A Risk-Based Approach to Transferring a Mature Biopharmaceutical Process - The authors present risk-evaluation and mitigation strategies for transfer of the manufacturing process of a recombinant gly

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A Risk-Based Approach to Transferring a Mature Biopharmaceutical Process
The authors present risk-evaluation and mitigation strategies for transfer of the manufacturing process of a recombinant glycoprotein.


BioPharm International
Volume 25, Issue 2, pp. 41-49

Gap example # 3: primary recovery equipment


Figure 5: Process flow diagram of the tangential flow filtration step.
In the primary-recovery step of the process, the cell culture fluid from the production bioreactor is fed via a rotary pump to a multi-membrane tangential flow filtration (TFF) system. The filtrate (i.e., permeate) is collected in the harvest tank while the retentate is recycled back to the production bioreactor, as shown in Figure 5. The facility fit analysis indicated that the TFF feed pump was different between the sending and receiving sites. Because the receiving site was a multi-product facility and the feed pump was used for several products, it was highly desirable to adapt the process to the existing equipment at the receiving site if possible. The difference in the TFF feed pump could potentially change the turbulent-eddy size distribution to which the cells were exposed in the TFF flow path and thereby cause different levels of cell lysis during the primary recovery operation (13, 14). The performance of the primary recovery step, such as step yield and processing time, could be affected as a result. Additionally, cellular enzymes, such as glycosidases, proteases, or reductases, may be released as a result of varied cell lysis and could potentially affect product quality. An extremely high energy-dissipation rate due to the feed pump difference could also affect product quality. However, this was considered unlikely given the type of pump at the receiving site and available information from the literature on the effect of high shear on proteins (15, 16). Therefore, this gap in the TFF equipment was classified as a medium risk.

Laboratory-scale TFF systems typically do not represent the performance of manufacturing-scale systems well. Additionally, manufacturing-scale pump performance cannot be reproduced in the laboratory. Therefore, the risk-mitigation plan was to perform full-scale engineering runs to assess the potential effect on process performance and modify any TFF process parameters if necessary.


Figure 6a: Tangential flow microfiltration trans-membrane pressure (TMP) profiles of the engineering runs. Gray and back lines are typical TMP profiles from the sending site.
The TFF operation is run by controlling the filtrate flow rate at a predetermined target until the trans-membrane pressure (TMP) reaches a maximum limit, after which the filtrate-flow rate is reduced to maintain the TMP at the maximum limit. The switch between the concentration phase and the diafiltration phase is based on a target-concentration factor. TFF operation ends once a target diafiltration volume has been reached. The TMP and filtrate turbidity profiles of the engineering runs were compared with two typical manufacturing runs from the sending site in Figures 6a and 6b, respectively. It was evident from the first two engineering runs that the equipment difference likely resulted in a higher level of cell lysis and thus caused higher filtrate turbidity and TMP. In fact, the first engineering run was terminated before reaching the target diafiltration volume because of the low filtrate flowrate. For the third engineering run, the initial filtrate flow-rate target and the maximum TMP limit were reduced to improve the performance of the TFF step.


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