Abstract
Biopharmaceutical companies are required to control subvisible and visible particles in their products to ensure a consistent manufacturing process, assess product quality, as well as address potential safety concerns. Subvisible particles cover the size range between 1 and 100 μm, while particles >100 μm are generally considered to be visible [1]. According to USP guidelines, particles are classified into three different categories, namely, extrinsic, intrinsic, and inherent particles [1]. Extrinsic particles are defined as foreign particles unrelated to the manufacturing process, while intrinsic particles arise from the manufacturing process or primary packaging. Inherent particles can result from drug product degradation and can contain proteinaceous and/or other formulation components [2]. These three particle types are associated with different risk profiles, and an appropriate risk and safety assessment must be performed in order to set up an appropriate control strategy. In general, occurrence of extrinsic particles should be eliminated, and intrinsic particle types must be monitored/controlled to minimize their occurrence, while potential inherent particles must be well characterized and their presence justified and monitored/controlled over the product shelf life [3]. Thus, unless otherwise stated, hereafter the main focus will be given to the inherent particle type. In the last few years, more occurrences of inherent particles such as proteinaceous or fatty acid particles have prompted companies to develop more complex and risk-based control systems to control levels of these specific particle types. For this, general safety assessments based on prior knowledge and clinical experience with such inherent particles are required to demonstrate patient safety and guarantee product quality.
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References
Mach H, Bhambhani A, Meyer BK, Burek S, Davis H, Blue JT, et al. The use of flow cytometry for the detection of subvisible particles in therapeutic protein formulations. J Pharm Sci. 2011;100(5):1671–8.
Saggu M, Liu J, Patel A. Identification of subvisible particles in biopharmaceutical formulations using Raman spectroscopy provides insight into polysorbate 20 degradation pathway. Pharm Res. 2015;32(9):2877–88.
Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJ, Middaugh CR, Winter G, et al. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J Pharm Sci. 2009;98(4):1201–5.
Labrenz SR. Ester hydrolysis of polysorbate 80 in mAb drug product: evidence in support of the hypothesized risk after the observation of visible particulate in mAb formulations. J Pharm Sci. 2014;103(8):2268–77.
Boll B, Bessa J, Folzer E, Quiroz AR, Schmidt R, Bulau P, et al. Extensive chemical modifications in the primary protein structure of IgG1 subvisible particles are necessary for breaking immune tolerance. Mol Pharm. 2017;14(4):1292–9.
Singh SK, Afonina N, Awwad M, Bechtold-Peters K, Blue JT, Chou D, et al. An industry perspective on the monitoring of subvisible particles as a quality attribute for protein therapeutics. J Pharm Sci. 2010;99(8):3302–21.
Shieh IC, Patel AR. Predicting the agitation-induced aggregation of monoclonal antibodies using surface tensiometry. Mol Pharm. 2015;12(9):3184–93.
Khan T, Mahler H-C, Kishore SR. Key interactions of surfactants in therapeutic protein formulations: a review. Eur J Pharm Biopharm. 2015;97:60.
Kishore RK, Kiese S, Fischer S, Pappenberger A, Grauschopf U, Mahler H-C. The degradation of Polysorbates 20 and 80 and its potential impact on the stability of biotherapeutics. Pharm Res. 2011;28(5):1194–210.
Bessa J, Boeckle S, Beck H, Buckel T, Schlicht S, Ebeling M, et al. The immunogenicity of antibody aggregates in a novel transgenic mouse model. Pharm Res. 2015;32(7):2344–59.
Filipe V, Jiskoot W, Basmeleh AH, Halim A, Schellekens H, Brinks V. Immunogenicity of different stressed IgG monoclonal antibody formulations in immune tolerant transgenic mice. MAbs. 2012;4(6):740–52.
Bi V, Jawa V, Joubert MK, Kaliyaperumal A, Eakin C, Richmond K, et al. Development of a human antibody tolerant mouse model to assess the immunogenicity risk due to aggregated biotherapeutics. J Pharm Sci. 2013;102(10):3545–55.
Zolls S, Tantipolphan R, Wiggenhorn M, Winter G, Jiskoot W, Friess W, et al. Particles in therapeutic protein formulations, part 1: overview of analytical methods. J Pharm Sci. 2012;101(3):914–35.
Barnard JG, Rhyner MN, Carpenter JF. Critical evaluation and guidance for using the Coulter method for counting subvisible particles in protein solutions. J Pharm Sci. 2012;101(1):140–53.
Demeule B, Messick S, Shire SJ, Liu J. Characterization of particles in protein solutions: reaching the limits of current technologies. AAPS J. 2010;12(4):708–15.
Saggu M, Patel AR, Koulis T. A random forest approach for counting silicone oil droplets and protein particles in antibody formulations using flow microscopy. Pharm Res. 2017;34(2):479–91.
Zhou C, Krueger AB, Barnard JG, Qi W, Carpenter JF. Characterization of nanoparticle tracking analysis for quantification and sizing of submicron particles of therapeutic proteins. J Pharm Sci. 2015:n/a–a.
Patel AR, Lau D, Liu J. Quantification and characterization of micrometer and submicrometer subvisible particles in protein therapeutics by use of a suspended microchannel resonator. Anal Chem. 2012;84(15):6833–40.
Valeur E, Gueret SM, Adihou H, Gopalakrishnan R, Lemurell M, Waldmann H, et al. New modalities for challenging targets in drug discovery. Angew Chem Int Ed Engl. 2017;56(35):10294–323.
Manning M, Patel K, Borchardt R. Stability of protein pharmaceuticals. Pharm Res. 1989;6(11):903–18.
Mach H, Arvinte T. Addressing new analytical challenges in protein formulation development. Eur J Pharm Biopharm. 2011;78(2):196–207.
Ríos QA, Lamerz J, Da Cunha T, Boillon A, Adler M, Finkler C, et al. Factors governing the precision of subvisible particle measurement methods-a case study with a low-concentration therapeutic protein product in a prefilled syringe. Pharm Res. 2015;33:450.
McCrone WC. The particle atlas; an encyclopedia of techniques for small particle identification [by] Walter C. McCrone [and] John Gustav Delly . Delly JG, Palenik SJ, editors. Ann Arbor: Ann Arbor Science Publishers; 1973.
USP <1787> Subvisible Particulate Matter in Therapeutic Protein Injections.
Rosenberg AS. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev Biol. 2003;112:15–21.
Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJA, Middaugh CR, Winter G, Fan Y-X, Kirshner S, Verthelyi D, Kozlowski S, Clouse KA, Swann PG, Rosenberg A, Cherney B. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J Pharm Sci. 2009;98(4):1201–5.
Narhi LO, Schmit J, Bechtold-Peters K, Sharma D. Classification of protein aggregates. J Pharm Sci. 2012;101(2):493–8.
Johns J, Golfetto P, Bush T, Fantozzi G, Shabushnig J, Perry A, et al. Achieving “zero” defects for visible particles in injectables. PDA J Pharm Sci Technol. 2018;72(6):640–50.
Mathonet S, Mahler HC, Esswein ST, Mazaheri M, Cash PW, Wuchner K, et al. A biopharmaceutical industry perspective on the control of visible particles in biotechnology-derived injectable drug products. PDA J Pharm Sci Technol. 2016;70(4):392–408.
USP <1790> Visual Inspection of Injections.
Knapp JZ, Kushner HK. Generalized methodology for evaluation of parenteral inspection procedures. J Parenter Drug Assoc. 1980;34(1):14–61.
Hindelang F, Roggo Y, Zurbach R. Forensic investigation in the pharmaceutical industry: identification procedure of visible particles in (drug) solutions and different containers by combining vibrational and X-ray spectroscopic techniques. J Pharm Biomed Anal. 2018;148:334–49.
Loosli V, Germershaus O, Steinberg H, Dreher S, Grauschopf U, Funke S. Methods to determine the silicone oil layer thickness in sprayed-on siliconized syringes. PDA J Pharm Sci Technol. 2018;72(3):278–97.
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Messick, S., Saggu, M., Ríos Quiroz, A. (2020). Chapter 11: Particles in Biopharmaceuticals: Causes, Characterization, and Strategy. In: Jameel, F., Skoug, J., Nesbitt, R. (eds) Development of Biopharmaceutical Drug-Device Products. AAPS Advances in the Pharmaceutical Sciences Series, vol 35. Springer, Cham. https://doi.org/10.1007/978-3-030-31415-6_11
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DOI: https://doi.org/10.1007/978-3-030-31415-6_11
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