Docstoc

The International Pharmacopoeia Overview - Pharmexcil

Document Sample
The International Pharmacopoeia Overview - Pharmexcil Powered By Docstoc
					      The International Pharmacopoeia

                                             Overview
                                         Caroline Mendy
        Technical Officer - Quality Assurance and Safety: Medicines




Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
The International Pharmacopoeia – Ph. Int


 Scope
 WHO Consultative procedure
 4th Edition
 APIs monographs features
 What's new


2 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                       Pharmacopoeias

Pharmacopoeias may be:


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

 Regional                       e.g. European

 International The International Pharmacopoeia




  3 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                      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




 4 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
            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)




 5 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
         The 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


6 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
          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!



7 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
           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]



8 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                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"



 9 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
       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…


 10 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
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




11 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
  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…)


12 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
  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…)



13 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                  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.




14 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
       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

 15 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
       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


 16 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
      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

17 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
      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.



18 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                     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)



19 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                       Requirements 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




20 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
         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

21 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
         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


22 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                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…



23 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
24 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
            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/


 25 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                       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


26 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                          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




27 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                           Chemical name in                    Cross-reference
                                           accordance with IUPAC                      to
                                           nomenclature rules                  a general method




                                                     CAS number




                                                 Alternative tests




                                       International chemical
                Reagents               reference substance (ICRS)



28 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                    List of known and potential impurities that
                    have been shown to be controlled by this
                                   monograph




29 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
           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).




30 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
   APIs Monographs – Methods of analysis
General methods                                                         Monographs tests
 Physical and physicochemical                                          Where use general method
e.g. UV and IR spectrophotometry,                                          • Provide specific details or
   pH, chromatography                                                      • Modify

 Chemical                                                              Where no general method
e.g. general identification, limit tests,                                  • Provide full details
   sulfated ash, water

 Biological
e.g. sterility, bacterial endotoxins

 Materials of plant origin
e.g. ash, iodine value

  31 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
           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)
32 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
             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                             contamination
                    Lamivudine                                       Heparin sodium
                   alkyl mesilates                                 histamine-like substances
                    Nelfinavir mesilate                              Streptomycin sulfate



33 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                       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



34 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
       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



35 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
 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



36 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
 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


37 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
           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



38 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
    International Infrared Reference Spectra

 Established by WHO COLLABORATING CENTRE FOR CHEMICAL
  REFERENCE SUBSTANCES
 155 International Infrared Reference Spectra
    (125 published in                                100,0
                                                       90
                                                             W1 0 52 3 2 T




    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   2800   2400   2000   1800 1600   1400   1200   1000   800   600   400,0
                                                                                                            cm-1




39 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                  Newly adopted monographs -
                   42nd WHO Expert Committee

   •      Lumefantrine                                                   •     Zinc sulfate
   •      Artemether and lumefantrine                                    •     Zinc sulfate tablets,
          tablets                                                               paediatric
                                                                         •     Zinc sulfate oral solution,
   •      Rifampicin, isoniazid and
                                                                                paediatric
          ethambutol tablets
   •      Rifampicin and isoniazid                                       •     Magnesium sulfate injection
          dispersible tablets
   •      Rifampicin, isoniazid and
          pyrazinamide dispersible
          tablets


40 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                Newly adopted monographs -
               43rd WHO Expert Committee (1)

•   Artemether and Lumefantrine oral                                           •   Efavirenz capsules
    suspension                                                                 •   Efavirenz oral solution
•   Chloroquine sulfate oral solution                                          •   Emtricitabine
•   Quinine sulfate tablets                                                    •   Nevirapine
                                                                               •   Nevirapine oral
•   Cycloserine                                                                    suspension
•   Cycloserine capsules                                                       •   Nevirapine tablets
•   Ethambutol hydrochloride tablets                                           •   Zidovudine, Lamivudine
                                                                                   and Nevirapine tablets
•   Mebendazole
•   Oseltamivir phosphate
•   Chewable Mebendazole tablets


41 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                Newly adopted monographs -
               43rd WHO Expert Committee (2)

  •       Fludeoxyglucose (18F)                                         •      Sodium iodide (131I) injection
          injection                                                     •      Sodium iodide (131I) solution
  •       Gallium citrate (67Ga)                                        •      Sodium pertechnetate
          injection                                                            (99mTc) injection (fission)
  •       Thallous chloride (201Tl)                                     •      Sodium pertechnetate
          injection                                                            (99mTc) injection (non-fission)
  •       Iobenguane (123I) injection
  •       Technetium (99mTc)
          pentetate complex
          injection




42 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                     Work 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



43 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
           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)




44 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
         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




45 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
         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




46 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009
                                           Thank you !




47 | Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:111
posted:7/23/2011
language:English
pages:47