Public Standards for Artemisinin and Derivatives in · Public Standards for Artemisinin and...
Transcript of Public Standards for Artemisinin and Derivatives in · Public Standards for Artemisinin and...
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 1 |
Public Standards for
Artemisinin and Derivatives in
The International Pharmacopoeia
Dr Herbert Schmidt
Technologies, Standards and Norms
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 2 |
The International Pharmacopoeia
– Scope and main features
– Process of developing monographs
– Standards for ACT medicines and their
active ingredients
– Upcoming monographs and ICRS
– Conclusion
Topics
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 3 |
The International Pharmacopoeia
current 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
– ultimate aim is to promote affordable, safe, efficacious and good
quality medicines
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 4 |
Prequalification of Medicines
– works in close cooperation with
national regulatory agencies and
partner organizations
– evaluates medicines, APIs and
quality control laboratories
– performs inspections of
manufacturing and clinical sites
– builds capacity of staff from national regulatory authorities, QC
laboratories, and from manufacturers or other private companies
– facilitates access to medicines that meet unified standards of
quality, safety and efficacy
Prequalification Team – Medicines
Role of The International Pharmacopoeia - furnishes public standards that underpins the PQ Programme
- promotes affordable, safe, efficacious and good quality medicines
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 5 |
The International Pharmacopoeia
– Scope and main features
– Process of developing monographs
– Standards for ACT medicines and their
active ingredients
– Upcoming monographs and ICRS
– Conclusion
Topics
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 6 |
Process designed
– to ensure wide consultation and
transparency
– to ensure that texts are based on
current scientific knowledge
– to enable continuous revision
– to ensure revisions and new texts are
available in a timely manner
Publication
– WHO Technical Report Series, 970,
Annex 1
Monograph Development Process
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 7 |
Main features of the process
– is based on the work and decisions of the WHO Expert
Committee on Specifications for Pharmaceutical Preparations
(ECSPP)
• texts and reference standards are approved/revised/suppressed by EC
– is governed by publicly available rules and procedures
• "schedule for the adoption process" outlining the development history is
included in each working document
– seeks feedback of all interested parties
– applies conflict of interest and confidentiality rules
Monograph Development Process
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 8 |
The International Pharmacopoeia
– Scope and main features
– Process of developing monographs
– Standards for ACT medicines and their
active ingredients
– Upcoming monographs and ICRS
– Conclusion
Topics
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 9 |
10 monographs for ACTs finished products and fixed dose
combinations
– Artenimol tablets
– Artemether and lumefantrine oral suspension / tablets
– Artemether capsules / injection / tablets
– Artemotil injection / tablets
– Artesunate for injection / tablets
5 monographs active ingredients for ACTs
– Artemether, Artemisinin, Artemotil, Artenimol, Artesunate
The International Pharmacopoeia
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 10 |
new/revised ACT specifications in the 4th supplement
(online since 20 August 2014)
– Monograph on Artemisinin (Revision)
– Recommendations for quality requirements when plant-derived
artemisinin is used as a starting material in the production of
antimalarial active pharmaceutical ingredients
• reprint from the WHO Technical Report Series 970, 2011
– Artemisinin ICRS
The International Pharmacopoeia
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 11 |
Same methods can now be applied to test Artemisinin API
and starting material, only the limits are different
Comparison of Artemisinin requirements
Parameter
Artemisinin
API
3rd supplement
Artemisinin
API
4th supplement
Artemisinin
Starting
Material (SM)
Identity IR or other tests IR or other tests IR
Content
97.0% to 102.0%
(assay A: HPLC)
98.0% to 102.0%
(assay B: UV absorbance)
97.0% to 102.0%
(HPLC)
95.0% to 102.0%
(HPLC)
Related substances Gradient HPLC Isocratic HPLC Isocratic HPLC
Sulfated ash NMT 1.0 mg/g NMT 1.0 mg/g -
LOD NMT 5.0 mg/g NMT 5.0 mg/g NMT 10.0 mg/g
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 12 |
Related
substances
Artemisinin API
3rd supplement
Artemisinin API
4th supplement
Artemisinin
Starting
Material
none > 0.5% (nominal) - -
one > 0.25% (nominal) - -
rest ≤ 0.25% (nominal) - -
total ≤ 1,0% (nominal) - -
artemisitene - ≤ 0.15% (real) ≤ 0.2% (real)
9-epi-artemisinin - ≤ 0.3% (real) ≤ 1.0% (real)
rest - ≤ 0.15% (nominal) ≤ 0.5% (nominal)
total - ≤ 1.0%
(nominal and real)
≤ 3.0%
(nominal and real)
Comparison of Artemisinin requirements
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 13 |
nominal limits for impurities – a dilution of the test solution is used as the reference solution
– example
• test solution is diluted by the factor 100
• to test for nominal limit of 1% both solutions are analyzed
• the peak area of the impurity in the test solution should not be greater than the peak area of the main peak in the diluted solution
real limits for impurities – a dilution of the test solution is used as the reference solution
and correction factors are used to compensate for different response factors or
– a solution of a reference substance of the impurity is used
Difference between real and nominal limits
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 14 |
different response factors of artemisinin and artemisitene
– "This translates to a 37x larger response factor for artemisitene
relative to artemisinin. At 215 nm this becomes 43x." (Ref. 1)
revised tests for related substances
– “... the area of any peak corresponding to impurity A, when
multiplied by a correction factor of 0.027, is not greater than ...”
Difference between real and nominal limits
Artemisinin Artemisitene
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 15 |
intended to be used according to
– the monograph on Artemisinin
– the specification for Artemisinin used as a starting material
– other monographs in The International Pharmacopoeia
available from WHO custodian centre for ICRS (EDQM)
– price of 70 € per vial plus delivery charges
– more info on EDQM website
qualitative, quantitative and system suitability standard
– assigned content: 99.8% m/m of artemisinin
Artemisinin ICRS
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 16 |
use as a system suitability standard
– contains artemisitene to enable user to evaluate the suitability of
the analytical system in use
• "The test is not valid unless the resolution factor between the peaks due
to impurity A and artemisinin is at least 4."
Artemisinin ICRS
Artemisinin Artemisitene
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 17 |
The International Pharmacopoeia
– Scope and main features
– Process of developing monographs
– Standards for ACT medicines and their
active ingredients
– Upcoming monographs and ICRS
– Conclusion
Topics
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 18 |
Survey to identity monographs on medicines to be
developed with priority
– Which of the medicines listed in
• Sections of the EML covered by the PQ Progamme
(Medicines for maternal, newborn, child and adolescent health;
Antimalarial medicines; Antiviral medicines including antiretrovirals;
Antituberculosis medicines; Medicines for tropical diseases)
• Medicines for UN Commission on Life-saving commodities
– are not yet subject to a monograph by a major pharmacopoeia?
• The International Pharmacopoeia, British Pharmacopoeia, Chinese
Pharmacopoeia, Indian Pharmacopoeia, United States Pharmacopeia
Upcoming monographs and ICRS
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 19 |
Identified ACT medicines currently lacking a public
standard
– ARTEMETHER AND LUMEFANTRINE DISPERSIBLE
TABLETS (HIGH PRIORITY)
– ARTENIMOL AND PIPERAQUINE PHOSPHATE TABLETS
(UNDER ELABORATION)
– ARTESUNATE AND AMODIAQUINE TABLETS (HIGH
PRIORITY)
– Artesunate and mefloquine tablets (medium priority)
– ARTESUNATE AND PYRONARIDINE TABLETS (HIGH
PRIORITY)
– ARTESUNATE RECTAL CAPSULES (HIGH PRIORITY)
Upcoming monographs and ICRS
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 20 |
revision of existing monographs
– tests for related substances in some API monographs are under
investigation to evaluate if they reflect current regulatory practice
ICRS
– α-Artemether ICRS
• to be used in artemether related substance test according to the
monographs on Artemether and lumefantrine tablets/oral suspension
• distribution may start November/December
Upcoming monographs and ICRS
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 21 |
The International Pharmacopoeia
– Scope and main features
– Process of developing monographs
– Standards for ACT medicines and their
active ingredients
– Upcoming monographs and ICRS
– Conclusion
Topics
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 22 |
How can you contribute to WHO standard setting
activities?
– by providing comments on monographs sent out for consultation
• http://www.who.int/medicines/areas/quality_safety/quality_assurance/proje
cts/en/
– by providing specifications and test methods for medicines and
active pharmaceutical ingredients (including samples of the
products)
– by donating candidate material for the establishment of
International Chemical Reference Substances
Support provided in the past is greatly acknowledged
Conclusion
Thank you very much
for your kind attention !
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 24 |
1. Stringham RW, Pennell M, Cabri W et al., Identification of
impurities in artemisinin, their behavior in high performance
liquid chromatography and implications for the quality of derived
anti-malarial drugs; Journal of Chromatography A, 1218 (2011)
6838-6842
References
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 25 |
– ACT Artemisinin-based combination therapy
– API Active pharmaceutical ingredient
– EDQM European Directorate for the Quality of Medicines Healthcare
– EML Model list of essential medicines
– EOI Expression of interest
– MS Member States
– mPQP Prequalification of medicines programme
– PQ Prequalification
– Ph.Int. The International Pharmacopoeia
– QC Quality control
– SSFFC Substandard/spurious/falsely-labelled/falsified/ counterfeit medical products
Abbreviations
Backup
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 27 |
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/
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 28 |
Phase 1
– identify pharmaceutical products for which QC specifications
need to be developed
Phase 2 - 3
– contact manufacturers for provision of QC specifications and
samples
Phase 4 - 7
– identify and contact QC laboratory for collaboration in the project
and making the necessary arrangements with them. Laboratory
will perform development, testing and validation
Monograph Development Process
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 29 |
Phase 8
– draft specification is mailed to Expert Advisory Panel and
specialists for comment and is provided on the WHO web site
Phase 9 and 10
– contact collaborating manufacturers to ascertain the availability
of candidate material to establish International Chemical
Reference Substances (ICRS)
– support of WHO host organization responsible for the
establishment of ICRS (EDQM)
Monograph development
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 30 |
Phase 11 - 13
– discuss comments received during the global consultative
process
• with contract laboratories and WHO collaborating centres, conduct
additional laboratory testings, if necessary
• at an informal consultation with experts and specialists
Phase 14
– recirculate revised draft
Phase 15
– repeat phase 8-15 until the draft is suitable for adoption
Monograph development
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 31 |
Phase 16
– present draft to ECSPP for possible formal adoption. If not
adopted repeat phase 8 to 14 as often as necessary.
Phase 17 to 19
– include agreed changes and confirm amended text by
correspondence with relevant experts
Phase 20 and 21
– publish adopted text in The International Pharmacopoeia and/or
Ph. Int. web site
Monograph development
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 32 |
Partners
– within WHO
• Prequalification Team – Medicines
• WHO disease programmes (Stop TB, Roll-Back Malaria, HIV/AIDS,
Neglected Tropical Diseases, etc.)
• Secretariat of the EC on the Selection and Use of Essential Medicines
– regulatory bodies
• national regulatory authorities
• regional or interregional regulatory groups – Association of Southeast Asian Nations (ASEAN)
– Pan American Network for Drug Regulatory Harmonization (PANDRH)
– International Conference on Harmonization (ICH)
Monograph development
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 33 |
Partners
– organizations and associations
• International organizations: – UN Commission on Life-Saving Commodities
– UNAIDS, UNICEF, IAEA, World Bank
• international professional and other associations, non-state actors – IFPMA-IGPA-WSMI, IPEC, FIP, WMA, MSF
– standard-setting bodies…
• pharmacopoeia commissions and secretariats – e.g. Brazilian, BP, IP, JP, Ph.Eur, Ch.P, USP, and PDG
Monograph development
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 34 |
Partners
– experts
• WHO Expert Panel on The International Pharmacopoeia and
Pharmaceutical Preparations (official nomination process)
• specialists from all areas for specific projects (regulatory, university,
industry…)
– laboratories
• national or regional quality control laboratories
• WHO Collaborating Centres (official nomination process)
Monograph development
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 35 |
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 36 |
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 37 |
WHO TRS 981 (2012)
Dr Herbert Schmidt
Artemisinin Conference, Guangzhou, 23 and 24 September 2014 38 |