Reducing Fill Risk in Drug Product Manufacture Utilizing New State-of-the-Art Systems and Platforms
In this podcast we talked with DQ Wang, PhD, and Vice President, Formulation, Fill and Finish of WuXi Biologics about their DP4 multi-product fill & finish facility featuring the Vanrx SA25 robotic, gloveless, isolator-based filling system. The system significantly reduces drug product fill risk and provides greater aseptic assurance. The facility is the first in China to use this technology platform and the system fits perfectly with “scale- out” manufacturing paradigms. This highly-flexible platform can easily transition between various Container Closure Systems (CCS) such as vials, pre-filled syringes and cartridges including the new Ready-To-Use (RTU) formats.
We began the interview by talking about the completion of pre-filled syringe drug product runs in one of WuXi Biologics’ drug product fill facilities in Wuxi, China. What made these runs so unique is that they were produced in a new state-of-the-art facility that utilizes the Vanrx SA25 system. The system allows WuXi Biologics to greatly reduce risk for each fill and the amount of human intervention compared to traditional automated fill lines. Dr. Wang went on to say that it also allows them to perform fills for the first time using pre-filled syringes. He noted that adding this capability is another huge step towards their goal of building open-access technology platforms with the most comprehensive capabilities and capacities in the global biologics industry.
I followed up by asking DQ how human intervention can be reduced even further than what is already prevalent in the industry with automated fill lines. He explained that this gloveless, isolator-based system performs fully programmable, robotic functions for all aspects of the fill. The fully robotic functions include VHP sterilization of the container closures, liquid dispensing in the CCS of choice using a single flow path, capping, and delivery of the batch. After those steps, the Clean in Place (CIP) function is also programmed into the run. Lastly, there is integrated programmable and robotic air and particle sampling among other in-process checks and an integrated electronic batch record (EBR). All of this is done without human intervention, thereby removing one of the key areas where mistakes can be made during drug product manufacture.
Next I asked about the CCS chosen, pre-filled syringes, and whether the unit was dedicated solely to this type of configuration. He clarified that the unit is highly flexible and that it can handle a wide variety and sizes of CCS, such as vials and cartridges, in addition to pre-filled syringes. Additionally, the unit is able to handle the new simplified, two-component Ready-to-Use (RTU) CCS. These RTU formats reduce in-run risks. By design, the RTU formats reduce rejection rates caused by particles and other part defects that are more common in traditional rubber stopper and aluminum crimp seal configurations. He added that the system is also capable of performing inert gas overlays and for PFS and cartridges offers a servo-driven vacuum plunger design for bubble-free fills. Thus, the system is very adaptable to a wide-range of CCS types.
We transitioned the discussion to the primary drivers behind their decision to implement the Vanrx SA25 system in this new DP facility. DQ explained that their focus is always on patient safety and there are many reasons why the system is ideal from that perspective. There were other time and economic drivers as well. WuXi Biologics’ manufacturing goal is to quickly and safely advance their customers’ remarkable therapies to market. They knew that through this systems’ modular design and installation ease that it would accelerate the process of adding DP filling capacity, especially when compared to conventional filling systems. The qualification and validation of the process also takes less time due to the design properties of the modular system. This system has more standardization throughout the different filling operations and thus this standardization can reduce costs and time to clinic or market. It also fits perfectly with WuXi Biologics’ “scale-out” manufacturing paradigm.
Then I asked DQ if he could elaborate about the cost savings that can be achieved with this system. He said that this is actually one of the key benefits of implementing a filling unit like this. Overall a system like this reduces the cost of drug product operations because it requires less space and thus was less capital intensive. It requires fewer operators (2 versus 10 in traditional filling lines) and less training is required. With automated EM and RCS sampling and an integrated electronic batch record, there is less workload. This means reduced overall operating expenses and cost on a per run basis. Because of its single-use component only design and automated CIP after every run, you can also achieve faster changeover. With changeovers in as little as 45 minutes, you can complete more runs per unit of time and the yearly cleaning and qualification shut-down costs are cut in half.
I then asked DQ if he could explain the WuXi Biologics “scale-out” paradigm and how the Vanrx SA25 system fits for that purpose. To help explain this paradigm, he used WuXi Biologics’ drug substance (DS) manufacture as an example. For DS manufacture, WuXi Biologics uses single-use bioreactors. This allows them to obtain the scale needed without scaling up to larger stainless steel tanks. There are multiple benefits to this approach including, reducing any scale-up risks to product quality. It also greatly reduces the process validation effort required during late phase manufacturing, because the scale of manufacturing, from a bioreactor perspective, has not changed.
DQ then explained that similarly, for the Vanrx system, due to the small footprint, modular design of the unit, lower capital requirements and speed to install and validate, additional Vanrx systems can be added to scale-out the DP production. This is much less costly and time consuming than installing and validating a new dedicated commercial scale fill line. Like the bioreactor example, the late phase process validation is greatly reduced by simply using another identical Vanrx system. He added that WuXi Biologics is in the process of installing more Vanrx systems in several of their new manufacturing facilities in China and the USA.
I wanted to understand a bit more about the risk reduction element of the system. DQ told me about how being gloveless and robotic means less human intervention and thus higher aseptic processing control. The robotic functions are simply more reliable and precise. Thus, filling is done more accurately, with fewer mistakes and rejected product during QA review. The system is isolator-based and uses only single-use components, which is ideal from an aseptic processing perspective. WuXi Biologics has achieved 10X less variability during dispensing using the systems’ advanced peristaltic pump compared to the traditional peristaltic pumps. There is a single-flow path for the drug product into the container thus reducing risk further. With the integrated EBR they are even able to reduce the risk of human mistakes in the generation and review of batch records.
I then asked how long WuXi Biologics has been utilizing the system and what has been the performance thus far. DQ described how the system came on-line and was GMP- ready in early Q3 2019. They used the system to successfully fill four batches of pre- filled syringes (PFS) with an acceptance rate of up to 99.1%. For vial filling, their acceptance rate is even higher, at 99.6%. Since their first GMP run using this system in July 2019, they have had 0 EM excursions, have successfully passed all 4 media fills with a 100% success rate, have also successfully completed over 20 batches of drug product in RTU vials, and passed 7 client quality audits with no critical findings. He added that the system has allowed them to expand their capacity and helped to keep all projects on their intended timeline. With many runs now scheduled through end of 2020 and into next year, they are continuously adding and validating more CCS types and expect to have validated cartridges for use in the system by 2021.
We then discussed whether regulatory agencies had approved drug product from these systems. DQ said that they know that multiple clinical trials are now being conducted using DP manufactured in this system and several BLAs are pending. Large pharma is also steadily adopting and installing these systems as well. RTUs container closures are also now in widespread use in the industry.
I wanted to follow up on the utilization of RTUs and why the industry would move towards these new CCS. DQ explained that the material used in RTUs results in a reduction in particulates, which is an advantage. With the RTUs, there is no glass-to- glass contact during the fills and the potential for breakage or glass particulates is eliminated. There are advantages at the clinical site as well, these configurations tend to open easier and have fewer risks associated with damaging doctors’ gloves as they open or work with these CCS.
In terms of cost, fewer components results in less cleaning and sterilization costs. Two- part CCS also help reduce per run costs, storage costs and inventory space. RTUs provide greater flexibility and efficiency because most manufacturers use the same tubs for various sizes of RTUs, which makes loading and unloading very efficient. There is also an added benefit of high cosmetic quality.
With so many advantages to this system, I asked DQ if they were moving entirely to this type of DP filling system. He said that from a CMO perspective, there are significant advantages in using the Vanrx system especially for multi-use, multi-product and multi- CCS facilities. Product types like orphan products or other product types that need to be made “on-demand” are also ideal for a system like this. However, these systems cannot completely replace the traditional fill line yet. There are some economies of scale for which the traditional fill lines still have an advantage, for example with blockbuster drugs. There are also many drug companies that still need to use a particular CCS, which requires the traditional fill line. At WuXi Biologics, they still operate traditional isolater-based automated fill lines, when it is a better fit for clients and they are needed. However, the Vanrx system along with the use of RTU CCS has fulfilled a regulatory agency quality-by-design mission of continuous improvement and implementation of state-of-the-art technologies to reduce risk, lower costs and increase efficiency in biologics drug production. In the end, what benefits the patient is what really matters.