dr herbert schmidt quality workshop, copenhagen, 27 may 2015 1 |1 | the international pharmacopoeia...

Dr Herbert SchmidtQuality Workshop, Copenhagen, 27 May 2015

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The International Pharmacopoeia

Dr Herbert SchmidtTechnologies, Standards and Norms


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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

Outline


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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



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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

WHO Model List of Essential Medicines

Role of The International Pharmacopoeia -provides public standards for medicines listed on the WHO EML


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Treatment guidelines– provide evidence-based and up to date

treatment recommendations – help WHO Member States to formulate

their policies and strategies

WHO Treatment Guidelines

Role of The International Pharmacopoeiaprovides public standards for medicines listed in WHO Treatment Guidelines


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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

Radiopharmaceuticals

Role of The International Pharmacopoeia- assists Member States in their efforts to ascertain the quality of radiopharmaceuticals


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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/

http://apps.who.int/phint/en/p/about/


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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


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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


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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!"


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– 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

Outline


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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


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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



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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.



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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.

Ph. Int. Work Plan 2015/2016


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High Priorities 2015/2016

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


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High Priorities 2015/2016

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


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– 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

Outline


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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


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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


http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf?ua=1







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Do the impurities make a difference in the safety of the capreomycin?

– Lee et al., International Journal ofAntimicrobial Agents 22 (2003) 81-83• Single dose toxicity in mice• LD50

– Capacin: 949 mg/kg– Capastat: 676 mg/kg

• conclusion: removal of impuritiesdecreased the toxicity of capreomycinwithout affecting its efficacy



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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



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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



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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 ■ ■


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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



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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”



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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

Summary

Thank you very muchfor your kind attention !

dr herbert schmidt quality workshop, copenhagen, 27 may 2015 1 |1 | the international pharmacopoeia...

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