Recent progress in drying technologies for improving the stability and delivery efficiency of biopharmaceuticals (original) (raw)

Abstract

Background Most biopharmaceuticals are developed in liquid dosage forms that are less stable than solid forms. To ensure the stability of biopharmaceuticals, it is critical to use an effective drying technique in the presence of an appropriate stabilizing excipient. Various drying techniques are available for this purpose, such as freeze drying or lyophilization, spray drying, spray freeze-drying, supercritical fluid drying, particle replication in nonwetting templates, and fluidized bed drying. Area covered In this review, we discuss drying technologies and their applications in the production of stable solid-state biopharmaceuticals, providing examples of commercially available products or clinical trial formulations. Alongside this, we also review how different analytical methods may be utilized in the evaluation of aerosol performance and powder characteristics of dried protein powders. Finally, we assess the protein integrity in terms of conformational and physicochemical stability and biological activity. Expert opinion With the aim of treating either infectious respiratory diseases or systemic disorders, inhaled biopharmaceuticals reduce both therapeutic dose and cost of therapy. Drying methods in the presence of optimized protein/stabilizer combinations, produce solid dosage forms of proteins with greater stability. A suitable drying method was chosen, and the process parameters were optimized based on the route of protein administration. With the ongoing trend of addressing deficiencies in biopharmaceutical production, developing new methods to replace conventional drying methods, and investigating novel excipients for more efficient stabilizing effects, these products have the potential to dominate the pharmaceutical industry in the future.

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References (147)

  1. Adali MB, Barresi AA, Boccardo G, Pisano R (2020) Spray freeze- drying as a solution to continuous manufacturing of pharma- ceutical products in bulk. Processes 8:709
  2. Ahrer K, Buchacher A, Iberer G, Jungbauer A (2004) Detection of aggregate formation during production of human immunoglobu- lin G by means of light scattering. J Chromatogr A 1043:41-46
  3. Ahrer K, Buchacher A, Iberer G, Jungbauer A (2006) Thermodynamic stability and formation of aggregates of human immunoglobulin G characterised by differential scanning calorimetry and dynamic light scattering. J Biochem Biophys Methods 66:73-86
  4. Alexander AJ, Hughes DE (1995) Monitoring of IgG antibody ther- mal stability by micellar electrokinetic capillary chromatog- raphy and matrix-assisted laser desorption/ionization mass spectrometry. Anal Chem 67:3626-3632
  5. Ali ME, Lamprecht A (2014) Spray freeze drying for dry powder inhalation of nanoparticles. Eur J Pharm Biopharm 87:510-517
  6. Anselmo AC, Gokarn Y, Mitragotri S (2019) Non-invasive delivery strategies for biologics. Nat Rev Drug Discovery 18:19-40
  7. Awotwe-Otoo D, Agarabi C, Read EK, Lute S, Brorson KA, Khan MA (2015) Product and process understanding to relate the effect of freezing method on glycation and aggregation of lyophilized monoclonal antibody formulations. Int J Pharm 490:341-350
  8. Bardoliwala D, Patel V, Javia A, Ghosh S, Patel A, Misra A (2019) Nanocarriers in effective pulmonary delivery of siRNA: cur- rent approaches and challenges. Ther Deliv 10:311-332
  9. Bjelošević M, Zvonar Pobirk A, Planinšek O, Ahlin Grabnar P (2020) Excipients in freeze-dried biopharmaceuticals: contributions toward formulation stability and lyophilisation cycle optimisa- tion. Int J Pharm 576:119029
  10. Butreddy A, Janga KY, Ajjarapu S, Sarabu S, Dudhipala N (2021) Instability of therapeutic proteins-an overview of stresses, stabilization mechanisms and analytical techniques involved in Lyophilized proteins. Int J Biol Macromol 167:309-325
  11. Carvalho N, Hoque ME, Oliver VL, Byrne A, Kermode M, Lambert P, Mcintosh MP, Morgan A (2020) Cost-effectiveness of inhaled oxytocin for prevention of postpartum haemorrhage: a modelling study applied to two high burden settings. BMC Med 18:201
  12. Chen AZ, Li L, Wang SB, Lin XF, Liu YG, Zhao C, Wang GY, Zhao Z (2012) Study of Fe 3 O 4-PLLA-PEG-PLLA magnetic micro- spheres based on supercritical CO 2: preparation, physicochemi- cal characterization, and drug loading investigation. J Supercrit Fluids 67:139-148
  13. Chen Y, Liao Q, Chen T, Zhang Y, Yuan W, Xu J, Zhang X (2021a) Freeze-drying formulations increased the adenovirus and pox- virus vaccine storage times and antigen stabilities. Virol Sin 36:365-372
  14. Chen Y, Mutukuri TT, Wilson NE, Zhou Q (2021b) Pharmaceutical protein solids: drying technology, solid-state characterization and stability. Adv Drug Deliv Rev 172:211-233
  15. Cohen J (2022) First self-copying mRNA vaccine proves itself in pan- demic trial. Science 376:446-446
  16. Costa C, Casimiro T, Corvo ML, Aguiar-Ricardo A (2021) Solid dos- age forms of biopharmaceuticals in drug delivery systems using sustainable strategies. Molecules 26:7653
  17. Dechraksa J, Suwandecha T, Srichana T (2020) Deposition pattern of polydisperse dry powders in andersen cascade impactor-aero- dynamic assessment for inhalation experimentally and In silico. Turk J Pharm Sci 17:20
  18. Dhahir RK, Al-Nima AM, Al-Bazzaz FY (2021) Dry powder inhal- ers: main characteristics, classifications and novel drug delivery systems review. Lat Am J Pharm 40:34-43
  19. Ding L, Tang S, Wyatt TA, Knoell DL, Oupický D (2021) Pulmonary siRNA delivery for lung disease: review of recent progress and challenges. J Control Release 330:977-991
  20. Duralliu A, Matejtschuk P, Stickings P, Hassall L, Tierney R, Williams DR (2020) The influence of moisture content and temperature on the long-term storage stability of freeze-dried high concentration immunoglobulin G (IgG). Pharmaceutics 12:303
  21. Egli J, Esposito C, Müri M, Riniker S, Wennemers H (2021) Influ- ence of lipidation on the folding and stability of collagen triple helices-an experimental and theoretical study. J Am Chem Soc 143:5937-5942
  22. El-Hammadi MM, Arias JL (2022) Recent advances in the surface functionalization of PLGA-based nanomedicines. Nanomateri- als (basel) 12:354
  23. Emami F, Vatanara A, Najafabadi AR, Kim Y, Park EJ, Sardari S, Na DH (2018a) Effect of amino acids on the stability of spray freeze-dried immunoglobulin G in sugar-based matrices. Eur J Pharm Sci 119:39-48
  24. Emami F, Vatanara A, Park EJ, Na DH (2018b) Drying technologies for the stability and bioavailability of biopharmaceuticals. Phar- maceutics 10:131
  25. Emami F, Vatanara A, Vakhshiteh F, Kim Y, Kim TW, Na DH (2019) Amino acid-based stable adalimumab formulation in spray freeze-dried microparticles for pulmonary delivery. J Drug Deliv Sci Technol 54:101249
  26. Engineers AIOC & Committee AIOCEETP (2003) Spray dryers: a guide to performance evaluation. Wiley Engstrom JD, Lai ES, Ludher BS, Chen B, Milner TE, Williams RO, Kitto GB, Johnston KP (2008) Formation of stable sub- micron protein particles by thin film freezing. Pharm Res 25:1334-1346
  27. Entegrion I (2020) Comparison of the efficacy & safety of resusix with FP24 in patients with acquired coagulopathy. US National Library of Medicine
  28. Faghihi H, Vatanara A, Najafabadi AR, Ramezani V, Gilani K (2014) The use of amino acids to prepare physically and conforma- tionally stable spray-dried IgG with enhanced aerosol perfor- mance. Int J Pharm 466:163-171
  29. Faghihi H, Najafabadi AR, Daman Z, Ghasemian E, Montazeri H, Vatanara A (2019) Respiratory administration of infliximab dry powder for local suppression of inflammation. AAPS Pharm- SciTech 20:128
  30. Faghihi H, Darabi M, Mirmoeini M, Vatanara A (2021) Formula- tion and evaluation of inhalable microparticles of Rizatriptan Benzoate processed by spray freeze-drying. J Drug Deliv Sci Technol 62:102356
  31. FDA (2014) NovoSeven® RT, coagulation factor VIIa (recombinant) for intravenous use only. Lyophilized powder for solution for injection. https:// www. fda. gov/ media/ 70442/ downl oad FDA (2020) SEVENFACT® [coagulation factor VIIa (recombinant)- jncw] Lyophilized powder for solution, for intravenous use. https:// www. fda. gov/ media/ 136610/ downl oad.
  32. FDA (2021a) RYPLAZIM (plasminogen, human-tvmh) lyophilized powder for reconstitution, for intravenous use. https:// www. fda. gov/ media/ 149806/ downl oad FDA (2021b) INBRIJA™ (levodopa inhalation powder), for oral inhalation use. https:// www. acces sdata. fda. gov/ drugs atfda_ docs/ label/ 2018/ 20918 4s000 lbl. pdf
  33. Fernando D, Siederer S, Singh S, Schneider I, Gupta A, Powell M, Richards D, Mcintosh MP, Lambert P, Fowles S (2017) Safety, tolerability and pharmacokinetics of single doses of oxytocin administered via an inhaled route in healthy females: rand- omized, single-blind, phase 1 study. EBioMedicine 22:249-255
  34. Filipe V, Hawe A, Carpenter JF, Jiskoot W (2013) Analytical approaches to assess the degradation of therapeutic proteins. TrAC, Trends Anal Chem 49:118-125
  35. Garidel P, Pevestorf B, Bahrenburg S (2015) Stability of buffer-free freeze-dried formulations: a feasibility study of a monoclonal antibody at high protein concentrations. Eur J Pharm Biopharm 97:125-139
  36. Gaumet M, Vargas A, Gurny R, Delie F (2008) Nanoparticles for drug delivery: the need for precision in reporting particle size parameters. Eur J Pharm Biopharm 69:1-9
  37. Gill P, Moghadam TT, Ranjbar B (2010) Differential scanning calo- rimetry techniques: applications in biology and nanoscience. J Biomol Tech JBT 21:167
  38. Glaxosmithkline (2015) Safety, tolerability and pharmacokinet- ics (PK) study of oxytocin (GR121619) administered Via an inhaled route in healthy female volunteers Gomez M, Mccollum J, Wang H, Ordoubadi M, Jar C, Carrigy NB, Barona D, Tetreau I, Archer M, Gerhardt A (2021) Develop- ment of a formulation platform for a spray-dried, inhalable tuberculosis vaccine candidate. Int J Pharm 593:120121
  39. Guo J, Tu H, Atouf F (2020) Measurement of macro-and micro- heterogeneity of glycosylation in biopharmaceuticals: a phar- macopeia perspective. Future Sci. https:// doi. org/ 10. 4155/ fdd-2020-0021
  40. Haeuser C, Goldbach P, Huwyler J, Friess W, Allmendinger A (2020) Impact of dextran on thermal properties, product quality attrib- utes, and monoclonal antibody stability in freeze-dried formula- tions. Eur J Pharm Biopharm 147:45-56
  41. Hawe A, Sutter M, Jiskoot W (2008) Extrinsic fluorescent dyes as tools for protein characterization. Pharm Res 25:1487-1499
  42. Hawe A, Kasper JC, Friess W, Jiskoot W (2009) Structural properties of monoclonal antibody aggregates induced by freeze-thawing and thermal stress. Eur J Pharm Sci 38:79-87
  43. He S, Gui J, Xiong K, Chen M, Gao H, Fu Y (2022) A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases. J Nanobiotechnol 20:1-22
  44. Hickey AJ, Stewart IE (2022) Inhaled antibodies: quality and perfor- mance considerations. Hum Vaccin Immunother 18:1940650
  45. Houde DJ, Berkowitz SA (2014) Biophysical characterization of pro- teins in developing biopharmaceuticals. Newnes
  46. Hu Y, Ma C, Sun M, Guo C, Shen J, Wang J, Nie F, Gao B (2019) Preparation and characterization of nano amitriptyline hydro- chloride particles by spray freeze drying. Nanomedicine (lond) 14:1521-1531
  47. Hufnagel S, Xu H, Sahakijpijarn S, Moon C, Chow LQ, Williams Iii RO, Cui Z (2022) Dry powders for inhalation containing mono- clonal antibodies made by thin-film freeze-drying. Int J Pharm 618:121637
  48. Imamura K, Ogawa T, Sakiyama T, Nakanishi K (2003) Effects of types of sugar on the stabilization of protein in the dried state. J Pharm Sci 92:266-274
  49. Intelligence M (2022) Biopharmaceutical market-growth, trends, COVID-19 impact, and forecast (2019-2027). https:// www. mordo rinte llige nce. com/ indus try-repor ts/ global-bioph armac eutic als-market-indus try.
  50. Ji HY, Oh SR, Lee HK, Na DH, Lee HS (2011) Liquid chromatog- raphy-electrospray ionization tandem mass spectrometry for the quantification of styraxlignolide A in rat plasma. J Sep Sci 34:1828-1833
  51. Jiskoot W, Crommelin D (2005) Methods for structural analysis of protein pharmaceuticals. Springer Science & Business Media Jocelyn P (1967) The standard redox potential of cysteine-cystine from the thiol-disulphide exchange reaction with glutathione and lipoic acid. Eur J Biochem 2:327-331
  52. Jovanovic N, Bouchard A, Hofland GW, Witkamp GJ, Crommelin DJ, Jiskoot W (2006) Distinct effects of sucrose and trehalose on pro- tein stability during supercritical fluid drying and freeze-drying. Eur J Pharm Sci 27:336-345
  53. Jovanovic N, Bouchard A, Hofland GW, Witkamp GJ, Crommelin DJ, Jiskoot W (2008a) Stabilization of IgG by supercritical fluid dry- ing: optimization of formulation and process parameters. Eur J Pharm Biopharm 68:183-190
  54. Jovanovic N, Bouchard A, Sutter M, Van Speybroeck M, Hofland GW, Witkamp GJ, Crommelin DJ, Jiskoot W (2008b) Stable sugar- based protein formulations by supercritical fluid drying. Int J Pharm 346:102-108
  55. Kankala RK, Lin XF, Song HF, Wang SB, Yang DY, Zhang YS, Chen AZ (2018) Supercritical fluid-assisted decoration of nanopar- ticles on porous microcontainers for codelivery of therapeu- tics and inhalation therapy of diabetes. ACS Biomater Sci Eng 4:4225-4235
  56. Karimi M, Kamali H, Mohammadi M, Tafaghodi M (2022) Evaluation of various techniques for production of inhalable dry powders for pulmonary delivery of peptide and protein. J Drug Deliv Sci Technol 69:103186
  57. Keil TWM, Feldmann DP, Costabile G, Zhong Q, Da Rocha S, Mer- kel OM (2019) Characterization of spray dried powders with nucleic acid-containing PEI nanoparticles. Eur J Pharm Biop- harm 143:61-69
  58. Kelly SM, Jess TJ, Price NC (2005) How to study proteins by cir- cular dichroism. Biochim Biophys Acta Proteins Proteom 1751:119-139
  59. Keyhan Shokouh M, Faghihi H, Darabi M, Mirmoeini M, Vatanara A (2021) Formulation and evaluation of inhalable microparticles of Rizatriptan Benzoate processed by spray freeze-drying. J Drug Deliv Sci Technol 62:102356
  60. Kim SJ, Kim CW (2016) Development and characterization of sodium hyaluronate microparticle-based sustained release formulation of recombinant human growth hormone prepared by spray-drying. J Pharm Sci 105:613-622
  61. Kim NA, Lim DG, Lim JY, Kim KH, Jeong SH (2014) Comprehen- sive evaluation of etanercept stability in various concentrations with biophysical assessment. Int J Pharm 460:108-118
  62. Kim NA, Hada S, Thapa R, Jeong SH (2016a) Arginine as a protein stabilizer and destabilizer in liquid formulations. Int J Pharm 513:26-37
  63. Kim Y, Park EJ, Na DH (2016b) Antibody-drug conjugates for tar- geted anticancer drug delivery. J Pharm Investig 46:341-349
  64. Kumar V, Sharma VK, Kalonia DS (2009) In situ precipitation and vacuum drying of interferon alpha-2a: development of a single- step process for obtaining dry, stable protein formulation. Int J Pharm 366:88-98
  65. Kunde SS, Ghosh R, Wairkar S (2022) Emerging trends in pulmo- nary delivery of biopharmaceuticals. Drug Discovery Today 27:1474
  66. Li HY, Song X, Seville PC (2010) The use of sodium carboxym- ethylcellulose in the preparation of spray-dried proteins for pulmonary drug delivery. Eur J Pharm Sci 40:56-61
  67. Liang W, Pan HW, Vllasaliu D, Lam JK (2020) Pulmonary delivery of biological drugs. Pharmaceutics 12:1025
  68. Liao YH, Brown MB, Martin GP (2004) Investigation of the stabili- sation of freeze-dried lysozyme and the physical properties of the formulations. Eur J Pharm Biopharm 58:15-24
  69. Liao Q, Lam IC, Lin HH, Wan LT, Lo JC, Tai W, Kwok PC, Lam JK (2020) Effect of formulation and inhaler parameters on the dispersion of spray freeze dried voriconazole particles. Int J Pharm 584:119444
  70. Lumen Bioscience, Inc (2020) A phase 1 randomized, double-blind, placebo-controlled, dose-escalation, safety and pharmacoki- netic study of LMN-101 in healthy volunteers. Clinicaltrials. gov. July 3, 2020. https:// clini caltr ials. gov/ ct2/ show/ NCT04 098263
  71. Maa YF, Nguyen PA, Sweeney T, Shire SJ, Hsu CC (1999) Protein inhalation powders: spray drying vs spray freeze drying. Pharm Res 16:249-254
  72. Maa YF, Ameri M, Shu C, Payne LG, Chen D (2004) Influenza vac- cine powder formulation development: spray-freeze-drying and stability evaluation. J Pharm Sci 93:1912-1923
  73. Marple VA, Roberts DL, Romay FJ, Miller NC, Truman KG, Van Oort M, Olsson B, Holroyd MJ, Mitchell JP, Hochrainer D (2003) Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: design. J Aerosol Med 16:283-299
  74. Marple VA, Olson BA, Santhanakrishnan K, Roberts DL, Mitchell JP, Hudson-Curtis BL (2004) Next generation pharmaceutical impactor: a new impactor for pharmaceutical inhaler testing. Part III. Extension of archival calibration to 15 L/min. J Aerosol Med 17:335-343
  75. Massant J, Fleurime S, Batens M, Vanhaerents H, Van Den Mooter G (2020) Formulating monoclonal antibodies as powders for reconstitution at high concentration using spray-drying: Treha- lose/amino acid combinations as reconstitution time reducing and stability improving formulations. Eur J Pharm Biopharm 156:131-142
  76. Mato YL (2019) Nasal route for vaccine and drug delivery: features and current opportunities. Int J Pharm 572:118813
  77. Matthews AA, Ee PLR, Ge R (2020) Developing inhaled protein thera- peutics for lung diseases. Mol Biomed 1:11
  78. Mcarthur AJ, Oliver VL, Lambert P, French E, Harker J, Mcintosh MP (2017) A design of experiments approach to optimising spray drying yield and production efficiency of a model inhaled powder for global health applications. Iran J Pharm Res 16:74
  79. Menzen T, Friess W (2014) Temperature-ramped studies on the aggre- gation, unfolding, and interaction of a therapeutic monoclonal antibody. J Pharm Sci 103:445-455
  80. Merkus HG (2009) Particle size measurements: fundamentals, practice, quality. Springer Science & Business Media
  81. Milani S, Faghihi H, Roulholamini Najafabadi A, Amini M, Montazeri H, Vatanara A (2020) Hydroxypropyl beta cyclodextrin: a water- replacement agent or a surfactant upon spray freeze-drying of IgG with enhanced stability and aerosolization. Drug Dev Ind Pharm 46:403-411
  82. Miwata K, Okamoto H, Nakashima T, Ihara D, Horimasu Y, Masuda T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H (2018) Intratra- cheal administration of siRNA dry powder targeting vascular endothelial growth factor inhibits lung tumor growth in mice. Mol Ther Nucl Acids 12:698-706
  83. Miyamoto K, Ishibashi Y, Akita T, Yamashita C (2021) Systemic deliv- ery of hGhrelin derivative by lyophilizate for dry powder inhala- tion system in monkeys. Pharmaceutics 13:233
  84. Monaci L, Van Hengel AJ (2007) Effect of heat treatment on the detec- tion of intact bovine β-lactoglobulins by LC mass spectrometry. J Agric Food Chem 55:2985-2992
  85. Mutukuri TT, Wilson NE, Taylor LS, Topp EM, Zhou QT (2021) Effects of drying method and excipient on the structure and physical stability of protein solids: freeze drying vs. spray freeze drying. Int J Pharm 594:120169
  86. Na DH, Park EJ, Kim MS, Cho CK, Woo BH, Lee HS, Lee KC (2011) Characterization of two ricin isoforms by sodium dodecyl sul- fate-capillary gel electrophoresis and capillary isoelectric focus- ing. Bull Korean Chem Soc 32:4253-4257
  87. National Institute of A, Infectious D, Network HIVVT, Bill, Melinda Gates F, Medical Research C, Sanofi Pasteur ASC, Glaxosmith- kline (2018) A safety and immune response study of 2 experi- mental HIV vaccines. https:// Clini calTr ials. gov/ show/ NCT02 404311
  88. Newton G, Raabe O, Mokler B (1977) Cascade impactor design and performance. J Aerosol Sci 8:339-347
  89. Nordisc N (2021) NovoSeven® RT, coagulation factor Viia (recombi- nant)for intravenous use only. Lyophilized powder for solution for injection. https:// www. novos evenrt. com/? & utm_ source= bing& utm_ medium= cpc& utm_ term= novos even% 20rt& utm_ campa ign=1_ All_ Shared_ BR_ Brand ed& utm_ conte nt=-dc_ pcrid_ 73804 98281 9897_ pkw_ novos even% 20rt_ pmt_ be_ slid__ & msclk id= d3ecf d5483 14163 065e5 9feeb 1ca8e 40& gclid= d3ecf d5483 14163 065e5 9feeb 1ca8e 40& gclsrc= 3p. ds
  90. Nuchuchua O, Every HA, Hofland GW, Jiskoot W (2014) Scalable organic solvent free supercritical fluid spray drying process for producing dry protein formulations. Eur J Pharm Biopharm 88:919-930
  91. Nuchuchua O, Nejadnik MR, Goulooze SC, Lješković NJ, Every HA, Jiskoot W (2017) Characterization of drug delivery particles pro- duced by supercritical carbon dioxide technologies. J Supercrit Fluids 128:244
  92. O'sullivan A, Ryan KM, Padrela L (2022a) Production of biophar- maceutical dried-powders using supercritical co2 technology. J Supercrit Fluids 187:105645
  93. O'sullivan A, Ryan KM, Padrela L (2022b) Production of biophar- maceutical dried-powders using supercritical CO2 technology. J Supercrit Fluids 187:105645
  94. Oetjen GW (2004) Freeze-drying. Wiley
  95. Ollikainen E, Bonabi A, Nordman N, Jokinen V, Kotiaho T, Kostiainen R, Sikanen T (2016) Rapid separation of phosphopeptides by microchip electrophoresis-electrospray ionization mass spec- trometry. J Chromatogr A 1440:249-254
  96. Orth M, Kieckhefen P, Pietsch S, Heinrich S (2022) Correlating gran- ule surface structure morphology and process conditions in fluid- ized bed layering spray granulation. KONA Powder Part J 39:230
  97. Osman N, Kaneko K, Carini V, Saleem I (2018) Carriers for the tar- geted delivery of aerosolized macromolecules for pulmonary pathologies. Expert Opin Drug Deliv 15:821-834
  98. Park EJ, Na DH (2010) Microchip electrophoresis for monitoring covalent attachment of poly (ethylene glycol) to proteins. Anal Biochem 400:304-306
  99. Park EJ, Kim MS, Choi YL, Shin YH, Lee HS, Na DH (2012) Liq- uid chromatography-tandem mass spectrometry to determine the stability of collagen pentapeptide (KTTKS) in rat skin. J Chromatogr B 905:113-117
  100. Park EJ, Sun Kim M, Suk Lee H, Choon Lee K, Hee Na D (2015) Differences in electrophoretic behavior between linear and branched PEG-conjugated proteins. Electrophoresis 36:918-923
  101. Park HJ, Yoon TJ, Son WS, Lee CJ, Kim SN, Song SU, Lee YW (2019) Precipitation of VEGF from mesenchymal stem cell culture supernatant using the PCA process. J Supercrit Fluids 151:40-48
  102. Parray HA, Shukla S, Perween R, Khatri R, Shrivastava T, Singh V, Murugavelu P, Ahmed S, Samal S, Sharma C, Sinha S, Luthra K, Kumar R (2021) Inhalation monoclonal antibody therapy: a new way to treat and manage respiratory infections. Appl Microbiol Biotechnol 105:6315-6332
  103. Pinto JT, Faulhammer E, Dieplinger J, Dekner M, Makert C, Nieder M, Paudel A (2021) Progress in spray-drying of protein pharma- ceuticals: literature analysis of trends in formulation and process attributes. Drying Technol 39:1415-1446
  104. Poursina N, Vatanara A, Rouini MR, Gilani K, Rouholamini Najafab- adi A (2015) Systemic delivery of parathyroid hormone (1-34) using spray freeze-dried inhalable particles. Pharm Dev Technol 2015:1-7
  105. Prankerd RJ, Nguyen TH, Ibrahim JP, Bischof RJ, Nassta GC, Olerile LD, Russell AS, Meiser F, Parkington HC, Coleman HA, Mor- ton DA, Mcintosh MP (2013) Pulmonary delivery of an ultra- fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries. PLoS ONE 8:e82965
  106. Quarta E, Chierici V, Flammini L, Tognolini M, Barocelli E, Can- toni AM, Dujovny G, Probst SE, Sonvico F, Colombo G (2020) Excipient-free pulmonary insulin dry powder: pharmacoki- netic and pharmacodynamics profiles in rats. J Control Release 323:412-420
  107. Rahman A, Austin A, Begum T, Anwar I (2021) Post-partum hemor- rhage is still killing mothers in Bangladesh: inhaled oxytocin (IHO) can help. Research. https:// doi. org/ 10. 21203/ rs.3. rs- 402427/ v1
  108. Ramezani V, Vatanara A, Najafabadi AR, Gilani K, Nabi-Meybodi M (2013) Screening and evaluation of variables in the formation of antibody particles by spray drying. Powder Technol 233:341-346
  109. Ramezani V, Vatanara A, Najafabadi AR, Shokrgozar MA, Khabiri A, Seyedabadi M (2014) A comparative study on the physicochemi- cal and biological stability of IgG 1 and monoclonal antibodies during spray drying process. DARU J Pharm Sci 22:1
  110. Rana MM (2021) Polymer-based nano-therapies to combat COVID-19 related respiratory injury: progress, prospects, and challenges. J Biomater Sci Polym Ed 32:1219-1249
  111. Rehman AU, Busignies V, Coelho Silva Ribeiro M, Almeida Lage N, Tchoreloff P, Escriou V, Charrueau C (2021) Fate of tableted freeze-dried siRNA lipoplexes in gastrointestinal environment. Pharmaceutics 13:1807
  112. Sahakijpijarn S, Moon C, Koleng JJ, Christensen DJ, Williams Iii RO (2020) Development of remdesivir as a dry powder for inhalation by thin film freezing. Pharmaceutics 12:1002
  113. Sahin E, Grillo AO, Perkins MD, Roberts CJ (2010) Comparative effects of pH and ionic strength on protein-protein interactions, unfolding, and aggregation for IgG1 antibodies. J Pharm Sci 99:4830-4848
  114. Saluja V, Amorij JP, Kapteyn JC, De Boer AH, Frijlink HW, Hinrichs WL (2010) A comparison between spray drying and spray freeze drying to produce an influenza subunit vaccine powder for inha- lation. J Control Release 144:127-133
  115. Sandra K, Vandenheede I, Sandra P (2014) Modern chromatographic and mass spectrometric techniques for protein biopharmaceutical characterization. J Chromatogr A 1335:81-103
  116. Sarciaux JM, Mansour S, Hageman MJ, Nail SL (1999) Effects of buffer composition and processing conditions on aggregation of bovine IgG during freeze-drying. J Pharm Sci 88:1354-1361
  117. Schüle S, Frieß W, Bechtold-Peters K, Garidel P (2007) Conforma- tional analysis of protein secondary structure during spray-dry- ing of antibody/mannitol formulations. Eur J Pharm Biopharm 65:1-9
  118. Shah S, Famta P, Raghuvanshi RS, Singh SB, Srivastava S (2022) Lipid polymer hybrid nanocarriers: Insights into synthesis aspects, characterization, release mechanisms, surface functionalization and potential implications. Coll Interf Sci Commun 46:100570
  119. Sharma A, Khamar D, Cullen S, Hayden A, Hughes H (2021) Inno- vative drying technologies for biopharmaceuticals. Int J Pharm 609:121115
  120. Singh S, Tank NK, Dwiwedi P, Charan J, Kaur R, Sidhu P, Chugh VK (2018) Monoclonal antibodies: a review. Curr Clin Pharmacol 13:85-99
  121. Spink CH (2008) Differential scanning calorimetry. Methods Cell Biol 84:115-141
  122. Tai J, Han M, Lee D, Park IH, Lee SH, Kim TH (2022) Different meth- ods and formulations of drugs and vaccines for nasal administra- tion. Pharmaceutics 14:1073
  123. Tang M, Hattori Y (2021) Effect of using amino acids in the freeze- drying of siRNA lipoplexes on gene knockdown in cells after reverse transfection. Biomed Rep 15:1-7
  124. Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, Morimoto K, Tanaka T, Yamaguchi E, Takahashi A (2019) Inhaled GM-CSF for pulmonary alveolar proteinosis. N Engl J Med 381:923-932
  125. Thakkar SG, Warnken ZN, Alzhrani RF, Valdes SA, Aldayel AM, Xu H, Williams Iii RO, Cui Z (2018) Intranasal immunization with aluminum salt-adjuvanted dry powder vaccine. J Control Release 292:111-118
  126. Tian F, Sane S, Rytting JH (2006) Calorimetric investigation of protein/amino acid interactions in the solid state. Int J Pharm 310:175-186
  127. Tyagi P, Trivedi R, Pechenov S, Patel C, Revell J, Wills S, Huang Y, Rosenbaum AI, Subramony JA (2021) Targeted oral peptide delivery using multi-unit particulates: drug and permeation enhancer layering approach. J Control Release 338:784-791
  128. Vass P, Démuth B, Hirsch E, Nagy B, Andersen SK, Vigh T, Verreck G, Csontos I, Nagy ZK, Marosi G (2019) Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals. J Control Release 296:162-178
  129. Vermeer AW, Norde W (2000) The thermal stability of immunoglobu- lin: unfolding and aggregation of a multi-domain protein. Bio- phys J 78:394-404
  130. Wang W, Singh S, Zeng DL, King K, Nema S (2007) Antibody struc- ture, instability, and formulation. J Pharm Sci 96:1-26
  131. Wang SH, Kirwan SM, Abraham SN, Staats HF, Hickey AJ (2012) Stable dry powder formulation for nasal delivery of anthrax vac- cine. J Pharm Sci 101:31-47
  132. Wang T, Liu YD, Cai B, Huang G, Flynn GC (2015) Investigation of antibody disulfide reduction and re-oxidation and impact to bio- logical activities. J Pharm Biomed Anal 102:519-528
  133. Wang JL, Hanafy MS, Xu H, Leal J, Zhai Y, Ghosh D, Williams Iii RO, Smyth HDC, Cui Z (2021) Aerosolizable siRNA-encapsulated solid lipid nanoparticles prepared by thin-film freeze-drying for potential pulmonary delivery. Int J Pharm 596:120215
  134. Wanning S, Süverkrüp R, Lamprecht A (2015) Pharmaceutical spray freeze drying. Int J Pharm 488:136-153
  135. Wilson EM, Luft JC, Desimone JM (2018) Formulation of high-per- formance dry powder aerosols for pulmonary protein delivery. Pharm Res 35:195
  136. Wu J, Wu L, Wan F, Rantanen J, Cun D, Yang M (2019) Effect of ther- mal and shear stresses in the spray drying process on the stability of siRNA dry powders. Int J Pharm 566:32-39
  137. Wu HT, Chuang YH, Lin HC, Chien LJ (2021) Characterization and aerosolization performance of hydroxypropyl-beta-cyclodextrin particles produced using supercritical assisted atomization. Poly- mers 13:2260
  138. Wuhan Recogen Biotechnology Co L (2022) Safety, reactogenicity, and immunogenicity study of a lyophilized COVID-19 mRNA vaccine. https:// Clini calTr ials. gov/ show/ NCT05 366296
  139. Xu PY, Kankala RK, Pan YJ, Yuan H, Wang SB, Chen AZ (2018) Overcoming multidrug resistance through inhalable siRNA nan- oparticles-decorated porous microparticles based on supercritical fluid technology. Int J Nanomed 13:4685-4698
  140. Yoshida H, Kuwana A, Shibata H, Izutsu KI, Goda Y (2017) Com- parison of aerodynamic particle size distribution between a next generation impactor and a cascade impactor at a range of flow rates. AAPS PharmSciTech 18:646-653
  141. Zhang H, Cui W, Gross ML (2014) Mass spectrometry for the biophysi- cal characterization of therapeutic monoclonal antibodies. FEBS Lett 588:308-317
  142. Zhang Q, Gong L, Zhang Y, Shen Y, Shen L, Cao L, Han G, Hu F, Zhao F, Chen Z (2021a) Room-temperature-storable chemilu- minescence freeze-drying mixes for detection of SARS-CoV-2 neutralizing antibody. Dry Technol 2021:1-8
  143. Zhang Y, Davis DA, Aboulfotouh K, Wang J, Williams D, Bhamb- hani A, Zakrewsky M, Maniruzzaman M, Cui Z, Williams RO (2021b) Novel formulations and drug delivery systems to admin- ister biological solids. Adv Drug Deliv Rev 172:183-210
  144. Zhao P, Hou X, Yan J, Du S, Xue Y, Li W, Xiang G, Dong Y (2020) Long-term storage of lipid-like nanoparticles for mRNA delivery. Bioact Mater 5:358-363
  145. Zhu Q, Chen Z, Paul PK, Lu Y, Wu W, Qi J (2021) Oral delivery of proteins and peptides: challenges, status quo and future perspec- tives. Acta Pharm Sinica B 11:2416-2448
  146. Zolls S, Tantipolphan R, Wiggenhorn M, Winter G, Jiskoot W, Friess W, Hawe A (2012) Particles in therapeutic protein formulations, Part 1: overview of analytical methods. J Pharm Sci 101:914-935
  147. Zoulikha M, Xiao Q, Boafo GF, Sallam MA, Chen Z, He W (2021) Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome. Acta Pharm Sinica B 12:600