Establishing Impurity Specifications for Antibiotics; Draft Guidance for Industry

The commenter requests clarification in the draft guidance regarding the use of alternative compendial monographs (such as the European Pharmacopeia) for unspecified impurities and degradation products. They argue that the guidance should explicitly state that these criteria are appropriate if there are no toxicological concerns, similar to the language provided for specified impurities.

The commenter suggests updating the draft guidance to explicitly allow for the use of non-animal models (NAMs) as an alternative to traditional 14-90 day in vivo studies. They provide specific proposed language to incorporate into the document to align with the FDA Modernization Act 2.0.

The commenter suggests that the draft guidance should incorporate process and product knowledge when establishing acceptance criteria for total impurities or degradation products. They provide specific line references and proposed language to ensure these factors are considered alongside individual impurity criteria.

The Parenteral Drug Association (PDA), a non-profit international professional association of pharmaceutical industry professionals, submitted comments to improve the draft guidance. They advocate for harmonizing the guidance's terminology with International Council for Harmonisation (ICH) standards and suggest specific technical updates regarding impurity definitions and analytical product parameters.

The Association for Accessible Medicines (AAM), representing generic and biosimilar pharmaceutical manufacturers, supports the draft guidance but requests more specific impurity thresholds and clearer guidance on its application to products currently under development. They argue that more detailed specifications are necessary to ensure regulatory consistency with international standards and to prevent supply chain disruptions.

The commenter suggests specific language revisions to the draft guidance to clarify that identification thresholds can be consistent with ICH Q3A(R2) and ICH Q3B(R2) standards. They provide specific text examples to ensure the guidance allows for these established limits or other justified limits.

Xellia Pharmaceuticals, a global producer of fermentation-based antibiotics, supports the FDA's initiative to establish specific impurity guidelines for these products. They argue that current ICH guidelines are insufficient for complex fermentation profiles and propose specific, higher thresholds for different classes of antibiotics to align with European (EMA) standards.

The commenter points out that the draft guidance fails to address unidentified impurities or degradation products. They specifically note the lack of detailed discussion regarding establishing limits for unspecified impurities that fall above the identification threshold.

HEC PHARM Co., LTD. argues that the proposed impurity thresholds are too stringent for antibiotics manufactured by fermentation and semi-synthesis, as these products are inherently mixtures of related compounds. The company requests higher, risk-based thresholds aligned with EMA guidelines to ensure that the development and availability of these essential medicines are not impeded by impractical manufacturing requirements.