Since the retirement of CVM Guidance for Industry (GFI) #42 “Animal Drug Manufacturing Guidelines – Series of Four Guidelines,” which was withdrawn in October 2019, the animal health industry has been anticipating guidance from the CVM on these topics. The first of four anticipated guidance documents was issued on March 18, 2024 as a draft (here), and it is open for comments until May 17, 2024. This draft guidance, GFI #285 “Manufacture of Batches in Support of Original NADAs, ANADAs, and CNADAs,” is short, but packed with information; it includes information that was previously provided in GFI #42 Guidelines I-IV (however, it is not inclusive of all topics in those guidelines). It covers the topics of: Selection of Batches; Drug Substance (DS) Source; Drug Product (DP) Manufacture, the amount of stability required; and Considerations for Changes in DS Source or DP Manufacturing Site after Manufacture of Primary Batches. It is noted in the introduction that GFI #285 does not apply to Intentional Genomic Alterations (IGA) in animals, nor to Animal Cells, Tissues, and Cell- and Tissue-Based Products (ACTP). Major changes are in bold.

Previously, New Animal Drug Applications (NADAs), Conditional Approval of New Animal Drug Applications (CNADAs), and the associated Investigational New Animal Drug files (INADs) were required to have three primary batches manufactured in support of their new animal DP, and this is not changing. Abbreviated New Animal Drug Applications (ANADAs) and the associated Generic Investigational New Animal Drug files (JINADs) were only required to have one primary batch under GFI #42; however, the CVM is now aligning with the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) Stability guidances, and requiring three primary batches for JINADs/ANADAs. The CVM does state that for animal drugs intended for a Minor Use or Minor Species (MUMS animal drugs), the applicant should contact the Office of New Animal Drug Evaluation’s Division of Manufacturing Technologies (ONADE DMT) to discuss the appropriate number of batches. All of the DS and DP batches made in support of an application should be manufactured under Current Good Manufacturing Practices (CGMPs) at sites that are in compliance with CGMPs at the time of manufacture, and DS and DP sites proposed for commercial manufacturing should be in compliance with CGMP at the time of application approval. Batches should be at least 10% of the proposed commercial batch size (exceptions may be allowed for true solutions). Bracketing can be applied as outlined in Section III of the draft GFI; however, if you intend to use bracketing, applicants should consider submitting a protocol with the proposed bracketing approach. Lastly, but perhaps of most interest to manufacturers of animal DPs, is the statement that the CVM anticipates this change in the number of batches for JINADs/ANADAs will need to be implemented within one year from the date of the publication of the FINAL version of GFI #285, which gives some needed time to those in late-stage development.

GFI #285 discusses DS sources for DPs (INADs/NADAs/CNADAs/JINADs/ANADAs) and states that only a single source of DS should be submitted in the original application; applicants that wish to qualify an additional source should submit the required information post-approval in supplemental applications, as was stated in GFI #42. At least two different batches of DS from the proposed source should be used in the DP batches used in the original application. This information is not new, but due to the change in the number of batches needed for ANADA applicants, it is important to note. In Section VI, the CVM does make a provision covering a situation in which the original DS source becomes unavailable during review (e.g., site closure, deficient CGMP status, etc.) and states that, in such a case, the applicant should request a meeting with the DMT to discuss the path forward.

For new DS sources post-approval, a minimum of one pilot scale batch of DP should be manufactured using the new DS supplier (see Section VI of GFI #285 for additional information). A comparison of the DS’s Critical Quality Attributes (CQAs) must also be provided, including impurity profiles, polymorphism, and particle size, as well as a comparison of specifications and batch analysis. Executed and Master Batch Records (BRs) will also need to be included, as well as release and stability data, as is required for the original batches.

Both sections V and VI discuss DP manufacturing sites. As was previously required, primary batches for an original application should be manufactured at the same site proposed for commercial production, under CGMP, using the same/comparable process, controls, and equipment, and should be no less than 10% of the proposed commercial batch size. In accordance with VICH, six months of stability data (at both long-term and accelerated storage conditions) should be included in the CMC technical section for the primary batches for all application types. However, the CVM is allowing for three months of stability data to be provided at the time of submission, and the application to be amended with additional stability data while the pending original application is in the review queue. If a new commercial facility is required to be used pre-approval, the applicant should request a meeting with the DMT to determine potential approaches. However, post-approval, one batch of DP should be acceptable in most cases for the transfer of a DP to a new site, if the new site’s equipment is of the same design and operating principles, and other changes are minimal.

Though not all these changes will be met with exuberance from the animal health industry, it is good to have some direction again as industry has been struggling with the lack of guidance since GFI #42 was withdrawn. If you have any questions or need for assistance with animal-health applications, please contact