蛋白质类生物制品几种不合格冻干外观及解决方案
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摘要
冻干即真空冷冻干燥,是利用升华的原理使物料脱水的一种干燥技术,其广泛用于生物制品,特别是蛋白质类生物制品的生产,以保护生物制品生物活性成分。外观是冻干制品的重要质量属性之一,合格的冻干制品外观应是疏松多孔、色泽均匀、质地细腻的固体。在大规模生产中,由于冻干参数复杂、设备操作的灵活性等因素,冻干制品的饼块有时会出现收缩、裂化、塌陷、雾化、回熔、喷瓶、结膜等不合格外观,从而造成极大的经济损失。现就近年来在蛋白质类生物制品冻干过程中易发生的几种不合格外观及解决方案作一概述。
Freeze-drying or vacuum freeze-drying is a drying technique that utilizes the principle of sublimation to dehydrate materials. It is widely used in the production of biological products, especially for protein preparation, so as to protect biologically active components of biological products. Appearance is one of the important quality attributes of freeze-dried products. The appearance of qualified freeze-dried products should be in a porous structure, with uniform color and texture. However, in a large-scale production, due to factors such as complicated freeze-drying parameters and flexibility of equipment operation, sometimes the freeze-dried cake will lead to unqualified appearances, such as shrinkage, cracking, collapse, fogging, melting back, ejection, etc. These unqualified freeze-dried appearances resulted in great economic losses. Several unqualified appearances that are prone to occur in the lyophilization of protein biologics and the relevant solutions in recent years are summarized.
Freeze-drying or vacuum freeze-drying is a drying technique that utilizes the principle of sublimation to dehydrate materials. It is widely used in the production of biological products, especially for protein preparation, so as to protect biologically active components of biological products. Appearance is one of the important quality attributes of freeze-dried products. The appearance of qualified freeze-dried products should be in a porous structure, with uniform color and texture. However, in a large-scale production, due to factors such as complicated freeze-drying parameters and flexibility of equipment operation, sometimes the freeze-dried cake will lead to unqualified appearances, such as shrinkage, cracking, collapse, fogging, melting back, ejection, etc. These unqualified freeze-dried appearances resulted in great economic losses. Several unqualified appearances that are prone to occur in the lyophilization of protein biologics and the relevant solutions in recent years are summarized.
引文
[1] ANAMUR C, WINTER G, ENGERT J. Stability of collapse lyophilized influenza vaccine formulations[J]. Int J Pharm, 2015, 483(1/2):131-141.
[2] ARSICCIO A, PISANO R. Application of the quality by design approach to the freezing step of freeze-drying: Building the design space[J]. J Pharm Sci, 2018,107(6):1586-1596.
[3] WALTERS R H, BHATNAGAR B, TCHESSALOV S, et al. Next generation drying technologies for pharmaceutical applications[J]. J Pharm Sci, 2014, 103(9):2673-2695.
[4] 吴俊柱, 吕运才, 柳燕. 冻干过程中喷瓶现象浅析[J]. 齐鲁药事, 2004, 23(5):58.
[5] DURALLIU A, MATEJTSCHUK P, WILLIAMS D R. Humidity induced collapse in freeze dried cakes: A direct visualization study using DVS[J]. Eur J Pharm Biopharm, 2018, 127:29-36.
[6] KORANG-YEBOAH M, SRINIVASAN C,SIDDIQUI A, et al. Application of optical coherence tomography freeze-drying microscopy for designing lyophilization process and its impact on process efficiency and product quality[J]. AAPS PharmSciTech, 2018, 19(1):448-459.
[7] MCCOY T. Effect of lyophilizate collapse on the stability of protein biopharmaceuticals[J]. J Steroid Biochem, 2011, 5(5):471-479.
[8] KASPER J C, WINTER G, FRIESS W. Recent advances and further challenges in lyophilization[J]. Eur J Pharm Biopharm, 2013, 85(2):162-169.
[9] HARA H, TAGIRI M, HWANG I S, et al. Adverse effect of cake collapse on the functional integrity of freeze-dried bull spermatozoa[J]. Cryobiology, 2014, 68(3):354-360.
[10] CLEARFIELD D, WEI M. Investigation of structural collapse in unidirectionally freeze cast collagen scaffolds[J]. J Mater Sci Mater Med, 2016, 27(1):1-8.
[11] GEH K J ,HUBERT M, WINTER G. Progress in formulation development and sterilisation of freeze-dried oligodeoxynucleotide-loaded gelatine nanoparticles[J]. Eur J Pharm Biopharm, 2018, 129:10-20.
[12] OHORI R, AKITA T, YAMASHITA C. Effect of temperature ramp rate during the primary drying process on the properties of amorphous-based lyophilized cake, Part 2: Successful lyophilization by adopting a fast ramp rate during primary drying in protein formulations[J]. Eur J Pharm Biopharm, 2018, 130:83-95.
[13] 刘树强. 德国CHRIST冻干机LyoControl系统在冷冻干燥工艺中测量凝固点的研究[D]. 北京:北京大学, 2012.
[14] PATEL S M, NAIL S L, PIKAL M J, et al. Lyophilized drug product cake appearance: What is acceptable?[J]. J Pharm Sci, 2017,106(7):1706-1721.
[15] AWOTWE OTOO D, AGARABI C, KHAN M A. An integrated process analytical technology (PAT) approach to monitoring the effect of supercooling on lyophilization product and process parameters of model monoclonal antibody formulations[J]. J Pharm Sci, 2014, 103(7):2042-2052.
[16] ST?RTZEL P, GIESELER H, GIESELER M, et al. Freeze-drying of L-arginine/sucrose-based protein formulations, Part 2: Optimization of formulation design and freeze-drying process conditions for an L-arginine chloride-based protein formulation system[J]. J Pharm Sci, 2015, 104(12):4241-4256.
[17] WANG D Q, HEY J M, NAIL S L. Effect of collapse on the stability of freeze-dried recombinant factor VIII and alpha-amylase[J]. J Pharm Sci, 2004, 93(5):1253-1263.
[18] CHATTERJEE K, SHALAEV E Y, SURYANARAYANAN R. Partially crystalline systems in lyophilization: I. Use of ternary state diagrams to determine extent of crystallization of bulking agent[J]. J Pharm Sci, 2005, 94(4):798-808.
[19] PASSOT S, FONSECA F, BARBOUCHE N, et al. Effect of product temperature during primary drying on the long-term stability of lyophilized proteins[J]. Pharm Dev Technol, 2007, 12(6):543-553.
[20] DEPAZ R A, PANSARE S, PATEL S M. Freeze-drying above the glass transition temperature in amorphous protein formulations while maintaining product quality and improving process efficiency[J]. J Pharm Sci, 2016, 105(1):40-49.
[21] ETZL E E, WINTER G, ENGERT J. Toward intradermal vaccination: Preparation of powder formulations by collapse freeze-drying[J]. Pharm Dev Technol, 2014, 19(2):213-222.
[22] SCHERSCH K, BETZ O, GARIDEL P, et al. Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins III: Collapse during storage at elevated temperatures[J]. Eur J Pharm Biopharm, 2013, 85(2):240-252.
[23] KASPER J C, FRIESS W. The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals[J]. Eur J Pharm Biopharm, 2011, 78(2):248-263.
[24] ABDUL-FATTAH A M, OESCHGER R, ROEHL H, et al. Investigating factors leading to fogging of glass vials in lyophilized drug products.[J]. Eur J Pharm Biopharm, 2013, 85(2):314-326.
[25] KRALCHEVSKY P A, DANOV K D, DENKOV N D. 7 Chemical physics of colloid systems and interfaces[M]//Handbook of Surface and Colloid Chemistry. London:CRC PRESS,2008:197-377.
[26] STRALLER G, LEE G. Shrinkage of spray-freeze-dried microparticles of pure protein for ballistic injection by manipulation of freeze-drying cycle[J]. Int J Pharm, 2017, 532(1):444-449.
[27] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes. part I: Final-product assessment[J]. J Pharm Sci, 2015, 104(1):155-164.
[28] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes part 3: Hydrophobic vials and the question of adhesion[J]. J Pharm Sci, 2015, 104(6):2040-2046.
[29] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes. part II: Kinetics[J]. Pharm Res, 2015, 32(8):1-13.
[30] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes. part IV: Effects of freezing protocol[J]. Int J Pharm, 2015, 495(1):52.
[31] VOLLRATH I, PAULI V, FRIESS W, et al. Evaluation of heat flux measurement as a new process analytical technology monitoring tool in freeze drying[J]. J Pharm Sci, 2017, 106(5):1249-1257.
[32] 滑金标, 李清侠. 药物冻干过程中常见问题及解决方案[J]. 海峡药学, 2014, 26(2):99-100.
[33] WITTAYA-AREEKUL S, NEEDHAM G F, MILTON N, et al. Freeze-drying of tert-butanol/water cosolvent systems: A case report on formation of a friable freeze-dried powder of tobramycin sulfate[J]. J Pharm Sci, 2002, 91(4):1147-1155.
[34] LIU D, GALVANIN F, YU Y. Formulation screening and freeze-drying process optimization of ginkgolide b lyophilized powder for injection[J]. AAPS PharmSciTech, 2018, 19(2):541-550.
[35] ESFANDIARY R, GATTU S K, STEWART J M, et al. Effect of freezing on lyophilization process performance and drug product cake appearance[J]. J Pharm Sci, 2016, 105(4):1427-1433.
[36] CHERRY C L, MILLWARD H, COOPER R, et al. A novel approach to sterile pharmaceutical freeze-drying[J]. Pharm Dev Technol, 2014, 19(1):73-81.
[2] ARSICCIO A, PISANO R. Application of the quality by design approach to the freezing step of freeze-drying: Building the design space[J]. J Pharm Sci, 2018,107(6):1586-1596.
[3] WALTERS R H, BHATNAGAR B, TCHESSALOV S, et al. Next generation drying technologies for pharmaceutical applications[J]. J Pharm Sci, 2014, 103(9):2673-2695.
[4] 吴俊柱, 吕运才, 柳燕. 冻干过程中喷瓶现象浅析[J]. 齐鲁药事, 2004, 23(5):58.
[5] DURALLIU A, MATEJTSCHUK P, WILLIAMS D R. Humidity induced collapse in freeze dried cakes: A direct visualization study using DVS[J]. Eur J Pharm Biopharm, 2018, 127:29-36.
[6] KORANG-YEBOAH M, SRINIVASAN C,SIDDIQUI A, et al. Application of optical coherence tomography freeze-drying microscopy for designing lyophilization process and its impact on process efficiency and product quality[J]. AAPS PharmSciTech, 2018, 19(1):448-459.
[7] MCCOY T. Effect of lyophilizate collapse on the stability of protein biopharmaceuticals[J]. J Steroid Biochem, 2011, 5(5):471-479.
[8] KASPER J C, WINTER G, FRIESS W. Recent advances and further challenges in lyophilization[J]. Eur J Pharm Biopharm, 2013, 85(2):162-169.
[9] HARA H, TAGIRI M, HWANG I S, et al. Adverse effect of cake collapse on the functional integrity of freeze-dried bull spermatozoa[J]. Cryobiology, 2014, 68(3):354-360.
[10] CLEARFIELD D, WEI M. Investigation of structural collapse in unidirectionally freeze cast collagen scaffolds[J]. J Mater Sci Mater Med, 2016, 27(1):1-8.
[11] GEH K J ,HUBERT M, WINTER G. Progress in formulation development and sterilisation of freeze-dried oligodeoxynucleotide-loaded gelatine nanoparticles[J]. Eur J Pharm Biopharm, 2018, 129:10-20.
[12] OHORI R, AKITA T, YAMASHITA C. Effect of temperature ramp rate during the primary drying process on the properties of amorphous-based lyophilized cake, Part 2: Successful lyophilization by adopting a fast ramp rate during primary drying in protein formulations[J]. Eur J Pharm Biopharm, 2018, 130:83-95.
[13] 刘树强. 德国CHRIST冻干机LyoControl系统在冷冻干燥工艺中测量凝固点的研究[D]. 北京:北京大学, 2012.
[14] PATEL S M, NAIL S L, PIKAL M J, et al. Lyophilized drug product cake appearance: What is acceptable?[J]. J Pharm Sci, 2017,106(7):1706-1721.
[15] AWOTWE OTOO D, AGARABI C, KHAN M A. An integrated process analytical technology (PAT) approach to monitoring the effect of supercooling on lyophilization product and process parameters of model monoclonal antibody formulations[J]. J Pharm Sci, 2014, 103(7):2042-2052.
[16] ST?RTZEL P, GIESELER H, GIESELER M, et al. Freeze-drying of L-arginine/sucrose-based protein formulations, Part 2: Optimization of formulation design and freeze-drying process conditions for an L-arginine chloride-based protein formulation system[J]. J Pharm Sci, 2015, 104(12):4241-4256.
[17] WANG D Q, HEY J M, NAIL S L. Effect of collapse on the stability of freeze-dried recombinant factor VIII and alpha-amylase[J]. J Pharm Sci, 2004, 93(5):1253-1263.
[18] CHATTERJEE K, SHALAEV E Y, SURYANARAYANAN R. Partially crystalline systems in lyophilization: I. Use of ternary state diagrams to determine extent of crystallization of bulking agent[J]. J Pharm Sci, 2005, 94(4):798-808.
[19] PASSOT S, FONSECA F, BARBOUCHE N, et al. Effect of product temperature during primary drying on the long-term stability of lyophilized proteins[J]. Pharm Dev Technol, 2007, 12(6):543-553.
[20] DEPAZ R A, PANSARE S, PATEL S M. Freeze-drying above the glass transition temperature in amorphous protein formulations while maintaining product quality and improving process efficiency[J]. J Pharm Sci, 2016, 105(1):40-49.
[21] ETZL E E, WINTER G, ENGERT J. Toward intradermal vaccination: Preparation of powder formulations by collapse freeze-drying[J]. Pharm Dev Technol, 2014, 19(2):213-222.
[22] SCHERSCH K, BETZ O, GARIDEL P, et al. Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins III: Collapse during storage at elevated temperatures[J]. Eur J Pharm Biopharm, 2013, 85(2):240-252.
[23] KASPER J C, FRIESS W. The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals[J]. Eur J Pharm Biopharm, 2011, 78(2):248-263.
[24] ABDUL-FATTAH A M, OESCHGER R, ROEHL H, et al. Investigating factors leading to fogging of glass vials in lyophilized drug products.[J]. Eur J Pharm Biopharm, 2013, 85(2):314-326.
[25] KRALCHEVSKY P A, DANOV K D, DENKOV N D. 7 Chemical physics of colloid systems and interfaces[M]//Handbook of Surface and Colloid Chemistry. London:CRC PRESS,2008:197-377.
[26] STRALLER G, LEE G. Shrinkage of spray-freeze-dried microparticles of pure protein for ballistic injection by manipulation of freeze-drying cycle[J]. Int J Pharm, 2017, 532(1):444-449.
[27] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes. part I: Final-product assessment[J]. J Pharm Sci, 2015, 104(1):155-164.
[28] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes part 3: Hydrophobic vials and the question of adhesion[J]. J Pharm Sci, 2015, 104(6):2040-2046.
[29] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes. part II: Kinetics[J]. Pharm Res, 2015, 32(8):1-13.
[30] ULLRICH S, SEYFERTH S, LEE G. Measurement of shrinkage and cracking in lyophilized amorphous cakes. part IV: Effects of freezing protocol[J]. Int J Pharm, 2015, 495(1):52.
[31] VOLLRATH I, PAULI V, FRIESS W, et al. Evaluation of heat flux measurement as a new process analytical technology monitoring tool in freeze drying[J]. J Pharm Sci, 2017, 106(5):1249-1257.
[32] 滑金标, 李清侠. 药物冻干过程中常见问题及解决方案[J]. 海峡药学, 2014, 26(2):99-100.
[33] WITTAYA-AREEKUL S, NEEDHAM G F, MILTON N, et al. Freeze-drying of tert-butanol/water cosolvent systems: A case report on formation of a friable freeze-dried powder of tobramycin sulfate[J]. J Pharm Sci, 2002, 91(4):1147-1155.
[34] LIU D, GALVANIN F, YU Y. Formulation screening and freeze-drying process optimization of ginkgolide b lyophilized powder for injection[J]. AAPS PharmSciTech, 2018, 19(2):541-550.
[35] ESFANDIARY R, GATTU S K, STEWART J M, et al. Effect of freezing on lyophilization process performance and drug product cake appearance[J]. J Pharm Sci, 2016, 105(4):1427-1433.
[36] CHERRY C L, MILLWARD H, COOPER R, et al. A novel approach to sterile pharmaceutical freeze-drying[J]. Pharm Dev Technol, 2014, 19(1):73-81.