Development of Stable Lyophilized Protein Drug Products

Abstract

Freeze drying, or lyophilization is widely used for biopharmaceuticals to improve the long term storage stability of labile molecules. This review examines general theory and practice of rational lyophilization of biopharmaceuticals. Formulation development involving the selection of appropriate excipients, their associated physical properties, and mechanism of action in achieving a stable drug product are primary considerations for a successful lyophilization program. There are several parameters considered critical on the basis of their relationship to lyophilization cycle development and protein product stability. This along with the importance of analytical methods to provide insight toward understanding properties of drug product stability and cake structure are discussed. Also, aspects of instability found in lyophilized biopharmaceutical products, their degradation pathways and control are elucidated. Finally, container-closure requirements and drug product handling are described in context of the caveats to avoid compromising drug product quality.

Protein-poly(amino acid) precipitation stabilizes a therapeutic protein l-asparaginase against physicochemical stress

“…A lyophilized formulation can greatly enhance conformational stability of protein by restricting mobility and can minimize chemical reactions in the presence of water (2). At present, 50% of the therapeutic proteins approved for clinical application by the US Food and Drug Administration (FDA) are lyophilized formulations (3). However, lyophilized formulations require a long dissolution time, which places a limitation on their practical usage (4).…”

Advance Understanding of Buffer Behavior during Lyophilization

“…During the formulation development, buffering capacity and the potential for buffer catalysis are two main buffer properties to consider. The general rule of thumb is not to exceed the effective buffer capacity by maintaining pH within one unit from its pK a [39]. For freeze-dried products, special consideration needs to be made for buffer selection including buffer crystallization during freezing, impact on collapse temperature of the freeze-concentrated solution and T g (glass transition temperature) of the dried formulation, and the volatility of the buffer components under vacuum [40].…”

Lyophilized Biologics

“…Among the many different and practical solutions for maintaining the integrity of biopharmaceuticals until sufficient expiry, lyophilization has been the most extensively researched [4,5,21]. This is primarily due to the high stability provided by a dried powder formulation.…”