The importance of the Regulatory Starting Material or RSM in regulatory strategy has gained significant attention over the past few years. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have weighed in on the topic, and have come to definitive conclusions concerning the manufacture and quality expectations of the RSM. Regulators have published guidances that underscore the importance of incorporating suppliers who possess strong analytical and quality infrastructure, and a more sophisticated supplier is needed to meet the new stringent requirements.
The FDA defines an RSM as follows: ‘A starting material is incorporated as a significant structural fragment into the structure of the drug substance.’ Significant structural fragment in this context is intended to distinguish starting materials from reagents, solvents or other raw materials. The applicant should provide a justification for how each proposed starting material is appropriate, based on:
- The ability of analytical procedures to detect impurities in the starting material;
- The fate and purge of those impurities and their derivatives in subsequent processing steps; and
- How the proposed specification for each starting material will contribute to the control strategy.
‘The relationship between risk and number of steps from the end of the manufacturing process is the result of two factors, one concerning the physical properties of the drug substance and the other concerning the formation, fate, and purge of impurities.’1
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