Process development in the biotech industry leads to investments around hundred of millions of dollars. It is important to mitigate costs without neglecting the quality of process development. Biopharmaceutical process development is important for companies to develop new processes and be first to market, improve a pre‐established process, or start manufacturing a product available by patent expiry (biosimilars). Laboratory automation enables methodical and standardized process development. Miniaturization and parallelization empower laboratories to screen several experimental conditions and define operating windows for purification processes, improving process robustness. Together, they allow for fast and accurate process development in a fraction of the time and cost of nonminiaturized/nonparallel process development approaches. The most widely used High‐Throughput Screening technique is a liquid‐handling station and microfluidics is taking its first steps in process development. Both are attractive scale‐down tools for the characterization of bioprocesses and allow thousands of experiments to be performed per day. High‐Throughput Process Development (HTPD) has helped to achieve major breakthroughs in process optimization, both for upstream and downstream processing. Continuous processing is the next step in process development which leads to cost reduction, higher productivity and better quality control; the integration of upstream and downstream processes is seen as a major challenge. In this review, we will focus on the state‐of‐the‐art of miniaturized techniques for process development in the biotechnology industry, and how automation and miniaturization drive process development. A comparison between liquid‐handling stations and microfluidics is made and an indication is given of which tools are still lacking for HTPD in the context of Integrated Continuous Biomanufacturing. © 2021 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

Continuous manufacturing is an indicator of a maturing industry, as can be seen by the example of the petrochemical industry. Patent expiry promotes a price competition between manufacturing companies, and more efficient and cheaper processes are needed to achieve lower production costs. Over the last decade, continuous biomanufacturing has had significant breakthroughs, with regulatory agencies encouraging the industry to implement this processing mode. Process development is resource and time consuming and, although it is increasingly becoming less expensive and faster through high‐throughput process development (HTPD) implementation, reliable HTPD technology for integrated and continuous biomanufacturing is still lacking and is considered to be an emerging field. Therefore, this paper aims to illustrate the major gaps in HTPD and to discuss the major needs and possible solutions to achieve an end‐to‐end Integrated Continuous Biomanufacturing, as discussed in the context of the 2019 Integrated Continuous Biomanufacturing conference. The current HTPD state‐of‐the‐art for several unit operations is discussed, as well as the emerging technologies which will expedite a shift to continuous biomanufacturing.

In this study, we developed a microfluidics method, using a so-called H-cell microfluidics device, for the determination of protein diffusion coefficients at different concentrations, pHs, ionic strengths, and solvent viscosities. Protein transfer takes place in the H-cell channels between two laminarly flowing streams with each containing a different initial protein concentration. The protein diffusion coefficients are calculated based on the measured protein mass transfer, the channel dimensions, and the contact time between the two streams. The diffusion rates of lysozyme, cytochrome c, myoglobin, ovalbumin, bovine serum albumin, and etanercept were investigated. The accuracy of the presented methodology was demonstrated by comparing the measured diffusion coefficients with literature values measured under similar solvent conditions using other techniques. At low pH and ionic strength, the measured lysozyme diffusion coefficient increased with the protein concentration gradient, suggesting stronger and more frequent intermolecular interactions. At comparable concentration gradients, the measured lysozyme diffusion coefficient decreased drastically as a function of increasing ionic strength (from zero onwards) and increasing medium viscosity. Additionally, a particle tracing numerical simulation was performed to achieve a better understanding of the macromolecular displacement in the H-cell microchannels. It was found that particle transfer between the two channels tends to speed up at low ionic strength and high concentration gradient. This confirms the corresponding experimental observation of protein diffusion measured via the H-cell microfluidics.

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