IMPROVING THE STABILITY OF BIOPHARMACEUTICALS BY APPLYING LYOPHILIZATION
Keywords:
lyophilization, stability, biological drugs, active substances, excipientsAbstract
Lyophilization in the pharmaceutical field continuously evolves and expands its applications, particularly in the design and formulation of biopharmaceutical products with critical stability during transport and long-term storage. This article aims to highlight the latest advancements and to explain the challenges in the lyophilization of the key groups of biological drugs.
This scientific paper is based on available scientific literature in the field of the application of lyophilization in biological drugs (Google Scholar, Science Direct, Scopus). Comparative and compilation methods were used.
Understanding the fundamental theoretical postulates of lyophilization is crucial for comprehending the physicochemical changes occurring in the structure of biologically active substances, blood components and modern delivery systems for biologically active substances. This review summarizes the expanded scope of pharmaceutical applications based on lyophilization by discussing specific aspects of lyophilization formulations of antibodies, peptides, vaccines, other therapeutic proteins, nanoparticles and nanocapsules, liposomes, blood components and non-gene vectors. New formulation aspects and storage systems, as well as the importance of the freezing step, are also discussed. Formulation development that involves selection of appropriate excipients, understanding their physical properties, and determining the mechanisms of action for achieving a stable pharmaceutical product are essential for a successful lyophilization program. Additionally, the study provides insight into new stabilization concepts for biopharmaceutical products, process analytical technology (PAT), and quality by design (QbD), which are highly relevant and will contribute to future advancements and improvements in the lyophilization process.
The broad range of pharmaceutical applications based on lyophilization highlights the continuous importance and significance of this process in the pharmaceutical field. Developing a stable lyophilized biopharmaceutical product can be challenging, as multiple factors must be considered to prevent its instability. By carefully evaluating and selecting key excipients and with optimization оf the pH value, a stable lyophilized biopharmaceutical formulation with an acceptable shelf life can be designed successfully.
References
Abdelwahed, W., Degobert, G., Stainmesse, S., & Fessi, H. (2006). Freeze-drying of nanoparticles: Formulation, process and storage considerations☆. Advanced Drug Delivery Reviews, 58(15), 1688–1713. https://doi.org/10.1016/j.addr.2006.09.017
Allison, S. Dean, & Anchordoquy, T. J. (2001). Lyophilization of Nonviral Gene Delivery Systems. In M. A. Findeis, Nonviral Vectors for Gene Therapy (Vol. 65, pp. 225–252). New Jersey: Humana Press. https://doi.org/10.1385/1-59259-139-6:225
Allison, S.D., & Anchordoquy, T. J. (2000). Mechanisms of protection of cationic lipid-DNA complexes during lyophilization. J.Pharm.Sci., 89, 682–691.
Andia, I., Perez-Valle, A., Del Amo, C., & Maffulli, N. (2020). Freeze-Drying of Platelet-Rich Plasma: The Quest for Standardization. International Journal of Molecular Sciences, 21(18), 6904. https://doi.org/10.3390/ijms21186904
Cao, W., Piedmonte, D. M., Ricci, M. S., & Yeh, P. Y. (2014). Formulation, Drug Product, and Delivery: Considerations for Fc‐Fusion Proteins. In S. M. Chamow, T. Ryll, H. B. Lowman, & D. Farson (Eds.), Therapeutic Fc‐Fusion Proteins (1st ed., pp. 115–154). Wiley. https://doi.org/10.1002/9783527675272.ch05
Chang, B. S., Reilly, M., & Chang, H. (2015). Lyophilized Biologics. In D. Varshney & M. Singh (Eds.), Lyophilized Biologics and Vaccines. New York: Springer. Retrieved from https://doi.org/10.1007/978-1-4939-2383-0_6
Chang, S. B., & Fischer, N. L. (1995). Development of an efficient single-step freeze-drying cycle for protein formulations. Pharmaceutical Research, 12(6), 831–837. https://doi.org/doi:10.1023/a:1016200818343
De Beer, T. R. M., Vercruysse, P., Burggraeve, A., Quinten, T., Ouyang, J., Zhang, X., … Baeyens, W. R. G. (2009). In-line and real-time process monitoring of a freeze drying process using Raman and NIR spectroscopy as complementary process analytical technology (PAT) tools. Journal of Pharmaceutical Sciences, 98(9), 3430–3446. https://doi.org/10.1002/jps.21633
Fernandez-Moure, J., Maisha, N., Lavik, E. B., & Cannon, J. W. (2018). The Chemistry of Lyophilized Blood Products. Bioconjugate Chemistry, 29(7), 2150–2160. https://doi.org/10.1021/acs.bioconjchem.8b00271
Franzé, S., Selmin, F., Samaritani, E., Minghetti, P., & Cilurzo, F. (2018). Lyophilization of Liposomal Formulations: Still Necessary, Still Challenging. Pharmaceutics, 10(3), 139. https://doi.org/10.3390/pharmaceutics10030139
Giordano, A., Barresi, A. A., & Fissore, D. (2011). On the Use of Mathematical Models to Build the Design Space for the Primary Drying Phase of a Pharmaceutical Lyophilization Process. Journal of Pharmaceutical Sciences, 100(1), 311–324. https://doi.org/10.1002/jps.22264
Guidance for Industry PAT - A Framework for Innovative Pharmaceutical Development, manufacturing, and Quality Assurance. (2004). US Food and Drug Agency. Retrieved from https://www.gmp-compliance.org/files/guidemgr/PAT-FDA-6419fnl.pdf
Hirsjärvi, S., Peltonen, L., & Hirvonen, J. (2009). Effect of Sugars, Surfactant, and Tangential Flow Filtration on the Freeze-Drying of Poly(lactic acid) Nanoparticles. AAPS PharmSciTech, 10(2), 488–494. https://doi.org/10.1208/s12249-009-9236-z
ICH guideline Q8 (R2) on pharmaceutical development. (2017). European Medicines Agency, Committee for Human Medicinal Products. Retrieved from https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-considerations-ich-guideline-q8-r2-pharmaceutical-development-step-5_en.pdf
Kasper, J. C., Wiggenhorn, M., Resch, M., & Friess, W. (2013). Implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization. European Journal of Pharmaceutics and Biopharmaceutics, 83(3), 449–459. https://doi.org/10.1016/j.ejpb.2012.10.009
Kasper, J. C., Winter, G., & Friess, W. (2013). Recent advances and further challenges in lyophilization. European Journal of Pharmaceutics and Biopharmaceutics, 85(2), 162–169. https://doi.org/10.1016/j.ejpb.2013.05.019
Kasraian K, Deluca PP. (1995). The effect of tertiary butyl alcohol on the resistance of the dry product layer during primary drying. Pharm Res 12:491–5.
L. Remmele, R., Krishnan, S., & J. Callahan, W. (2012). Development of Stable Lyophilized Protein Drug Products. Current Pharmaceutical Biotechnology, 13(3), 471–496. https://doi.org/10.2174/138920112799361990
Miyajima, K. (1997). Role of saccharides for the freeze-thawing and freeze drying of liposome. Advanced Drug Delivery Reviews, 24(2–3), 151–159. https://doi.org/10.1016/S0169-409X(96)00454-1
Nail, S. L., & Johnson, W. (1992). Methodology for in-process determination of residual water in freeze-dried products. Dev.Biology, 137–151.
Nail, S. L., & Searles, J. A. (2008). Elements of quality by design in development and scaleup of freeze-dried parenterals. Biopharm International, 21(1), 44–52.
Ozaki, K., & Hayashi, M. (1997). The Effects of Glucose Oligomers (Maltodextrins) on Freeze-Drying Liposomes. Chemical and Pharmaceutical Bulletin, 45(1), 165–170. https://doi.org/10.1248/cpb.45.165
Patel, S. M., & Pikal, M. (2009). Process Analytical Technologies (PAT) in freeze-drying of parenteral products. Pharmaceutical Development and Technology, 14(6), 567–587. https://doi.org/10.3109/10837450903295116
Ghadiri, M., Ebrahim, A., & Shojaosadati, S. A. (2021). Freeze-drying of nanoparticles: A review on recent advances and future trends. Journal of Nanoscience and Nanotechnology, 21(6), 3250–3265. https://doi.org/10.1166/jnn.2021.19583
Zhang, X., Zhang, Y., Li, Y., & Chen, Y. (2020). Recent developments in lyophilization of biopharmaceuticals: Challenges and future directions. European Journal of Pharmaceutics and Biopharmaceutics, 153, 97–109. https://doi.org/10.1016/j.ejpb.2020.06.014
Kumar, S., Arora, R., & Garg, R. (2021). Lyophilization of protein therapeutics: Advances and challenges. Journal of Pharmaceutical Sciences, 110(8), 2607–2618. https://doi.org/10.1016/j.xphs.2021.03.015
Lee, S. M., Kim, D. K., & Han, J. (2020). Application of process analytical technology (PAT) in lyophilization of biologics: Current status and future prospects. International Journal of Pharmaceutics, 577(1), 119052. https://doi.org/10.1016/j.ijpharm.2020.119052
Liu, X., Wu, C., & Wang, S. (2021). Advances in freeze-drying of liposomes for pharmaceutical applications. Drug Development and Industrial Pharmacy, 47(5), 703–710. https://doi.org/10.1080/03639045.2021.1884184
Ochoa, N., Fajardo, R., & Santoyo, A. (2021). Lyophilization of therapeutic antibodies: Critical factors and recent advances. Pharmaceutical Research, 38(2), 344–356. https://doi.org/10.1007/s11095-020-02883-0
