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Cell and Gene Therapy: CMC Challenges Lay Ahead

There is now hope for cures in rare diseases that were previously out of reach with traditional drugs and biologics. This was the collective perception of my fellow attendees at the PDA – Cell and Gene Therapy Conference in San Diego, Dec. 5-6, 2017. Such an outcome was not surprising given the stunning progress the field has experienced over the past few years. Some of these highlights included:

• Recent approvals of CAR-T products (Kymriah and Yescarta) and AAV gene therapy Luxturna late in 2017, are driving the flow of capital into cell and gene therapy (CGT) companies and technologies.
• FDA Product Reviewer Zenobia Taraporewala, Ph.D., reports that there were 1503 active INDs in the cell and gene therapy area.
• CBER’s Office of Tissues and Advanced Therapies had received approximately 40 active AAV gene therapy and 81 active CAR-T cell INDs as of November 2017.
• Gene editing has unlocked new approaches to cell and gene therapy.
• FDA regulatory options for accelerated approval (Breakthrough Therapy, and Regenerative Medicine Advanced Therapy (RMAT) Designation) change the landscape and influence development decisions.

The accelerated approval options noted in the bullet above have promoted rapid clinical advancement. However, CMC activities have not kept pace and are lagging behind the clinical progress. Limited manufacturing data and experience has hindered the ramp-up of planning for manufacturing process scale-up, comparability, and commercial manufacturing. Comparability studies are usually necessary because process and manufacturing site changes are inevitable as development continues. These comparability studies may be challenging due to lack of product understanding as well as limited knowledge of critical quality attributes, (COAs).

The two product technologies receiving the most attention were:

• In vivo gene therapy using adeno-associated virus (AAV) vectors
• CAR-T cell therapy

The key CMC challenges for AAV gene therapies presented at the conference are consistent with our experience from working in this field. They are summarized below in two categories, analytics, and upstream processing:

• Analytics are currently rudimentary, expect escalating regulatory requirements
• Dosing is normally based on genome copies, but this doesn’t measure activity of product
• There is a chance to re-create replication competent AAV, but methods to detect an active virus have very low sensitivity
• DNA residual levels are far above what is normally tolerated for biologicals
• Upstream processing is still in early days
• There is a concern over cell substrates with no long-term traceability, and with using transformed cells
• HEK 293 cell culture with plasmid transfection is the most common platform, but it is difficult to scale-up
• There is a limit on how much AAV vector that a cell can produce, so a process will need more cells and/or improved potency, to be able to supply some markets/disease indications

For the development of autologous CAR-T therapies, the key challenges from a CMC perspective are in the analytical and manufacturing areas:

• Analytical challenges:
• Complex products
• Setting up the appropriate analytics, knowing what to assay for, knowing the critical quality attributes
• Testing for purity and potency
• Product understanding comes later in development through manufacturing and clinical trial experience
• Manufacturing challenges:
• Variability of the starting material (patient-to-patient variability)
• Aseptic processing
• Viral clearance not possible
• Limited product stability information
• Small lot size and number

Across both product technologies, regulators expect that CGT companies follow “Control Strategy” principles (see ICH Q-11), and all of the same cGMP principles apply to these products as for biologics. The Control Strategy for these products matures during the product lifecycle, as with biologics. The difference for CGT products is that many products are on a fast-track, so CMC activities can be lagging, which compounds the inherent challenges in developing these more complex products. Elements of the Control Strategy may necessarily be implemented later in development compared to biologics, and, fortunately, the regulators understand this.

Our industry now has a “moral imperative” to deliver these new treatments to patients. It appears clear that the CGT industry will add another exciting chapter to the evolution of biotherapeutics.

Blog article by: Doug Miller

The following BioProcessBlogs from BPTC address other issues related to cell and gene therapies.

QbD and Quality Systems Challenges Ahead as Cell Therapy Moves Forward

Supercharged T-Cells Battle Cancer But Will GxP Compliance Be Their Kryptonite?

The Other CAR-T Race: Manufacturing