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18 Pharmaceutical Technology ® Bio/Pharma Outsourcing Innovation eBook 2023 PharmTech.com Manufacturing f lexibility (modular design) • Reducing total footprint • Shortening campaign turnover times • Decreasing operating costs • Minimizing cross-contamination risk • Enabling simple installation • Offering a design that is beneficial for closed pro- cessing operations • Avoiding costly, laborious, and time-consuming 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 person- alized medicine, orphan drugs, and gene therapy mo- dalities (commonly described as advanced therapy medicinal products [ATMPs]) gaining momentum. There are currently more than 1000 ATMPs progress- ing through clinical trials toward potential commer- cial supply (3). In contrast to the typical blockbuster m Ab drugs, which demand ver y large production scales using mostly Chinese hamster ovar y (CHO)- based platform processes and stainless-steel biore- actors, ATMPs often require the manufacturing and scale f lexibility offered by SUTs. Previously, stainless-steel bioreactors have had a particular advantage over single-use (SU) bioreactors: their large capacit y, common ly 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 K now i ng a nd qua l i f y i ng t he processes i nvolved in an ATMP's manufacturing at the various scales, including commercial scale, is a key regulatory re- qu i rement a nd sa feg ua rd s produc t qua l it y a nd patient safet y. Appropriate process development, characterization, scale-up, and validation are, there- fore, important exercises. When looking at the scalability of a manufactur- ing process, particularly upstream, there are many importantfactors that must be considered. Consid- eration of these aspects is an important part of the overall product's life cycle and includes: • Inherent scalability 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 experiment (DoE) and multi-variant data analysis (MVDA) approaches can be used to achieve higher throughput process mod- eling. For example, Sartorius Ambr 250 and Ambr 15 sys- tems enable upstream scale-down modeling of up to 24 or 48 parallelized and miniaturized bioreactors, respectively. Such scale-down DoE work enables the definition of critical operation/process/material parameters, critical controlling parameters/set-points, and operating/ac- ceptable ranges and their influence on the products' crit- ical quality attributes. Additional supportive, risk-based scale-down/-up simulation software is available (Sarto- rius, BioPat Process Insights) and such software can sig- nificantly 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 complexity is further compounded with challenges associated with the chosen host cell line, as its key performance indi- cators 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 considerations required during scaling. Many SU bioreactors have been designed with scalability in mind to ease potential dif- ficulties involved in upstream development with both adherent and suspension cell lines.