Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design(QbD) i...Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design(QbD) in the field of pharmacy, which is based on the thorough understanding of how materials and process parameters affect the quality profile of final products. The application of QbD in drug formulation and process design is based on a good understanding of the sources of variability and the manufacture process. In this paper,the basic knowledge of QbD, the elements of QbD, steps and tools for QbD implementation in pharmaceutics field, including risk assessment, design of experiment, and process analytical technology(PAT), are introduced briefly. Moreover, the concrete applications of QbD in various pharmaceutical related unit operations are summarized and presented.展开更多
Quality by Test (Qb T) was the only way to guarantee the quality of drug products before FDA launches current Good Manufacturing Practice (c GMP)[1], which is an approach without clear understanding of the processes. ...Quality by Test (Qb T) was the only way to guarantee the quality of drug products before FDA launches current Good Manufacturing Practice (c GMP)[1], which is an approach without clear understanding of the processes. In order to solve this problem,FDA generalized Quality by Design (QbD) in the field of pharmacy (2)In pharmaceutical industry, Qb D brings cost-efficiency and simplicity of manufacturing process into reality.展开更多
Compared to small molecule process analytical technology （PAT） applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell...Compared to small molecule process analytical technology （PAT） applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell culture process is essential to establish an appropriate process control strategy for biotechnology product PAT applications. Inline spectroscopic techniques for real time monitoring of bioreactor cell culture process have the distinct potential to develop PAT approaches in manufac- turing biotechnology drug products. However, the use of inline Fourier transform infrared （FTIR） spectroscopic techniques for bioreactor cell culture process monitoring has not been reported. In this work, real time inline FTIR Spectroscopy was applied to a lab scale bioreactor mAb IgG3 cell culture fluid biomolecular dynamic model. The technical feasibility of using FTIR Spectroscopy for real time tracking and monitoring four key cell culture metabolites （including glucose, glutamine, lactate, and ammonia） and protein yield at increasing levels of complexity （simple binary system, fully formulated media, actual bioreactor cell culture process） was evaluated via a stepwise approach. The FTIR fingerprints of the key metabolites were identified. The multivariate partial least squares （PLS） calibration models were established to correlate the process FTIR spectra with the concentrations of key metabolites and protein yield of in-process samples, either individually for each metabolite and protein or globally for all four metabolites simultaneously. Applying the 2＇ld derivative pre-processing algorithm to the FTIR spectra helps to reduce the number of PLS latent variables needed significantly and thus simplify the interpretation of the PLS models. The validated PLS models show promise in predicting the concentration profiles of glucose, glutamine, lactate, and ammonia and protein yield over the course of the bioreactor cell culture process. Therefore, this work demonstrated the technical feasibility of real time monitoring of the bioreactor cell culture process via FTIR spectroscopy. Its implications for enabling cell culture PAT were discussed.展开更多
基金financially supported by Talents Project of Liaoning Province, China (LR2013047)
文摘Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design(QbD) in the field of pharmacy, which is based on the thorough understanding of how materials and process parameters affect the quality profile of final products. The application of QbD in drug formulation and process design is based on a good understanding of the sources of variability and the manufacture process. In this paper,the basic knowledge of QbD, the elements of QbD, steps and tools for QbD implementation in pharmaceutics field, including risk assessment, design of experiment, and process analytical technology(PAT), are introduced briefly. Moreover, the concrete applications of QbD in various pharmaceutical related unit operations are summarized and presented.
文摘Quality by Test (Qb T) was the only way to guarantee the quality of drug products before FDA launches current Good Manufacturing Practice (c GMP)[1], which is an approach without clear understanding of the processes. In order to solve this problem,FDA generalized Quality by Design (QbD) in the field of pharmacy (2)In pharmaceutical industry, Qb D brings cost-efficiency and simplicity of manufacturing process into reality.
文摘Compared to small molecule process analytical technology （PAT） applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell culture process is essential to establish an appropriate process control strategy for biotechnology product PAT applications. Inline spectroscopic techniques for real time monitoring of bioreactor cell culture process have the distinct potential to develop PAT approaches in manufac- turing biotechnology drug products. However, the use of inline Fourier transform infrared （FTIR） spectroscopic techniques for bioreactor cell culture process monitoring has not been reported. In this work, real time inline FTIR Spectroscopy was applied to a lab scale bioreactor mAb IgG3 cell culture fluid biomolecular dynamic model. The technical feasibility of using FTIR Spectroscopy for real time tracking and monitoring four key cell culture metabolites （including glucose, glutamine, lactate, and ammonia） and protein yield at increasing levels of complexity （simple binary system, fully formulated media, actual bioreactor cell culture process） was evaluated via a stepwise approach. The FTIR fingerprints of the key metabolites were identified. The multivariate partial least squares （PLS） calibration models were established to correlate the process FTIR spectra with the concentrations of key metabolites and protein yield of in-process samples, either individually for each metabolite and protein or globally for all four metabolites simultaneously. Applying the 2＇ld derivative pre-processing algorithm to the FTIR spectra helps to reduce the number of PLS latent variables needed significantly and thus simplify the interpretation of the PLS models. The validated PLS models show promise in predicting the concentration profiles of glucose, glutamine, lactate, and ammonia and protein yield over the course of the bioreactor cell culture process. Therefore, this work demonstrated the technical feasibility of real time monitoring of the bioreactor cell culture process via FTIR spectroscopy. Its implications for enabling cell culture PAT were discussed.
