Molecule and Manufacturability Assessment Leading to Robust Commercial Formulation for Therapeutic Proteins

Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 6)


The transfer of lead molecules from discovery into process development at a relatively fast pace requires a process of candidate selection that assesses if a candidate is not only active and safe but also “manufacturable.” Formulation and process stability of potential candidates help narrow down lead candidates at an early stage, prior to large-scale manufacturing, by a process of rank-ordering properties generated from process and long-term stability studies. Such an assessment of the molecules’ manufacturability is especially useful when binding affinity and bioactivity are comparable among the various candidates under question. This chapter reviews several case studies that explore the utility of early-stage molecule or manufacturability assessments in moving forward therapeutic candidate/s by finely balancing potency and pharmacokinetics with the manufacturing capability of the candidate/s under question.


Dynamic Light Scattering Particle Load Formulation Candidate High Molecular Weight Species Subvisible Particle 
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  1. Badmington F, Wilkins R, Payne M, Honig ES (1995) Vmax testing for practical microfiltration train scale-up in biopharmaceutical processing. Pharm Technol 19:64–76Google Scholar
  2. Cromwell MEM, Hilario E, Jacobson F (2006) Protein aggregation and bio-processing. AAPS J 8:E572–E579PubMedCrossRefGoogle Scholar
  3. Grillo AO (2010) Late-state formulation development and characterization of biopharmaceuticals. In: Jameel F, Hershenson S (eds) Formulation and process development strategies for manufacturing biopharmaceuticals. Wiley, Hoboken, NJ, pp 161–171CrossRefGoogle Scholar
  4. Jameel F, Padala C, Rathore N, Gupta K, Sethuraman A (2010) Impact of uncontrolled vs. controlled rate freeze thaw technologies on process performance and product quality. PDA J Pharm Sci and Technol 64(4):290–298Google Scholar
  5. Jiang Y, Ramachander R, Wen J, Li C, Li J, Angell N, Bondarenko P, Narhi L (2008) Manufacturability assessment for a successful therapeutic product. 236th ACS National Meeting, Division of Biochemical Technology, BIOT110, Philadelphia, PA, p 49Google Scholar
  6. Kiese S, Papppenberger A, Friess W, Mahler HC (2008) Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci 97(10):4347–4366PubMedCrossRefGoogle Scholar
  7. Kolhe P, Holding E, Lary A, Chico S, Singh SK (2009) Large scale freezing of biologics: understanding protein and solute concentration changes in a cryovessel—part I. BioPharm Int 23(6):53–60Google Scholar
  8. Lashmar UT, Vnanderburgh M, Little SJ (2007) Bulk freeze-thaw of macromolecules—effect of cryoconcentration on their formulation and stability. BioProcess Int 5(6):44–54Google Scholar
  9. Nakano K, Ishiguro T, Konishi H, Tanaka M, Sugimoto M, Sugo I et al (2010) Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. Anticancer Drugs 21:907–916PubMedCrossRefGoogle Scholar
  10. Narhi LO, Jiang Y, Deshpande R, Kang S, Shultz J (2010) Approaches to control protein aggregation during bulk production. In: Wang W, Roberts CJ (eds) Aggregation of therapeutic proteins. Wiley, Hoboken, NJ, pp 257–299CrossRefGoogle Scholar
  11. Nayak A, Coladene J, Bradford V, Perkins M (2011) Characterization of subvisible particle formation during the filling pump operation of a monoclonal antibody solution. J Pharm Sci 100(10): 4198–4204Google Scholar
  12. Ramachander R (2008) Manufacturability assessments for early stage therapeutic candidate screenings. Presented at the IBC BPI Meeting, Anaheim, CAGoogle Scholar
  13. Rathore N, Rajan R (2008) Current perspectives on stability of drug products during formulation, fill and finish operations. Biotechnol Prog 24:504–514PubMedCrossRefGoogle Scholar
  14. Rathore AS, Winkle H (2009) Quality by design for biopharmaceuticals. Nat Biotechnol 27:26–34PubMedCrossRefGoogle Scholar
  15. Rehder DS, Chelius D, McAuley A, Dillon TM, Xiao G, Crouse-Zeineddini J, Vardanyan L, Perico N, Mukku V, Brems DN, Matsumura M, Bondarenko PV (2008) Isomerization of a single aspartyl residue of anti-epidermal growth factor receptor immunoglobulin gamma2 antibody highlights the role avidity plays in antibody activity. Biochemistry 47(8):2518–2530PubMedCrossRefGoogle Scholar
  16. Singh SK, Kolhe P, Wang W, Nema S (2009) Large-scale freezing of biologics: a practitioner’s review, part 1: fundamental aspects. BioProcess Int 7(9):32–44Google Scholar
  17. Yadav S, Sreedhara A, Kanai S, Liu J, Lien S, Lowman H, Kalonia DS, Shire SJ (2011) Establishing a link between amino acid sequences and self-associating and viscoelastic behavior of two closely related monoclonal antibodies. Pharm Res 28(7):1750–1764, Epub 2011 Apr 6PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  1. 1.Product Attribute SciencesAmgen, Inc.Thousand OaksUSA
  2. 2.Drug Product TechnologyAmgen, Inc.Thousand OaksUSA

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