Contamination Control Strategies for Cell and Gene Therapy Facilities at INTERPHEX 2024

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At INTERPHEX 2024, BioPharm International® attended a panel discussion on contamination control strategies (CCS) for cell and gene therapies. The panel featured James N. Polarine, a senior technical service manager, STERIS Corporation; Matt Hofacre, senior director of technical services for the equipment and services group, STERIS corporation; Marsha Steed, founder and president, Steed MicroBio; David Talmage, vice president of education, Parenteral Drug Association (PDA); and Vanessa Vasadi Figueroa, chief microbiologist, VVF Science. The panel gave an overview of a CCS, going into detail on what regulatory bodies are requiring from manufacturers, as well as the best practices in regard to contamination control in clean rooms. The panelists went over challenges associated with cell and gene clean rooms, the most common ways that contamination occurs, and how manufacturers can implement a contamination control strategy, even without the resources for a fully isolated clean room.

As reviewed by Steed, a CCS is a “planned set of controls for microorganisms, endotoxins/pyrogen, and particles derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance, excipient, and dug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control” (1). With new requirements put forward in Annex 1 and advanced therapy medicinal products (ATMP) guidance, a CCS is now mandatory for cell and gene therapy facilities.

Figueroa pointed out that these guidelines aren’t new to manufacturing. This is already a part of the industry, she said, and now it’s being formalized. Instead of the responsibility being on finish product release, the responsibility has shifted upward into to the process, she said. Every part of the process is critical for contamination control, and it is everyone’s responsibility now to understand the process and minimize contamination. The largest source of contamination, Figueroa emphasized, is people, followed by raw materials and process materials. She said that it’s important for manufacturers to check raw materials and process materials in house and to demand higher quality products from vendors. Having some version of a control process is a good business strategy, she said, whether it is being required or not.

The significance of human risk was brought up again by Talmage. People are critical in this process, he said, and the environment is crucial to preventing contamination. While the medicine of cell and gene therapy is innovative and groundbreaking, in a lot of cases the environment it’s being done in is a typical lab environment, and the behaviors of people translate into that environment. What Talmage often sees, he said, is a lack of gowning. Wearing multiple pairs of sterile gloves, and sterile sleeves, is very important, as well as considering the material flow.

Hofacre brought an engineering perspective to the discussion, mentioning the equipment that regulatory bodies want to see when they inspect facilities. The ideal, he said, are closed, automated systems with as little contact and contamination as possible. But in the industry right now most processing is done by people in open clean rooms, with material management being a high source of contamination. Not all manufacturers are ready to switch to a totally isolated environment, so Hofacre said that putting in place good practices is a big step in lowering contamination. Having a dedicated, single pass, with one way in and one way out, helps prevent recirculation contamination risk.

When making a CCS, it’s also important to consider how individual people behave, said Talmage. You need to consider how a person sits, how they rest their arms, and how long they’re going to be in that environmental. Looking at the ergonomics, not just from a biocontrol standpoint, but from an operator fatigue standpoint. Developers should consider the operator: they should take variables such as arm length and height into consideration, for example, before designing something that an operator would need to reach into. Polarine brought up the importance of decontamination (decon). He said that he often sees people bring items in without passing through decon, and without wiping the item down before use. Carts are a big offender in this; even if companies have carts set aside, they still need to be properly wiped down with disinfectant and sporicide before use.

Steed talked about her own experience with bio safety cabinets (BSCs), saying that they were innovative when they were first used in the lab, but that now many years later there are multiple, better options in the form of isolators. A traditional ATMP incubator has a risk of contamination and cross contamination, with the risk of mold developing in the incubators due to human error. With modern isolators, human interactions can be kept to a minimum, greatly reducing risk. One of the advantages of isolators is that they’re empty chambers, so they’re easy to set up, Steed said, and they are a much more sterile environment if used properly. There are many options for isolators, with some examples being closed robotic isolators, and isolators with glove ports for manipulations. Closed robotic isolators reduce human intervention but can be expensive to set up. Many companies instead opt for isolators with glove ports, or a modular option that has some steps inside the incubator (such as thawing the starting material) and some steps outside (such as culture mixing and transferring oxygen). One thing to keep in mind with these isolators, Steed said, is that the smaller a manipulation is, the harder it is to do through the glove ports. Operators should consider this limitation in dexterity when doing manipulations.

Figueroa said that biologics should learn from the mistakes that have been made in traditional pharma and get into isolators as soon as possible. If that isn’t feasible, she recommended starting out with a BSC or implementing alternative tools. Manufacturers should map out a sequence of operation steps, and anything that isn’t necessary for the process should be removed from the area. People need to be trained, she said, and an aseptic culture has to be established. Operators need to maintain a certain level of discipline while at work, and companies need to take the topic out of training once or twice a year and into everyday conversation. Talmage added that Technical Report #90 (TR90) from PDA has a program for the culture of aseptic behavior.

Hofacre agreed that while isolators are the preferred option, most facilities aren’t at the point yet where they can use them. He outlined an alternative option for open cleanroom suites, called integrated vaporized hydrogen peroxide (VHP) systems, which can create a bio decontamination container without isolators. Instead of bringing in mobile equipment or setting up equipment each time, companies can build a centralized generator that is piped to each individual cleanroom. He gave an example of a contract development and manufacturing organization that did cell and gene therapy and had 17 suites, who was able to decontaminate each individual suite with a VHP system while the other suites were still in operation.

As Figueroa said, the most important part of the process comes down to mindset. She encouraged companies starting a CCS to document where they are in their process today. They should document all controls, outline current elements, and then see where they can improve. That way companies can understand if their current controls are enough, or if more are needed. Steed encouraged manufacturers to work with the regulators to get current requirements down. Regulatory bodies are willing to help companies get a strategy down, she said. No matter where a company is at in their process, having better contamination control is a goal that benefits everyone.

Reference

1. Polarine, J; Hofacre, M; Steed, M; Talmage, D; Figueroa, V. Panel Discussion: Contamination Control Strategies for Cell and Gene Therapy Facilities. Presentation at the INTERPHEX Conference, New York City, New York, Apr. 16–18, 2024.