Lyophilization - Points to Consider for Successful Process Transfer to Manufacturing
Lyophilization - Points to Consider for Successful Process Transfer to Manufacturing
Stelios C. Tsinontides, Ph.D.
Merck & Company
Abstract
Lyophilization (Freeze Drying) is widely used in the pharmaceutical industry to manufacture stable pharmaceutical products from unstable drug or biological active ingredients. The formulated solution is filled into vials, frozen, and subsequently heated at very low pressure to produce a highly porous cake with low moisture, sealed under partial vacuum. The lyophilization process involves heat and mass transfer phenomena; thus it is necessary to scale these phenomena appropriately from research to commercial scale units to ensure that product quality attributes remain the same upon scale-up. Contrary to typical process equipment (e.g., tanks, reactors, blenders) lyophilizers of different scales are not geometrically similar, and thus the use of dimensional analysis to scale-up the process can not be readily applied; yet, it is critical that scale-up be completed in a timely and effective manner to ensure timely product commercialization. In this short review, a number of factors that could influence successful scale-up of the process are discussed, and a methodology is presented on how to address them for successful and timely technical process transfer.
Introduction
Freeze drying is widely used in the pharmaceutical and biotechnology industries to render labile unstable formulations into stable products. The products are filled into appropriate dosage packages for long shelflife stability. Processing of such unstable formulated solutions is very similar among products and industries. Critical steps involve compounding the formulated solution and filtering it through sterilizing grade filters since the active ingredient and solution are likely to be thermally unstable and can not be terminally sterilized. The sterile solution is filled into vials and transferred into a lyophilizer in an aseptic operation or by using automated processing equipment within a set of interconnected isolators. The product vials are then frozen, and subsequently heated at vacuum conditions to remove the solvent from the formulation to produce a dried product cake. The final product, sealed under vacuum or with an inert gas, can be stored for extended periods of time until time of use after re-constitution with designated diluent( s).
Comprehensive reviews of principles and practice of freeze drying in pharmaceutical and biological industries are widely reported in pharmaceutical literature [1,2,3,8,9]. These articles generally include discussions on applied aspects of product formulation, development, the fundamental principles of heat and mass transfer during freezing, primary and secondary drying, equipment design, and process monitoring. The modeling aspects of the process have been pursued by a different set of researchers in chemical engineering to investigate the dynamic behavior of primary and secondary drying, and to integrate theoretical model predictions with experimental data[5,6,7,10]. Overall, the study of freeze drying has been an interdisciplinary effort and the collective knowledge has provided the industry with needed physical- chemical understanding of the different stages of the process and engineering tools to develop, design, and optimize cycles for different pharmaceutical and biological products. However, issues of technology transfer and scale-up have attracted limited attention, despite being a critical step to product commercialization. An attempt to address technology transfer issues was made by Kinnarney [4] who successfully identified several process and package-related items that could be impacted upon scale-up from R&D practices. Kinnarney [4] provided practical suggestions to mitigate the scale-up effects on product quality attributes, such as duplicating, as much as possible, R&D packages (vials, stoppers, and methods of preparation), process variables (filling times, vial loading density on the shelf, shelf temperatures, etc.), and process monitoring devices (temperature and pressure measuring devices). However, such approaches, while ideal, could prove impractical in most cases due to supply chain and equipment differences. Most recently, the author and co-workers provided a systematic methodology for successfully scaling up the lyophilization cycle of a labile pharmaceutical product by coupling experimental data at pilot plant and manufacturing scale with mathematical modeling [11].
The purpose of this review article is rather complementary to the recently published technical article, as it provides more specific guidance on process transfer than that found in Kinnarney [4]. This article discusses additional process and product-related factors and parameters that could affect the lyophilization cycle scale-up process. Specific guidance is provided on how to address changes in packaging, equipment, and process in an effective manner to ensure successful and timely technology transfer to manufacturing.
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Votes:16