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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.
RF-PECVD법에 의한 투명 다이아몬드상 탄소 박막 합성
김태규,신영호,조현,김진곤,Kim, Tae-Gyu,Shin, Yeong-Ho,Cho, Hyun,Kim, Jin-Kon 한국결정성장학회 2012 韓國結晶成長學會誌 Vol.22 No.4
RF-PECVD(radio frequency plasma enhanced chemical vapor deposition)법을 이용하여 $CH_4+SiH_4+Ar$ 혼합 가스로부터 유리 기판 위에 투명 다이아몬드상 카본(diamond-like carbon, DLC)을 합성하였다. 공정압력과 rf-파워, $CH_4/SiH_4/Ar$ 혼합비, 그리고 증착 시간은 각각 0.1 torr, 100W, 20 : 1 : 1, 20분이었다. DLC가 증착된 유리와 증착되지 않은 유리의 투과도를 가시광선 영역에서 비교하였고, DLC가 증착된 유리의 경도, 표면 조도와 두께를 nanoindenter와 AFM으로 측정하였다. DLC가 증착된 유리의 투과도는 증착되지 않은 유리와 비교할 때 380 nm 파장에서 약 83 %, 500 nm 이상의 파장에서는 95 % 이상 수준이었다. DLC가 증착된 유리의 경도는 증착되지 않은 유리의 약 2.5배이었다. 증착된 DLC 박막은 매우 고른 표면을 보였으며 20분 증착 후 두께는 150 nm 이상으로 나타났다. Transparent diamond-like carbon (DLC) films were synthesized on glass using radio frequency plasma enhanced chemical vapor deposition method from the gas mixture of $CH_4$, $SiH_4$ and Ar. The pressure, the rf-power, $CH_4/SiH_4/Ar$ ratio, and the deposition time were 0.1Torr, 100W, 20 : 1 : 1, and 20 min, respectively. The optical transmittances of DLC-deposited glass and uncoated glass were compared with each other in the visible light regions. The DLC-deposited glass showed transmittance of approximately 83 % and 95 % as compared to the uncoated glass for the wavelength of 380 nm and 500 nm, respectively. The hardness and roughness of DLC-coated glass have been measured by nanoindentation and AFM, respectively. The DLC-coated glass showed a little less or similar optical transmittance compared to the uncoated glass, while the hardness of DLC-coated glass was 2.5 times higher than that of the uncoated glass. The deposited DLC film had the very smooth surface and was thicker than 150 nm after deposition for 20 min.
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.