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


Figure 6b: Filtrate turbidity profiles of the engineering runs. Gray and back lines are typical profiles from the sending site.
As shown in Figures 6a and 6b, although the total processing time was increased as a result of reducing the filtrate flow rate, these modifications improved the filtrate turbidity profile of the third engineering run. The overall step yield and product-quality results of the third engineering run were comparable to those of the typical runs from the sending site (data not shown). Therefore, the performance of the TFF system at the receiving site using the modified process parameters was deemed acceptable and the risk from the TFF equipment gap was successfully mitigated.

Gap example # 4: viral clearance strategy

One risk that was identified early on during the transfer was not caused by facility fit constraints, but by the gap between the licensed process and the current industry standards and regulatory expectations around viral clearance. This risk was classified as a high risk. To mitigate this risk, two process improvements were made: improving the robustness of the acid-treatment step for viral inactivation, and changing the virus-removal filter to improve the process capability for removing adventitious viruses.


Figure 7: Effect of the target pH for the acid-treatment step on aggregate levels in the pH-neutralized pool and purified pool. The red line represents the limit in the bulk-product release specification.
The effectiveness of viral inactivation via acid treatment depends on temperature, pH, and duration of the treatment. Although pH 3.8 inactivates model retroviruses, subsequent studies have found that the performance of viral inactivation is more robust at pH 3.6 and below (17, 18). An exploratory study was performed at small scale to evaluate the effects of lower pH and longer durations for the acid-treatment step. As expected, an inverse correlation was found between pH and the glycoprotein aggregate level in the pH neutralized pool. It was observed that lower pH resulted in higher aggregate levels, as shown in Figure 7. However, the subsequent chromatography steps were able to reduce the percent aggregate level in the purified pool well below the limit for the bulk-product release specification. In a follow-up study, several product-quality attributes including the aggregate level were analyzed to validate the acceptable pH range and duration for the acid-treatment step. Product-quality analysis for the engineering runs also demonstrated that the full-scale performance of this step was acceptable.

In the past decade, more virus removal filters have become commercially available (19–21). The process transfer presented an opportunity to change the virus removal filter. A small virus-retentive filter was selected to replace the current virus-removal filter. This selection was based on considerations for the existing process capability for viral clearance, characteristics of the product pools (e.g., protein concentration), and current industry standards. Sizing of the new small virus-retentive filter was performed at small-scale. The performance of the viral-filtration step was also evaluated during the engineering runs to confirm appropriate sizing of this filter and acceptable process performance at full-scale.

Overall, the potential gap in the viral-clearance strategy of the process was closed by improving process robustness and leveraging current process technologies.


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