CRED Getting the CMC Dossier Right 2024

28/08/2024

Starting Materials: Impact and Enough

Two key considerations: Impact to DS impurity profile and enough GMP to provide regulatory oversight and assurance against cross contamination. ICH Q11 Q&A provides clarification

First, identify which steps impact the impurity profile of the drug substance. These should be in Section 3.2.S.2.2

● Definition of impact: – For non-mutagenic impurities, the ICH Q3A identification threshold serves to identify the level above which the impurity impacts the drug substance – For mutagenic impurities, 30% of the ICH M7 acceptable limit serves to identify the level above which the impurity impacts the drug substance (unless ICH S9 applies) – Exceptions for “persistent” impurities (which can be normal, chiral and/or mutagenic) Then, consider if the step immediately upstream need to be carefully controlled (with regards to impact to DS) – If yes, redefine SM If these considerations lead to only a small number of chemical transformation steps, then to mitigate the risks associated with contamination or future changes to the synthetic route, one or more steps would generally be added in Section 3.2.S.2.2 of the CTD

The role of the control strategy in mitigating risks from changes will also be a consideration

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Starting Materials: In-depth Impurity Knowledge is Required to Identify SMs

To apply the general principles, sufficient knowledge of the manufacturing process and understanding of the origin, fate and purge of impurities is necessary before defining the SMs. This can include:

• Understanding of the origin of impurities that impact the drug substance

• Understanding of how impurities are generated and removed during the manufacturing process

• Evaluation of the risk of carryover of any mutagenic materials into the drug substance (incl nitrosamines)

• Understanding of the impact of variability of the operating conditions on the DS CQAs

The availability of this critical information may drive the value and risk of seeking regulatory input on the SM selection ahead of the submission

Starting materials that are commercially available and used in other (non-pharmaceutical) industries are normally accepted regardless of their place of introduction, but these still require an appropriate control strategy (e.g. specification that ensures product quality)

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