Demonstration of Bioequivalence for Type A Medicated Articles: Question and Answer

1. What is the purpose of this Q and A with regards to the approvals of Type A medicated articles (TAMAs)?

   • Based on the complexities the Center for Veterinary Medicine (CVM) has encountered in the approval of TAMAs, CVM intends for this Q and A to clarify the various pathways available for demonstrating bioequivalence of TAMAs and the impact of critical quality attributes described in the Chemistry, Manufacturing, and Controls (CMC) technical section and post-approval supplements on bioavailability.

2. Does a completed Bioequivalence (BE) technical section satisfy the data requirements of the CMC technical section or the Human Food Safety (HFS) technical section?

   • No; the BE technical section only covers the bioequivalence of a generic product, and its reference listed new animal drug (RLNAD). The data used to demonstrate BE is not intended to satisfy the requirements of the other technical sections. However, the BE technical section data may be used to support the requirements for completion of the other technical sections.
     Sponsors are encouraged to meet with CVM to discuss how appropriate studies can be designed and conducted to maximize the use of the resulting data, such that one study can generate data to satisfy applicable areas of multiple technical sections where possible.

3. Does the approach to demonstrating BE affect the expectations for the CMC technical section?

   • No; all sponsors of generic TAMAs should provide full CMC information in the respective abbreviated new animal drug application (ANADA) or generic investigational new animal drug (JINAD) file, including medicated feed studies to support the proposed Blue Bird labels. Draft guidance for industry (GFI) #292: CMC Considerations for Type A medicated articles includes further details on the information needed to support the CMC technical section for TAMAs. 

4. How can BE be demonstrated for TAMAs?

   • BE for TAMAs can be demonstrated by conducting in vivo BE studies, such as blood level, pharmacologic endpoint, or clinical endpoint studies (as documented in GFI #35: Bioequivalence Guidance), solubility studies (as outlined in GFI #171: Demonstrating Bioequivalence for Soluble Powder Oral Dosage Form Products and Type A Medicated Articles Containing Active Pharmaceutical Ingredients Considered to Be Soluble in Aqueous Media), or combinations of in vivo and other studies (as described in GFI #279: Demonstrating Bioequivalence for Type A Medicated Articles Containing Active Pharmaceutical Ingredient(s) Considered to be Poorly Soluble in Aqueous Media, That Exhibit Little to No Systemic Bioavailability, and Are Locally Acting). Further, the requirement to demonstrate BE through in vivo studies may be waived (biowaiver) if the BE of the drug product is self-evident as described in 21 CFR 320.22.

5. What TAMAs qualify for a biowaiver?

   • The principles underlying TAMAs that may qualify for a biowaiver are outlined in GFI #35 and GFI #171 and are based on the solubility characteristics of the drug substance(s) in the TAMA. TAMAs that are true solutions or are expected to be dissolved to form a true solution before administration generally qualify for a biowaiver (GFI #35). TAMAs with drug substances that are considered adequately soluble in aqueous media will also be considered for a biowaiver (GFI #171). However, under GFI #171 if the drug substance is altered in a way that impacts solubility (compacted, granulated, complexation with calcium, etc.) or if the TAMA is manufactured using a process that may affect the bioavailability of the drug substance (roller compaction, excipient effects, etc.), then additional data may be requested to satisfy the requirements of 21 CFR 320.22 and support granting a biowaiver. 

6. For TAMAs that do not meet the solubility recommendations outlined in GFIs #35 or #171, can CVM consider a biowaiver request based on the same source of drug substance and the same manufacturing methods as that of the RLNAD?

   • In general, CVM would not be able to evaluate a biowaiver based on the same source of drug substance and the same manufacturing methods without access to the files associated with the approval of the RLNAD. Therefore, without a letter of authorization or a right of reference from the sponsor of the RLNAD, a generic sponsor would not be able to provide the necessary data to support a biowaiver request, and consequently, CVM would not be able to consider such a request.

7. Have biowaivers based on the same source of drug substance and the same manufacturing process as the RLNAD been granted in the past?

   • Yes, under a previous version of GFI #171 (version 2016), biowaivers were considered based on the same drug substance source and manufacturing method if the proposed product was a TAMA containing the same active and inactive ingredient(s) and produced using the same manufacturing processes as the RLNAD. The 2016 guidance further went on to caution “However, this approach is probably practical only for situations in which the sponsor of the proposed drug product also manufactures or, perhaps, formerly manufactured the RLNAD as well”. GFI #171 was updated in 2021 to remove the language for the consideration of biowaivers based on the same drug substance source and same manufacturing methods. The language was removed in the 2021 version of the guidance because generic sponsors do not typically have access to the information necessary to support a biowaiver based on the same drug substance source, same manufacturing method option.

8. Will products that have been granted a biowaiver, where the biowaiver was supported by data demonstrating the use of the same drug substance source and same manufacturing process as the RLNAD, be affected by the language withdrawn from the 2021 GFI #171 Guidance document?

   • If the sponsor of the approved generic product maintains the approved source of the drug substance and makes no changes to the manufacturing process or formulation of the drug product, then there is no effect on the biowaiver or generic product approval. However, there is a possibility that a change to the drug substance source, product formulation, or manufacturing process may impact the bioavailability of the drug substance. Therefore, CVM may require additional data to support the continued validity of the biowaiver used to support BE and product approval if any changes are proposed.

9. Do responses to the questions presented in this Q and A affect previously submitted data used to support an approval of an ANADA?

   • The contents of this Q and A describe CVM’s approach to determining BE of TAMAs and should be considered a clarification of existing practices. If an ANADA for a product has been approved, then the information in this Q and A will not impact CVM’s previous evaluation of the data used to support the product approval. For products that have not yet been approved, CVM does not anticipate the responses in the Q and A will impact previous conclusions around bioequivalence, however, consistent with the standards applicable to the review of all technical sections, CVM will review the application as a whole prior to approval and may re-evaluate any technical section where new concerns have arisen.

10. Does the methodology by which BE is demonstrated in support of an ANADA affect the expectations for data intended for use to support post-approval changes?

    • Once a product is approved, regardless of the pathway to approval, any post-approval changes should be evaluated to assess the effect of the change on the bioavailability of the TAMA. CVM recommends that sufficient data be generated with the primary batches used for approval to allow comparison to support that the respective post-approval changes do not impact bioavailability of the drug product. For example: for a TAMA with a poorly soluble drug substance that did not rely on elements described in GFI #171 or GFI #279, it still may be useful to have information on the particle size distribution of the drug substance used in clinical studies and an idea of the solubility profile of the drug substance and/or TAMA, to serve as a comparator to support post-approval changes that may impact bioavailability. 

11. Are there any considerations on the use or exclusion of excipients (e.g., anti-dusting oil, povidone, other excipients) in the formulation of TAMAs that differ qualitatively or quantitatively from those used in the RLNAD formulation?

    • Yes, if the generic formulation differs from the RLNAD formulation, address the effect of the differences on the bioavailability of the drug substance(s) in the TAMA. Any change in excipient(s) or in the quantities of an excipient(s) that may affect the BE of the TAMA may also affect the determination of BE of the proposed product relative to that of the RLNAD. For example, the use of oils as anti-dusting agents or as lubricants could also coat other components of the formulation and slow the release of the drug substance which in turn could affect the BE of the TAMA if used in different amounts than present in the RLNAD.

12. When the particle size of the drug substance is a critical quality attribute associated with bioavailability of the TAMA, such as for TAMAs with a poorly soluble drug substance as indicated in GFI #279, how can sponsors approach setting specifications for particle size?

    • Generally, a two-point particle size specification on the drug substance will control the particle size distribution. The distribution can be determined using the processes described in GFI #279 (Section V.A.). The approach to setting specifications will depend on the distribution itself as well as the method used. When using the sieve method, a narrow distribution may have specifications that bracket the range and wider distributions may have one of the specifications within the distribution. When using the laser diffraction method, a “not less than” specification based on the D50 and a “not more than” specification based on the D90 values from the primary batches is generally a reasonable approach.

13. Whom can I contact to get further information?

    • You may contact the Office of Generic Animal Drugs with general questions at:
      AskOGAD@fda.hhs.gov