Avoid CMC Challenges by Thinking Slow, Not Fast-Discussions at USP’s Workshop

November 2, 2022By Holly N. Brevig, Senior Regulatory Device and Biologics Expert

On October 26, 2022, US Pharmacopeia (USP) Biologics Stakeholder Forum held a workshop on “Collaborating to solve CMC challenges and support efficient development of lentiviral-mediated CART cell therapies.”  Panelists discussed CMC challenges for CART therapies, including potency assay development, analytical method transfer, and demonstrating comparability.  Panelists also provided advice and recommendations on how they approach potential these challenges as well as potential areas for standards development.  USP aims to identify tools and solutions that may facilitate CART therapy development and mentioned potentially writing an information chapter on developing assays for CART therapies based on the workshop’s panel discussion.

The workshop included presentations by USP on its available standards for advanced therapies, FDA/CBER on CMC challenges for CART cell therapies, and industry approaches to potency testing during CART development, and using Analytical Quality by Design (AQbD) principles in potency assay development.   The majority of the workshop was spent on Q&A and included discussions on too many topics to write about in this blog.

USP opened the workshop with a description of its organization, each of its applicable standards for advanced therapies, including its standards (general chapters) <1046> Cell and Tissue Based Products and <1047> Gene Therapy Products, and its microbial related chapters open for comment: <74> Solid Phase Cytometry-Based Rapid Microbial Methods for Detection of Contamination in Short Shelf-Life Products, <77> Mycoplasma Nucleic Acid Amplification Tests, and <1114> Microbial Control Strategies for Cell Therapy Products.

FDA/CBER (the Agency) provided an overview of CMC challenges for CART development (e.g., limited manufacturing experience, in-process testing, product characterization, product stability data, assay development and qualification), CMC expectations for late-stage CART cell development (have a controlled manufacturing process, well developed and qualified analytical methods, and sufficient manufacturing experience), and regulatory considerations for potency assay development.  Some key points the Agency shared included the following:

  • Your product is only as good as the process-demonstrate your manufacturing process consistently produces drug product as per your critical process parameters (CPPs)
  • Have qualified potency assay(s) prior to conducting your pivotal study
  • Agency often sees issues when the drug product is put on an expedited manufacturing or an expedited clinical program
    • As the clinical program for the drug product matures, the CMC information should mature hand in hand
  • Early product characterization and concurrent matrix-based assay development are often seen as a key for product development and licensure success
    • Helps you move forward in drug development and quicker later in development (i.e., avoid CMC bottleneck prior to initiating pivotal study)
    • You’ll have the data to support comparability for when changes are made
    • May help you avoid analytical bridging studies
    • Allows you to determine which potency assay(s) are most relevant for your product
  • Don’t assume that product characterization is not needed when using an automated piece of equipment that is generating CART products. Use of automation does not allow for bypassing FDA requirements with respect to method transfer comparability.
  • Although not expected at the pivotal study stage, successful sponsors validate early
    • Opportunity for feedback from FDA if provided pre-BLA
  • Avoid running Process Performance Qualification (PPQ) prior to validating your methods
  • A replication competent lentivirus (RCL) testing exemption can be requested after you’ve obtained several lots showing that you can repeatedly generate RCL negative drug product
  • It is less likely for a company to be granted a RCL testing exemption if IND B vector uses a different length of viral vector backbone or is manufactured in a different way than the IND A vector
  • The ultimate goal of a comparability study is not to demonstrate that the products are identical, but to demonstrate you can consolidate clinical data from these lots
    • Release testing alone is not sufficient
    • The bar for demonstrating comparability is high if a manufacturing change is introduced in the middle of a Phase 2 pivotal study versus if a sponsor introduces a process improvement between Phase 1 and before starting the Phase 2 pivotal study

Panelists stated that a reference standard should be incorporated into your strategy for method monitoring, which then informs how your methods may change over time.  You also want your reference standard to reflect the manufacturing process.  Overall, it appeared from the workshop discussions that potential standards relevant to CART cell therapies include particle size, particle number, for the cell line, and infectious titers.

Stay tuned for USP white paper(s) on the workshop’s discussion as well as USP information chapters on lenti-viral vector cell therapies.  USP is currently looking for volunteers to serve as scientific experts on the Lentivirus Cell Therapy Expert Panel who will develop lenti-viral vector standards.