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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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!"

11. 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

12. 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

13. 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

14. 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.

15. 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.

16. 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

17. 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

18. 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

19. 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)
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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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”

27. 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

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