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Impurity Identification

ICH Q3A covers drug substances and Q3B covers drug products. These guidelines define what investigations and documentation should be made in investigating impurities and degradation products seen in stability studies at recommended storage conditions. They categorise impurity types, e.g. organic and inorganic, and define levels at which impurities/degradates should be identified. They discuss setting of specification limits for impurities and qualification (i.e. establishing biological safety).

Evaluation of degradation products usually begins with HPLC screening of samples from bench-top stressing experiments (i.e. acid, base, oxidative, reductive, heat, etc.) or of aged samples. Generally, once degradation of around 5 to 10% is achieved at each stress condition, chromatograms are evaluated and significant peaks identified for further investigation. This is done in conjunction with evaluation of samples from longer accelerated stability studies, to avoid spending effort on impurities that will never form in practice. Mass balances are always used to check that nothing is missed.

If indicated, identification of degradates is undertaken using techniques such as mass spectroscopy (to obtain molecular weight and structural information). NMR may also be utilised.

Since the number of impurities/degradates is not known at the outset, these studies are usually priced according to the number of impurities/degradates to be identified. Therefore, the selection of peaks for further investigation is always undertaken in collaboration with the sponsor, to ensure that the sponsor retains control of expenditure.

Such studies may also form part of validation of the stability-indicating capability of methods.