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22 Pharmaceutical Technology ® Quality and Regulatory Sourcebook eBook March 2024 PharmTech.com Aseptic MAnufActuring factor had more influence than others, then that could result in a different ranking value, but it is doubtful it would have much effect on the overall relative ranking. Further, this team did not identify any interdepen- dencies of the risk factors that could alter the final risk ranking of any intervention away from current outcome; however, companies are encouraged to look for any such possibilities while building their risk model. There are different methods to assess and evalu- ate risks. A qualitative risk evaluation method was used to describe this approach. It is a basic visual risk block approach that team members can grasp quickly without a great deal of training. It also provides an effective manner to visually present the method to the reader. The result of the IREM discussions, analysis, and conclusions are summarized in Tables I–VI. [Click here to view tables]. For each step and each risk fac- tor spreadsheets were created to list the interventions and respective risk factor values. These values were retrieved from other documents including batch re- cords, training procedures, SOPS, observation logs, and operator interviews. Table I su m m a r i zes t he combi ned r i sk fac tor rank ing criteria obtained f rom the individual in- tervention spreadsheets. The risk factors were then combined with other risk factors to provide the risk classes as noted in risk evaluation Tables II–V. [Click here to view tables]. Apart from the above-mentioned risk levels, there is a fourth category of risk defined by the team that is "Very High". This is an extreme risk posed by a combination of high-risk level of an intervention and high-risk human skill/experience factor as described below. The team decided to add the category of "very high risk" to distinguish between high-risk activities that could continue with additional controls in place to mitigate such risk, until more permanent fixes could be employed, and those activities that the IREM re- vealed to be so high risk as to be improper and, as a result, not allowed. The risk level limits (e.g., for duration) were iden- tified based on the trend of intervention durations in a specific compounding line that the team chose, which has a proven history of many years. These lim- its are not to be considered as a general requirement across the board for all aseptic compounding lines. Based on experience and process understanding, companies should develop their own logic for choos- ing these criteria. Risk level based on operator skills/experience and determined Risk Class. Af ter establishing a combined Risk Class, the overall relative risk was established using the aforementioned operator skills and demonstrated experience. Risk control/mitigation. After evaluating each inter- vention against the factors mentioned above, the next step is to control or mitigate the risks. A strategic ap- proach was defined as per Table VI [Click here to view Table VI] mentioned actions against each risk ranking to mitigate and manage the different risk levels. All the interventions would be further evaluated for new risk level after the mitigation actions. Application of the risk model. Once the Risk tool is developed, now the job is to execute the same in the shop floor. Table VII presents some examples of the interven- tions important for the discussion [Click here to view Table VII]. Final discretion. The time when this risk evaluation was done, the company had produced three batches of the product in the previous six months, and all the time the same experienced operator was involved. However, it was acknowledged that this dependence on a single operator could be risky in terms of business continuity of the product, especially when the demand for the said product increases. Hence, the immediate need was to deploy more experienced operators to run this operation. But the cross functional team at the site involved in this IREM process was apprehensive about a different challenge altogether. Due to the involvement of oper- ators' skill/experience factor in the risk level of the in- tervention, the final risk to the product could be highly dynamic and complex when multiple operators are in- volved in a particular aseptic operation. Hence, solely depending on the operator's skill level to control risk in the above scenario could be catastrophic in certain circumstances. This scenario led to a wider discussion in the com- pany with the involvement of cross functional SMEs and senior management representatives in several brainstorming sessions to identify a more robust and practicable solution. The team from site engineering, projects, and external vendors was engaged to identify engineering solutions to mitigate risks identified by the team. However, the changes proposed were so sig- nificant that it could lead to a long execution time and regulatory change process. Hence, finally, the company decided to suspend production of this product in this way and site transfer it to another more compliant pro- duction facility. What could the company have done differently? There is no substitute to barrier technologies (such as RABS or isolators) when it comes to manual aseptic pro- cessing. However, it is also true that it requires a very high installation and qualification time with sizeable capital investment. In a situation such as this, where the product is a critical lifesaving drug, the decision becomes critical to manage the product and patient risk, versus risk of drug shortage. Following are the risk mitigation recommendations in the above-men- tioned scenario: