1. The International Pharmacopoeia Overview Caroline Mendy Technical Officer - Quality Assurance and Safety: Medicines Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009

2. 2 |2 | The International Pharmacopoeia – Ph. Int Scope WHO Consultative procedure 4 th Edition APIs monographs features What's new

3. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 3 |3 | Pharmacopoeias Pharmacopoeias may be: National e.g. Brazilian, British, Chinese, Indian, Japanese, Mexican, Spanish, United States Regional e.g. European International The International Pharmacopoeia

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

5. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 5 |5 | 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)

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

7. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 7 |7 | 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!

8. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 8 |8 | 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]

9. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 9 |9 | 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"

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

11. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 11 | 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

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

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

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

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

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

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

18. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 18 | … 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. WHO Procedure for the preparation of drug Quality Control specifications (4) …..or why it takes so long….

19. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 19 | 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)

20. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 20 | Requirements for samples

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

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

23. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 23 | 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…

24. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 24 |

25. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 25 | The International Pharmacopoeia  current: 4 th Edition + 1 st Supplement  Consolidated in : 2 Volumes - Vol. 1: pharmaceutical substances (A-O) - Vol. 2: pharmaceutical substances (P-X) + dosage forms + radiopharmaceuticals + methods of analysis + reagents 1 st Supplement - new requirements and revisions Available in Publication, CD-ROM and Online http://www.who.int/medicines/publications/pharmacopoeia/overview/

26. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 26 | 4 th Edition – (1) 4 th 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

27. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 27 | 4 th 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

28. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 28 | CAS number Cross-reference to a general method Cross-reference to a general method Alternative tests Chemical name in accordance with IUPAC nomenclature rules International chemical reference substance (ICRS) Reagents

29. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 29 | List of known and potential impurities that have been shown to be controlled by this monograph

30. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 30 | 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).

31. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 31 | APIs Monographs – Methods of analysis General methods Physical and physicochemical e.g. UV and IR spectrophotometry, pH, chromatography Chemical e.g. general identification, limit tests, sulfated ash, water Biological e.g. sterility, bacterial endotoxins Materials of plant origin e.g. ash, iodine value Monographs tests Where use general method Provide specific details or Modify Where no general method Provide full details

32. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 32 | 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 )

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

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

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

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

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

38. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 38 | 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

39. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 39 | International Infrared Reference Spectra  Established by WHO COLLABORATING CENTRE FOR CHEMICAL REFERENCE SUBSTANCES  155 International Infrared Reference Spectra (125 published in Ph.Int 4 th Ed. Suppl. 1) IR-spectrum of lamivudine

40. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 40 | Newly adopted monographs - 42 nd 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

41. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 41 | Newly adopted monographs - 43 rd 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

42. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 42 | Newly adopted monographs - 43 rd WHO Expert Committee (2) Fludeoxyglucose ( 18 F) injection Gallium citrate ( 67 Ga) injection Thallous chloride ( 201 Tl) injection Iobenguane ( 123 I) injection Technetium ( 99m Tc) pentetate complex injection Sodium iodide ( 131 I) injection Sodium iodide ( 131 I) solution Sodium pertechnetate ( 99m Tc) injection (fission) Sodium pertechnetate ( 99m Tc) injection (non-fission)

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

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

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

46. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 46 | 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

47. Quality of Active Pharmaceutical Ingredients, Hyderabad, September 2009 47 | Thank you !