Research Progress on Forced Degradation of Biopharmaceuticals

doi:10.19586/j.2095-2341.2021.0171

Current Biotechnology ›› 2022, Vol. 12 ›› Issue (2): 236-242.DOI: 10.19586/j.2095-2341.2021.0171

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Research Progress on Forced Degradation of Biopharmaceuticals

Xiaoteng ZHANG(), Jianjun HAN, Yan BAI()

North China Pharmaceutical Jintan Biotechnology Co. ，Ltd. ，Shijiazhuang 050035，China

Received:2021-10-20 Accepted:2021-12-03 Online:2022-03-25 Published:2022-03-25
Contact: Yan BAI

蛋白类药物强制降解研究进展

张晓腾(), 韩建军, 白燕()

华北制药金坦生物技术股份有限公司，石家庄 050035

通讯作者: 白燕
作者简介:张晓腾 E-mail：447663259@qq.com；

Abstract

Abstract:

The forced degradation studies can reveal the possible degradation pathway of medicine， and provide support for the formulation development， storage and transportation of biopharmaceuticals. Therefore， the forced degradation studies paly important roles in biopharmaceuticals research and development， however， there were no standard guidelines on the selection of forced conditions， action time and degradation degree. The commonly used forced degradation conditions （high temperature， pH， oxidation， light， repeated freezing-thawing and shaking or stirring） and the effects of different forced degradation conditions on protein drugs were summarized in this paper， and reasonable design suggestions were put forward， in order to provide reference for the selection of forced degradation studies conditions of biopharmaceuticals.

Key words: biopharmaceuticals, forced degradation, forced conditions

摘要：

强制降解试验可以揭示药物可能的降解途径，为蛋白类药物制剂组方的开发、储存、运输提供支持，因此，强制降解研究在蛋白类药物研发中具有重要作用，但目前关于强制条件的选择、作用时间和降解程度尚无标准指南。综述了目前常用的强制降解条件（高温、pH、氧化、光照、反复冻融和震荡或搅拌）及不同强制降解条件对蛋白类药物的影响，并提出了相关设计建议，以期为蛋白类药物的强制降解试验条件的选择提供参考。

关键词: 蛋白类药物, 强制降解, 强制条件

CLC Number:

Q493.2

Xiaoteng ZHANG, Jianjun HAN, Yan BAI. Research Progress on Forced Degradation of Biopharmaceuticals[J]. Current Biotechnology, 2022, 12(2): 236-242.

张晓腾, 韩建军, 白燕. 蛋白类药物强制降解研究进展[J]. 生物技术进展, 2022, 12(2): 236-242.

References 53

1	BECK A, WAGNER-ROUSSET E, AYOUB D, et al.. Characterization of therapeutic antibodies and related products[J]. Anal. Chem., 2013, 85(2): 715-736.
2	张忠兵,韦薇,罗建辉.生物类似药糖基化相似性评价中的审评思考[J].中国新药杂志,2020,29(21):2476-2480.
3	周爱萍.生物治疗药物和生物类似药研究进展[J].中国新药杂志,2017,26(3):296-299.
4	HELENE K, MURALIDHARAN M, SCHNEIDER Z, et al.. Antibodies to watch in 2020[J]. MAbs, 2020, 12(1): 1-8.
5	FDA. New Drug Therapy Approvals 2019 [EB/OL]. [2020-01-06]. .
6	WANG W. Instability, stabilization, and formulation of liquid protein pharmaceuticals[J]. Int. J. Pharm., 1999, 185(2): 129-188.
7	ALEXIS O, JOSEB F, MATIAS L. New trends in analysis of biopharmaceutical products[J]. Curr. Pharm. Anal., 2007, 3(4):230-248.
8	DHAMA K, MUNJAL A, HMN I. Recent advances and novel strategies for the development of biomedical therapeutics: state-of-the-art and future perspectives[J]. Int. J. Pharm., 2017, 13(7): 929-933.
9	GAVINA J, BRITZ-MCKIBBIN P. Protein unfolding and conformational studies by capillary electrophoresis[J]. Curr. Anal. Chem., 2007, 3(1): 17-31.
10	MCAVAN B S, BOWSHER L A, Powell T, et al.. Raman spectroscopy to monitor post-translational modifications and degradation in monoclonal antibody therapeutics[J]. Anal. Chem., 2020, 92(15): 10381-10389.
11	DIDIER C, VERONIQUE H, WOINET B, et al.. A spray freeze dried micropellet based formulation proof-of-concept for a yellow fever vaccine candidate[J]. Eur. J. Pharm. Biopharm., 2019, 142: 334-343.
12	DIDER C. Accurate prediction of vaccine stability under real storage conditions and during temperature excursions[J]. Eur. J. Pharm. Biopharm., 2018, 125: 76-84.
13	HALLEY J, CHOU Y R, CICCHINO C, et al.. An Industry perspective on forced degradation studies of biopharmaceuticals: survey outcome and recommendations[J]. J. Pharm., 2019, 109(1): 6-21.
14	HASELLBERG R, BRINKS V, HAWE A, et al.. Capillaryelectrophoresis-mass spectrometry using noncovalently coated capillariesfor the analysis of biopharmaceuticals[J]. Anal. Bioanal. Chem., 2011, 400: 295-303.
15	LIM A, DOYLE B L, KELLY G M, et al.. Characterization of a cathepsin D protease from CHO cell-free medium and mitigation of its impact on the stability of a recombinant therapeutic protein[J]. Biotechnol. Prog., 2018, 34(1): 120-129.
16	DOVGAN T, GOLGHALYANI V, ZURLO F, et al.. Targeted CHO cell engineering approaches can reduce HCP-related enzymatic degradation and improve mAb product quality[J]. Biotechnol. Bioeng., 2021, 118: 3821-3831.
17	PACEA L, WONG R L, ZHANG Y T, et al.. Asparagine deamidation dependence on buffer type, pH, and temperature[J]. J. Pharm., 2013, 102(6): 1712-1723.
18	PERICO N, PURTELL J, DILLON T M, et al.. Conformational implications of an inversed pH-dependent antibody aggregation[J]. J. Pharm., 2009, 98(9): 3031-3042.
19	PATEL J, KOTHARI R, TUNGA R, et al.. Stability considerations for biopharmaceuticals, part 1: overview of protein and peptide degradation pathways[J]. Bioprocess Int., 2011, 9(1): 20-31.
20	SINGH S K, MISHRA A, GOEL G, et al.. Modulation of granulocyte colony stimulating factor conformation and receptor binding by methionine oxidation[J]. Protein, 2020, 86(1): 1-13.
21	GRAF T, ABSTIENS K, WEDEKIND F, et al.. Controlled polysorbate 20 hydrolysis — a new approach to assess the impact of polysorbate 20 degradation on biopharmaceutical product quality in shortened time[J]. Eur. J. Pharm. Biopharm., 2020, 152: 318-326.
22	LIU H, GAZZ-BULSECO G, ZHOU L. Mass spectrometry analysis of photo-induced methionine oxidation of a recombinant human monoclonal antibody[J]. J. Am. Soc. Mass Spectrom., 2009, 20(3): 525-528.
23	SCHEICH C. Photo-degradation of therapeutic proteins: mechanistic aspects[J]. Pharm. Res., 2020, 37(3): 2763-2768.
24	REID LO, VIGNONI M, MARTINS-FROMENT N, et al.. Photochemistry of tyrosine dimer: when an oxidative lesionof proteins is able to photoinduce further damage[J]. Photochem. Photobiol. Sci., 2019, 18(7): 1732-1741.
25	HEMMLER D, GONSIOR M, POWERS L C, et al.. Simulated sunlight selectively modifies Maillard reaction products in a wide array of chemical reactions[J].Chemistry, 2019, 25(57): 13208-13217.
26	KAUR H, KAMALOV M, BRIMBLE M A. Chemical synthesis of peptidescontaining site-specific advanced glycation endproducts[J]. Acc. Chem. Res., 2016, 49(10): 2199-2208.
27	JACOBITZ A W, DYLSTRA A B, SPAHR C, et al.. Effects of buffer composition on site-specific glycation of lysine residues in monoclonal antibodies[J]. J. Pharm., 2019, 109(1): 1606-1615.
28	LAMORE S D, AZIMIAN S, HORN D, et al.. The malondialdehyde-derived fluorophore DHP-lysineis a potent sensitizer of UVA-induced photooxidative stress inhuman skin cells[J]. J. Photochem. Photobiol. B, 2010, 101(3): 251-264.
29	LATYPOV R F, HOGAN S, LAU H, et al.. Elucidation of acid-induced unfolding and aggregation of human immunoglobulin IgG1 and IgG2 Fc[J]. J. Biolog. Chem., 2011, 287(2): 1381-1396.
30	HAUPTMANN A, PODGOREK K, KUZMAN D, et al.. Impact of buffer, protein concentration and sucrose addition on the aggregation and particle formation during freezing and thawing[J]. Pharm. Res., 2018, 35(5): 101-117.
31	KEVIN P, KEN T, CHAD E, et al.. Solution pH jump during antibody and Fc-fusion protein thaw leads to increased aggregation[J]. J. Pharm. Anal., 2018, 8(5): 302-306.
32	JUN Z, CHRISTOPHER W, FENG H, et al.. Structural changes and aggregation mechanisms of two different dimers of an IgG2 monoclonal antibody[J]. Biochemistry, 2018, 57(37): 5466-5479.
33	BEE J S, STEVENSON J L, MEHTA B, et al.. Response of a concentrated monoclonal antibody formulation to high shear[J]. Biotechnol. Bioeng., 2009, 103(5): 936-943.
34	WANG W, NEMA S, TEAGARDEN D. Protein aggregation-pathways and influencing factors[J]. Int. J. Pharm., 2010, 390(2): 89-99.
35	MAA Y F, HSU C C. Effect of high shear on proteins[J]. Biotechnol. Bioeng., 2015, 51(4): 458-465.
36	MARCH D, BIANCO V, FRANZESE G. Protein unfolding and aggregation near a hydrophobic interface[J]. Polymers, 2021, 13(1): 156-170.
37	FLEISCHMAN M L, CHUNG J, PAUL E P, et al.. Shipping induced aggregation in therapeutic antibodies: utilization of a scale down model to assess degradation in mAbs[J]. J. Pharm. Sci., 2016, 106(4): 994-1000.
38	SSK A, SMP B, RS C, et al.. Key factors governing the reconstitution time of high concentration lyophilized protein formulations[J]. Eur. J. Pharm. Biopharm., 2021, 165: 361-373.
39	JEAN-RENE A, RODRIGUES M A, SERGUEI T, et al.. Freezing of biologicals revisited: scale, stability, excipients, and degradation stresses[J]. J. Pharm. Sci., 2020, 109(1): 44-61.
40	AL-HUSSEIN A, GIESELER H. Investigation of histidine stabilizing effects on LDH during freeze-drying[J]. J. Pharm. Sci., 2013, 102(3): 813-826.
41	SEIFERT I, FRIESS W. Improvement of arginine hydrochloride based antibody lyophilisates[J]. Int. Pharm., 2020, 589: 118589-118688.
42	ARAKAWA T, PRESTRELSKI S J, KENNEY W C, et al.. Factors affecting short-term and long-term stabilities of proteins[J]. Adv. Drug Deliv. Rev., 2001, 46: 307-326.
43	王静,赵文静,胡春梅,等.蛋白/多肽类药物脂质体的研究进展[J].化工技术与开发,2017,46(8):32-36.
44	HE P, TANG Z, LIN L, et al.. Novel biodegradable and pH-sensitive poly (ester amide) microspheres for oral insulin delivery[J]. Macromol. Biosci., 2012, 12(4): 547-556.
45	YU Y, SHAO Y, ZHOU M, et al.. Polyethylene glycol-derived polyelectrolyte-protein nanoclusters for protein drug delivery[J]. RSC Adv., 2021, 46: 521-532.
46	Houser J, KOSOUROVA J, KUBICKOVA M, et al.. Development of 48-condition buffer screen for protein stability assessment[J]. Biophys. Struc. Mech., 2021, 50: 461-471.
47	RABE M, KERTH A, BLUME A, et al.. Albumin displacement at the air-water interface by Tween (Polysorbate) surfactants[J]. Eur. Biophys. J., 2020, 49: 533-547.
48	EBEL C, EISENBERQ H, GHIRLANDO R. Probing protein-sugar inter⁃actions[J]. Biophys. J., 2000, 78(1): 385-393.
49	PALMER B, ANGUS K, TAYLOR L, et al.. Design of stability at ex⁃treme alkaline pH in streptococcal protein G [J]. J. Biotechnol., 2008, 134(3): 222-230.
50	WALTHER R, ZELIKIN A N. Chemical (neo) glycosylation of biological drugs[J]. Adv. Drug Deliv. Rev., 2021, 171: 62-76.
51	OYAMA K, OHKURI T, OCHI J, et al.. Abolition of aggregation of CH₂ domain of human IgG1 when combining glycosylation and protein stabilization[J]. Biochem. Biophys. Res. Commun., 2021, 558: 114-119.
52	KANAZAWA I, NOSTU M, TANAKA K, et al.. An open-label longitudinal study on the efficacy of switching from insulin glargine or detemir to degludec in type 2 diabetes mellitus[J]. Int. Med., 2015, 54(13): 1591-1598.
53	ZHENG J, MA B, TSAI C J, et al.. Structural stability and dynamics of an amyloid-forming peptide GNNQQNY from the yeast prion Sup-35[J]. Biophys. J., 2006, 91(3): 824-833.

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Research Progress on Forced Degradation of Biopharmaceuticals

蛋白类药物强制降解研究进展

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