Expert offers advice for developing successful cell and gene therapy product quality system

Building a quality system for a cell and gene therapy (CGT) product requires a solid foundation based on knowledgeable staff, well-defined roles and decision-making, data integrity, independence of quality, effective procedures, and third-party oversight, according to a recent presentation at the Orange County Regulatory Affairs Discussion Group annual conference.

Early development of a CGT product involves a variety of different stakeholders, including hospitals, patients, cell processing centers, and other vendors. The interactions between these entities become more complex as a product reaches commercialization, John McShane, principal consultant, cell and gene therapy, compliance and business development at Lachman Consultants, told attendees.

As a product moves from development to commercialization, it “brings up the whole concept about comparability between the different cell processing sites, and to make sure that your product is staying the same,” he said.

Although 21 CFR 210.2(c) exempts investigational drugs and biological products in human Phase 1 clinical studies from compliance with current good manufacturing practice (cGMP) regulations, McShane said that parts of cGMP still apply for Phase 1 CGT products—namely, through adherence to cGMP requirements for written policies, manufacturing environments, controlled equipment, and data reporting. Manufacturers are also responsible for safety, identity, strength, purity, and quality (SISPQ) as well as the “the hazards and risks that might adverse the quality of the Phase 1 investigational drug.”

When a product moves from Phase 1 to 2, 21 CFR 210 and 211 apply except in certain cases, while 210 and 211 fully apply in Phase 3 and beyond, McShane said. “The expectation is of Phase 2 is that the company is complying with the 211s, albeit with some exceptions, like process validation not being required at that point,” he explained. “So we have a situation where a fair amount of cGMP is required for cell and gene therapy.”

The fundamentals of a quality system for CGT products are broadly applicable across companies, and starts with knowledgeable and well-trained staff that have well-defined roles and responsibilities. “For cell and gene therapy, given the high tech nature of the production, that’s incumbent on you to make sure that your people know what they’re doing and really why they’re doing it,” McShane said. “There should be clear decision-making and defined roles, responsibilities. I see some companies not necessarily empowering quality to be a decision-maker at the table or a decision-maker in general.”

Data that is accurate and reliable is also important, as is independence of quality, effective written procedures, and third party oversight, he added. “A company cannot delegate its accountability for quality product when working with [contract manufacturing organizations],” McShane said.

Quality system challenges and considerations

The quality management system should cover a product end to end, McShane said. “You have to define what the endpoints are,” he explained. “Are any vectors included in your GMP bubble? What are your critical materials, and how much do you need to be able to control those things?”

The quality systems need to be fit for purpose, which includes having in place quality and technical agreements, timelines for investigation and deviations, and appropriate standards. “The whole thought process around timeliness for investigations and deviations is a little different for cell and gene therapy, where typically in old line pharma, you would make sure that you had the impact assessment, the cause completed, and the deviation signed off prior to shipping,” he said. “In this particular case with CGT, you may only get to the impact assessment before you ship just because of the short vein-to-vein time.”

Companies also need to have a plan in place for non-conforming products, McShane noted. “If you don't meet specifications, but yet you have material that could help a patient, now you have to make a decision on whether or not you can ship that product to that patient—and that does happen,” he said.

Other challenges including ensuring there are no gaps in a product’s chain of custody, pedigree, and chain of identity, and that companies have a good product understanding, “because you're going to be relying on that in terms of impact on safety and efficacy for your process as well as any deviations,” McShane said.

“One of the main tenets of good processing is actually to look at your processes and determine which ones of those processes can be turned into closed systems so that there’s no chance of any environmental contaminants or human-derived contaminants into a system,” he said. “If you can make your process closed, you’re going to be pretty far ahead.”

A critical element of quality systems is considering aseptic operations and technique as well as scheduling. “These cell processing centers are not necessarily huge centers in terms of the volume that they can take,” he said, noting that companies should consider where and when to ship in and their own availability of raw materials.

Building the quality system

A quality system should be developed alongside the beginning of product development and consist of “a written plan that will change and get updated as the company progresses.” Start with details about core activities with an “early emphasis on data integrity,” McShane explained.

“Continue to update your quality system and increase rigor before the needs arise,” he said. “Your early goal is to have a working quality management system in place prior to manufacturing for first-in-human, and you need to emphasize patient safety. The end goal is successful licensure of your product, enabling a strong quality management system.”

McShane suggested companies develop a “Phase 1 readiness checklist” that includes documentation, controls, data, roles and responsibilities, operations, types of materials used, potential hazards and action plans, information on work areas and equipment, and third-party oversight.

“You’re going to check through all these various areas before you start production, basically as a stage gate,” he said. “Documentation means all your procedures, any of your risk assessments, and so on and so forth. There really is a real need to make sure that you’re ready, because if you're not ready, it'll be very hard for you to end up with making quality product.”

Readying for inspection

For pre-approval inspection, companies should have four objectives: readiness for commercial manufacturing, conformance to application, ability to undergo a data integrity audit, and a commitment to quality in pharmaceutical development.

“The fourth objective is new as of 2022,” McShane said. “They're going to look back and say, ‘Were you in control from a quality perspective during your development phase?’ That’s an important factor, and something that you really have to think about as you prepare for an inspection.”

To prepare for a pre-approval or pre-license inspection, companies should be able to speak to any chemical, manufacturing, and controls (CMC) concerns raised by US Food and Drug Administration (FDA) inspectors, and be able to show a connection from development, to validation, to master batch record, and CMC, McShane explained.

“If you’ve had information requests, that’s important to make sure that you can adequately defend where you’re at and show that the FDA concerns are unfounded,” he said. “You’ve got to look at your major deviations, particularly from the process performance qualification and update them as required. I would say that you need to be able to present on those, just because the FDA is going to look at your process performance qualification runs.”

More broadly, companies preparing for inspection should develop a list of topics and then assign experts to develop presentations, gather documents, and perform mock inspections, including the tour route for inspectors. “That happens in the first day and sets the tone for the rest of the inspection,” McShane said.

McShane pointed out that FDA never waives the requirement to reinspect a site in the event of a complete response letter resulting from manufacturing issues identified during inspection.

“The site will have to remediate the issues before refiling,” he said. “The approval delay is generally 12 to 18 months, and you can think about the lost revenue and the lost first-mover advantage amongst you and your competitors.”

Quality culture

McShane emphasized the need for a quality culture throughout the process.

“I've seen so many companies, as they transition from preclinical to clinical, to commercial, that they need to change the organization and the quality system to adjust to cGMP and ensuring safety and compliance,” he said.

“Many of these companies struggle with this transition,” he added, particularly in areas of investigation, process controls, data integrity, personnel training, procedure, and adequacy.

“What you really have to emphasize is that quality culture is important and is foundational to having a robust quality system, because you can have all the paper in the world, but if nobody's following it, you don't really have a quality system,” he said. “You’ve got to live that quality system all the way through the organization, from the people at the floor level to the C-suite.”

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Expert offers advice for developing successful cell and gene therapy product quality system

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