Reflection paper on the requirements for
selection and justification of starting materials for the manufacture of
chemical active substances
The EMA
has revised and re-issued its reflection paper on API starting materials in
order to further clarify what information firms should supply. The paper
centers on the following problem statement:
Disagreements
between applicants and quality assessors on the suitability of proposed
starting materials have become more frequent in recent times. This suggests
that the current guidelines, intentionally high level to allow application to
the wide range of chemical syntheses submitted to regulatory authorities, are
open to interpretation. Furthermore, it is increasingly common for applicants to
propose very short synthetic routes with complex custom-synthesized starting
materials. Another trend is for some, or all, of the active substance
manufacture to be outsourced to third parties. The use of external sources for
any steps in a manufacturing process may lead to a higher degree of risk to quality
of the active substance than would be expected were the full manufacturing
process to be carried out by the applicant or a single active substance
manufacturer alone. This document strives to expand on some of the points in
ICH Q11 in order to harmonise opinions between assessors and clarify the
requirements for applicants.
Additionally,
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.4 A detailed description of the manufacturing process of the active
substance is required, along with a flow chart of transformations employed to
synthesize starting materials including all solvents, reagents, catalysts and
processing aids used, in order to facilitate a proper assessment. Since steps
deemed critical should be carried out under Good Manufacturing Practice (GMP),
an appraisal of the criticality of all transformations in the full synthetic
route on the quality of the active substance is needed. The description of the manufacturing
process should be sufficiently detailed to demonstrate that the process and its
associated control strategy will consistently provide active substance of
satisfactory quality. Starting materials can only be justified once the
criticality of all steps has been discussed. Often, starting materials are
selected and then only subsequent steps are discussed. This is not sufficient.
A scheme of synthetic steps carried out to synthesize the proposed
non-commodity starting materials should be provided as part of the justification
of starting material selection.
Posted by Dr. Tim Sandle