Industry asks FDA for harmonization, clarification in fermentation, semi-synthetic antibiotics guidance
Several industry groups and drugmakers have written to the US Food and Drug Administration (FDA) to ask the agency to harmonize its recent draft guidance on developing fermentation and semi-synthetic antibiotics with those of other global regulators. They also said the guidance lacked significant detail and asked the agency to harmonize terminologies.
In April, FDA published the draft guidance aimed at setting impurity limits for antibiotics produced through fermentation or semi-synthetic methods. The agency said it is intended to address a gap in managing impurities for such antibiotics, since current guidance does not address controlling impurities or their degradation (RELATED: FDA draft guidance sets impurity controls for most antibiotics, Regulatory Focus, 20 April 2026).
Several stakeholders commented on the draft guidance. The Association for Accessible Medicines (AAM) argued that, unlike guidance from European regulators, FDA's guidance lacked clarity and detail. The group said it is important for the agency to develop guidance that aligns with international regulators to enable a more streamlined regulatory pathway.
"The draft guidance is very general and lacks specific recommendations regarding establishing specific thresholds for impurities in the products covered by the guidance," said AAM. "In contrast, the European Medicines Agency (“EMA”) has issued more specific guidance on acceptance criteria that includes thresholds for reporting, identification, and qualification for certain categories of active substance.
"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. "In addition, some of our members have observed that some FDA reviewers seem to be applying the thresholds in the EMA guideline during their reviews, although FDA has not announced its intention to do so, and other FDA reviewers may be taking a different approach."
AAM asked FDA to publish a more detailed guidance clarifying expectations for establishing thresholds for impurities to avoid changing expectations and inconsistent reviews. The group argued that the changes would reduce regulatory uncertainty, prevent unintended consequences that affect product availability, and help sponsors plan better.
AAM also noted that while FDA said the guidance would not be applied retrospectively, it wants to know how the agency plans to apply the guidance to marketed products, applications under development, and currently pending applications.
"AAM’s members recommend that the Agency clarify now how applicants with antibiotic drug products that are currently under development for approval under abbreviated new drug applications (“ANDAs”) should establish specifications for impurities during the period before the guidance is finalized," said the group. "Our members also need to know what changes will trigger the need to reconsider their current acceptance criteria, for example, a change of active pharmaceutical ingredient supplier in the post-approval setting."
The Parenteral Drug Association (PDA) also asked FDA to harmonize with other regulatory bodies. The group asked the agency to harmonize terminologies with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s scientific guidelines.
"Specifically, PDA encourages the use of the term 'drug substance' in place of 'active pharmaceutical ingredient (API)' as defined in ICH’s harmonized tripartite guideline ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products," said PDA. "This harmonization of terminology will promote consistency between the guidance documents and reduce potential confusion and misinterpretation.
"Additionally, PDA recommends aligning the use of the terms 'degradation products' and 'impurities' to ICH’s definitions as well," the group added.
More specifically, PDA recommended that FDA adopt a single, harmonized term, based on ICH's definition, to cover a wide range of impurities while clarifying their subcategories. The group said the term should be used in the context of drug substances, while degradation products would be used to refer to impurities formed in drug products.
Another terminology recommendation proposed by PDA was to clarify the term antibiotic drug. The group proposed that an antibiotic drug be defined as a drug substance that consists of a mixture of compounds, as well as a drug product.
New York-based Pfizer provided its feedback on the guidance and echoed PDA's comments, noting that it should consider harmonization with ICH. More specifically, it 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.
Pfizer also said that acceptance of total impurities in drug substances or total degradation products in drug products should take into account the process and product knowledge, as well as the acceptance criteria for individual impurities. Furthermore, the company said that the guidance should 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.
"The concept of impurity grouping should be included where justified," Pfizer added.
Danish drugmaker Xellia Pharmaceuticals also referenced the ICH Q3A and Q3B guidelines, which it said exclude peptide, fermentation, and semi-synthetic products, leading to a knowledge gap in how impurity limits should be established for the antibiotics referenced in FDA's guidance. The company, which makes fermentation and semi-synthetic antibiotic drug substances and drug products, said FDA's guidance also fails to provide clarification for adjusted thresholds for impurities in products such as its own.
"In the case of fermentation-based active substances, which consist of more than one active moiety, the impurity profile is usually very complex and the thresholds in the ICH Q3A and Q3B cannot be considered applicable," said Xellia. "It is therefore recommended that higher thresholds are proposed for fermentation products which can be used for the US market."
"In the European market the EMA guideline on setting specifications for related impurities in antibiotics (EMA/CHMP/CVMP/QWP/199250/2009 corr) published 30 June 2012, includes a special threshold for fermentation products," the company added. "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."
Echoing other stakeholders, Xellia asked FDA to ensure it harmonizes terminologies and thresholds with EMA and ICH.
