Purpose
In order to align with the current Federal Drug Administation (FDA) requirements to reduce viral risk associated with the current Unclogerall® purification process at the Boston Production Facility (BPF), a viral clearance filtration step must be introduced into the manufacturing process. The proposed viral reduction step would be added after the last purification column step and prior to the final formulation of the drug substance. A laboratory scale study was completed and concluded that the addition of a viral clearance filtration step to the Unclogerall® manufacturing process reduces the viral risk level to align with FDA requirements for Biotechnology products derived from cell lines of human or animal origin. This memo will describe the new process step and will evaluate the feasibility of implementing this change at the BPF without impacting the current manufacturing production schedule. Background In April 2015, the discovery of a virus, Nastivirus 2107, required the shutdown of manufacturing operations at the BPF to perform a complete sanitization of the facility. An investigation was completed which concluded the virus was introduced into the product stream through a nutrient used during the manufacturing process. The infiltration of the manufacturing process by this virus is indicative of a need to improve the robustness of viral removal processes. Following the introduction of the virus, the FDA issued the Big Pharma Co. BPF a Form 483 warning letter indicating that the site must verify that the viral reduction of the Unclogerall® manufacturing process aligns with the recently updated industrial guidance. In order to align with the current FDA Guidance, a study must be performed to measure that a minimum of a 9 log10 reduction takes place throughout the manufacturing process. The log10 reduction value (LRV) is calculated for each purification process step. The LRV calculated for all process steps are then summed to obtain an overall reduction factor for the manufacturing process. Using this value, the potential contamination level in the final drug substance can be calculated1. Confirmation Study Big Pharma Co. has performed a laboratory scale viral clearance study of the Unclogerall® manufacturing process with the inclusion of a final viral clearance filtration step after the last purification column operation. The conclusion of the study was by including the viral filtration step the overall LRV of the manufacturing process was 10. The current value of the manufacturing process performed at the BPF has a LRV of 7. Therefore, the addition of the viral filtration step into the Unclogerall® manufacturing process aligns the Unclogerall® LRV with the FDA Guidance for viral reduction of a LRV equal to or greater than 9. Implementation Proposal The success of the viral clearance study to align Unclogerall production with the FDA Guidance for viral reduction makes a clear case for implementing the viral clearance step. Figure 1 shows the current Unclogerall® manufacturing process with the addition of the proposed viral clearance filtration step. Figure 1. …show more content…
Unclogerall® Manufacturing Process
An initial implementation scope has been evaluated and will be discussed in further detail. The topics addressed include:
• Viral clearance filtration system and operation steps requirements
• Segregation requirements of pre-viral and post-viral process materials and areas.
• Impact and Requirements for Implementation
Viral Clearance Filtration System and Operational Steps
The viral clearance filtration operation is straight-forward and requires the transfer of the in-process Unclogerall® material through a viral filter using a constant differential pressure. An overview of the viral filtration process is outlined in Table 1.
Table 1. Viral Clearance Filtration Steps
Step Number Description Process Overview
1 System Setup • Setup viral clearance filtration system
• Flush the filter and preform pre-use integrity test
• Equilibrate the viral clearance filter prior to product filtration
2 Viral Clearance
Process Step • Pressurize vessel and filter product through viral clearance filter
• Perform inline 0.2 µm sterile filtration downstream of viral filtration • Collect filtered product in collection vessel
3 System Break Down • Flush the filter and perform a post-use integrity test • Breakdown of viral clearance system System Setup The viral clearance filtration system setup involves installing the cartridge style viral clearance filter onto the filtration skid and the inlet and outlet valves, reducers, and instrument tees are attached
In order to align with the current Federal Drug Administation (FDA) requirements to reduce viral risk associated with the current Unclogerall® purification process at the Boston Production Facility (BPF), a viral clearance filtration step must be introduced into the manufacturing process. The proposed viral reduction step would be added after the last purification column step and prior to the final formulation of the drug substance. A laboratory scale study was completed and concluded that the addition of a viral clearance filtration step to the Unclogerall® manufacturing process reduces the viral risk level to align with FDA requirements for Biotechnology products derived from cell lines of human or animal origin. This memo will describe the new process step and will evaluate the feasibility of implementing this change at the BPF without impacting the current manufacturing production schedule. Background In April 2015, the discovery of a virus, Nastivirus 2107, required the shutdown of manufacturing operations at the BPF to perform a complete sanitization of the facility. An investigation was completed which concluded the virus was introduced into the product stream through a nutrient used during the manufacturing process. The infiltration of the manufacturing process by this virus is indicative of a need to improve the robustness of viral removal processes. Following the introduction of the virus, the FDA issued the Big Pharma Co. BPF a Form 483 warning letter indicating that the site must verify that the viral reduction of the Unclogerall® manufacturing process aligns with the recently updated industrial guidance. In order to align with the current FDA Guidance, a study must be performed to measure that a minimum of a 9 log10 reduction takes place throughout the manufacturing process. The log10 reduction value (LRV) is calculated for each purification process step. The LRV calculated for all process steps are then summed to obtain an overall reduction factor for the manufacturing process. Using this value, the potential contamination level in the final drug substance can be calculated1. Confirmation Study Big Pharma Co. has performed a laboratory scale viral clearance study of the Unclogerall® manufacturing process with the inclusion of a final viral clearance filtration step after the last purification column operation. The conclusion of the study was by including the viral filtration step the overall LRV of the manufacturing process was 10. The current value of the manufacturing process performed at the BPF has a LRV of 7. Therefore, the addition of the viral filtration step into the Unclogerall® manufacturing process aligns the Unclogerall® LRV with the FDA Guidance for viral reduction of a LRV equal to or greater than 9. Implementation Proposal The success of the viral clearance study to align Unclogerall production with the FDA Guidance for viral reduction makes a clear case for implementing the viral clearance step. Figure 1 shows the current Unclogerall® manufacturing process with the addition of the proposed viral clearance filtration step. Figure 1. …show more content…
Unclogerall® Manufacturing Process
An initial implementation scope has been evaluated and will be discussed in further detail. The topics addressed include:
• Viral clearance filtration system and operation steps requirements
• Segregation requirements of pre-viral and post-viral process materials and areas.
• Impact and Requirements for Implementation
Viral Clearance Filtration System and Operational Steps
The viral clearance filtration operation is straight-forward and requires the transfer of the in-process Unclogerall® material through a viral filter using a constant differential pressure. An overview of the viral filtration process is outlined in Table 1.
Table 1. Viral Clearance Filtration Steps
Step Number Description Process Overview
1 System Setup • Setup viral clearance filtration system
• Flush the filter and preform pre-use integrity test
• Equilibrate the viral clearance filter prior to product filtration
2 Viral Clearance
Process Step • Pressurize vessel and filter product through viral clearance filter
• Perform inline 0.2 µm sterile filtration downstream of viral filtration • Collect filtered product in collection vessel
3 System Break Down • Flush the filter and perform a post-use integrity test • Breakdown of viral clearance system System Setup The viral clearance filtration system setup involves installing the cartridge style viral clearance filter onto the filtration skid and the inlet and outlet valves, reducers, and instrument tees are attached