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The guideline makes clear that an assessment of the mutagenic potential is not required for the following types of DSs and DPs:

 Biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin.

Close scrutiny of this highlights some anomalies; certainly many peptides and oligonucleotides are synthetic/semisynthetic in nature, and it is perhaps difficult to rationalize their exclusion (indeed, there was some commentary about these classes in the penultimate draft version of the guideline).

Established excipients are confirmed as also being out of scope. However, the guidance does indicate that it may be applicable for new synthetic excipients. “The safety risk assessment principles of this guideline can be used, if warranted, for impurities in excipients that are used for the first time in a drug product and are chemically synthesized.”

The position in relation to extractables and leachables is somewhat ambiguous, while stating that the guidance is not applicable to leachables, it states that “Application of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used, if warranted.” In practice the use of the TTC in the assessment of mutagenic impurities has become common.