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PharmTech.com Trends in Manufacturing eBook May 2023 Pharmaceutical Technology ® 17 Cleanrooms As discussed, f lex ibi lit y at tributes can look fa- vorable at first glance, but when planned out, with all necessar y precautionar y actions and costs, the promise can turn into disappointment. It is thus essent ia l to pla n a head, def i ne a nd descr ibe a l l necessary actions, and compare the options like-for- like in a comprehensive manner. There typically is not a "one size fits all" solution, but what is more and more recognized are hybrid solutions, for example, podular for critical cleanroom areas and modular for auxiliary and support areas. Conclusion Flexibility has been stated as a major decision factor in cleanroom infrastructures as new therapies without well-defined processes and/or new process technologies for the different unit operations are still forthcoming. Furthermore, contract manufacturing organizations TABLE I. Common flexibility scenarios to consider. CAPEX is capital expenditure. Scenario Description Design completion In most instances, the design effort must be fully completed before construction can begin. The design timelines can drift and delay the project completion. If there is flexibility in the start of the construction before a fully completed project design, the project timeline may be met or accelerated. Shell building completion Typically, the shell building, including utilities, require completion before cleanroom infrastructure installation can start. Construction is typically sequential and therefore will require a lengthy timeline for completion. Flexibility in this instance would be a potential parallel construction method, utilizing the timeframe to construct all the individual components at one time. Shell building choice Not every cleanroom construction approach allows a wide variety of choices regarding the structural element of the shell building. Commonly, cleanroom components and structures are hung from the shell building's roofline. Shell building flexibility would be defined as using any shell building without the need for additional structural integrity costs. It is certainly much easier to find a warehouse type building than a structurally reinforced shell building. Cleanroom classification change It may be that cleanroom classification needs to be changed from Grade C to B and vice versa. The design of the cleanroom needs to be flexible enough to accommodate this requirement. Cleanroom pressure change The flexibility needs here is the requirement to switch a positive pressure cleanroom area to a negative pressure area. This will also influence the pressure cascade and the auxiliary areas. Scaling out When cleanroom areas need to be scaled and expanded, the expansion can cause an entire cleanroom infrastructure shutdown, especially when the air handling and cleanroom areas are not segregated. Flexibility in this case would mean the existing processing spaces are still running and utilized, even when additional cleanroom areas are introduced into the building. Excursion actions When a cleanroom area experiences an increasing or unacceptable particulate count or microbial excursion, the root cause must be investigated and rectified, which typically requires the cleanroom area to be shut down. When the entire infrastructure is interconnected to a centralized air handling unit, the entire infrastructure will be affected by the shutdown. Decentralized, segregated air handling avoids that risk and created the flexibility of actions against the excursion and have certain areas still being functional. Cleanroom area expansion Two neighboring cleanroom areas may need to be merged to expand the processing space, or alternatively need to be segregated. The flexibility in this case would be to be able to remove wall sections between the two cleanrooms to join the two. Delayed CAPEX Sometimes a primary infrastructure is implemented, and plans are made to add another processing step to that infrastructure at a later stage. Ideally, the addition of the next process step can be done in a flexible manner by adding that area when needed without interrupting the processes in the existing infrastructure, or at least minimize any disruption. The cleanroom design here allows to add without major undertaking and creates the benefit of CAPEX decision flexibility. Mechanical space Depending on the cleanroom area needs, the personnel and material flows and the shell building area constraints, the mechanical components placement should be flexible enough to have the ability to accommodate an optimal use of the available area. Minor changes after completion Minor changes may need to be made after the completion of the project. This can be at the qualification or early stage of the process utilization, when the end-user realizes that the layout is not ideal, or perhaps that the processes changes later and requires a modified layout. The infrastructure components need to be flexible enough to allow for a layout change. Major changes after completion A process unit operation may no longer be required and needs to be replaced by a different one, or a unit operation needs a total reconfiguration of the cleanroom area. In these cases, the reconfiguration needs to happen without major disruption of other process areas and lengthy shutdowns must be avoided. Re-use In most cases, cleanroom infrastructures are a sunk cost, and the cleanroom units or areas cannot be repurposed. Long-term use flexibility means that any cleanroom area should be repurposable and re-used over many years. Mobility Some clinical-scale processing infrastructures are built into a shell building which cannot support future commercial manufacturing. Here the flexibility requirement would allow to move the processing spaces to the end-site once established, instead of being fixed-installed without the possibility to recoup the asset.