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18 Pharmaceutical Technology ® Quality and Regulatory Sourcebook eBook March 2024 PharmTech.com Aseptic MAnufActuring cess may be carried out in the presence of an operator or any of his body parts in a grade-A environment. Due to such dependence on people and their close contact in the aseptic environment, these operations pose particular challenges. The variety of skill levels in a facility and daily individual performance variability of the operators, makes determining and mitigating risk more difficult. The application of IREM methodology for risk assessment aids in the objective identification of such risks and the development of mitigation strat- egies. This article presents a few real-world examples of how the IREM model has been used for manual and semi-automated aseptic operations. Case study This case involves the use of IREM to determine the relative risk of interventions performed during an aseptic compounding operation. T he product se- lected in this case study is a sterile suspension for in- jection, which is compounded in two parts. The first part is compounded in a grade-C area, which is then transferred to an aseptic compounding area for ad- dition of sterile API. The aseptic compounding area houses a mixing vessel with inline homogenization facility under a grade-A environment surrounded by grade-B. The grade-A environment is maintained by a laminar flow hood enclosed with a rigid barrier (not fully closed, just extended down below the working height of the vessel) and glove ports. Post compound- ing, the vessel is transferred manually to the filling area by removing this rigid barrier. Process description. The two parts of compound- ing activity for this product are as follows: • preparation of aqueous non-sterile bulk of vehi- cle in grade-C compounding area and transfer of the same to the aseptic compounding area through sterile filtration. • asept ic addit ion of pre-ster i lized A PI in t he filtered bulk from the previous step in aseptic compounding area (grade-A), which is protected with a conventional laminar flow unit with rigid barrier (open type) and glove ports. The steps involved in this process are described in Figure 1 [Click here to view Figure 1]. Team formation. A cross-functional team (consist- ing of production operators, microbiologists, engi- neers, validation experts, and QA) was formed with a given objective of identifying the risk factors associ- ated with aseptic process interventions and design a risk evaluation tool to identify the risk levels associ- ated with this aseptic compounding line using a con- ventional laminar air f low unit with rigid barriers. Each inter vention connected to this production line was brainstormed from a risk perspective by the team. As a starting point, the team used the inputs from part one of this article to determine potential risk factors and approaches to reduce them. The team f urther worked with engineers to understand the possibilities of process and equipment design solu- tions to eliminate certain interventions and mitigate risks with some of the interventions. Identification of the risk factors. At this point, the team's main goal was to discover the risk variables connected to aseptic compounding operations that could be quantified objectively. The following inher- ent interventions were identified for identification of the risk factors and subsequently building the risk evaluation tool: • setting up for filtration/filter integrity • transferring the sterile API in triple laminated pack to the grade-A aseptic compounding area • cutting open the final pack before charging the API into the vessel • API charging in the compounding vessel • addition of pH buf fer in the vessel for pH ad- justment • closing the lid of the compounding vessel • sample collection. The team recognized that even if all the risks asso- ciated with the interventions could not be determined objectively, there might be some aspects of such inter- vention that could be measured. After team discussion and refinement, the following risk factors and ratio- nale were decided for the risk assessment. Duration of intervention. Duration, measured by number of minutes to complete the intervention, was considered an important risk factor. The longer the duration, the higher the potential risk of contami- nation. Based on the historic data review from com- mercial batches and the media fill study from past years, most of the interventions were found to take between three and 10 minutes to perform. This "most" level was defined as normal. Therefore, any dura- tion less than normal or less than three minutes was considered a lower risk concern; any duration above normal, or more than 10 minutes, was considered a higher risk concern. Here, the data for determining duration could be attained from activity/observation logs, training materials, and interviews. The team selected duration because they assumed that if an inter vention or activity posed a risk, the longer it occurred, the greater the risk. It is important to note that the duration here indicates the average time required by the trained aseptic area operators to perform an activity, and it relies on deliberate and controlled behavior and movements. Therefore, it should not be confused with the speed of perform- ing a given intervention, where a faster pace could also pose a higher risk if those movements were per- formed too quickly. It is important to emphasize that the IREM is used to assess well-designed, qualified, and properly performed interventions by pre-qual-