Davidson School of Chemical Engineering, Purdue University, West Lafayette, Indiana, USA.
School of Aeronautics and Astronautics, Purdue University, West Lafayette, Indiana, USA.
Pharm Res. 2018 Apr 11;35(6):115. doi: 10.1007/s11095-018-2395-4.
Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying.
In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique.
The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process.
Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.
在冷冻干燥过程中监测工艺条件对于确保冷冻干燥药物产品的质量至关重要。残余气体分析以前曾应用于冷冻干燥应用中，用于检测泄漏、确定初级和次级干燥的终点、监测灭菌过程以及测量复杂溶剂。本研究的目的是研究各种配方在冷冻干燥过程中工艺气体的时间演变，以更好地了解各种分子化合物在初级干燥过程中的相对提取速率。
在这项研究中，残余气体分析用于监测典型药物水配方在冷冻干燥过程中产品室内气体的分子组成。残余气体分析也用于确定初级干燥终点，并与使用比较压力测量技术获得的结果进行比较。
在冷冻干燥过程中，观察到溶剂蒸气、溶解在其中的物质以及（用于维持产品室内设定点压力的气体）的动态。除了水蒸气和氮气外，所有考虑的水配方中最丰富的两种气体是氧气和二氧化碳。特别是，观察到二氧化碳和氧气的相对浓度因配方而异，这种观察结果源于这些物质的不同溶解度。这一结果对产品在冷冻干燥过程中的保质期和稳定性有影响。
使用残余气体分析对几种代表性配方在冷冻干燥过程中的腔室工艺气体组成进行了定量分析。该技术的优势在于能够在冷冻干燥过程中测量各种物质的相对浓度。这一功能使残余气体分析在从终点确定到质量保证的众多应用中具有实用性。与其他方法相比，残余气体分析能够确定工艺气体中的氧气和水蒸气含量。这些化合物已被证明直接影响产品的保质期。有了这些结果，残余气体分析技术为实时冷冻干燥过程控制和更好地理解冷冻干燥药物产品的配方和处理效果提供了一种潜在的新方法。
