Definition of Active Pharmaceutical Ingredient WHO

Working document QAS/11.426/Rev.
1
July 2011
RESTRICTED
DEFINITION OF ACTIVE PHARMACEUTICAL

INGREDIENT
REVISED DRAFT FOR COMMENT
Should you have any comments on the attached revision, please send these to
Dr S. Kopp, Manager, Medicines Quality Assurance Programme, Quality Assurance and
Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland;
fax: (+41 22) 791 4730 or e-mails: kopps@who.int with a copy to Ms Marie Gaspard
(gaspardm@who.int) by 10 September 2011.
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Working document QAS/11.426/Rev.1
page 2
SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/11.426

Definition of active pharmaceutical ingredient
Date
First draft prepared by Professor T.G. June 2011

Dekker for the Prequalification Programme
Discussion held during the Informal WHO 12-14 July 2011

Consultation on Specifications for The
International Pharmacopoeia and quality
control laboratory issues
Revised draft circulated for comments to August 2011

the WHO Expert Advisory Panel on the
International Pharmacopoeia
Consolidation of comments September 2011
Discussion at forty-sixth meeting of the 10-14 October 2011

WHO Expert Committee on Specifications
for Pharmaceutical Preparations
Further follow-up action as required

page 3
DEFINITION OF ACTIVE PHARMACEUTICAL INGREDIENT
Background
In many WHO guidelines the following definition for an active pharmaceutical ingredient
(API) (in the singular) is found under the Glossary (for instance it appears three times in
the recently published WHO Technical Report Series, No. 961):
"active pharmaceutical ingredient (API)
Any substance or combination of substances used in a finished pharmaceutical
product (FPP), intended to furnish pharmacological activity or to otherwise have
direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or
to have direct effect in restoring, correcting or modifying physiological functions in
human beings."
This definition implies, for example, that commercially available premixes of APIs (such
as the popular amoxicillin + clavulanic acid premix) can be regarded as an API, which is
not correct. This definition thus may lead to misinterpretation.
Proposal
It is proposed that the above definition be changed by deleting “or mixture of
substances”, in accordance with the definition already appearing in WHO Technical
Report Series, No. 961, Annex 10 (Procedure for prequalification of pharmaceutical
products):
"active pharmaceutical ingredient (API)
A substance used in a finished pharmaceutical product (FPP), intended to furnish
pharmacological activity or to otherwise have direct effect in the diagnosis, cure,
mitigation, treatment or prevention of disease, or to have direct effect in restoring,
correcting or modifying physiological functions in human beings."
If this is agreed to, it should be applicable to future WHO documentation or any current
documentation whenever revised.
Motivation
The moment an API is mixed with another API, or with an excipient, it is no more
considered an API. This is best illustrated by the guidelines mentioned below.
The current draft Guideline on submission of documentation for a multisource (generic)
finished pharmaceutical product (FPP): quality part (QAS/10.373/Rev.1), line 1944,
reads:
"For a mixture of an API with an excipient, the blending of the API with the
excipient is considered to be the first step in the manufacture of the final product
and, therefore, the mixture does not fall under the definition of an API. The
page 4
only exceptions are in the cases where the API cannot exist on its own. Similarly,
for a mixture of APIs, the blending of the APIs is considered to be the first step in
the manufacture of the final product. Sites for such manufacturing steps should be
included in this section."
Exceptions referred to in the above paragraph are rare and only a few are found in the
PhEur, for instance Moxidectin and Streptomycin Sulphate (“stabilizers may be added”).
EMA’s Note for guidance on start of shelf-life of the finished dosage form
(CPMP/QWP/072/96) states (biologicals excluded):
"The date of production of a batch is defined as the date that the first step is
performed involving combination of the active ingredient with other ingredients.
For medicinal products consisting of a single active ingredient filled into a
container, the initial date of the filling operation is taken as the date of production."
It is clear from the above that the definition of the API should only be with respect to a
single substance and should exclude “combination of substances”.
[Note from the secretariat: The proposed change was supported during the informal
consultation on specifications for medicines and quality control laboratory issues held on
12-13 July 2011.]
***

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Working document QAS/11.426/Rev.

DEFINITION OF ACTIVE PHARMACEUTICAL

REVISED DRAFT FOR COMMENT

SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/11.426

First draft prepared by Professor T.G. June 2011

Discussion held during the Informal WHO 12-14 July 2011

Revised draft circulated for comments to August 2011

Consolidation of comments September 2011

Discussion at forty-sixth meeting of the 10-14 October 2011

Further follow-up action as required

DEFINITION OF ACTIVE PHARMACEUTICAL INGREDIENT

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