A fundamental tenet for drug product development is that a clear and deep understanding of the product is required to appropriately develop and characterize it. Exploring product attributes early in development will facilitate identifying which critical quality attributes (CQAs) to focus on in later clinical phases.

At the ISPE Annual Meeting held in Orlando, Florida, in early November 2022, Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) Division of Cellular and Gene Therapies Branch Chief Melanie Eacho discussed common issues her office sees in early phase development and in Biologics License Applications (BLAs) for Cell and Gene Therapy (CGT) products submitted for approval.

Part Three of the four-part story focuses on Eacho’s discussion of product CQAs, lot release, and device considerations. Part One focused on insights into FDA’s New Office of Therapeutic Products, and Part Two explored common CMC issues in early development.

Exploring Product CQAs

As part of developing product Critical Quality Attributes (CQAs), Eacho advised exploring the attributes early to help decide on relevant tests for later phase studies.

She provided the ICH Q8(R2) definition for CQAs: “A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.”

Exploring more than one method may also be helpful in the future to identify a more efficient or reliable method, and importantly, to establish product comparability to facilitate the inevitable manufacturing changes that occur.

In addition, doing so will help identify new manufacturing facilities since comparability studies will be needed for those purposes.

For example, Eacho recommended evaluating multiple measures of CQAs, especially potency, looking at a matrix of assays, orthogonal methods, and stability-indicating assays.

Lot Release Considerations

Lot release specifications, Eacho pointed out, exist to set expectations for product safety and quality. Setting the lot or product release specifications requires a lot of data collection.

“During the early phase of your study, you want to be able to explore as much as you can, determine what attributes to include, and some of your lot release specs to set appropriate lot release criteria for these specs,” Eacho said. “And many of those will fall under the identity and potency assays, which are important because these are what determine when to cut off if some of your lots are not meeting the release criteria.”

Common issues that FDA sees when choosing product release specifications are summarized below in Figure 1.

CGT3 Figure 1 — **Figure 1** | **Common Issues with Choosing Product Release Specifications**

Eacho annotated the list by pointing out the importance of having justifications for the specifications and posing some related questions:

Is the release criterion a key product attribute?
What is the set acceptance criterion? How is it set? Do you have data to support it?

Keyword Search in the Redica Systems Platform

In the above section, Eacho states, “Setting the lot or product release specifications requires a lot of data collection.” When collecting data and researching this area, utilizing keyword search in Redica Systems can be helpful.

Since we want to take a look at documents containing the phrase “lot release” we will first head over to the documents tab and type out our desired phrase in the search bar at the top of the page. See figure 2.

The results from the search totaled 819 documents. 707 are FDA non-conformance documents (483s, Warning Letters, and EIR), and 112 are from regulatory surveillance signals.

To take a peek at the contents of these documents and other search capabilities of the Redica Systems Platform, schedule a working session with us today.

Medical Device Considerations

Another important element of CGT product development that is the subject of communication between product developers and the agency is the proposed method of administering the product.

“As simple as it may be, this is something that we encounter a lot. Even something like an intradermal injection or an IV infusion,” Eacho explained. “Information on the syringe and the needle gauge is very informative to understand the worst case conditions, and identifying the cells that will be affected so that we can determine compatibility of the cellular product with the delivery system.”

Here are a few questions she proposed answering:

If delivery is by catheters, for example, are you using an FDA-cleared or approved device that is intended to deliver a drug?
Are there any cumulative endotoxin concerns from the cell product in the delivery device for products delivered, especially to the intraocular space? There is a much lower endotoxin limit due to the potential for developing Toxic Anterior Segment Syndrome (TASS) – a sterile inflammatory condition localized to the anterior segment of the eye following intraocular surgery.

Eacho advised knowing the FDA regulatory status of the delivery device and performing comparability of the cellular product once passed through the delivery device to show that the product before and after passage through the delivery device is unchanged.

Also, be sure to verify that the amount intended to be delivered is delivered out of the delivery system.

No matter how simple or complex the delivery device, Eacho pointed out, it should be tested for compatibility with the final product and for safety, including:

Biocompatibility
Shear forces and clumping
Product stability at high concentrations, and
How much product is delivered

In summary for this third installment of our four-part series:

Evaluate multiple measures of CQAs
Know the FDA regulatory status of the delivery device
Perform comparability of the cellular product once passed through the delivery device to show that the product before and after passage through the delivery device is unchanged

Stay tuned for the last installment detailing the insights Eacho provided:

Part Four: CMC Expectations And Challenges In Late Phase Development.