ATMP Manufacturing Risks
In the first of four parts, we went in-depth on the origin of regulatory-related manufacturing challenges seen in the industry and what guidelines need to be applied early on. Now, we examine the process production risks associated with certain ATMP products and how we might address them with an effective contamination control strategy
Contamination Control Strategy
Many challenges have been met in ATMP manufacturing (Table 1), of which the development of a proper Contamination Control Strategy (CCS) for ATMPs is a frequently re-occurring one. The lack of a proper CCS may lead to recalls, regulatory scrutiny, and (temporary) revoking of manufacturing licenses. The CCS requires identifying, scientifically evaluating, and controlling potential risks related to product quality and patient safety. Progress has previously written in detail about CCS (see Progress: Notes on Annex-1).
Table 1. Specific manufacturing risks related to ATMPs.
One part of CCS for ATMPs is the prevention and monitoring of bioburden levels. One must avoid high bioburden levels as elevated levels may speed up drug product degradation and inevitably vary the drug’s potency. Also, in case of a contaminated product, a facility may be shut down for extended periods until the culprit has been found and removed. Many smaller drugs can be manufactured sterile by incorporating virus or bacterial removal steps after critical manufacturing steps assuring low in-process bioburden levels. These steps tend to enable high drug purity (i.e., fewer contaminants in the case of ATMPs) which also support a more consistent drug potency level. However, in-process removal of contaminants for ATMPs is challenging because ATMPs tend to be larger, unstable, and prone to aggregation (often clogging filters), and have comparable properties to potential bacterial or viral contaminates. Furthermore, their similar physiochemical identity also requires more complex detection assays for protecting purity and identity compared to small molecules where “quick” industry-standard biophysical tests may suffice.
Single-use sterile connectors and high cleanroom-grade areas are common strategies to reduce contamination risks in the ATMP field. For example, working in a cleanroom Grade B instead of D can reduce the bioburden risk by >95%. We also see that many Grade A isolators in Grade C/D cleanrooms are installed instead of the more traditional BSC in Grade A/B cleanrooms. These restricted access barrier systems (RABS) can improve aseptic performance and process separation for ATMP processes. Furthermore, tube-welding or sterile connectors are the preferred choice for many ATMP processes, where the closed tubes or pre-assembled tube kits are γ-irradiated, autoclaved, and packed. Then, the tubes are welded in the manufacturing rooms where every connection is visually inspected. However, tube welding may introduce particles complicating validation studies. Additionally, single-use plastic connections or single-use plastics may require more extractable and leachable studies (E&L). Yet, a closed process (e.g., by tube-welding and sterile connectors) can be placed in a ballroom Grade C cleanroom with more products produced next to each other instead of having to maintain many small product- /campaign-designated Grade B cleanrooms.
Another ATMP manufacturing risk is the variability in the yield of the product, the purity of the starting material, and the (genetic) stability of the product. For example, differences in (donor) starting material for cell therapy products increase cell count variability and batch success rates. For example, the genetic background of a patient or the difference in the number of chemotherapies. Many hospital techniques – such as the needle-puncture technique for biopsies or apheresis – are taking along microorganisms from the surface of the skin (or skin glands) into the starting material of ATMPs. This is a much smaller challenge for viral vector gene therapies as they have well-characterized and germ-free cell lines as starting materials. Viral vector products tend to have more challenges with (epi-)genetic drifts that may change viral vector titers over time, unstable reference standards, and difficult potency assays (the need to show consistent biological activity of the expressed transgene of a viral vector introduced to a target cell).
In summary, ATMPs have a higher risk for contamination and require a tight(er) contamination control strategy/risk reduction step than other products.