White paper on high‐throughput process development for integrated continuous biomanufacturing

Abstract

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.

Process analytical technique (PAT) miniaturization for monoclonal antibody aggregate detection in continuous downstream processing

“…33 The crucial element for PAT application in a continuous downstream process is to gather real-time information for process control. 75,82 However, especially for the chromatography steps, implementing PAT can be challenging because of the typical short process times (in the time frame of minutes). 62 Rathore et al demonstrated that, with on-line analytical liquid chromatography (with the measurement performed in 30 min), continuous monitoring of the chromatography step for aggregate peaks can be achieved.…”

“…The crucial element for PAT application in a continuous downstream process is to gather real‐time information for process control 75,82 . However, especially for the chromatography steps, implementing PAT can be challenging because of the typical short process times (in the time frame of minutes) 62 .…”

Design of millidevices to expedite apparent solubility measurements

“…40 Unfortunately, these devices are not widely used in laboratories. 36 Most of these microdevices require a clean-room environment for their fabrication, 41 which is not available in most laboratories. Besides the lack of appropriate facilities, the cost and expertise to develop and fabricate such microdevices are another drawback.…”

“…35 Furthermore, it is important to highlight that microdevices can lead to more automated labs and miniaturized analyses. 36 Characterization of protein solutions using microdevices has been already described, 37,38 to select flocculating agents 39 or investigate protein phase behavior. 40 Unfortunately, these devices are not widely used in laboratories.…”

Design of a microfluidic mixer channel: First steps into creating a fluorescent dye‐based biosensor for mAb aggregate detection

“…[6] However, these techniques are characterized by lengthy analysis times. [1,7] Fluorescent dyes, such as SYPRO Orange and 4-4-bis-1-phenylamino-8-naphthalene sulfonate (Bis-ANS), are sensitive to the hydrophobicity of the surrounding environment. Since aggregate formation generates hydrophobic unfolded protein structures, these fluorescent tags can be used to rapidly detect this phenomenon.…”