Nitin Rathore would like to thank Cylia Chen and Oscar Gonzalez of Amgen, Inc. for their support in conducting these studies
and Wenchang Ji, Erwin Freund, and Ed Walls for review and useful feedback. Arnold McCauley would like to thank Sekhar Kanapuram,
Hyo Jin Lee, Alexis Leuras, Lyanne Wong, and Rahul Rajan, all from Amgen Inc., for providing data, editing the manuscript,
and helpful discussions.
Satish K. Singh, PhD, is a research fellow at Pfizer Inc., global biologics, Chesterfield, MO, Nitin Rathore, PhD, is senior scientist in process development and Arnold McAuley, PhD, is scientist in formulation and analytical research, both at Amgen, Inc., Thousand Oaks, CA. Anurag S. Rathore, PhD, is a consultant, Biotech CMC Issues and a faculty member in the department of chemical ?engineering at the Indian Institute
of Technology, Delhi, India, email@example.com
Rathore is also a member of BioPharm International's editorial advisory board.
1. Frokjaer S, Otzen DE. Protein drug stability: A formulation challenge. Nature. 2005;4:298–306.
2. Rathore N, Rajan RR. Current perspectives on stability of protein drug products during formulation, fill and finish operations.
Biotechnol Prog. 2008;24:504–14.
3. Nail SL, Searles JA. Elements of quality by design in development and scale-up of freeze-dried parenterals. BioPharm Int.
4. Singh SK. Storage consideration as part of the formulation development program for biologics. American Pharm Rev. 2007;10:26–33.
5. Jones C. FDA's position on visual inspections: particulate matter and glass. PDA Visual Inspection Forum; 2007 Oct; Bethesda,
6. Das T, Nema S. Protein particulate issues in biologics development. American Pharm Rev. 2008;May/June:52–7.
7. USP 29–NF 24 (suppl. 2) General Chapter <788>. Particulate matter in injections. US Pharmacopeial Convention; 2006; Rockville,
8. European Pharmacopoeia. European Pharmacopoeia Commission, Council of Europe, European Department for the Quality of Medicines.
Particulate contamination: visible particles. 5th ed, 2005; Vol. 5.0 (incl. suppl. 5.1). General Chapter 2.9.20.
9. Japanese Pharmacopoeia. Society of Japanese Pharmacopoeia. Insoluble particulate matter test for injections. 15th ed.
2006. General Chapter 6.07.
10. Carpenter JF. Randolph TW, Jiskoot W, Crommelin DJ, Middaugh CR, et al. Overlooking subvisible particles in therapeutic
protein products: Gaps that may compromise product quality. J Pharm Sci. 2009;98(4):1201–05.
11. Braun A, Kwee L, Labow MA, Alsenz J. Protein aggregates seem to play a key role among the parameters influencing the
antigenicity of interferon alpha (IFN-alpha) in normal and transgenic mice. Pharm Res. 1997;10:1472–78.
12. Rosenberg A. Effects of protein aggregates: an immunological perspective. AAPS J. 2006;8(3):E501–07.
13. Remmele JR. RL, Callahan WJ, Krishnan S, Zhou L, Bondarenko PV, Nichols AC, et al. Active dimer of epratuzumab provides
insight into the complex nature of antibody aggregate. J Pharm Sci. 2006;95(1):126–45.
14. Wisniewski R. Developing large-scale cryopreservation systems for biopharmaceutical products. BioPharm Int. 1998;11:50–6.
15. Bhatnagar B, Bogner RH, Pikal MJ. Protein stability during freezing: separation of stresses and mechanisms of protein
stabilization. Pharm Dev Technol. 2007;12:505–23.