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6 BioPharm International ® Manufacturing and Facilities eBook 2023 www.biopharminternational.com Manufacturing: Single-uSe SySteMS sterility is maintained, strict regulations must be fol- lowed. Recently, Annex 1 of the European Union's good manufacturing practice (GMP) guidance has been re- vised and its new version outlines detailed and strict sterile processing rules (3). These guidelines must be followed to ensure effective sterile drug manufacture, which is essential to obtain drug approval. Annex 1 aims to incorporate aseptic processing by minimizing environmental exposure and limiting the number of manual handling steps. Using quality risk management-based approaches, the recent additions to the guidance include: • Contamination control strategy (CCS). The CCS acts as a living document, outlining and examin- ing each process and validation procedure across the cleanroom to ensure they meet quality stan- dards. This document will be constantly reviewed to ensure all possible sterile considerations and risks have been identified and mitigated to ensure product sterility. • Cleanroom requirements. These include efficient and effective cleanroom design and operation, including the use of restricted access barrier sys- tems, comprehensive design and specifications for airflow patterns and air pressure, and verified equipment and personnel training to provide a high degree of assurance that the largest risks of contamination have been eliminated. • Pharmaceutical quality system (PQS). Related to the International Council for Harmonisation (ICH) Q10 quality management system guidance, PQS outlines specific requirements for sterile manu- facture, including risk management and process understanding, to de-risk sterile manufacture (4,5). These strategies aim to ensure sterile integrit y throughout manufacture. Incorporating SUTs into manufacture is one method to help introduce sterile product integrity. These disposable systems assure the same level of sterility as stainless steel-built cleanroom equipment but require no cleaning or validation to prevent cross-contamination or bioburden. The risk of exposure resulting in non-sterile products is also significantly reduced, saving time and reducing costs. De-risking SUT solutions Before incor poration into manufacturing, the re- vised Annex 1 sets out several risks associated with SUTs, which should be addressed as part of the CCS, including: • product interaction with the contact surface (e.g., adsorption or the formation of leachables and ex- tractables) • fragile nature of SUTs compared to steel-based cleanroom systems • complexit y of assembly, with various connec- tions and individual components required • risk of holes and leakage • potential of compromising sterility of the system when opening the outer packaging • risk of particulate contamination (4). Assessing and mitigating these hazards is an es- sential part of SUT manufacture and should be com- pleted by the provider before incorporation into asep- tic processing lines. When they are constructed to high standards, fit- for-purpose and off-the-shelf SUT solutions can be instrumental in maintaining sterility throughout the drug manufacturing process. Transfer between equipment poses a significant contamination risk. By introducing SUT solutions such as split butterf ly valves and f lexible bag systems, which provide ste- rility, these risks can be mitigated. These systems allow the transfer of a product from one container to another without exposure to the outside environ- ment. Helping to reduce material vulnerability by closing manufacturing systems, SUTs can also help to streamline production, minimizing manual han- dling and accelerating drug production. Therefore, SUT systems offer an alternative solution to steel- based cleanroom equipment. Guaranteeing robust SUTs Annex 1 outlines that systems must be designed to maintain integrit y throughout processing under the intended operating conditions. The structural integrity of the single-use components is necessary as the system may be subject to extreme conditions (e.g., due to cold-chain requirements), either during routine processing or transportation. Questions as to whether SU Ts, which are of ten formed of plastic, would be robust enough to with- stand the production process often arise. Loss of in- tegrity would lead to exposure of the product to the environment, losing sterility and posing a safety risk. Maintaining sterile integrity is essential for therapies that are injected into the body, such as [advanced therapy medicinal products].