- 4 декабря 2014
- API, GMP, ICH Q11, MCB, WCB, активный фармацевтический ингредиент, АФИ, банки клеток, Главный банк клеток, действующее вещество, исходное сырье, исходное сырье для производства действующего вещества, клеточные субстраты, НПП, Рабочий банк клеток,
According to the Part II: Basic Requirements for Active Substances used as Starting Materials of the EU GMP Guide, the manufacturer should designate and document the rationale for the point at which production of the active substance begins.
This document defines an “Active Substance Starting Material” as ‘a raw material, intermediate, or an active substance that is used in the production of an active substance and that is incorporated as a significant structural fragment into the structure of the active substance. An Active Substance Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. Active Substance Starting Materials normally have defined chemical properties and structure’.
For synthetic processes, production of the active substance begins at the point at which „Active Substance Starting Materials” are entered into the process. For other processes (e.g. fermentation, extraction, purification, etc.), a designation of the active substance production starting point should be established on a case-by-case basis.
Why is the designation of the active substance production starting point so important?
From this point on, appropriate GMP as defined in the Part II: Basic Requirements for Active Substances used as Starting Materials of the EU GMP Guide should be applied to these intermediate and/or active substance manufacturing steps.
According to revised Chapter 5: Production of the EU GMP Guide, supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified.
A selection of starting materials and source materials was widely described in ICH Q11 Guideline on development and manufacture of drug substances (chemical entities and biotechnological/biological entities).
Some general principles which should be considered when selecting starting materials and source materials are given below (according to ICH Q11):
- for synthetic drug substances
- adequate controls on the drug substance and drug substance manufacturing process (including appropriate controls for impurities)
- a starting material should be a substance of defined chemical properties and structure
- a starting material is incorporated as a significant structural fragment into the structure of the drug substance
- for semi-synthetic drug substances (where the structural constituents have been introduced by a combination of chemical synthesis and elements of biological origin (e.g., obtained from fermentation or by extraction from botanical material))
- the manufacturing process might be described starting from the source material (microorganism or botanical material)
- isolated intermediate can also be proposed as the starting material (under some conditions)
- for biotechnological/biological drug substances (according to ICH Q5A, Q5B, and Q5D guidelines)
- cell banks are the starting point for manufacture of biotechnological drug substances and some biological drug substances (cell banks should be well defined, characterised and qualified; the concept of a two-tiered cell bank, in which the Master Cell Bank (MCB) which is used to generate Working Cell Banks (WCBs), is generally accepted as the most practical approach to providing a supply of cell substrate for continued manufacture of the product; with reference to viral safety – thorough characterisation/screening of cell substrate starting material in order to identify which, if any, viral contaminants are present is required; it should be pointed out here that the characterisation and testing of banked cell substrates is a critical component of the control of biotechnological and biological products).
It seemed that broadly described considerations related to the selection of starting/source materials will help applicants in this matter but reality is quite different. It was noted, that recently disagreements between applicants and quality assessors on the suitability of proposed starting materials have become more frequent because of misunderstandings and open interpretation of the statements of aforementioned section of ICH Q11 guideline.
To clarify some of the expectations of EU competent authorities arising from the guidance found in ICH Q11 regarding the information to be submitted in marketing authorisation dossiers to justify the selection of starting materials, EMA published a document entitled Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances. It relates to synthetic and semi-synthetic drug substances. This document should harmonise opinions between assessors and clarify the requirements for applicants.
Some examples of deficiencies found by assessors are presented below:
- proposing very short synthetic routes with complex custom-synthesized starting materials
- multiple synthetic transformations carried out in one vessel without intermediate isolations (“one pot reactions”)
- the term “significant structural fragment” is frequently misinterpreted by applicants as meaning structural proximity to the active substance
- statements from applicants/manufacturers such as “we commit to carrying out manufacture of starting materials to GMP and are willing to be inspected” are not acceptable since production of the API starting material is currently excluded from application of the EU GMP Guide
- a statement that a material is commercially available may not be considered sufficient to justify it as a starting material without additional supporting information
- the information submitted by applicants or Active Substance Master File (ASMF) holders to justify the selection of starting materials and their proposed specifications is often insufficient to allow adequate assessment of suitability.
It is important to add here that similar problems related to staring materials were found by EDQM after first assessment of new applications for Certificates of Suitability (CEP) and are reported in the document entitled Top ten deficiencies New Applications for Certificates of Suitability.
Ranking of deficiencies related to staring materials and found by EDQM assessors are presented below:
- absence of discussion on the carry-over of impurities/by-products from key materials in the process (starting materials, intermediates)
- proposed starting material not accepted
- absence of comparison of the quality of the final substance obtained with starting materials from different suppliers
- incomplete specifications for the declared starting materials.
Examples of possible implications caused by the inappropriate selection and justification of starting material:
- redefinition of the starting material further back in the synthesis
- providing updated CTD (Common Technical Document) sections
- delay in registration procedure.
We cordially invite everyone who is interested in active substance (API) development, manufacture and information required to be provided in Module 3 of Common Technical Document (CTD) sections 3.2.S.2.2 – 3.2.S.2.6 to participate in a planned open training. Please check back later for details related to the date, place and programme (under Open trainings).
The training course is also available for companies as in-house training.