title: Process development in the QbD paradigm: Role of process integration in process optimization for production of biotherapeutics.
abstract: Biotherapeutics have become the focus of the pharmaceutical industry due to their proven effectiveness in managing complex diseases. Downstream processes of these molecules consist of several orthogonal, high resolution unit operations designed so as to be able to separate variants having very similar physicochemical properties. Typical process development involves optimization of the individual unit operations based on Quality by Design principles in order to define the design space within which the process can deliver product that meets the predefined specifications. However, limited efforts are dedicated to understanding the interactions between the unit operations. This paper aims to showcase the importance of understanding these interactions and thereby arrive at operating conditions that are optimal for the overall process. It is demonstrated that these are not necessarily same as those obtained from optimization of the individual unit operations. Purification of Granulocyte Colony Stimulating Factor (G-CSF), a biotherapeutic expressed in E. coli., has been used as a case study. It is evident that the suggested approach results in not only higher yield (91.5 vs. 86.4) but also improved product quality (% RP-HPLC purity of 98.3 vs. 97.5) and process robustness. We think that this paper is very relevant to the present times when the biotech industry is in the midst of implementing Quality by Design towards process development. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:355-362, 2016.
authors.affiliation: Dept. of Chemical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India.
authors.forename: Anurag S
authors.initials: AS
authors.lastname: Rathore
authors.affiliation: Dept. of Chemical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India.
authors.forename: Mili
authors.initials: M
authors.lastname: Pathak
authors.affiliation: Dept. of Chemical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India.
authors.forename: Avinash
authors.initials: A
authors.lastname: Godara
mesh_terms: D001702:Biopharmaceutics; D002851:Chromatography, High Pressure Liquid; D016179:Granulocyte Colony-Stimulating Factor / Q000032:analysis / Q000096:biosynthesis*; D011786:Quality Control
chemical_list: D016179:Granulocyte Colony-Stimulating Factor
keywords: Quality by Design (QbD); critical quality attributes (CQA); multimode chromatography; process integration; protein refolding