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16 Pharmaceutical Technology ® Quality and Regulatory Sourcebook eBook March 2024 PharmTech.com Aseptic MAnufActuring jective, data-driven risk assessment is becoming even more important to assess the risk of interventions in a more holistic way and with true representation of ac- tual shopfloor conditions in any given line. This need reflects the current expectations of global regulators as defined in the contamination control strategy (CCS) and QRM sections of European Union and Pharma- ceutical Inspection and Co-operation Scheme (PIC/S) Annex 1 guidance and regulations (2,3). One key aspect that differentiates IREM from other risk assessment tools is that it empowers those per- forming aseptic processing activities to design their ow n risk assessment model and establish a m iti- gation strategy for themselves. IREM involves the people from the shopf loor or cleanroom who are re- sponsible for performing the process control activi- ties. This helps identif y the core risk elements and risk mitigation steps. As such, it creates a better sense of awareness and ownership by those individuals for mitigating those risks. This article focuses on manual or semiautomatic aseptic processes, which have come into significant use due to expansion of ATMP manufacturing and other complex biopharmaceutical manufacturing processes, and aseptic compounding that requires manua l aseptic man ipulations during t hese pro- cesses. The need for guidance to identify and mitigate aseptic processing risks for ATMPs and certain other manual operations has become a significant concern in the industry. The authors present a case study to illustrate the use of an IREM to evaluate the risks posed by inter ventions during aseptic compound- ing. The IREM team is encouraged to use a keyword approach to choose risk factors and ranking criteria that are meaningful and fit the circumstances at the site. In the following case study and in the previous article, five risk factors were identified as opposed to the three identified in early IREM publications (4). The factors and associated criteria selected may not necessari ly be optima l or applicable to ot her teams and other sites and are not meant to present prescriptive or exclusive risk factors and ranking criteria. However, they are still defendable, have a scientific basis, and are meaningful for the determi- nation of relative risk ranking and mitigation for this site and circumstances. It is important that, for this site and circumstances, the risk factors and ranking criteria are applicable, have a defendable and scien- tific basis, and are meaningf ul to the assessment team. The f lexibility of allowing the team to choose its own risk factors and criteria helps ensure that the company will use the IREM to its full potential, to establish and mitigate the line-specific risk factors, and not merely go through the formality of a risk as- sessment exercise. Risk of interventions in aseptic processing Irrespective of the t y pe of manufacturing system used, interventions in an aseptic process pose some level of risk of microbiological contamination. But the magnitude of such risk could be much higher when it i nvolves m a nua l or sem iautom at ic pro- cesses in a less contained grade-A environment, as compared to highly contained automated processes. However, manual aseptic processing is used in cer- tain types of biopharmaceutical operations, where product sensitive to microbiological contamination cannot be manufactured using an automated process due to batch size limitations, high machine wastages, or process complexities involved in automation. Un- derstanding the relative microbiological risk of these interventions provides valuable input for designing, qualification, monitoring, controlling, and improv- ing interventions and aseptic processes. An effective risk assessment should be objective, accurate, and useful. It is most useful when it cap- tures the relevant risk factors pertaining to a specific line as identified by the people who are on the ground. There has been a significant amount of work done in the past by industry experts to build risk assessment models specific to aseptic processes. The uniqueness of the IREM is that it is designed to be performed by all levels of aseptic processing personnel from man- agement to the shopf loor or cleanroom personnel. This allows for a more complete design of risk evalu- ation and mitigation criteria that empowers all levels of operating personnel. It develops awareness and ap- preciation of the associated risks amongst shop f loor operators, which can lead to a reduction of the overall risk level and improve the sterility assurance level. Building the IREM The IREM follows a set of steps and assumptions that include the following: • Establishing the risk question. Before begin- ning the risk assessment, it is important that the The need for guidance to identify and mitigate aseptic processing risks for ATMPs and certain other manual operations has become a significant concern in the industry.