A critical parameter of cell and gene therapy manufacturing is microbiological contamination control, for both patient safety and regulatory compliance. Clean, decontaminated work areas plus a closed process are common expectations in the regulatory guidance designed to reduce risk of contamination. Pragmatic process design in clinical development and then scaled for commercial manufacture could be an opportunity to build robust contamination control and reduce validation.

Good Manufacturing Practices are the foundational regulatory requirements to protect the patient by preventing contaminated product in its life cycle. The latest ‘incentive’ from proposed European Union (EU) Guidelines to Good Manufacturing Practice for Manufacture of Sterile Medicinal Products, Annex 1 revisions is ensuring presence of a robust Contamination Control Strategy (CCS).

It requires:

• Clear governance oversight
• Full transparency of the operation as it impacts contamination control
• A continuous or ongoing effort to monitor the identified controls to ensure they are fit for purpose.     

Risk assessment is the standard approach to determine appropriate options for process and facility controls, as part of the contamination control strategy. Training and oversight of operator aseptic skills, consistent following of procedures and adequate gowning practices, are substantial factors that influence contamination prevention. Among the most critical factors that complement these influences come from robust design and operations of the facility infrastructure.

Risk-based Solution
Simplicity in design has a positive influence on contamination control. Biopharmaceutical processes have increased complexity, thus an increased risk from possible contamination. Similarly, cell therapy manufacture has a complex process flow. Some of the key steps in the complex process are: cell separation/isolation, transduction, expansion, and harvest. The FDA Guidance for Human Somatic Cell Therapy and Gene Therapy (March, 1998) indicate the importance of preventing adventitious contamination when handling human cells. Many of the manual steps that are or used to be performed in single or multiple biosafety cabinets with multiple manual transfers of materials now have options available to improve containment by using closed systems designed to reduce the risk of contamination by ‘closing the process’. The Pharmaceutical Inspection Co-operation Scheme (PIC/S) Good Manufacturing Practices for Advanced Therapy Medicinal Products (Annex 2A, February 2022) and European Commission (EC) Good Manufacturing Practice for ATMPs, Volume 4 (November, 2017) provide guidance for closed systems. New advanced technologies exist that have assisted in improving the design of the complex process. Sterile, single use containers are common with these designs. While new aseptic connectors may improve these steps, the use of tube sealing can add a risk, if not performed in a closed environment or if the integrity of the seal fails. Manual activities have a high risk for contamination and performing them in biosafety cabinets (not built for a closed system) within cleanrooms may not be the best choice. Also, high classification cleanrooms are expensive to build and operate. Isolators can offer a better controlled environment, separation of people from direct interface with operations performed, possible allowance of an adjacent lower classified cleanroom, along with the added capability of validated decontamination.

A closed system has become the standard for sterility testing across the pharmaceutical and biopharmaceutical network. Isolators are now the best practice expectation for performing sterility testing in any laboratory. The intended outcome of this design is microbial contamination control. The same consideration is used for closing process steps in advanced therapy manufacture. The isolator offers a sealed enclosure, positive (or negative) pressure environment, human intervention only through sealed gloves (or fully enclosed with no gloves), and capability for automated and validated hydrogen peroxide decontamination (built-in or connected). Closing and automating this process adds value to the manufacturing operation and can save development and production time. Proactive development at the clinical stage can also include investigation of such parameters as peroxide penetrability of storage container materials to ensure protection of cell viability. When isolators are included as part of clinical manufacture design, the subsequent change for scale to commercial advanced therapy manufacture is less complex and could reduce repetition of validation, saving time and costs.  An additional benefit for implementing an isolator in clinical manufacture is the importance of early training in this technology to ensure consistency throughout process development.

Keep in mind that process design alone cannot ensure robust contamination control. Most engineering controls require a robust infrastructure and ongoing training and oversight of operator activities. Taking the right approach to preventing microbial contamination is inclusive of stepwise training and learning. It is significantly important that operators must be trained appropriately to perform with consistent aseptic skill and behavior which will ensure consistency for a stable and effective control programme.