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20 BioPharm International ® Partnerships for Outsourcing eBook May 2023 www.biopharminternational.com Manufacturing cleaning-in-place/sterilizing-in-place validation (the latter aspect is particularly challenging when manufacturing viruses). In 2018, more than 66% of pharmaceutical com- panies were found to prefer SUTs over permanent technologies (2). SUTs for advanced therapy medicinal products SUTs are likely to increase in popularity with personal- ized medicine, orphan drugs, and gene therapy modal- ities (commonly described as advanced therapy medic- inal products [ATMPs]) gaining momentum. There are currently more than 1000 ATMPs progressing through clinical trials toward potential commercial supply (3). In contrast to the typical blockbuster mAb drugs, which demand very large production scales using mostly Chi- nese hamster ovary (CHO)-based platform processes and stainless-steel bioreactors, ATMPs often require the manufacturing and scale flexibility offered by SUTs. Previously, stainless-steel bioreactors have had a particular advantage over single-use (SU) bioreactors: their large capacit y, commonly reaching 10,000– 20,000 L. Most vendors for SU bioreactors restricted their products to 2000–2500 L scale. This was in part due to pressure challenges from the increased weight of the liquid medium and handling issues. However, in the past five years, SU bioreactors have become commercially available at working volumes of 5000 L (ThermoFisher, HyPerforma DynaDrive) (4) and even 6000 L (ABEC Inc.). In situations requiring scaling-up above the vol- ume offered by SU bioreactors, scaling-out (increase the number of bioreactors in parallel) or process-in- tensification (normally, a high cell density perfusion process) must be considered. However, not all cell lines and processes are easily suitable for or adapt- able to perfusion, leading to additional challenges. Determining process scalability Knowing and qualif ying the processes involved in an ATMP's manufact uring at t he various sca les, i nclud i ng com mercia l sca le, is a key reg u lator y requirement and safeguards product qualit y and patient safet y. Appropriate process development, characterization, scale-up, and validation are, there- fore, important exercises. When looking at the scalability of a manufacturing process, particularly upstream, there are many impor- tantfactors that must be considered. Consideration of these aspects is an important part of the overall prod- uct's life cycle and includes: • Inherent scalabilit y of the engineered system (e.g., bioreactor design and critical engineering parameters) • Manufacturing processing steps • Properties and characteristics of the organism (e.g., mammalian cell line like CHO or HEK293) • Resulting product (e.g., mAb or live virus titer). Additional factors that must be considered and the potential factors they will impact can be seen in Figure 1. These encompass input considerations such as the choice between SUTs and stainless-steel sys- tems and output considerations including defining critical scaling parameters. If sufficient time and effort are not taken when considering these factors, the project can quickly become very costly, as it can delay the time to market. Scale-down models Usage and qualification of an appropriate scale-down model is of critical importance, as it can reduce costs and shorten timelines. The use of the design of exper- iment (DoE) and multi-variant data analysis (MVDA) approaches can be used to achieve higher throughput process modeling. For example, Sartorius Ambr 250 and Ambr 15 systems enable upstream scale-down modeling of up to 24 or 48 parallelized and miniatur- ized bioreactors, respectively. Such scale-down DoE work enables the definition of critical operation/process/material parameters, criti- cal controlling parameters/set-points, and operating/ acceptable ranges and their influence on the products' critical quality attributes. Additional supportive, risk- based scale-down/-up simulation software is available (Sartorius, BioPat Process Insights) and such software can significantly reduce workload and, therefore, timelines for successful scale-up operations and the risk of late-stage expensive failures. Scalability of upstream processes Challenges surrounding scalability predominantly concern upstream bioreactor scale-up, as this is often more complex as compared with mostly linear scale-up of downstream processing (DSP) steps. This complex- ity is further compounded with challenges associated with the chosen host cell line, as its key performance indicators are vital for scaling up and down. Depending on whether a cell line can grow as adherent cultures or in suspension will drastically impact the consider- ations required during scaling. Many SU bioreactors have been designed with scalability in mind to ease po- tential difficulties involved in upstream development with both adherent and suspension cell lines. Scaling suspension cell line upstream processes. Scaling up the early phase of a suspension process is mostly straightforward. Non-baffled shake flasks are available at scales between 125 mL and 5 L and allow for linear scale-up for all commonly used cell lines (e.g., CHO-S, HEK293/T, HeLa S3). Between scales, the working volume is normally kept constant, with typ- ical values of 10–30%. When moving forward to the bioreactor scale, there are several important parame-