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PharmTech.com Quality and Regulatory Sourcebook eBook March 2024 Pharmaceutical Technology ® 17 Aseptic MAnufActuring team understand the objective of the exercise by defining a risk question that sets the objective of the assessment. A possible risk question might be: What are the measurable factors that can help define the risk of microbiological contam- ination of sterile product during performance of the intervention? And what is their measurabil- ity, accuracy of measurement, and correlation to that risk? • Defining the intervention. To determine the risk of the inter vention, one must define the inter- vention. It is important to decide whether the intervention is the combination of a set of ma- nipulations or activities; or each manipulation or activity is a separate inter vention. To start, the intervention should be defined as it would be in the aseptic process procedure. • Selecting a diverse team and experienced fa- cilitator. The IREM is based on identifying the el- ements of an intervention that contribute risk to product sterility. These elements are determined by a diverse team using a keyword approach. The team is facilitated and is made up of as many of the aseptic processing stakeholders as possible, including representatives from aseptic filling, set-up, maintenance, environmental monitoring, quality assurance (QA), quality control/microbi- ology, validation, engineering, quality and man- ufacturing management, and regulatory affairs. • Using the keyword approach. With the keyword approach, the team focuses on the risk elements, criteria, and wording that is meaningful to them. As such, the outcome may not be what other teams in other companies may select, but it is what is true for the team performing the assess- ment. This is important, because it helps ensures ownership, familiarity, and usef ulness of the IREM outcome for that organization. To prop- erly use the IREM model, the participants should have knowledge of the risk associated with the performance of interventions. This knowledge can be obtained from historical performance and monitoring data, experimental studies, air visualization studies, production logs and yield reports, media fill results, failure investigations, and published papers and opinions (5,6,7,8,9,10). It is also important that the team recognize that no one element may define the risk. The risk is a combination of all elements. • Identifying quantifiable risk factors. The im- pact of an intervention may not correlate to mi- crobiological contamination of product, making it difficult or not feasible to measure the risk posed by the intervention. The IREM is designed to uncover those elements or parts of the inter- vention that affect risk and can be measured. To maintain a level of simplicity, it is important to limit the number of risk elements that will need to be compared and assessed. It should be noted that these elements or factors may not have the precision to be the sole means to measure the risk or have a perfect correlation to the risk. However, because they can be measured and they have a relation to inter vention risk, they can be used to help determine the relative risk of interventions. • Ensuring that the data are available. The data and criteria by which the risk factor is measured must be available for those performing the IREM. As the factors are identified, the source of the data needed to meet the criteria should be iden- tified. Most of these data should be available in procedures, manufacturing instructions, batch and aseptic process simulation (APS) activity/ob- servation logs, and training materials, or from interviews of those performing or observing the interventions. • Setting the ranking criteria. To avoid bias and predetermined outcomes, it is important that the criteria, procedure, and rules be set before the assessment is performed, and that, once set, these are not changed for a given assessment, even if the outcome is not what was expected. • Assessing qualified, well designed, and prop- erly performed interventions. The IREM should not be used to justify the acceptability of other- wise unacceptable interventions or poor aseptic practices. Where the IREM or other assessment or evaluation identifies unacceptable or poor aseptic practices, those practices should be cor- rected or excluded from the aseptic process. • Reducing high risks. Because the objective of risk management is not merely to identif y or rank risk, but to reduce risk and improve the pro- cess, wherever possible interventions ranked as high risk should be reduced to acceptable levels. While all intervention risk should be reviewed and where possible reduced, more at tention should be placed on risks that the IREM identi- fies as posing a higher risk to product sterility. • Following up: Residua l risks resulting f rom mitigation efforts should be evaluated for neg- ative, unintended consequences of those actions or changes. The results of the IREM should be reviewed periodically to confirm that the IREM assumptions and criteria remain effective and optimal, and that any additional needed risk mitigation actions are performed. In contrast to automated processes, where a human intervention may only occasionally or irregularly be needed, a manual or semiautomated operation might be designed in such a way that the entire aseptic pro-