World Health Organization 17/04/2017 The International Pharmacopoeia Dr Herbert Schmidt Technologies, Standards and Norms

World Health Organization Outline 17/04/2017 The role of The International Pharmacopoeia in Public Health for WHO Member States for the WHO Prequalification Programme in setting global quality requirements for medicines added value of the capreomycin monographs

The International Pharmacopoeia contains analytical methods and specifications for active pharmaceutical ingredients (API) finished pharmaceutical products radiopharmaceuticals focuses on medicines Model List of Essential Medicines Invitations to submit EOI for product evaluation to PQTm WHO/UN specific disease programmes

WHO Model List of Essential Medicines World Health Organization WHO Model List of Essential Medicines 17/04/2017 Essential Medicines satisfy priority health care needs are selected with due regard to disease prevalence, evidence on efficacy and safety and comparative cost-effectiveness are listed on WHO Model List of Essential Medicines (EML), which guides the development of national and institutional EMLs guides the procurement and supply of medicines in the public sector, schemes that reimburse medicine costs, medicine donations, and local medicine production Role of The International Pharmacopoeia - provides public standards for medicines listed on the WHO EML

WHO Treatment Guidelines World Health Organization WHO Treatment Guidelines 17/04/2017 Treatment guidelines provide evidence-based and up to date treatment recommendations help WHO Member States to formulate their policies and strategies Role of The International Pharmacopoeia provides public standards for medicines listed in WHO Treatment Guidelines

Radiopharmaceuticals World Health Organization Radiopharmaceuticals 17/04/2017 The International Pharmacopoeia publishes monographs on radiopharmaceuticals developed in close collaboration with IAEA and EDQM existing monographs to be updated and additional new specifications for radiopharmaceuticals to be developed Role of The International Pharmacopoeia - assists Member States in their efforts to ascertain the quality of radiopharmaceuticals

The International Pharmacopoeia is ready to use “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.” is free for use by WHO Member States http://apps.who.int/phint/en/p/about/

The International Pharmacopoeia main areas of work medicines for maternal, newborn, child and adolescent health antimalarial medicines antiviral medicines including antiretrovirals antituberculosis medicines medicines for tropical diseases provides public standards for major public health needs Ph.Int. monographs are often the only publicly available compendial standards for priority medicines

The International Pharmacopoeia applies current international standards comply with harmonized regulatory standards (WHO, ICH, PDG) focus on technical aspects most relevant for developing countries Ph.Int. aims at global applicability of its methods/specifications for complex, technically demanding methods less sophisticated tests are given as an alternative, if equally satisfying rational use of International Chemical Reference substances (ICRS) in situ preparation of impurities for identification purposes quantification of impurities by comparing their responses with the response of the parent compound in a diluted sample solution along with the establishment of correction factors to compensate for differences in the responses of the impurity and the parent compound

The International Pharmacopoeia applies current international standards rational use of International Chemical Reference substances (ICRS) (continued) provision of International Infrared Reference Spectra (IIRS) for use in identification tests; provision of assay methods not requiring reference substances, like titrations and UV spectrophotometry using absorptivity values. These methods shall be provided as alternatives in particular to chromatographic assays in monographs for pharmaceutical substances. "These strategies shall be applied when, during the elaboration of the methods, evidence could be obtained that the intended measures are equally satisfying to conclusively demonstrate conformance to the applicable standards!"

World Health Organization Outline 17/04/2017 The role of The International Pharmacopoeia in Public Health for WHO Member States for the WHO Prequalification Programme for setting global quality requirements for medicines added value of the capreomycin monographs

Prequalification Team – Medicines World Health Organization Prequalification Team – Medicines 17/04/2017 PQ Programme works in close cooperation with national regulatory agencies and partner organizations assesses dossiers submitted for invited medicines and APIs (HIV/Aids, TB, MA, IN, RH, NTD) performs inspections of quality control laboratories, manufacturing and clinical sites builds capacity of staff from national regulatory authorities, QC laboratories, and from manufacturers

Prequalification Team – Medicines World Health Organization Prequalification Team – Medicines 17/04/2017 Key output list of prequalified products used by UN agencies (e.g. UNAIDS and UNICEF) to guide their procurement decisions tool for any organization involved in bulk purchasing of medicines

Prequalification Team – Medicines World Health Organization Prequalification Team – Medicines 17/04/2017 API/FPP has to meet the claimed compendial standard (Ph.Int., BP, Ph.Eur., JP, USP) or an in-house standard if applicant claims Ph. Int. standards monograph tests and limits should be included in dossier, but different tests or limits may be accepted provided they are equally satisfying and fully validated by the manufacturer If tested the product must comply with the Ph. Int. requirements requested limits may be tighter than the monograph limits Pharmacopoeial standards are publicly-available compliance specifications that allow for an independent check of the quality of a product at any time during its shelf-life. Although release specifications must be compatible with pharmacopoeial specifications, they may differ in several respects.

World Health Organization Ph. Int. Work Plan 2015/2016 17/04/2017 Setting priorities for monograph elaboration monographs for essential medicines listed in EOI 6th Invitation RH medicines (October 2014) 11th Invitation antimalarial medicines (October 2014) 12th Invitation HIV/AIDS, hepatitis B/C medicines (September 2014) 2nd Invitation influenza-specific antiviral medicines (June 2009) 12th Invitation antituberculosis medicines (December 2013) 3rd Invitation medicines against neglected tropical diseases (July 2013) 1st Invitation zink sulfate (November 2008) that have not yet been subject to a monograph published by another major pharmacopoeia USP 38; IP 2014 (incl. Addendum 2015), BP 2015, CP 2010, JP 16 will be developed with HIGH PRIORITY.

World Health Organization High Priorities 2015/2016 17/04/2017 ABACAVIR, EFAVIRENZ AND LAMIVUDINE TABLETS ABACAVIR, LAMIVUDINE AND NEVIRAPINE DISPERSIBLE TABLETS ARTEMETHER AND LUMEFANTRINE DISPERSIBLE TABLETS ARTENIMOL AND PIPERAQUINE PHOSPHATE DISPERSIBLE TABLETS ARTESUNATE AND AMODIAQUINE TABLETS ARTESUNATE AND MEFLOQUINE TABLETS ARTESUNATE AND PYRONARIDINE TABLETS ARTESUNATE RECTAL CAPSULES ATAZANAVIR AND RITONAVIR TABLETS DOLUTEGRAVIR TABLETS EFAVIRENZ, LAMIVUDINE AND TENOFOVIR TABLETS ENTECAVIR ORAL SOLUTION ENTECAVIR SCORED TABLETS ESTRADIOL VALERATE AND NORETHISTERONE ENANTATE INJECTION

World Health Organization High Priorities 2015/2016 17/04/2017 ETRAVIRINE TABLETS FLUCYTOSINE SLOW RELEASE TABLETS LAMIVUDINE AND TENOFOVIR TABLETS LINEZOLID ORAL SUSPENSION MOXIFLOXACIN TABLETS NORETHISTERONE ENANTATE INJECTION NORETHISTERONE TABLETS P-AMINOSALICYLIC ACID GRANULES FOR ORAL SOLUTION PROTIONAMIDE TABLETS PYRAZINAMIDE DISPERSIBLE TABLETS RALTEGRAVIR TABLETS RIBAVIRIN SYRUP RITONAVIR ORAL SOLUTION SIMEPREVIR CAPSULE SOFOSBUVIR TABLET TERIZIDONE CAPSULES TERIZIDONE TABLETS ZANAMIVIR POWDER FOR INHALATION

World Health Organization Outline 17/04/2017 The role of The International Pharmacopoeia in Public Health for WHO Member States for the WHO Prequalification Programme for setting global quality requirements for medicines added value provided by the capreomycin monographs

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Ph. Int. monographs Capreomycin sulfate Capreomycin injection Capreomycin to treat MDR-TB 9 Million people fell ill with TB; 1.5 Million died (in 2013) 450 000 patients developed MDR-TB TB is a leading killer of HIV-positive people causing one fourth of all HIV-related deaths. access to quality assured TB medicines is essential

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Adverse reactions nephrotoxicity 20–25% including proteinuria, reduced creatinine clearance, and depletion of potassium and magnesium ototoxicity (hearing loss) occurs more often among the elderly or those with pre-existing renal impairment and vestibular toxicity loss is generally not reversible upon discontinuation of therapy For more information see Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Do the impurities make a difference in the safety of the capreomycin? Lee et al., International Journal of Antimicrobial Agents 22 (2003) 81-83 Single dose toxicity in mice LD50 Capacin: 949 mg/kg Capastat: 676 mg/kg conclusion: removal of impurities decreased the toxicity of capreomycin without affecting its efficacy

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 First-ever pharmacopoeial test for related substances each impurities ≤ 2% only one impurity between 1 and 2% sum of all impurities ≤ 7% typical chromatogram showing the separation of the four main components (6, 8, 10 and 11) and related substances

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Comprehensive description produced by fermentation mixture of several structurally related components Ph. Int. provides: comprehensive information on structures, formulas, relative molecular weights and chemical names for all four major components information facilitates production and registration

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Alternative options for identity test Users may choose the option that can be performed using the equipment that is available in their laboratories Test Option 1 Option 2 A IR Spectrophotometry ■ B Thin-layer Chromatography C Absorption spectrum of solution in hydrochloric acid D Absorption spectrum of solution in sodium hydroxide E General identification test for sulfates

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Quantification of content other pharmacopoeias describe microbiological assays where the content is measured through the inhibitory effect on susceptible microorganisms Ph. Int. assay based on the same HPLC method used as the related substance test saves time and resources as the laboratory can perform two tests with the same analytical system

Capreomycin monographs: Added value for WHO Member States World Health Organization Capreomycin monographs: Added value for WHO Member States 17/04/2017 Suitable and easy to use reference substance Capreomycin RS is hygroscopic absorbs water from the atmosphere, difficult to weigh on analytical balance solution with defined concentration of reference substance will be lyophilized user has to add defined volume of solvent to the lyophilized powder Capreomycin RS is suitable for the intended use Definition API: "It contains not less than 70.0% of capreomycin, calculated with reference to the dried substance and taking into account the sum of capreomycin IA, IB, IIA and IIB. The contents of capreomycin IA and IB is not less than 90.0% of the sum of capreomycin IA, IB, IIA and IIB." leaflet of RS will contain the information “mg of component IA, IB, IIA and IIB (base)/vial”

World Health Organization Summary 17/04/2017 The International Pharmacopoeia provides publicly-available standards which allow for an independent check of the quality of a product at any time during its shelf-life. focuses on medicines listed on Model List of Essential Medicines Invitations to submit EOI for product evaluation to PQP WHO/UN specific disease programmes furnishes norms and standards that underpin the PQ programme contribute to the vision of affordable, safe, efficacious and good quality medicines for everyone, everywhere

Thank you very much for your kind attention ! World Health Organization 17/04/2017 Thank you very much for your kind attention !