Kim Y-S, Randolph TW, Stevens FJ, Carpenter JF. Kinetics and energetics of assembly, nucleation, and growth of aggregates and fibrils for an amyloidogenic protein insights into transition states from pressure, temperature, and co-solute studies*. J Biol Chem. 2002;277:27240–6.

Article  CAS  PubMed  Google Scholar 

Gerhardt A, Bonam K, Bee JS, Carpenter JF, Randolph TW. Ionic strength affects tertiary structure and aggregation propensity of a monoclonal antibody adsorbed to silicone oil–water interfaces. J Pharm Sci. 2013;102:429–40.

Article  CAS  PubMed  Google Scholar 

Kueltzo LA, Wang W, Randolph TW, Carpenter JF. Effects of solution conditions, processing parameters, and container materials on aggregation of a monoclonal antibody during freeze–thawing. J Pharm Sci. 2008;97:1801–12.

Article  CAS  PubMed  Google Scholar 

Roberts CJ. Protein aggregation and its impact on product quality. Curr Opin Biotech. 2014;30:211–7.

Article  CAS  PubMed  Google Scholar 

Murphy RM, Roberts CJ. Protein misfolding and aggregation research: Some thoughts on improving quality and utility. Biotechnol Progr. 2013;29:1109–15.

Article  CAS  Google Scholar 

den Engelsman J, Garidel P, Smulders R, Koll H, Smith B, Bassarab S, et al. Strategies for the assessment of protein aggregates in pharmaceutical biotech product development. Pharm Res. 2011;28:920–33.

Article  Google Scholar 

Kijanka G, Bee JS, Korman SA, Wu Y, Roskos LK, Schenerman MA, et al. Submicron size particles of a murine monoclonal antibody are more immunogenic than soluble oligomers or micron size particles upon subcutaneous administration in mice. J Pharm Sci. 2018;107:2847–59.

Article  CAS  PubMed  Google Scholar 

Ahmadi M, Bryson CJ, Cloake EA, Welch K, Filipe V, Romeijn S, et al. Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics. Pharmaceut Res. 2015;32:1383–94.

Article  CAS  Google Scholar 

Ribeiro R, Abreu TR, Silva AC, Gonçalves J, Moreira JN. Current applications of pharmaceutical biotechnology. Adv Biochem Eng Biotechnol. 2019;23–54.

Chisholm CF, Nguyen BH, Soucie KR, Torres RM, Carpenter JF, Randolph TW. In vivo analysis of the potency of silicone oil microdroplets as immunological adjuvants in protein formulations. J Pharm Sci. 2015;104:3681–90.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kannan A, Shieh IC, Negulescu PG, Suja VC, Fuller GG. Adsorption and aggregation of monoclonal antibodies at silicone oil–water interfaces. Mol Pharmaceut. 2021;18:1656–65.

Article  CAS  Google Scholar 

Narhi LO, Schmit J, Bechtold-Peters K, Sharma D. Classification of protein aggregates. J Pharm Sci. 2012;101:493–8.

Article  CAS  PubMed  Google Scholar 

Wong IY, Wong D. Chapter 104 - Special adjuncts to treatment. 2013;1735–83. Available from: https://www.sciencedirect.com/science/article/pii/B9781455707379001041.

Gaudric A, Tadayoni R. Chapter 117 - Macular hole. 2013;1962–78. Available from: https://www.sciencedirect.com/science/article/pii/B978145570737900117X.

Gelatt KN, Spiess BM, Gilger BC. Chapter 12 - Vitreoretinal surgery. 2011;357–87. Available from: https://www.sciencedirect.com/science/article/pii/B9780702034299000122.

Meyer BK. 4 - Material and process compatibility testing. 2012;67–82. Available from: https://www.sciencedirect.com/science/article/pii/B978190756818350004X.

Richard CA, Wang T, Clark SL. Using first principles to link silicone oil/formulation interfacial tension with syringe functionality in pre-filled syringes systems. J Pharm Sci. 2020;109:3006–12.

Article  CAS  PubMed  Google Scholar 

Garidel P, Kuhn AB, Schafer LV, Karow-Zwick AR, Blech M. High-concentration protein formulations: how high is high? Eur J Pharm Biopharm. 2017;119:353–60.

Article  CAS  PubMed  Google Scholar 

Thirumangalathu R, Krishnan S, Ricci MS, Brems DN, Randolph TW, Carpenter JF. Silicone oil- and agitation-induced aggregation of a monoclonal antibody in aqueous solution. J Pharm Sci [Internet]. 2009;98:3167–81. Available from: http://www.sciencedirect.com/science/article/pii/S0022354916330878.

Chisholm CF, Soucie KR, Song JS, Strauch P, Torres RM, Carpenter JF, et al. Immunogenicity of structurally perturbed hen egg lysozyme adsorbed to silicone oil microdroplets in wild-type and transgenic mouse models. J Pharm Sci [Internet]. 2017;106:1519–27. Available from: http://www.sciencedirect.com/science/article/pii/S0022354917300801.

Strehl R, Rombach-Riegraf V, Diez M, Egodage K, Bluemel M, Jeschke M, et al. Discrimination between silicone oil droplets and protein aggregates in biopharmaceuticals: a novel multiparametric image filter for sub-visible particles in microflow imaging analysis. Pharm Res. 2012;29:594–602.

Article  CAS  PubMed  Google Scholar 

Demeule B, Messick S, Shire SJ, Liu J. Characterization of particles in protein solutions: reaching the limits of current technologies. AAPS J. 2010;12:708–15.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jones LS, Kaufmann A, Middaugh CR. Silicone oil induced aggregation of proteins. J Pharm Sci. 2005;94:918–27.

Article  CAS  PubMed  Google Scholar 

Probst C. Characterization of protein aggregates, silicone oil droplets, and protein-silicone interactions using imaging flow cytometry. J Pharm Sci. 2019;109:364–74.

Article  PubMed  Google Scholar 

USP. <787> Subvisible particulate matter in therapeutic protein injections. 40th ed. 2017.

USP. <788> Particulate matters in injections. 40th ed. 2017.

2.9.19 PhEur. Pharmacopeia Europaea, Particulate contamination: Sub-visible particles,. 6th ed. 2008.

USP. <789> Particulate matter in ophthalmic solutions. 40th ed. 2017.

Shah M, Rattray Z, Day K, Uddin S, Curtis R, van der Walle CF, et al. Evaluation of aggregate and silicone-oil counts in pre-filled siliconized syringes: an orthogonal study characterising the entire subvisible size range. Int J Pharm [Internet]. 2017;519:58–66. Available from: https://www.sciencedirect.com/science/article/pii/S0378517317300157.

Gross J, Sayle S, Karow AR, Bakowsky U, Garidel P. Nanoparticle tracking analysis of particle size and concentration detection in suspensions of polymer and protein samples: influence of experimental and data evaluation parameters. Eur J Pharm Biopharm. 2016;104:30–41.

Article  CAS  PubMed  Google Scholar 

Nabhan M, Pallardy M, Turbica I. Immunogenicity of bioproducts: cellular models to evaluate the impact of therapeutic antibody aggregates. Front Immunol. 2020;11:725.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pham NB, Meng WS. Protein aggregation and immunogenicity of biotherapeutics. Int J Pharmaceut. 2020;585: 119523.

Article  CAS  Google Scholar 

Rane SS, Dearman RJ, Kimber I, Uddin S, Bishop S, Shah M, et al. Impact of a heat shock protein impurity on the immunogenicity of biotherapeutic monoclonal antibodies. Pharmaceut Res. 2019;36:51.

Article  Google Scholar 

Freitag AJ, Shomali M, Michalakis S, Biel M, Siedler M, Kaymakcalan Z, et al. Investigation of the immunogenicity of different types of aggregates of a murine monoclonal antibody in mice. Pharm Res. 2015;32:430–44.

Article  CAS  PubMed  Google Scholar 

JP. 6.07 Insoluble particulate matter test for injections. 16th ed. 2011.

Sharma DK, King D, Oma P, Merchant C. Micro-flow imaging: flow microscopy applied to sub-visible particulate analysis in protein formulations. AAPS J. 2010;12:455–64.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gross-Rother J, Blech M, Preis E, Bakowsky U, Garidel P. Particle detection and characterization for biopharmaceutical applications: current principles of established and alternative techniques. Pharm. 2020;12:1112.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Narhi LO, Jiang Y, Cao S, Benedek K, Shnek D. A critical review of analytical methods for subvisible and visible particles. Curr Pharm Biotechnol. 2009;10:373–81.

Article  CAS  PubMed  Google Scholar 

Barnard JG, Babcock K, Carpenter JF. Characterization and quantitation of aggregates and particles in interferon-β products: potential links between product quality attributes and immunogenicity. J Pharm Sci [Internet]. 2013;102:915–28. Available from: http://www.sciencedirect.com/science/article/pii/S0022354915311655.

Zoells S, Weinbuch D, Wiggenhorn M, Winter G, Friess W, Jiskoot W, et al. Flow imaging microscopy for protein particle analysis–a comparative evaluation of four different analytical instruments. AAPS J. 2013;15:1200–11.

Article  CAS  Google Scholar 

Zoells S, Gregoritza M, Tantipolphan R, Wiggenhorn M, Winter G, Friess W, et al. How subvisible particles become invisible-relevance of the refractive index for protein particle analysis. J Pharm Sci. 2013;102:1434–46.

Article  CAS  Google Scholar 

Sharma VK, Kalonia DS. Aggregation of therapeutic proteins. 2010;205–56.

USP. <1787> Informational chapter Measurement of subvisible particulate matter in therapeutic protein injections. 40th ed. 2017.

Werk T, Volkin DB, Mahler H-C. Effect of solution properties on the counting and sizing of subvisible particle standards as measured by light obscuration and digital imaging methods. Eur J Pharm Sci. 2014;53:95–108.

Article  CAS  PubMed  Google Scholar 

Krause N, Kuhn S, Frotscher E, Nikels F, Hawe A, Garidel P, et al. Oil-immersion flow imaging microscopy for quantification and morphological characterization of submicron particles in biopharmaceuticals. Aaps J. 2021;23:13.

Article  Google Scholar 

Cavicchi R, Ripple D. Improving diameter accuracy for dynamic imaging microscopy for different particle types. J Pharm Sci. 2019;109:488–95.

Article  PubMed  Google Scholar 

Fawaz I, Schaz S, Boehrer A, Garidel P, Blech M. Micro-flow imaging multi-instrument evaluation for sub-visible particle detection. Eur J Pharm Biopharm. 2023;185:55–70.

Article  CAS  PubMed  Google Scholar 

Kiyoshi M, Shibata H, Harazono A, Torisu T, Maruno T, Akimaru M, et al. Collaborative study for analysis of subvisible particles using flow imaging and light obscuration: experiences in Japanese biopharmaceutical consortium. J Pharm Sci [Internet]. 2019;108:832–41. Available from: http://www.sciencedirect.com/science/article/pii/S0022354918305057.

Weinbuch D, Zolls S, Wiggenhorn M, Friess W, Winter G, Jiskoot W, et al. Micro-flow imaging and resonant mass measurement (Archimedes)–complementary methods to quantitatively differentiate protein particles and silicone oil droplets. J Pharm Sci. 2013;102:2152–65.

Article  CAS  PubMed  Google Scholar 

Huang CT, Sharma D, Oma P, Krishnamurthy R. Quantitation of protein particles in parenteral solutions using micro-flow imaging. J Pharm Sci. 2009;98:3058–71.

Article