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Application of the Quality-by-Design (QbD) Approach for Erythropoietin Alpha Purification
김태규,서광석,권상오,Thomas A. Little,김미정,김찬화 대한화학회 2019 Bulletin of the Korean Chemical Society Vol.40 No.7
This study was aimed at process characterization and improving quality of purification of erythropoietin α, a biopharmaceutical agent. In biopharmaceutical manufacturing, quality should always be targeted to ensure safety and efficacy. Design-of-experiments?based approaches have been explored to rapidly and efficiently achieve an optimized yield and an increased understanding of a product and process variables affecting the product's critical quality attributes in the biopharmaceutical industry; this system is known as the quality-by-design approach. Changes in three critical process parameters?buffer pH, flow rate, and loading amount?were evaluated. Process characterization was conducted on a scaled-down model previously validated by comparison with data from a large-scale production facility. Seven critical quality attributes?relative aggregate content, host cell protein, host cell deoxynucleotides, endotoxin, Z-value (N-glycan score), relative content of charge isomers, and step yield?were analyzed. Multivariate regression analysis was performed to establish statistical prediction models for performance indicators and quality attributes; accordingly, we constructed contour plots and conducted a Monte Carlo simulation to clarify the design space. As a result of the optimization analysis of the purification process, it was confirmed that proven acceptance ranges were optimized as follows: loading amount (mg/mL) 0.4?4.0, buffer pH 7.0?8.0, and flow rate (mL/min) 0.5?1.6.
김태규,서광석,권상오,김희성,김준희,정민우,Thomas A. Little,김미정,김찬화 대한화학회 2019 Bulletin of the Korean Chemical Society Vol.40 No.10
This study is aimed to identify the process characterization of the cell culture of the biopharmaceutical erythropoietin alpha. In biopharmaceutical manufacturing, ensuring safety and efficacy should always be target qualities. The ?quality by design? initiative provides guidance on pharmaceutical development to facilitate design of products and processes that maximizes the product?s efficacy and safety profile while enhancing product manufacturability. Fundamental to this approach is an understanding of the relationship between the quality attributes of the product and their impact on safety and efficacy. The DoE approach focuses on quality-by-design (QbD). To implement QbD, we report on a case regarding the production of erythropoietin alpha using cultured Chinese hamster ovary cells. Changes in the four critical process parameters (CPPs) of RPM, pH, dissolved oxygen, and temperature were evaluated. To evaluate the DoE, the three CQAs of Z-value (N-glycan score), host cell protein content, and erythropoietin alpha concentration (titer) were monitored and analyzed. Multivariate regression analysis between CPPs and CQAs were used to identify the design space needed to satisfy the targeted CQAs. We used QbD techniques and found optimal conditions for the cell culture process of erythropoietin alpha. Monte Carlo simulation was used under the optimized conditions and the set points were verified. As a result, it was confirmed that the optimal operational range was RPM 191.1?209.0, bioreactor temperature 32?34 °C, pH 7.0?7.2, and dissolved oxygen 24.9?35.1. This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches.
김태규 대한금속재료학회(대한금속학회) 2000 대한금속·재료학회지 Vol.38 No.12
To obtain the thermodynamic properties of a multicomponent liquid alloy system over the whole range of concentration at an arbitrary temperature, the free volume theory has been applied to derive the formula of activity coefficients of liquid solutions based on the infinitely dilute solutions. The Monte-Carlo algorithm was used to calculate the nonlinear end value equations of binary systems, and the free volume parameters obtained were directly correlated with the activity coefficients of liquid binary, ternary and quaternary at an arbitrary temperature. The activities of Pb-Sn alloy system calculated by this method were verified in good agreement with the experimental values from the literature, and the three dimensional diagrams of a-X-T representing the temperature and concentration dependence of activities were successfully plotted. The calculated activities of ternary and quaternary systems at an arbitrary temperature have been statistically examined with the experimental values from the literature. Hence, this simple approach could be useful for analyzing thermodynamic properties of liquid alloy systems.
김태규 한국초등과학교육학회 2019 한국초등과학교육학회 학술대회 Vol.76 No.-
지레는 간단한 도구이지만, 질량, 무게, 힘, 회전력, 평형 및 에너지 보존 등의 물리 개념을 포함하여, 지레 실험은 기초적으로 실시되고 있다. 그러나 실제의 제1종 지레 실험에서 힘점의 힘을 측정하기가 수월하지 않다. 보편적으로 힘의 크기를 측정하기 위해서는 인장형용수철저울을 사용하고 있는데, 지레의 힘점에서 힘의 방향은 용수철저울과 반대이므로 보조적인 도구를 추가하여 지레의 힘점에서 힘의 크기를 측정한다. 이와 같은 어려움을 해결하기 위하여, 본 연구에서는 과학 모의실험 프로그램의 활용 및 다양한 실험 방법을 활용하고자 한다. 과학 모의실험 프로그램인 Interactive Physics를 이용하고, 지레의 질량, 힘점과 받침점사이의 거리, 받침점과 작용점 사이의 거리, 작용점 질량을 변인으로 설정하고, 이에 따라서 힘점에서의 힘의 크기 및 지레 막대의 기울어진 정도를 얻는다. 또한, 보다 수월하게 힘점에서 힘을 측정할 수 있도록 기존의 지레 실험 방법과 다르게, 영점 보정 추를 사용하여 용수철저울의 영점을 조정한 실험장치, 고정도르래를 사용하여 용수철저울에서 힘의 방향을 바꾼 실험 장치, 밀고 당기는 힘의 크기를 측정할 수 있는 압축-인장 측정기를 사용한 실험 장치, 영점 보정 추를 사용하여 전자저울의 영점을 조정한 실험 장치를 강구한다. 개발된 실험 장치의 실험 결과와 모의실험 프로그램 산출물로부터 지레 실험의 변인 특성을 분석한다.