What Is The Environmental Impact Of Continuous Biopharmaceutical Production?

Manufacturing offers many tantalizing opportunities for the future of biopharmaceuticals, from greater efficiencies to lower costs to improved process scalability. Many exciting new technologies are being investigated for upstream production and downstream purification of biopharmaceuticals in a continuous format. Although no commercialized biopharmaceuticals are currently in a fully continuous process and many technical challenges remain, many successes have been achieved with the use of perfusion bioreactors as well as strategies for downstream unit operations performed in a continuous format. In addition to the technical challenges of converting a bioproduction process to a fully continuous process, there are other challenges to implementing this technology, ranging from risk adversity (for example, not wanting to take the risk of converting an in-use batch process to a continuous process) to regulatory uncertainty, Then to data analysis and integration challenges.

An often overlooked aspect of continuous biopharmaceutical manufacturing (BCM) is its environmental impact compared to similar batch processes. It is widely accepted that the choice of mode of production has a direct impact on the environment and the health of the planet, and although some efforts have been made to quantify the direct environmental impact of biopharmaceutical production and to compare batch vs. A thorough assessment is necessary because the current piecemeal understanding of the impact of the individual components of a BCM system can lead to misinformation about its impact on the environment. For example, the heavy reliance on single-use production equipment (single-use technology, or SUT) in BCM processes can create the impression that they are less sustainable than comparable batch processes, even if consumables are only a part of the overall environmental impact. small portion.

Part 1 Assess The Environmental Impact Of The Production Process

There are many factors that affect the environmental impact of a biological production process, including how water and electricity are used, the physical footprint of the production facility, and the efficiency of the process. Industry has worked hard to develop quantitative assessment methods for the environmental impact of biological production processes.

Bioproduction processes using fermenters or bioreactors have significantly higher PMIs than processes used to produce small molecule active pharmaceutical ingredients (APIs). The average PMI for small molecule API processes is 100 to 200 kg/kg. However, it is estimated that, on average, 7,700 kg of input are required to produce 1 kg of mAb output. This input includes water used to prepare media and buffers, raw materials, and any other consumables used in the manufacturing process. However, one weakness of PMI when used as an assessment of environmental impact is that it does not take into account other factors not directly used in the production process, such as water used to clean equipment, electricity used to power facilities, or waste generated during production . Therefore, other indicators are needed to explain these environmental influences.

Other more inclusive methods for measuring environmental impact include life cycle assessment (LCA), cumulative energy demand (CED) and global warming potential (GWP, Table 1). These impact measures include other factors and thus go beyond the limitations of PMI. LCA takes into account historical data related to the process, but the assessment is more time-consuming and requires more environmental impact data. LCA can be used to examine the environmental impact of the process life cycle from raw material extraction to waste disposal. LCA studies require clearly defined system boundaries, covering the entire lifecycle of the process, and developing an inventory that takes into account a range of categories of environmental impact, including material and energy use. This type of assessment can be used to compare the environmental impact of two processes that may have similar PMIs but have very different overall impacts on the environment. Other measures, such as CED and GWP, also take into account the life cycle phase of the process. These analyzes are divided into three phases, including the supply chain phase, the use phase (actual production, including cleaning/sterilization in place [CIP/SIP]), and the end-of-life phase, which includes the disposal of consumables and the reuse and recycling of durable components. Various measures of these environmental impacts can be used to assess the overall environmental impact of the production process.

Part 2 Water Everywhere

Water is the largest contributor to the environmental impact of batch bioproduction processes. Water usage in biopharmaceuticals is more than 100 times that in small molecule production and can account for more than 90% of the PMI for such processes. It is estimated that a typical 20,000 L batch mAb production plant can use over 1.5 million gallons of water a year. Currently, the chromatography step in the downstream purification operation directly consumes the most water in the production process. In fact, one study calculated that all the chromatography steps in a monoclonal antibody consume 62% of the water in the overall antibody production process, and that by reducing the chromatography steps from three to two, the PMI of the process could be reduced by 50% above. In terms of upstream production, the water used for cell growth (which can be tens of thousands of liters in large facilities) comprises most of the water used directly for this part of the process. Steam heating used to maintain growth temperatures in many bioreactors exacerbates upstream water usage. The second largest contributor to direct water use in upstream processes is seed culture/bioreactor water use and accounts for 18% of the total PMI. Also, increasing the size of a bioreactor does not necessarily lead to a decrease in overall PMI, as the trend is for larger production tanks to have a higher PMI.

In addition to directly contributing to the PMI of water used in biopharmaceutical manufacturing, significant amounts of water are used to clean and sanitize equipment used in batch production. Stainless steel reuse equipment requires extensive cleaning between batches or campaigns and must then be steam sterilized (CIP/SIP). The cleaning process requires copious amounts of various detergents followed by multiple rinses with water. Then steam sterilize with more water. CIP/SIP operations dominate the water demand of stainless steel facilities, accounting for 40% of the GWP and CED of the process. The biopharmaceutical manufacturing process also uses water for injection (WFI), which is highly resource-intensive to produce. Municipal water is softened, filtered and subjected to reverse osmosis. This is followed by UV light treatment and continuous deionization to produce purified water, followed by distillation to produce WFI. One study used a conversion factor of 1.41 to calculate the PMI contribution of WFI compared to municipal water, i.e. 41% more resources were required to produce WFI than the water entering the plant, and 41% more resources were needed to produce WFI than the equivalent BCM process. Subprocesses tend to use more WFI.

BCM processes typically require less water than batch processes. In a head-to-head comparison of the 25-L batch mode process and the 25-L continuous mode process, the buffer volume was significantly reduced in the BCM process. For example, the Protein A capture step in the BCM process reduced media volume by 95% and buffer consumption by 44% compared to an equivalent batch operation. Flow-through chromatography, a process step well suited for continuous operation, can also greatly reduce buffer utilization by eliminating the need for rinsing and elution of the chromatography matrix. The use of membrane chromatography, rather than the more traditional packed column chromatography, can further reduce the use of buffers in the process, and the BCM process is well suited for the use of membrane chromatography. In fact, some unit operations in BCM may consume 90% less buffer than comparable batch process operations.

However, there may be trade-offs in water usage between BCM and batch processes during upstream production. Perfusion bioreactors used in BCM require more media than batch reactors, but this can be offset by media optimization and the use of perfusion bioreactors at the N-1 stage (N-1 perfusion refers to Intensification of cell growth in previous steps in reactor (N) to increase density and shorten incubation time in production reactors). Seeding the production bioreactor (N) at the higher cell density obtained at the N-1 stage allows the cells of the production bioreactor to reach the optimal density and more quickly to maximize mAb production, saving time and media . The final step of the BCM mAb process can also be significantly more buffer consuming than that used in standard batch diafiltration, reducing the environmental advantage of BCM to some extent. In the following, additional environmental advantages of BCM when combined with single-use technology (SUT) are presented, which do not require CIP/SIP activities, further reducing the overall water consumption of the process. As mentioned earlier, BCM processes can greatly increase capacity and process efficiency compared to batch processes, and these factors are inversely proportional to water consumption. The more efficient the process, the less water is needed to produce 1 kg of final product. When considering the overall water consumption of the process, BCMs using SUTs can significantly reduce the use of this valuable resource as well as the overall environmental impact of the process compared to fixed facility batch production.

Part 3 Summary

In our article comparing the environmental impact of biopharmaceutical batch production versus BCM, we summarize the various metrics used to assess the environmental impact of production and explore differences in water consumption, which is the largest contributor to the environmental impact of the process . In a follow-up article, we will examine how process efficiency, single-use technology, and process requirements play a role in the environmental impact of a process.