From the Editor: Guiding Potency Assurance in Cell Therapy from All Angles

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Wouter Van’t Hof, Contributing Editor

Cleveland Cord Blood Center

Cleveland OH, USA

What’s in Your CGT Product?

The shared responsibility of all of us cell and gene therapy developers involved with ISCT and with the ambition of bringing cell-based therapies to patient in need starts with being the experts in understanding our respective products in context of their intended use. Whether you are a laboratory scientist discovering novel activities and mechanisms of action of your favourite cell type, a technical specialist developing manufacturing protocols, a regulatory or quality expert guiding control of products and processes, or a translational medical scientist aiming to provide cellular therapy for a disease with unmet medical need, understanding product potency, i.e., the nature and the activities that are critical for a specific intended use is key for ultimate success. Describing and analysing the potency of cellular therapeutics is an intricate and multi-layered endeavour, which has been discussed by ISCT many a year in its past (for example, see 1).

At the closing of 2023, the FDA released a new guidance document, entitled “Potency Assurance for Cellular and Gene Therapy Products” (2). This is immediate and essential reading for all stakeholders in the CGT field. In keeping with the rapid advancement of cell therapies in recent years, the FDA’s intention is to guide effective product potency assurance that is at the same time constructive, feasible and flexible, yet stringent at its core principles. A great starting point for learning about this new guidance is provided by a publicly available 20 min pre-recorder webinar (3). Matthew Klinker, FDA’s Office of Therapeutic Products (OTP), provides a high-level introduction of the new “broad approach to assuring potency”, defined as the Potency Assurance Strategy (PAS). PAS applies to all stages of the product development lifecycle. Although manufacturing protocols are the fundaments to production of consistent product lots, measured by in-process in release testing, the scope of the PAS goes beyond manufacturing alone. Other product evaluations, including sterility and stability testing, are still required in parallel.

What is this Potency Assurance Strategy?

PAS consists of a multi-tiered strategy in which FDA prompts CGT developers to use the following elements in an iterative manner, using manufacturing and clinical data as they become available at the various development stages.

It starts by defining the critical quality attributes necessary to accomplish the intended therapeutic effect. This requires a fundamental understanding, not just of product properties and activities driving possible mechanisms of action, but also of the relevance of these properties in context of the specific clinical use pursued. Critical attributes might be different for the same product when used in different indications and the first task of CGT developers is to define that critical attribute package for each use.
Use of target product profiles (TPP) as the tool for defining and tracking potency assurance at all stages of development.
Establishing a risk assessment system to identify and review any factors that may negatively impact defined / assumed potency attributes. This again starts with, but is not limited to, the process of manufacture, and extends to exposure of products to different conditions during shipment, storage, and manipulation for infusion. Expected output of this exercise is establishing in the best way possible what the probabilities of occurrence of these risks are and what the severity of impact may be.
Following risk assessment, a risk mitigation mechanism should be instituted to minimize the risk.

FDA fully expects any PAS program to grow over time, requiring refinement during development, resulting in an increasingly fine-tuned product potency description, ideally involving quantitative bioassays and manufacturing and clinical data.

How will FDA Further Support Product Potency Assurance?

FDA Provides

Broad guidance on PAS with the objective of ensuring that every product lot has potency necessary to achieve the intended therapeutic effect
Guidance on data collection throughout development life cycle
Facilitate effective communications, with instructions on how and when to contact FDA for PAS discussion provided in the guidance
Review of PAS proposals submitted by CGT developers

CGT Developers are Expected to

Be the subject matter experts for their product, owning all aspects of PAS for each CGT product under development
Review FDA guidelines and implement the various layers of PAS activity
When ready, contact FDA for discussion of comprehensive PAS programs with description of all required tiers of potency assurance
Use PAS at all stages of development and refine the product potency as development continues

This new 2023 draft guideline for potency assurance provides a very useful and timely framework. Where the earlier guidance published in 2011 mainly focussed on potency tests, the 2023 document describes a broader approach, that can be flexible as needed, but remains stringent on core measures, such as definition of acceptable ranges for potency measures and weighing the relevance of data output from different measures. Who’d have “thunk” using FDA and flexibility in the same sentence a few decades ago? Here FDA appears true to its ambition of seeking to be conceptual and enabling of innovation in the world of the complex and ever evolving therapeutic modalities that CGT products comprise.

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