ICH Q3A(R2) - Impurities in New Drug Substances

What it says

Impurities in new drug substances arising during synthesis, purification or storage must be identified above defined reporting, identification and qualification thresholds that scale with the maximum daily dose, with a documented impurity profile compared against batches used in safety and clinical studies.

Paraphrased for plain-language clarity. Always verify against the current published regulation text.

What it means in practice

• This guideline addresses impurities in the drug substance itself, arising from synthesis or degradation before formulation, distinct from ICH Q3B(R2), which addresses degradation products that develop in the finished drug product.
• A new, previously uncharacterised impurity above the qualification threshold requires actual safety data demonstrating it does not pose an unacceptable risk, not simply analytical characterisation of its structure.
• The impurity profile of commercial-scale batches must be compared against the impurity profile of batches used to support safety and clinical studies, since a new manufacturing process or scale can introduce impurities not present in the batches originally used to establish safety.

What inspectors look for

• Whether impurities above the applicable identification and qualification thresholds have documented identification and, where required, genuine safety qualification data.
• Whether the impurity profile of current commercial production has been compared against the impurity profile of batches used in pivotal safety and clinical studies.
• Whether a change in synthetic route or scale was assessed for its potential to introduce new or increased impurities relative to the qualified profile.

Related regulations