Transcript The International Pharmacopoeia Overview Caroline Mendy Quality Assurance and Safety: Medicines

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
 WHO Expert Committee on Specifications for
Pharmaceutical Preparations
 WHO consultative procedure
 4th Edition - APIs monographs features
 What's new
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National/Regional Pharmacopoeias
 Medicines for a specific market
 Legally binding "official"
 Preparation by a national or
regional authority
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The International Pharmacopoeia
A 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 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
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The International 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!
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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]
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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?
 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?
 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
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WHO Expert Committee Report
Includes:
•
Important update on the Ph.Int
•
Proposed new work plan
•
Specifications for medicines (new adopted texts, revisions…)
•
Reference material (adopted International Chemical Reference
Substances, Infrared Reference Spectra)
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WHO 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 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...)
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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: IFPMAIGPA-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 )
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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 areas for specific projects
(regulatory, university, industry…)
With "recognized" Laboratories…
 National/Regional Quality control laboratories
 WHO Collaborating Centres (official nomination process)
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Scheme and interactions
WHO
Expert Committee
on Specifications
for
Pharmaceutical
Preparations
Public
inquiry
WHO
priorities
WHO
Secretariat
Partners
Collaborating
laboratories
Industry
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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 (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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WHO Procedure for the preparation of drug
Quality Control specifications (2)
…..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 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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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 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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WHO Procedure for the preparation of drug
Quality Control specifications (4)
…..or why it takes so long….
… 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 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 samples
200 units:
300 ml for:
2 x 40 g for:
5 g for:
5 g for:
some mg for:
tablets, capsules
oral solution/suspension, injection
API
unpurified API
intermediates
individual impurities
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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)
 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 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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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
http://www.who.int/medicines/publications/pharmacopoeia/overview/
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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
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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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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).
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APIs Monographs – Methods of analysis
General methods
Monographs tests
 Physical and physicochemical
e.g. UV and IR spectrophotometry,
pH, chromatography
Where use general method
• Provide specific details or
• Modify
 Chemical
e.g. general identification, limit tests,
sulfated ash, water
Where no general method
• Provide full details
 Biological
e.g. sterility, bacterial endotoxins
 Materials of plant origin
e.g. ash, iodine value
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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 for counter-ion
 Allows choice between
• infrared (+ counter-ion)
• other tests (+ counter-ion)
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APIs 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 – 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 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 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 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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Chemical name in
accordance with IUPAC
nomenclature rules
CAS number
Alternative tests
Reagents
International chemical
reference substance (ICRS)
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Cross-reference
to
a general method
List of known and potential impurities that
have been shown to be controlled by this
monograph
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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
 Established by WHO COLLABORATING CENTRE FOR CHEMICAL
REFERENCE SUBSTANCES
 155 International Infrared Reference Spectra
(125 published in
100,0
W105232T
90
Ph.Int 4th Ed. Suppl. 1)
80
70
60
50
%T
40
30
IR-spectrum of lamivudine
20
10
0,0
4000,0
3600
3200
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2800
2400
2000
1800
1600
cm-1
1400
1200
1000
800
600
400,0
Newly adopted monographs 44th WHO Expert Committee
•
•
•
•
•
Artesunate*
Artesunate tablets*
Amodiaquine tablets
Quinine bisulfate tablets
Quinine sulfate tablets*
•
•
•
•
Mebendazole*
Oseltamivir phosphate*
Oxytocin
Oxytocin injection
•
•
•
•
•
•
•
Lopinavir
Lopinavir and ritonavir tablets
Tenofovir disoproxil fumarate
Tenofovir tablets
Indinavir capsules
Saquinavir tablets
Efavirenz*
* Revised texts
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Newly adopted monographs 44th WHO Expert Committee
•
•
•
•
•
•
Amikacin*
Amikacin sulfate*
Amikacin injection
Kanamycin monosulfate
Kanamycin acid sulfate
Kanamycin injection
•
•
•
Tablets*
Capsules*
Radiopharmaceutical
preparations : 27 monographs
* Revised texts
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Forthcoming publication of Ph.Int
Provisional table of content (1)
•
•
•
•
•
Lumefantrine
Artemether and lumefantrine
tablets
Rifampicin, isoniazid and
ethambutol tablets
Rifampicin and isoniazid
dispersible tablets
Rifampicin, isoniazid and
pyrazinamide dispersible
tablets
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•
•
•
•
Zinc sulfate
Zinc sulfate tablets,
paediatric
Zinc sulfate oral solution,
paediatric
Magnesium sulfate injection
Forthcoming publication of Ph.Int
Provisional table of content (2)
•
•
•
Artemether and Lumefantrine oral
suspension
Chloroquine sulfate oral solution
Quinine sulfate tablets
•
•
•
Cycloserine
Cycloserine capsules
Ethambutol hydrochloride tablets
•
•
•
Mebendazole
Oseltamivir phosphate
Chewable Mebendazole tablets
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•
•
•
•
•
•
•
Efavirenz capsules
Efavirenz oral solution
Emtricitabine
Nevirapine
Nevirapine oral
suspension
Nevirapine tablets
Zidovudine, Lamivudine
and Nevirapine tablets
Work programme
 Entire Work Plan 2010 accessible on The Ph.Int website
http://www.who.int/medicines/publications/pharmacopoeia/Workplan2010.pdf
 Updated following 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 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
 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)
 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 !
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