Progress in spray-drying of protein pharmaceuticals: Literature analysis of trends in formulation and process attributes
Spray-drying is an inherently continuous and well-established industrial drying process. It can accelerate manufacturing of biopharmaceuticals and vaccine products, resulting in both an economic and health benefit. In this review, we cover a systematic assessment and discuss the spray-drying of diverse protein pharmaceuticals and excipients included therein, solvent systems applicable to these formulations, equipment used and, respective process parameters. Further, key quality aspects of spray-dried protein solids are discussed. Based on the overall trends, we present a concise perspective into the future of protein pharmaceuticals spray-drying.
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Article information: (2021) Progress in spray-drying of protein pharmaceuticals: Literature analysis of trends in formulation and process attributes, Drying Technology, DOI: 10.1080/07373937.2021.1903032
Introduction:
Protein pharmaceuticals are, normally, formulated as aqueous dosage forms. However, liquid dosage forms are often unstable, presenting limited shelf life that frequently requires storage and transport under refrigerated conditions. To overcome these limitations, protein pharmaceuticals can be formulated as a dry powder. Ideally, when in the powder form, the biomolecule, will remain stable and retain its activity for the intended periods (3 years or more) under ambient storage conditions. Traditionally, freeze-drying is the process of choice, when drying protein pharmaceuticals. In freeze-drying, the liquid formulation is first frozen and then the ice is removed by sublimation and desorption.[1] As of 2014, there are over 400 approved freeze-dried products by the United States Food and Drug Administration (U.S. FDA). The estimated annual growth of freeze-dried products for 2018 was 13.5%.[2] Many approved freeze-dried products are protein formulations (i.e. vaccines, antibodies, enzymes, peptide hormones, etc.) that emerged rapidly over the last years.[3] Likewise, the expansion of alternative drying processes able to sustainably support the rapid development of biopharmaceutical technologies, are a central need of this industry in years to come.
While freeze-drying presents numerous advantages, there are some inherent challenges. Namely, the difficulty to control the particle/cake properties and microstructures, inter-vial variability, challenge to process large quantities of material, enormous power, time, and resource consumption are some of the major hurdles. These have led many to the quest of finding alternative drying technologies, spray-drying being one of them.[4] Unlike spray-drying, other exploratory drying technologies reported for the processing of protein therapeutics, tend to be costly, time consuming, and not mature enough for industrial implementation. Moreover, one of the main advantages of spray-drying, and a critical driver in generating the interest of the industry in this technique, is the possibility for “continuous processing.”[4] This provides a promising and rapid solution in terms of large volume manufacturing in particular cases like the recent crisis caused by the coronavirus disease 2019 (COVID-19).
In the last 15 years, spray-drying has, in fact, been successfully applied in the production of a few protein pharmaceuticals (Table 1). In 2006, the inhaled insulin powder, Exubera® (Pfizer), became the first commercial spray-dried protein hormone (later withdrawn from the market). Spray-dried alternatives of Poly(lactic-co-glycolic acid) (PLGA) microspheres for depot liquid crystal formulation of triptorelin pamoate and lanreotide acetate were approved in 2010 and 2013, respectively. More recently, in 2015, Raplixa® (ProFibrix BV) became the first approved protein drug manufactured via aseptic spray-drying. Beyond these, other protein pharmaceuticals produced via spray-drying in a wide array of dosage forms are, presently under clinical development.[5]
In general, drying of protein pharmaceuticals can pose a risk to their chemical and physical stability.[6] Thus, it is of utmost importance to understand how spray-drying’s formulation and process parameters (and their interactions) impact the quality of protein pharmaceuticals. To that end, this review will extensively discuss the learnings achieved over the last 30 years of research conducted in the field of solid protein drug formulations produced by one-step spray-drying process. The following subtopics will be covered: classes of protein pharmaceuticals and excipients used in spray-drying; solvent systems applicable to these types of formulations; spray-dryer equipment used and process parameters applicable to protein formulations; quality aspects of spray-dried protein pharmaceuticals. At the end, we concisely discuss the perspectives on the protein spray-drying based on the identified trends, and identify some opportunities and gaps for the future research in the field.