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Despite the advent of many new therapies, therapeutic monoclonal antibodies remain a prominent biologics product, with a market value of billions of dollars annually. A variety of downstream processing technological advances have led to a paradigm shift in how therapeutic antibodies are developed and manufactured. A key driver of change has been the increased adoption of single-use technologies for process development and manufacturing. An early-stage developability assessment of potential lead antibodies, using both in silico and high-throughput experimental approaches, is critical to de-risk development and identify molecules amenable to manufacturing. Both statistical and mechanistic modelling approaches are being increasingly applied to downstream process development, allowing for deeper process understanding of chromatographic unit operations. Given the greater adoption of perfusion processes for antibody production, continuous and semi-continuous downstream processes are being increasingly explored as alternatives to batch processes. As part of the Quality by Design (QbD) paradigm, ever more sophisticated process analytical technologies play a key role in understanding antibody product quality in real-time. We should expect that computational prediction and modelling approaches will continue to be advanced and exploited, given the increasing sophistication and robustness of predictive methods compared to the costs, time, and resources required for experimental studies.

Continuous manufacturing of biologics (biopharmaceuticals) has been an area of active research and development for many reasons, ranging from the demand for operational streamlining to the requirement of achieving obvious economic benefits. At the same time, biopharma strives to develop systems and concepts that can operate at similar scales for clinical and commercial production—using flexible infrastructures, such as single-use flow paths and small surge vessels. These developments should simplify technology transfer, reduce footprint and capital investment, and will allow to react readily to changing market pressures while maintaining quality attributes. Despite a number of clearly identified benefits compared to traditional batch processes, continuous bioprocessing is still not widely adopted for commercial manufacturing. This paper details how industry-specific technological, organizational, economic, and regulatory barriers that exist in biopharmaceutical manufacturing are hindering the adoption of continuous production processes. Based on this understanding, the roles of process systems engineering (PSE), process analytical technologies, and process modeling and simulation are highlighted as key enabling tools in overcoming these multi-faceted barriers in today’s manufacturing environment. Of course, we do recognize that there is also a need for a clear set of regulations to guide a transition of biologics manufacturing towards continuous processing. Furthermore, the role played by the emerging fields of process integration and automation as well as digitalization is explored, as these are the tools of the future to facilitate this transition from batch to continuous production. Finally, an outlook focusing on technology, management, and regulatory aspects is presented to identify key concerted efforts required to drive the broad adaptation of continuous manufacturing in biopharmaceutical processes.

The production of clinically relevant quantities of human mesenchymal stromal cells (hMSCs) requires scalable and intensified manufacturing processes. For this reason, the applicability of alternating tangential flow filtration (ATF) and tangential flow depth filtration (TFDF) based cell retention systems for hMSC expansion on microcarriers (MCs) in perfusion mode was assessed. The processes were conducted in stirred tank bioreactors at a scale of 1.8 L and compared with repeated-batch cultivations. In the perfusion and repeated-batch control cultivations, competitive viable cell concentrations of ≈2.9 · 10 6 cells mL −1 were reached within a cultivation period of 5–7 days, resulting in an expansion factor of 41–57. The main difference between the operation modi was the aggregation behavior of the MCs. While the median MC aggregate diameter in the repeated-batch cultivation reached 470 μm, the ATF cell retention device constrained aggregate size to a median diameter of 250 µm. In the TFDF cultivation, the shear forces in the recirculation loop stripped most of the hMSCs from the MCs, resulting in the formation of spheroids that continued to proliferate, albeit at a decreased rate. While perfusion operation did not lead to increased productivity in this proof-of-concept study, manual handling and therefore contamination risk were reduced by replacing the repeated-batch process’s daily 80% medium exchanges with automated perfusion operation. Additionally, the ATF system was shown to be useful for medium removal and washing of the MCs prior to adding the harvesting solution, which is highly valuable for cultivations conducted at larger scales. While the feasibility of ATF based cell retention for MC expansion processes could be demonstrated, increased growth area to medium ratios, i.e., higher MC concentrations, still need to be investigated to leverage the full potential of the perfusion process mode.

In biopharmaceutical manufacturing, a new single-use technology using disposable equipment is available for reducing the work of change-over operations compared to conventional multi-use technology that use stainless steel equipment. The choice of equipment technologies has been researched and evaluation models have been developed, however, software that can extend model exposure to reach industrial users is yet to be developed. In this work, we develop and demonstrate a prototype of an online decision-support tool for the multi-objective evaluation of equipment technologies in sterile filling of biopharmaceutical manufacturing processes. Multi-objective evaluation models of equipment technologies and equipment technology alternative generation algorithms are implemented in the tool to support users in choosing their preferred technology according to their input of specific production scenarios. The use of the tool for analysis and decision-support was demonstrated using four production scenarios in drug product manufacturing. The online feature of the tool allows users easy access within academic and industrial settings to explore different production scenarios especially at early design phases. The tool allows users to investigate the certainty of the decision by providing a sensitivity analysis function. Further enrichment of the functionalities and enhancement of the user interface could be implemented in future developments.

In the manufacturing of parenterals such as injectables, multi-use technology and single-use technology are available, which have different advantages and disadvantages regarding cost, environment, quality or supply. As a part of the design methodology which considers the choice of these technologies as the prominent decision, this study proposes risk evaluation models for parenterals manufacturing processes. Novel evaluation indicators were developed for product quality and supply risks, which can be aggregated with other indicators, such as cost and environment, to produce a total score. Case study was performed to demonstrate the models following the activities of process synthesis, evaluation, sensitivity analysis, and decision-making. The result indicated that the process using single-use technology is superior when the weighting factors for cost, environment, quality and supply are equal.

This chapter presents a case study to describe the route of the first moss‐made biopharmaceutical (moss‐produced α‐galactosidase) for treatment of Fabry disease to the phase I clinical study. Single‐use bioprocessing technology is a central element in the production process. The lead product moss‐aGal has successfully completed a phase I clinical study and thus proved that the Bryotechnology is current good manufacturing practice (cGMP) compliant and an effective route for use of moss as an alternative expression system for production of biopharmaceuticals. With this case study, Greenovation has proven the manufacturing of moss‐aGal to be compliant with cGMP. The developed single‐use production process shows regulatory compliance and a maximum of flexibility. The current standard of a scale‐out approach with 200‐l Wave bioreactors is going to be updated by illuminated versions of single‐use stirred tank bioreactors in the near future.

This chapter contains sections titled: Current Single‐Use Technologies Future Single‐Use Operations Automation Requirements in Single‐Use Manufacturing Qualification and Validation Expectations Operator Training References

This chapter contains sections titled: Introduction Future of Single‐Use Bioreactor Technology Outlook: Transformation of Biomanufacturing through Single‐Use Technology

This article, written from an industry perspective, examines the current trend towards the implementation of single-use disposable technologies in the biopharmaceutical and biotechnology sectors. Single-use technologies are generally sterile, plastic disposable items implemented to replace traditional pharmaceutical processing items that require recycling, cleaning and in-house sterilisation. The forces driving the technological change are a mix of process efficiencies (including cost reduction) and sterility assurance. This article examines the advantages of some single-use systems used for aseptic processing, although in doing so a cautionary approach is adopted, particularly with regard to the validation requirements and practical considerations when such technologies are implemented.

This chapter discusses drug product formulation and filling challenges, describes end‐user process requirements, and provides an overview of single‐use technologies (SUS) that can be used to facilitate processing in this area. SUS are available at all steps of the process including final formulation and filling operations. The starting point for the discussion of end‐user needs with SUS suppliers is a well‐defined user requirement specification. The supplier has to manage the diverse nature of SUS, especially when these include a variety of subcomponent suppliers, and give assurance of the supply chain, quality, engineering, manufacturing, quality control, sterilization, packaging, transportation, and final operational performance of the systems. The multiproduct nature of DP manufacturing, trend for smaller drug batches, shorter time to market pressure, and new drug therapies reimbursement uncertainties ask for flexible and cost‐effective manufacturing.