FDA Draft Guidance on Fermentation-Derived Antibiotics Sparks Industry Calls for Global Harmonization
核心洞察
FDA released a draft guidance setting impurity controls for antibiotics produced via fermentation or semi-synthetic methods, addressing a longstanding regulatory gap.
The guidance provides recommendations for identifying, qualifying, and managing impurities and degradation products, referencing ICH Q3A(R), Q3B(R2), and M7(R2) frameworks.
Industry groups including AAM, PDA, Pfizer, and Xellia have urged FDA to harmonize terminology and thresholds with EMA and ICH guidelines to reduce regulatory uncertainty.
The US Food and Drug Administration has published a draft guidance document establishing impurity control standards for antibiotics manufactured through fermentation or semi-synthetic processes, filling what the agency acknowledges is a significant regulatory gap. The guidance, released in April, applies to antibiotic drugs subject to approval under new drug applications (NDAs), abbreviated new drug applications (ANDAs), and type II drug substance drug master files (DMFs) referenced in antibiotic NDAs and ANDAs.
The agency noted that a substantial proportion of antibiotics are produced via fermentation or semi-synthetic methods rather than through chemical synthesis. Due to the inherent complexity of these manufacturing processes, there is a higher likelihood of various potential impurities emerging. However, existing guidelines have not offered recommendations for controlling impurities and degradation products in drugs produced by these methods.
Scope and Core Recommendations
The draft guidance provides a framework for identifying, qualifying, and managing impurities and degradation products in fermentation-derived and semi-synthetic antibiotics. FDA emphasized that manufacturers must fully characterize these mixtures to identify any impurities, antibiotic-related analogs in the drug substances, and degradation products in the drug products.
For drug product specifications, manufacturers should address each identified degradation product, each specified unidentified degradation product, any unspecified degradation product with an acceptance criterion not exceeding the identification threshold, and total degradation products. For drug substances, specifications should include each specified identified impurity, each specified unidentified impurity, any unspecified impurity with an acceptance criterion not exceeding the identification threshold, and total impurities.
The guidance directs manufacturers to follow terminology established in the International Council for Harmonisation's Q3A(R) guidance on controlling impurities in new drug substances, ICH Q3B(R2) on controlling impurities in new drug products, and ICH Q6A on setting product specifications.
Analytical Validation and Acceptance Criteria
Manufacturers must describe analytical procedures used to test for degradation products and provide evidence that these procedures have been validated and are suitable under actual conditions of use. Validation should follow the ICH Q2(R2) guidance for industry on validating analytical procedures.
Acceptance criteria for impurities and degradation products should be established based on data from clinical trials, nonclinical studies, and comparative analyses of degradation products in a drug product relative to its respective reference listed drug (RLD). Other considerations include context of use, prior knowledge, publicly available information, and the accuracy of analytical procedures.
Acceptance criteria for specified impurities in drug substances or specified degradation products in drug products are considered appropriate if they do not exceed the qualification thresholds outlined in ICH Q3A(R) or ICH Q3B(R2), provided there are no toxicological concerns. If structural alerts for mutagenicity or signals for carcinogenicity exist, manufacturers must follow ICH M7(R2).
Where applicants wish to use acceptance criteria exceeding ICH qualification thresholds, they must justify the proposed limit. This justification may include a repeat-dose general toxicology study with the appropriate route of administration, conducted over 14 to 90 days depending on the indication, along with a risk assessment for mutagenic potential as outlined in ICH M7(R2).
Industry Calls for Harmonization
Several industry groups and drugmakers have submitted comments urging FDA to harmonize the draft guidance with international regulatory frameworks.
The Association for Accessible Medicines (搜索) (AAM) argued that FDA's guidance lacked the specificity found in European Medicines Agency (EMA) guidance. "The draft guidance is very general and lacks specific recommendations regarding establishing specific thresholds for impurities in the products covered by the guidance," AAM stated. "In contrast, the European Medicines Agency has issued more specific guidance on acceptance criteria that includes thresholds for reporting, identification, and qualification for certain categories of active substance."
AAM further noted that some of its members have observed FDA reviewers applying EMA guideline thresholds during reviews, despite the agency not having announced such an intention, while other reviewers may be taking different approaches—creating regulatory inconsistency.
"As FDA is aware, many drug development programs are global in nature, and consistency across health regulatory authorities is important to support efficient development of critical medicines that can be made available around the world to patients who need them," the group added.
The Parenteral Drug Association (搜索) (PDA) recommended that FDA harmonize terminologies with ICH scientific guidelines, specifically encouraging use of the term "drug substance" in place of "active pharmaceutical ingredient (API)" as defined in ICH Q6B. PDA also recommended aligning the use of "degradation products" and "impurities" to ICH definitions, and proposed clarifying the definition of an antibiotic drug as a drug substance consisting of a mixture of compounds, as well as a drug product.
Pfizer echoed PDA's comments on ICH harmonization and asked FDA to clarify that identification thresholds may be consistent with ICH Q3A(R2) and ICH Q3B(R2) thresholds or with an otherwise justified limit. The company also recommended that the guidance include language allowing the use of non-animal models, such as new approach methodologies, as alternatives to in vivo studies, consistent with the FDA Modernization Act 2.0. Pfizer further suggested that "the concept of impurity grouping should be included where justified."
Danish drugmaker Xellia Pharmaceuticals highlighted that ICH Q3A and Q3B guidelines exclude peptide, fermentation, and semi-synthetic products, creating a knowledge gap. The company noted that for fermentation-based active substances consisting of more than one active moiety, the impurity profile is typically very complex and ICH Q3A and Q3B thresholds "cannot be considered applicable." Xellia recommended higher thresholds for fermentation products and pointed to the EMA guideline on setting specifications for related impurities in antibiotics, published 30 June 2012, which includes a special threshold for fermentation products. "An alignment with this guideline would be highly desirable for pharmaceutical companies who develop products which are intended for registration in multiple markets covering both EU and US," Xellia stated.
AAM also raised concerns about the guidance's application to existing products, asking FDA to clarify how it plans to apply the guidance to marketed products, applications under development, and currently pending applications. The group recommended that FDA "clarify now how applicants with antibiotic drug products that are currently under development for approval under abbreviated new drug applications should establish specifications for impurities during the period before the guidance is finalized."
The deadline for comments on the draft guidance is 22 June, with submissions accepted at www.regulations.gov under docket number FDA-2025-D-6130.