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20 Pharmaceutical Technology ® Quality and Regulatory Sourcebook eBook March 2024 PharmTech.com Aseptic MAnufActuring ified operators. Process design and training should establish the correct and consistent duration for the intervention. In some cases, the company may determine the range of durations, by recording the durations of inter- ventions and determining where a majority, say 80%, fall as medium or normal. Then the 10% that fall below that duration would be of less concern, and the 10% that fall above that 80% would be of more concern. These levels 80%, 10%, and 10% shall be decided by the team based on a scientific rationale supported by past experiences before performing the IREM assess- ment and would denote a relative state of risk. Complexity of intervention. Complexity is consid- ered an indicator of difficulty in performing an inter- vention. It is assumed that an increase in difficulty poses a greater risk to product sterility. The criteria for measuring complexit y and difficult y are chal- lenging to objectively identify. What may be difficult for one person, may not be difficult for another. For that reason, the criteria of number of steps required to perform an intervention was initially used. The number of steps, as ref lected in a written procedure, is clearly objective. Where manual, repetitive activi- ties are performed, such as those used in ATMPs and manual aseptic processing, it may be prudent and appropriate to also consider risk factors that are con- tributed by fatigue. The question of what constitutes a step in determining the number of steps is raised from time to time. One recommendation is to use the number of steps listed in the procedure or instruction document as an objective and comparable guide. Fatigue poses a risk to the performance of the ac- tivity because it can contribute to lapses in aseptic technique. The best way to address the risks posed by fatigue is by minimizing its impact on interven- tion performance, through ergonomics or additional breaks, or by eliminating the fatigue causing activity through process redesign or automation. However, as noted earlier, in the case of certain manual aseptic processes such as those used for ATMPs, it may not be feasible to modify the process design or add automa- tion. In these cases, fatigue may still be a risk factor. Af ter deliberations, the team in the case study identified the weight of objects handled during the intervention as a predictor of fatigue because it can be a contributor to fatigue, and it can be measured. It was noted that the strength of individuals will var y, and, as a result the effect of the weight of ob- jects handled during the intervention will likely vary. However, while the weight of objects handled during the intervention is not an exact or direct indicator of complexity, it could be an indicator of risk if the weight resulted in more dif f icult y in performing the intervention or contributed to personnel fatigue. T herefore, t he tea m deter m ined t hat combin ing weight with number of steps was a sound risk-indi- cating factor for this site and this application. Proximity of intervention. The breaking of first air with nonsterile sleeves/gloves/objects should be avoided and not occur over sterile open exposed product/contact surfaces during the operation. In case of such interventions, the exposed critical area may be compromised and would require steps to re- move compromised material or re-establish aseptic conditions. Touching the direct or indirect product contact surfaces with gloved hands should be avoided and not occur during the operation. Such interventions need to be redesigned either by application of pro- cedural controls or engineering controls. If there are interventions that cause accidental/infrequent touching of such sterile surfaces, they also need to be improved. In case of such interventions, the exposed critical area may be compromised and would require steps to remove compromised material or re-estab- lish aseptic conditions. Although the proximity of intervention was con- sidered an important risk factor by the group, this posed a challenge in terms of setting measurement criteria. After a detailed deliberation on this subject, it was agreed that any intervention disrupting the first air may lead to the contamination of the critical environment, product contact surfaces, and product sterility. If the intervention involved the breaking or disruption of first air using a sterile object, such as forceps, or autoclaved parts, then it was considered a moderate risk concern. If the intervention involved the breaking of first air by something that was not sterile, such as the operator's sleeve or glove, then it was considered a higher risk concern. If the interven- tion did not occur in the critical area, or disrupt first air, then it was considered a lower-risk concern. Also, during the manual handling of materials and the equipment parts, multiple touches on the surfaces could pose a risk. It was felt necessar y to minimize the number of touches of different surfaces inside this grade-A environment and have awareness of the risks associated with it. An intervention that involves high likelihood of (unintentionally) touch- ing the product contact surfaces with gloved hands was considered high risk, whereas one involving the use of sterile forceps or other sterile tools to touch those surfaces was deemed medium risk, and one involving no need for/no likelihood of touching any such surfaces was deemed low risk. Human exposure/barrier. Interventions in closed barrier systems (e.g., isolators or closed restricted ac- cess barrier systems [RABS]) through glove ports may be less risky, as compared to interventions in open type barrier systems that call for bypassing such bar- riers or need the presence of the operator or a portion