FDA Finalizes Guidance On The Advanced Manufacturing Technologies Designation Program

By Kim Benton, Dark Horse Consulting

Among the flurry of FDA guidance for industry releases in the last days of December 2024 was Advanced Manufacturing Technologies Designation Program.¹ This finalized the draft guidance from December 2023. How much does the 2024 final guidance advance our understanding of how the Advanced Manufacturing Technologies (AMT) Designation Program will be implemented by FDA and how it can benefit innovators in the cell and gene therapy (CGT) field?

For those not familiar with the program, the purpose of the AMT Designation Program is to facilitate early adoption of AMTs that have the potential to benefit patients by improving manufacturing and supply dependability and optimizing development time of drug and biological products. The Food and Drug Omnibus Reform Act of 2022 (FDORA), which added section 506L² to the Federal Food, Drug, and Cosmetic Act, required FDA to initiate and issue guidance on an advanced manufacturing technologies (AMT) designation program.

What Were The Major Stakeholder Concerns About The 2023 Draft Guidance?

Twenty-five commentors submitted to the public docket³ on the 2023 draft guidance. Major themes of comments included:

• objection to strong FDA recommendation to meet with CDER Emerging Technology Team (ETT) or CBER Advanced Technologies Team (CATT) prior to submission of request for AMT designation
• request for clarification on which novel technologies FDA considers eligible
• request for clarification on the data required to support a request for AMT designation, including what qualifies as a model drug
• objection to the concept that FDA may “graduate” designated AMTs from the program
• objection that NDAs may cross-reference master files for AMTs but biologic license applications (BLA) may not
• request for clarification on benefits of AMT designation
• request for clarification on whether similar AMTs can receive AMT designation.

The 2024 final guidance added information to address most of the docket comments. In this article I summarize the content of the 2024 final guidance and major changes from the 2023 draft guidance, with a focus on CGT and biologics. Table 1 provides a quick reference for terms FDA uses for parties who may be involved in the AMT Designation Program, their roles and responsibilities, and how they may interact with FDA and benefits from the program.

Party	Definition*	Role and Responsibility	Interactions with FDA/Benefits of AMT Designation Program
Requestor	Person or organization that has developed a technology and has submitted an AMT designation request to FDA	Define the context of use for their proposed AMT Determine the types of supporting data and information to include in AMT designation request Prepare and submit AMT designation request to FDA	FDA may facilitate communication with requestors during request review.
Designated AMT Holder	A person or organization whose AMT designation request has been evaluated by FDA and granted designation under the program	Can authorize applicants to reference data and information about the designated AMT in their IND/BLA application Should communicate changes that could impact eligibility or the context of use for their designated AMTs to FDA	See below if holder is also the IND/BLA applicant. The guidance does not clearly define communications with FDA post AMT designation when the designated AMT holder is not the IND/BLA applicant.
Applicant	An entity that has submitted or plans to submit to a BLA or IND	Can use, reference, or rely** upon a designated AMT in the development or manufacturing of a drug if they are authorized to do so by the designated AMT holder or are themselves the AMT holder Should determine if the designated AMT is appropriate for their specific drug, incorporate the designated AMT into the drug’s development and manufacture, and submit drug-specific data in the application	Can request a meeting with FDA for preliminary discussion on using a designated AMT Can request subsequent meetings with FDA throughout the drug development process
FDA Designated Lead	FDA subject matter expert with demonstrated expertise in the manufacturing process, product type, or other elements specific to the proposed AMT	During AMT designation request review: May contact the requestor to obtain additional information or coordinate discussions with requestor regarding specific aspects of the proposed AMT For designated AMTs: Ensure that meetings with the applicant are collaborative and productive, including: Answer applicant questions about the information appropriate to be included in their IND/BLA application. Discuss the quality assessment of the applicant’s future IND/BLA applications that plan to use, reference, or rely upon a designated AMT. Facilitate the quality assessment of a BLA application for a drug manufactured using the designated AMT with the aim of making the assessment process more efficient.	NA

Table 1: Parties Involved, Roles, and Benefits of AMT Designation and Development.
* Definitions are from Q&A #2 of the 2024 final guidance.
**See Benefits of AMT Designation discussion about master files and BLAs.

Criteria For AMT Designation

Section 506L(b) stipulates that a method of manufacturing or combination of methods is eligible for AMT designation if it incorporates a novel technology or uses an established technique or technology in a novel way that will substantially improve the manufacturing process for a drug while maintaining equivalent, or providing superior, drug quality, including by:

• reducing development time for a drug using the designated manufacturing method; or
• increasing or maintaining the supply of a drug that is life-supporting, life-sustaining, or of critical importance to providing healthcare; or a drug that is on the drug shortage list under section 506E of the FD&C Act (21 U.S.C. 356e).

Stakeholder comments on the 2023 draft guidance requested clarification of how FDA will interpret “novel” in the statutory language. In the 2024 final guidance, FDA revised the Q&A #3 to clarify that a novel technology or an established technology used in a novel way is one for which FDA has limited assessment or inspectional experience, adding that this could be either a completely new technology or an existing technology with which FDA has experience in a significantly different use than the use now proposed. FDA stated that novelty is an essential but not the sole aspect of meeting the statutory criteria for AMT designation.

In the 2023 draft guidance, the Criteria section also included an FDA position that proposed candidates for AMT designation should also generally meet the eligibility criteria described in CDER’s Emerging Technology Program and CBER’s Advanced Technologies Program and strongly recommended engagement with ETT or CATT as a first step. This language was removed in the 2024 final guidance. The topic is addressed in Q&A #7, with the explanation that ETT and CATT discussions can begin earlier in the drug development process, whereas the Advanced Manufacturing Technologies Designation Program is intended for methods and technologies that, while still novel (or used in a novel way), are more mature, such as those for which model drug-specific data to support eligibility are available. Thus, a CATT meeting remains a good potential first interaction with CBER but is not a prerequisite for submission of an AMT designation request.

Content Of The AMT Designation Request

All AMT designation requests should include:

• A brief description of the proposed AMT and why it should be considered for AMT designation, including a brief explanation of how it incorporates a novel technology or uses an established technology in a novel way.
• The context of use for the proposed AMT, including information about the model drug used to generate manufacturing or development data submitted in the request.
• A detailed description of how the proposed AMT meets the eligibility criteria described in section 506L(b) of the FD&C Act in a particular context of use.
  • An outline of the steps of the proposed AMT, including information about where in the overall manufacturing process the proposed AMT is intended to be used.
  • Information about how the proposed AMT will ensure equivalent or superior drug quality, including the proposed control strategy.
  • A description of how the proposed AMT will reduce drug development time or how it will address a critical drug supply need.
  • Developmental data, including quality-related data generated through process development studies that evaluate the proposed AMT, and information that describes and justifies the proposed AMT’s context of use.
• Perceived regulatory, technical, or other challenges to implementation of the proposed AMT.
• If applicable, information about previous engagement with ETT or CATT.

AMT designation requests from requestors who are also IND/BLA applicants or prospective applicants should also include:

• The anticipated timeline for drug development activities that incorporate the proposed AMT, including the planned submission of any IND/BLA applications that would use, reference, or rely upon data and information about the proposed AMT in the same context of use.

AMT designation requests for a proposed AMT intended for use in manufacturing an approved drug should also include:

• A cross-reference to the existing application.
• Information demonstrating that the proposed AMT will increase or maintain the supply of the drug.
• Evidence that the proposed AMT will maintain equivalent or provide superior drug quality.

The 2024 final guidance added additional emphasis on the need to address context of use in several sections of the guidance and moved the Q&A on this topic to Q&A #1. The types of supportive data and information to include in a request depend on the specific method of manufacturing and its proposed context of use and should be determined by the requestor. The robustness of the data and information should be commensurate with the level of risk inherent to the process and proposed context of use.

Submission Process And Designation Determination

Designation requests should be emailed to a centralized FDA email address provided in the guidance. Secure email is available and recommended to protect priority information. FDA will acknowledge receipt, confirm whether the request is complete, and begin evaluation. No timeline is provided for acknowledgment and triage for completeness.

The designation request will be reviewed by a team of FDA experts from the center with jurisdiction over the type of drug that would incorporate the proposed AMT. The team will include staff from both centers if the proposed AMT may be used in drugs reviewed in both CDER and CBER. ETT or CATT members, senior FDA managers, and other experienced FDA staff may be included in the team. The team will evaluate the data and information submitted in the request, including information relating to the context of use, to determine if the proposed AMT meets the designation criteria and should receive AMT designation. A primary subject matter expert for the request will be selected to serve as the designated lead. This designated lead may facilitate contact with the requestor to obtain additional information about the AMT designation request or to coordinate discussions with the team concerning specific aspects of the proposed AMT during the designation determination process.

This process for AMT designation request submission and review differs from that of requests for expedited programs such as Fast Track (FT), Breakthrough (BT), or Regenerative Medicine Advanced Therapy (RMAT) designation. One likely reason is that FT, BT, and RMAT designation requests are submitted to an existing IND for which there is an assigned review team and corresponding supervisors. An AMT designation request may be submitted in the context of a specific IND or BLA by the sponsor/applicant or be submitted by the AMT developer independent of a specific product or application.

FDA is required to review and decide on requests for AMT designation within 180 days of receipt. FDA will deny requests that are incomplete or do not meet the criteria described in Section 506L(b) of the FD&C Act. A request that is denied AMT designation can be resubmitted if additional data and information to support eligibility become available.

In response to a docket comment, FDA added in Q&A #4 similar technologies, independently submitted by different requestors in separate AMT designation requests, would each be eligible for designation.

Life Cycle Of Designated AMTs

The concept of the life cycle of designated AMTs was the subject of multiple comments to the 2023 draft guidance. The first topic is the potential for changes to the designated AMT. Changes to a designated AMT should be reported to FDA via the same central email address used for submission of designation requests. FDA will assess the proposed changes and supporting data to confirm that the designated AMT continues to meet criteria for designation and maintains the same context of use for which the AMT was designated. FDA will communicate results of this evaluation to the AMT holder. It is the responsibility of the AMT holder to inform applicants about any changes to their designated AMT, including changes to the context of use.

The most controversial topic is that FDA may decide to graduate a designated AMT from the program, once it has been used in multiple approved applications (presumably meaning BLA) and transfer the review of future BLAs using that AMT to the standard review timeline. Docket comments stated that the statute did not include a provision to allow FDA to graduate designated AMTs from the program. FDA added language in the 2024 final guidance to explain its intent to consider graduation on a case-by-case basis. FDA states that “graduation would keep ATM designation aligned with the statutory prerequisite of novelty and facilitate further innovation over the program’s duration by leveraging FDA’s available AMT-related resources on new AMTs that continue to meet the program’s goal of encouraging adoption of novel technologies to shorten drug development times for critical medicines while maintaining or improving product quality.” A graduated AMT may request reentry into the AMT Designation Program if it can again be demonstrated to meet the statutory criteria, such as if the technology were proposed for use in a novel way. The process for reentry is not clarified in the 2024 final guidance but would presumably require a new request for AMT designation with supportive data.

Benefits Of AMT Designation

The lack of clearly defined benefits was the subject of multiple docket comments on the 2023 draft guidance. The section titled Potential Benefits from the 2023 draft guidance has been changed to Benefits in the 2024 final guidance. The benefits of AMT designation can be broadly summarized as communications with FDA to advise on the AMT implementation for the manufacturing of a specific product, with the aim to reduce the development time and facilitate the quality assessment in a BLA application for that product. Unlike existing expedited programs (Fast Track, Breakthrough, and Regenerative Medicine Advanced Therapy), no specific additional meetings or expedited timing are specified.

A wording change in the 2024 final guidance raises a question on which parties will be eligible for additional communications. The wording of the 2024 final guidance states “as resources permit, FDA intends to provide timely advice and to engage in additional communication, in the form of written correspondence or meetings, with applicants for a drug manufactured using a designated AMT” (emphasis added by this author). The 2023 draft guidance stated that the communications may be with “requestors, designated AMT holders, and applicants for a drug manufactured using a designated AMT.” In Q&A #7, which addresses the difference between ETT/CATT programs and the AMT Designation Program, there is discussion that “the designated AMT holder may not necessarily be the same entity as the applicant who ultimately uses a designated AMT” and “any meetings regarding the use of a designated AMT … would generally occur through the Advanced Manufacturing Technologies Designation Program.” It is possible that the FDA is open to meetings with any designated AMT holder but opted not to make a commitment in the 2024 final guidance because of resource uncertainties.

The other aim of the AMT Designation Program is to make the BLA assessment process more efficient. A long-term concern of industry is that adopting novel technologies with which FDA is unfamiliar will hinder the regulatory review process, because FDA may require additional information to be submitted and/or to require additional time for review. The 2024 final guidance states that the goal is that use of a designated AMT “will not increase the time or number of assessment cycles required to arrive at a quality-related decision and will not increase the time required to arrive at a decision regarding overall application approval. The knowledge and familiarity gained by FDA though the assessment of applications that use a particular designated AMT should streamline the assessment of subsequent applications that use the same designated AMT.”

Another benefit of the AMT Designation Program is that applicants may use, reference, or rely upon a designated AMT in their regulatory application. Master files are a common mechanism for submission of proprietary information to FDA and to permit cross-reference by other parties to support INDs or BLAs. The difference in how master files can be cross-referenced in licensure applications for drugs versus biologics and how this applies to designated AMTs was the topic of docket comments on the 2023 draft guidance from multiple parties. The 2024 final guidance provided additional explanation in Q&A #6 but maintained that “supporting data and information for the drug substance, drug substance intermediate, and drug product (DS/DSI/DP) be submitted directly to the BLA rather than be incorporated by reference to a DMF, consistent with 21 CFR 601.2(g)” because a BLA holder is expected to have knowledge of and control over the manufacturing process for the biological product. The exclusion in 21 CFR 601.2(g) against cross-referencing a master file in a BLA is limited to information about the drug substance, drug substance intermediate, and drug product. Certain types of information in a master file can be cross-referenced, such as certain equipment used in manufacturing. For a drug-biologic combination product, an applicant can cross-reference a master file for nonbiological product constituent parts. Master files can be cross-referenced in INDs for biologics, even for the drug substance, drug substance intermediate, and drug product.

Score Card

Earlier I highlighted seven themes of stakeholder docket comments falling into three areas of objections and four requests for clarification. FDA satisfactorily addressed only one of the objections. The expectation of interacting with ETT or CATT prior to submission of an AMT designation request was removed, but the concept of program graduation and the restriction on BLA cross-reference for DS, DSI, and DP remain. In my opinion, FDA gets a higher score on addressing the requests for clarification, with a lingering weakness being clarity on the communications benefits of AMT designation. Despite the lack of clearly specified communication benefits, those interested in AMT designation should be encouraged by the chance for FDA meetings and the intent of FDORA for the AMT designation process to shorten or otherwise optimize drug development. In addition, AMT designation can be expected to help technology developers attract partnerships with product developers.

References

1. Advanced Manufacturing Technologies Designation Program: Guidance for Industry. Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. 2024
2. Food and Drug Omnibus Reform Act of 2022 (FDORA), Section 506L
3. FDA Docket FDA-2023-D-4974

About The Author:

Kimberly Benton, Ph.D., served for over 22 years at the U.S. FDA/CBER in regulation of cell and gene therapy products before joining Dark Horse Consulting in January 2023 as master principal and head of regulatory. During her time at FDA/CBER, she served as associate director for regulatory management in the Office of Tissues and Advanced Therapies (now the Office of Therapeutic Products); deputy director of the Division of Cellular and Gene Therapies in the Office of Cellular, Tissue, and Gene Therapies; chief of the cell therapies branch; and CMC reviewer of cell therapies.