Comment from HEC Pharm Co, Ltd.

Comment on Section III.C.1 (Page 7, line 203-226 ) & Section III.C.2 (Page 9, line 261-277): We appreciate FDA’s efforts to address the unique challenges of impurity control for antibiotics manufactured by fermentation and semi-synthesis. However, we recommend clarifying the applicability of ICH Q3A/Q3B(R2) qualification thresholds to these products. 1. Scientific Justification for Differentiated Thresholds For antibiotics derived from fermentation, the active substance often consists of a mixture of closely related, biologically active compounds inherent to the manufacturing process. The thresholds outlined in ICH Q3A/Q3B guidelines were developed for single-chemical-entity drug substances and are not directly applicable to fermentation products derivatives thereof. Furthermore, given that antibiotic treatments are typically short-term (ranging from days to weeks), the safety concerns associated with related substances differ significantly from those for chronic-use medications. We propose that higher thresholds for antibiotic-related substances may be scientifically justified compared to ICH Q3 limits. 2. Specific Recommendation for Alternative Thresholds Specific Recommendations as below, which is in line with the EMA Guideline on setting specifications for related impurities in antibiotics. Active substances manufactured by fermentation, single compound: Acceptance criteria for related impurities should be set in accordance with the thresholds given below. Reporting threshold: 0.10% Identification and qualification thresholds: 0.15% Active substances manufactured by fermentation, family of compounds: Acceptance criteria for related impurities should be set in accordance with the thresholds given below. Reporting threshold: 0.10% Identification threshold: 0.15% Qualification threshold: 0.50%/0.2% The qualification threshold of 0.50% for structurally closely related impurities (see definition) is combined with a qualification threshold of 0.2% for other related impurities. Justification for claiming that a related impurity (compound not defined to be included in the active substance) is structurally closely related to the parent compounds should at least be based on evidence such as HPLC/mass spectrometry or the use of reference materials. The proposed 0.50%/0.2% limits are suggested to apply even for daily doses of ≥2 g, which may be relevant for some of these antibiotics. 3. Concern Regarding Antibiotics Accessibility and Development Finally, we wish to raise a significant concern regarding the potential impact of the current draft guidance on the availability and development of active substances manufactured by fermentation. Based on our industry knowledge and experience, we believe that most fermentation-based active substances would struggle to meet these stringent thresholds. Due to the inherent characteristics of such substances, it is challenging to achieve the proposed thresholds through process modifications. We are therefore concerned that applying these requirements as currently drafted may significantly impede the development of fermentation-based drug substances/ drug products. We strongly urge the FDA to consider a more flexible, risk-based approach that balances quality and safety with the practical realities of manufacturing these complex fermentation products and the critical need to maintain a robust and resilient antibiotic supply. Thank you for the opportunity to provide these comments. We are available to discuss these recommendations further with the Agency. Sincerely, Joe Yin Director of Quality and Regulatory Affairs Email: yinjiu@hec.cn HEC PHARM Co., LTD.