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Jerry Martin is Senior Vice President and Global Technical Director, Biopharmaceuticals at PALL Life Sciences.
Maintaining asepsis and sterility is the primary challenge to implementing aseptic techniques and sterile processes in biopharmaceutical manufacture. Efforts to reduce the risk of microbial contamination of aseptically filled biotech products beyond their already low level represent engineering challenges, that don?t really compliment the progress in biotech R&D.
Maintaining asepsis and sterility is the primary challenge to implementing aseptic techniques and sterile processes in biopharmaceutical manufacture. Efforts to reduce the risk of microbial contamination of aseptically filled biotech products beyond their already low level represent engineering challenges, that don’t really compliment the progress in biotech R&D.
Recent innovations in aseptic techniques and sterilisation in biopharmaceutical manufacturing that have been key to improving the process include the introduction of single-use disposable filtration and filling systems composed of large-scale sterilising filter capsules, polymeric biocontainers, tubing and sterile connectors. These pre‑assembled systems complete with validation and other documentation to meet regulatory and industry requirements are supplied pre‑sterilised by gamma irradiation, reducing both the number and risk of aseptic connections, as well as eliminating the user’s sterilisation and validation requirements. Closed pre‑sterilised systems provide higher assurance of maintaining sterility and cleanliness of fluid pathways up to the point of filling.
Quality control and compliance
In an industry where patient safety is paramount, regulatory changes have kept aseptic manufacturers on their toes. The latest revision of EU GMP Annex 1 (March 2009) calls for bioburden to be determined prior to the sterilisation for every batch of aseptically filled product. Traditional pharmaceutical microbiology quality control methods require at least 35 days to quantify microbial levels, so results are only available after processing. Conducting such tests on every batch is considered burdensome. The development of rapid microbiology technologies, such as adenosine triphosphate (ATP) bioluminescence and PCR nucleic acid‑based tests, however, makes such bioburden monitoring of pre‑sterilisation feeds, intermediates and raw materials feasible with minimal cost and labour, providing results within 24 h versus several days. Regulators in Europe and the US have encouraged the implementation of rapid microbiology methods and are working to ease regulatory validation requirements to facilitate broader implementation.
The future of aseptic techniques in bioprocessing
The increased use of preassembled, presterilised single-use filtration and filling systems to minimise aseptic connections and sterilisation will probably feature in the future of bioprocessing. More final filling will be done in isolators under robotic control to remove operator involvement the primary source of microbial contamination of aseptically filled products. Rapid microbiology methods will be incorporated for liquid feed and environmental monitoring. While 0.2 μm rated filters will continue to be the most widely used for the sterilisation of aseptically filled sterile drug products, high capacity 0.1 μm rated sterilising filters will be increasingly used for soy‑based media sterilisation in cell culture and aseptic fill validation to ensure absence of contaminating mycoplasma (e.g., Acholeplasma laidlawii). Although these technologies already exist they are not yet widely implemented. Innovations are needed to increase ease of use, reduce cost of installation and validation, and increase regulatory familiarity and acceptance. Improvements will be seen that further reduce media fill and product sterility test failures, product recalls and regulatory actions for insufficient sterility or sterilisation validation.