Impact of Formulations for Optimizing Lyophilization Process Development

Impact of Formulations for Optimizing Lyophilization Process Development
March/April 2005
Feroz Jameel, Ph.D. and Sugunakar Y. Patro, Ph.D.
Amgen, Inc.
APR
Abstract
In this brief review, we discuss the strategies and considerations for optimizing lyophilized protein formulations for commercial manufacturing. The impact of selected formulation excipients on the commercial lyophilization process with special emphasis on process scale-up and large-scale manufacturability is discussed. It is emphasized that, to develop a ?commercially viable? formulation, the formulation needs to be optimized not just for long-term stability of the molecule, but also for lyophilization process scale-up and manufacturability purposes.
1.0 Introduction
To successfully commercialize a therapeutic protein, it is necessary that the pharmaceutical products have an adequate shelf life, typically 18 months or more. Not all proteins possess this stability in the aqueous state because of their complex and yet fragile higher-order structures and their sensitivity to the microenvironment they are in. When a product does not have sufficient stability in aqueous solution, the product is typically lyophilized.
Lyophilization, which is also termed as ?Freeze Drying,? is a dehydration process that transforms solutions of labile materials into solids of sufficient stability for commercialization and storage. Lyophilization occurs in three phases: Freezing, Primary Drying and Secondary Drying. In the ?Freezing? phase, the water component of the solution is converted into ice leaving behind a matrix of either glassy and/or crystalline solute. The ?Primary Drying? phase involves the sublimation of frozen solid ice into vapor under vacuum, and often heat is applied to provide enthalpy of sublimation. The remaining unfrozen water mostly dispersed in the amorphous component of the matrix is removed through desorption in the ?Secondary Drying? phase at slightly elevated temperatures. Temperatures employed in secondary drying are usually higher than those used during primary drying, as heat is required for desorption.
For lyophilized therapeutic proteins, both the formulation and the lyophilization process are very critical for achieving and maintaining the therapeutic stability during commercialization and subsequent storage. An extensive body of literature exists discussing both the formulation [1] and process aspects of lyophilization [2], and the interested reader can refer to those articles. For commercial viability, however, the formulation design should not only consider the inherent stability of the molecule over the shelf life but also take into account the stability required to meet large-scale commercialization requirements. This communication focuses on those aspects of formulation design that are necessary for large-scale commercial processing.
2.0 Formulation Optimization Specifically Aimed at Large Scale Processing and Commercialization
For commercial manufacturing of protein therapeutics, the purified bulk drug substance needs to be processed and prepared for successful lyophilization and may go through freeze-thawing, formulation, mixing, filtration and filling operations prior to lyophilization. Although these unit operations are studied during the development at research scale, the stresses generated and the mechanisms of denaturation that occurred during these unit operations in a manufacturing setting are different as the stresses are dependent on scale, equipment and facility. Hence, in addition to stability achieved at laboratoryscale, the formulation should be designed to stabilize the drug against the instabilities that typically arise during large-scale manufacturing and commercialization operations in the cGMP environment. The rest of this section is organized to discuss such formulation considerations for (a) operations prior to lyophilization, (b) operation of lyophilization, and (c) operations post lyophilization.
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