In the final two months of the calendar year 2019, FDA’s Center for Biologics Evaluation and Research (CBER) took compliance actions against human tissue, cell, and gene therapy manufacturers that included the issuance of Untitled Letters, Warning Letters, and an administrative action to cease manufacturing.  These took place when the agency was in a period of enforcement discretion, which will come to an end in November (Note: more on enforcement discretion and CBER actions is available here).

At the Food and Drug Law Institute (FDLI) Enforcement, Litigation, and Compliance Conference held in Washington, DC in December 2019, Validant Principal Consultant Katie Laney explained ways in which manufacturers of human tissue, cell, and gene therapy products might avoid FDA enforcement actions, and how to address those actions if they take place.

Avoiding Enforcement: Understand Product Classification

FDA defines human cell, tissue, and cellular and tissue-based products (HCT/Ps) in 21 CFR Part 1271 as “articles containing or consisting of human cells or tissue that are intended for implantation, transplantation, infusion, or transfer into a human recipient.”  There are two broad categories of HCT/Ps with vastly different regulatory requirements, defined under sections 351 and 361 of the Public Health Services Act (PHSA).

Which section a product falls under can be a source of confusion, specifically regarding the interpretation of the terms “minimal manipulation” and “homologous use.”  An HCT/P regulated solely under Sec. 361 has extremely specific properties and does not require an IND or pre-market approval―the company or individual simply needs to declare that they meet the description of a 361 product.  However, agency or expert involvement in making that declaration is highly recommended.


Laney explained that one of the avenues that the agency has opened for consultation on this topic is the TRIP program―the Tissue Reference Group (TRG) Rapid Inquiry Program (TRIP).

TRIP was announced in June 2019 specifically to help manufacturers of HCT/Ps including stem cell treatments understand the appropriate regulatory pathways for their products.  It allows sponsors who believe their product falls under 361 requirements to get advice and consultation from the agency on proper minimal manipulation and homologous use of their products.

“The beauty of the TRIP program,” Laney said, “is that it is informal and non-binding.  It is an open forum for tissue manufacturers and processors to talk to the agency and get advice in a way that fuels open communication on a rapid-response timeline.  This can be unbelievably valuable for section 361 products.”

In addition, she pointed to the FDA’s pre-RFD (Request for Designation) program, which is also informal and non-binding, and provides guidance from the agency on proper classification and branch assignment of a product.  This can help product sponsors who, for example, are using a delivery mechanism for their product or might be combining their product with another agent.

The TRIP and pre-RFD consultation processes allow sponsors of cell, tissue, and gene therapies the opportunity to talk with the agency and get their advice before going through the RFD process, which is a formal and binding determination from the agency.  Engaging in these consultations can also help avoid enforcement actions.

GMP/GTP Gap Assessments

Laney noted that she often sees a lack of understanding by the cell tissue and genetic manufacturers of the regulatory space they are in and a lack of qualified internal resources to make regulatory determinations.  She encourages labs with products in development “to reach out and have third party assistance come in and do various assessments to avoid any enforcement action downstream.”

An assessment the firms find “most beneficial,” she said, is a Good Manufacturing Practices (GMP) or Good Tissue Practices (GTP) gap assessment, independent of whether it is a “tissue bank with legacy tissue products that are looking to expand into the cellular and gene therapy space or it is a research-based facility that is looking to develop a cell or a gene-based therapy.  They need to understand how the GMPs apply to their organization and build out accordingly.  That is an excellent way to avoid downstream enforcement actions.”

A gap assessment in this area, Laney said, should contain the following elements:

  • Identification of noncompliance to FDA regulations
  • Recommendations for corrective actions to ensure compliance
  • A nonbiased, thorough review of the Quality Management System
  • Professional and/or legal interpretation of FDA regulation(s) and Guidance for Industry documents
  • Enforcement actions in the area
  • Advice regarding product development and design changes
  • Advice on regulatory pathway determination and strategy for section 361 vs. 351 products
  • Explanation of Part 351 Investigational New Drug (IND) and Biologic License Application (BLA) processes, regulatory requirements, and timelines

Addressing Enforcement Actions

When a company is faced with addressing an enforcement action―for example, if it was marketing a product without FDA approval it thought was a part 361 product but an agency investigator inspected and said the product is a part 351 product―communication with the agency is, again, key.

One of the “best ways” for companies to open communication channels with FDA is through the pre-IND process, Laney said.  “This is another example of a consultation program offered by the agency where clients can begin communication, including tele-meetings and in-person meetings with the agency, to get guidance on the IND [Investigational New Drug] process and understand what data it will be required to submit.”

She explained that the process “gets you in front of the agency in an informal way that shows you are committed to addressing enforcement actions and that you are committed to the pre-market process that the agency has suggested to you.”

Laney provided an overview of the IND and Biological License Application (BLA) process, including what the timeline looks like and what the compliance requirements are across the IND and BLA process, and discussed the importance of understanding the process (see Figure 1).

“I think what is most important to see here is not only the amount of time that this process takes―which I think is something that is misunderstood by some manufacturers―but that the pilot studies, pivotal studies, and the BLA application are very important to understand, as well as the compliance requirements across the IND and BLA process,” Laney advised.

For those technologies that may have begun in the 361 space―self-designating in that way and then needing to upgrade to GMP―it is important to understand that the GTP requirements are in place from the beginning.

Laney also recommended that in addition to communicating with CBER, “engagement with local district offices in the event of a 483 report or something similar” is recommended “to ensure that appropriate containment and corrective action is taken for products that might be distributed in that area.”

The Validant Principal Consultant stressed the importance of HCT/P companies addressing enforcement issues to ensure that investigations into allegations or 483 reports of non-conformance are thorough, that adequate containment takes place, root cause analysis is performed, and appropriate corrective action and preventive action (CAPA) tasks are assigned and completed in a timely manner.  The CAPA actions, she said, should “take a larger systemic look at the entire quality management system and address issues from a systemic standpoint.”

This article was written and shared with the consent of the Author, Jerry Chapman with Link to the original article here.