ABSTRACT
The use of scaled-down models is an integral part of characterizing and validating industrial processes (US Food and Drug Administration [FDA] 1997; Q5A(R1) 1999; Godavarti, Petrone, et al. 2005; Seely 2005; European Agency for the Evaluation of Medicinal Products [EMEA] 2008; Parenteral Drug Association [PDA] 2008; Q8(R2) 2009). Characterization studies are used to identify critical parameters and establish process operating ranges and speciŒcations. These studies are almost exclusively limited to laboratory scale because of the large number of experiments that are performed. Process validation studies are conducted to conŒrm that when operated within the established operating ranges, the process performs as expected. These studies are designed to evaluate process consistency (conformance runs), evaluate viral clearance,
15.1 Introduction .................................................................................................. 411 15.2 Scaled-Down Chromatography Model VeriŒcation Using Multivariate
Analysis Tools ............................................................................................... 412 15.2.1 Platform PuriŒcation Process ........................................................... 413 15.2.2 Scale-Down of Chromatography Steps ............................................ 413 15.2.3 Generation of Small-Scale and Full-Scale Data Sets ....................... 415 15.2.4 Quantitative Comparison of Chromatography Elution Peaks .......... 416 15.2.5 VeriŒcation of Small-Scale Models Using MVA ............................. 417
15.2.5.1 Protein A Column .............................................................. 418 15.2.5.2 Cation Exchange Column .................................................. 423 15.2.5.3 Anion Exchange Column ................................................... 426
15.3 Scaled-Down Model ConŒrmation for Cell Culture Processes ................... 430 15.3.1 Principles of Scaled-Down Model QualiŒcation in Cell Culture ..... 431 15.3.2 VeriŒcation of Cell Culture Scaled-Down Models Using MVA
Approach ........................................................................................... 432 15.4 Summary ...................................................................................................... 438 References .............................................................................................................. 439
impurity clearance, and establish chromatography column lifetime (PDA 2008). While the conformance runs are typically conducted at large scale in a manufacturing facility, others are performed at laboratory scale because they are either impractical (impurity clearance) or not feasible from a safety perspective (viral clearance studies) at large scale. Column cycle studies are Œrst conducted at laboratory scale to establish a prospective lifetime, which is then veriŒed at large scale. In addition to playing a pivotal role in characterization and validation studies, laboratory-scale models are also used in raw material testing, evaluation of lot-to-lot variation in adsorbents, supporting manufacturing investigations, and to support process changes.
