market
  • Legally binding "official"
  • Preparation by a national or regional authority
the international pharmacopoeia a 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)
the international pharmacopoeia
The International Pharmacopoeia

Monographs and requirements for:

  • Active Pharmaceutical Ingredients (APIs)
  • Finished dosage forms
  • General methods/texts e.g. dissolution testing, tablets

Completed with:

  • General notices
  • Supplementary information,e.g. General guidelines for Chemical Reference Substances
  • Infrared reference spectra
the international pharmacopoeia6
TheInternational Pharmacopoeia

Scope since 1975

  • Model Lists of Essential Medicines

Essential 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 Programmes

e.g. treatment guidelines for Malaria, TB, HIV/AIDS and for children!

the international pharmacopoeia7
The International Pharmacopoeia
  • 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]

how does the ph int function
How does the Ph.Int function?
  • The Ph.Int is based on the work and decisions of the WHOExpert Committee on Specifications for Pharmaceutical Preparations
  • Aim over the last 60 years:

"to promote quality assurance and quality control of pharmaceuticals"

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…
outcome of the who expert committee
Outcome of the WHO Expert Committee?
  • Report
    • Summary of discussions
    • Recommendations to WHO + Member States
    • Presentation to WHO Governing Bodies for final comments, endorsement and implementation by Member States
  • WHO technical guidance
who expert committee report
WHO Expert Committee Report


  • Important updateon the Ph.Int
  • Proposednew work plan
  • Specifications for medicines (new adopted texts, revisions…)
  • Reference material(adopted International Chemical Reference Substances, Infrared Reference Spectra)
who consultative procedure
WHO Consultative procedure
  • This process is designed to ensure wide consultation and transparencyduring monograph development and to make the adopted texts available in a timely manner.
who does the work with partners 1
WHO does the work … with Partners (1)

Within WHO…

  • WHO disease programmes (Stop TB, Roll-Back Malaria, HIV/AIDS, Tropical Neglected Diseases, programmes on Children, Women's Health…)
  • Prequalification Programme – A United Nations Programme managed by WHO

With Regulatory Bodies…

  • National/Regional regulatory authorities
  • Regional/Interregional regulatory groups (ASEAN, ICH...)
who does the work with partners 2
WHO does the work … with Partners (2)

With Organizations and Associations…

  • International organizations (UNAIDS, UNICEF, IAEA, World Bank…)
  • International professional and other associations, NGOs (incl. industry, consumer associations: IFPMA-IGPA-WSMI, IPEC, FIP, WMA, MSF…)

With Standard-setting Bodies…

  • Pharmacopoeia Commissions and Secretariats (e.g. Brazilian, BP, IP, JP,Ph.Eur, Ch.P,USP, and PDG )
who does the work with partners 3
WHO does the work … with Partners (3)

With "recognized" Experts…

  • WHO Expert Panel on The International Pharmacopoeia and Pharmaceutical Preparations (official nomination process)
  • Specialists from all areasfor specific projects (regulatory, university, industry…)

With "recognized" Laboratories…

  • National/Regional Quality control laboratories
  • WHO Collaborating Centres (official nomination process)
scheme and interactions
Scheme and interactions


Expert Committee

on Specifications














who procedure for the preparation of drug quality control specifications 1 or why it takes so long
WHO Procedure for the preparation of drug Quality Control specifications (1)…..or why it takes so long….
  • Step 1: Identificationof 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
who procedure for the preparation of drug quality control specifications 2 or why it takes so long
WHO Procedure for the preparation of drug Quality Control specifications (2)…..or why it takes so long….
  • Step 5: Preparethe 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 theestablishment of International Chemical Reference Substances
  • Step 9: Follow the consultative process, mailing of draft specifications to Expert Panel and specialists
who procedure for the preparation of drug quality control specifications 3 or why it takes so long
WHO Procedure for the preparation of drug Quality Control specifications (3)…..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 resultsreceived 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

who procedure for the preparation of drug quality control specifications 4 or why it takes so long
WHO Procedure for the preparation of drug Quality Control specifications (4)…..or why it takes so long….

…If adoptedproceed 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.
manufacturer s involvement
Manufacturer'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)
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
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
comments on drafts
Comments 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…

the international pharmacopoeia26
The 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

4 th edition 1
4th Edition – (1)

4th Edition

  • Monographs on antiretrovirals (ARVs)
  • Revision of existing monographs
  • Improved presentation
  • Improved cross-referencing to general methods
  • Improved search functions for CD-ROM and online version
  • New notice on "manufacture"
  • New notice on impurities
  • New list of impurities shown to be controlled by tests
4 th edition 2
4th Edition (2)

First Supplement

  • About 30 new monographs for medicines for HIV/AIDS, TB and Malaria, including somefor children
  • Revisions, 125 IR reference spectra, supplementary info
monographs methods of analysis
Monographs – 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).

apis monographs methods of analysis
APIs Monographs – Methods of analysis

General methods

Physical and physicochemical

e.g. UV and IR spectrophotometry,

pH, chromatography


e.g. general identification, limit tests, sulfated ash, water


e.g.sterility, bacterial endotoxins

Materials of plant origin

e.g. ash, iodine value

Monographs tests

Whereuse general method

Provide specific details or


Whereno general method

Provide full details

apis monographs identification
APIs 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 forcounter-ion
  • Allows choicebetween
    • infrared(+counter-ion)
    • other tests(+counter-ion)
apis monographs manufacture
APIs Monographs – Manufacture

Statements under the heading "Manufacture"

  • serve toalert usersand may include
    • requirements/mandatory instructionstomanufacturers
    • guidance – when clear from wording
  • deal withaspects of quality not controlled within the body of the monograph
apis monographs assay
APIs 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 forWater
    • dried substance – if test forLoss on drying
apis monographs impurity control
APIs 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
apis monographs related substances
APIs 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
apis monographs related substances36
APIs Monographs – Related substances

General considerations

  • Any list of impuritiesprovided at the end of monograph
    • is not part of the requirements
    • is given for information
    • includes likely and potential impuritiesthat have been shown to be controlled by the requirements of the monograph
  • Other impurities may also be controlled
    • list may be extended



a general method

Chemical name in accordance with IUPAC nomenclature rules

CAS number

Alternative tests

International chemical reference substance (ICRS)


international chemical reference substances icrs
International Chemical Reference Substances (ICRS)
  • More than 200 ICRS + melting point 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
international infrared reference spectra
International Infrared Reference Spectra
  • 155 International Infrared Reference Spectra

(125 published in

Ph.Int 4th Ed. Suppl. 1)

IR-spectrum of lamivudine

newly adopted monographs 44 th who expert committee
Newly adopted monographs - 44th WHO Expert Committee


Artesunate tablets*

Amodiaquine tablets

Quinine bisulfate tablets

Quinine sulfate tablets*


Oseltamivir phosphate*


Oxytocin injection


Lopinavir and ritonavir tablets

Tenofovir disoproxil fumarate

Tenofovir tablets

Indinavir capsules

Saquinavir tablets


* Revised texts

newly adopted monographs 44 th who expert committee42
Newly adopted monographs - 44th WHO Expert Committee


Amikacin sulfate*

Amikacin injection

Kanamycin monosulfate

Kanamycin acid sulfate

Kanamycin injection



Radiopharmaceutical preparations : 27 monographs

* Revised texts

forthcoming publication of ph int provisional table of content 1
Forthcoming publication of Ph.IntProvisional table of content (1)


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

forthcoming publication of ph int provisional table of content 2
Forthcoming publication of Ph.IntProvisional table of content (2)

Artemether and Lumefantrine oral suspension

Chloroquine sulfate oral solution

Quinine sulfate tablets


Cycloserine capsules

Ethambutol hydrochloride tablets


Oseltamivir phosphate

Chewable Mebendazole tablets

Efavirenz capsules

Efavirenz oral solution



Nevirapine oral suspension

Nevirapine tablets

Zidovudine, Lamivudine and Nevirapine tablets

work programme
Work programme
  • Entire Work Plan 2010 accessible on The Ph.Int website

  • Updated following Expert Committee Meetings (e.g. new focus on anti-infectives)
  • Adopted monographs available on specific pages + drafts texts in future
who s strategy for quality control
WHO’s strategy for quality control
  • Step-wise approach:
    • Basic tests (identification)
    • Screening tests (TLC)
    • TheInternational Pharmacopoeia
    • International reference materials

(ICRS and IR reference spectra)

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