Scaledown of Biopharmaceutical Purification Operations

Abstract

Biotech‐based therapeutics have emerged as the growth engine for the pharmaceutical industry. Successful development and commercialization of biotech processes require the understanding of the relationships between the various attributes of the product and the product's clinical safety and efficacy, as well as, the effect of the different process parameters on the product's attributes. The complexity of the biotech products and the requirement for rigorous experimentation justify working at small scales. This article presents general guidelines and relevant parameters affecting scale‐down of the various unit operations involved in purification of proteins. The key parameters, assessment methods, assessment techniques, and challenges involved in scale‐down are discussed.

Process characterization strategy for a precipitation step for host cell protein reduction

“…This two-level, full-factorial study design comprised 18 experiments (including two center points using target values as described in the "Detailed description of the precipitation" for estimation of process variability). Thus, scaling of vessel design, mixing and filtration systems was not necessary, [22][23][24][25][26] and centrifuge tubes or small beakers with magnetic stir bars could be used. The design had 100% power for detecting differences in response of 2 SDs (see Table 2).…”

“…[4][5][6][7] However, there is limited published information on the characterization of precipitation steps under the QbD paradigm. [22][23][24] Vessel design (e.g., tank diameter to height ratio, impeller type and diameter, impeller placement, and baffle geometry) needs to mimic manufacturing scale tanks such that mixing (as defined by tip speed, power per volume ratio, shear, and/or residence time) results in the same precipitation endpoints (e.g., extent of precipitation and floc size distribution). 9,12,[14][15][16][17][18] The published literature for characterization of precipitation steps has focused mostly on product quality.…”

“…Precipitation is a method for impurity removal in biopharmaceutical processes [8][9][10][11][12][13][14][15] that can be advantageous, because it is often simple, gentle, inexpensive (relative to chromatography), and scalable. [22][23][24][25] Finally, the removal of the precipitate, for example (often by depth filtration, carries its own challenges. While some may explore process performance aspects of precipitation (e.g., sizing of filters for precipitate removal), the studies are not necessarily tailored to characterize and establish an appropriate control strategy as part of a manufacturing process.…”

“…9,12,[14][15][16][17][18] The published literature for characterization of precipitation steps has focused mostly on product quality. [22][23][24][25][26] Occasionally, filtration scale-down models are abandoned altogether and non-representative methods (such as benchtop centrifugation) are used instead. 9,15,[19][20][21] Precipitation steps call for special considerations when it comes to the design of the scale-down models used for characterization studies that are unique to this mode of separation.…”

“…Filtration for removal of precipitate was scaled based on constant filter grade, volume per area ratio, and flux [22][23][24][25][26]30. Filtration for removal of precipitate was scaled based on constant filter grade, volume per area ratio, and flux [22][23][24][25][26]30.…”