However, there are considerations unique to each unit operation that apply during scale-down. Constraints associated with
equipment or methodology may prevent a "true" scale-down of a unit operation. Dead volumes and hold times are typically greater
at manufacturing scale. Path lengths of detectors typically vary between instruments at the lab and the manufacturing plant.
Wetted materials (gaskets, valves, and pumps) are not likely to be the same at two scales. Differences in cassette design
between two scales may impact the outcome of lifetime studies of UF and DF membranes.
Scale-down studies certainly increase the chances for a successful validation campaign, but they only provide "guidance."
The actual "confirmation" must be made at large scale. The only exception to this is the viral-clearance validation studies
that are performed at small scale.
Anurag Rathore, is a principal scientist at Amgen Inc., 30W-2-A, One Amgen Center Drive, Thousand Oaks, CA 91320, 805.447.4491, fax 805.499.5008, arathore@amgen.com
Raj Krishnan and Stephanie Tozer work for Amgen Inc, Thousand Oaks, CA. Dave Smiley, Steve Rausch and Jim Seely work for Amgen Inc., Longmont, CO. Anurag Rathore is a member of the Editorial Advisory Board.
REFERENCES
1. ICH, Quality of biotechnological products: Viral safety evaluation of biotechnology products derived from cell lines of
human or animal origin. International Conference on Harmonization Step 4 Endorsement 1997 March. Available at:
http://www.fda.gov/cder/guideance/Q5A-fnl.pdf
2. Yamamoto S, Nomura M, Sano Y, Resolution of proteins in linear gradient elution ion exchange and hydrophobic interaction
chromatography. J. Chromatogr. 1987:409:101-110.O'Leary RM, Feuerheim D, Peers D, Xu Y, Blank GS. Determining the useful lifetime of chromatography resins,
Biopharm Int. 2001 Sept.; 14 (9):10-18.4.Rathore AS, Velayudhan A. Scale-up guidelines for preparative chromatography, Biopharm Int'l. 2003 Jan.; 16 (1):34-42.
3. O'Leary RM, Feuerheim D, Peers D, Xu Y, Blank GS. Determining the useful lifetime of chromatography resins, Biopharm Int'l. 2001 Sept.; 14 (9):10-18.4.
4. Rathore AS, Velayudhan A. Scale-up guidelines for preparative chromatography, Biopharm Int'l. 2003 Jan.; 16 (1):34-42.
5. Rathore AS, Wang A, Menon M, Riske F, Campbell J, Goodrich E, Martin J. Optimization, scale-up and validation issues in
filtration of biopharmaceuticals - Part I. Biopharm Int'l. 2004 August; 17 (8):50-58.
6. Lutz H, Siwak M, Carter J. Viral clearance performance and regulatory requirements, Poster, Biophex/Interphex, 2002 October
23-24; Santa Clara, CA.
7. Rathore AS, Sharma A, Zhang RJ, Chilin D. Scale-down modeling and characterization of a protein refolding step, Oral presentation,
227th American Chemical Society National Meeting, 2004 March 28-April 1; Anaheim, CA.
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