Public Standards for Artemisinin and Derivatives in · Public Standards for Artemisinin and Derivatives in The International Pharmacopoeia ... British Pharmacopoeia, Chinese

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



– 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



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


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






active ingredients


– Conclusion

Topics

Dr Herbert Schmidt


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


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


Dr Herbert Schmidt






active ingredients


– Conclusion

Topics

Dr Herbert Schmidt


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


Dr Herbert Schmidt


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


Dr Herbert Schmidt


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


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


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


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


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


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






active ingredients


– Conclusion

Topics

Dr Herbert Schmidt


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


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)


Dr Herbert Schmidt


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


Dr Herbert Schmidt






active ingredients


– Conclusion

Topics

Dr Herbert Schmidt


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


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


– 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



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/

Dr Herbert Schmidt


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


Dr Herbert Schmidt


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


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


Dr Herbert Schmidt


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


Dr Herbert Schmidt


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)


Dr Herbert Schmidt


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


Dr Herbert Schmidt


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)


Dr Herbert Schmidt


Dr Herbert Schmidt


Dr Herbert Schmidt


WHO TRS 981 (2012)

Dr Herbert Schmidt


Documents

Public Standards for Artemisinin and Derivatives in · Public Standards for Artemisinin and Derivatives in The International Pharmacopoeia ... British Pharmacopoeia, Chinese