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The authors compare the environmental impact of monoclonal antibody production using fixed-in-place processing and single-use systems.
Many biopharmaceutical companies have replaced or are planning to replace traditional multi-use process equipment (fixed-in-place stainless-steel fermenters, tanks, downstream processing equipment, and associated piping) with single-use systems to improve flexibility, productivity, and cost (1–3). The use of disposable components reduces or eliminates the need for extensive cleaning and steam sterilization between batches. However, single-use process technologies can also have negative environmental impacts because they involve the use and disposal of consumable materials.
Several previous studies have looked at environmental impacts of single use biopharmaceutical manufacturing technologies (4–7). To further understand the balance of environmental impacts, GE Healthcare in collaboration with GE's Ecoassessment Center of Excellence has completed an extensive study of the life-cycle environmental impacts of the full process train required to produce monoclonal antibodies (mAbs). The study compares the use of single-use versus traditional durable process technologies at 100-L, 500-L, and 2000-L scales. The scales were chosen to reflect the clinical phase, the scale-up phase, and the final production phase. Process data were derived in collaboration with BioPharm Services, developer of BioSolve, an industry-standard bioprocess model that can be used to build any process including those for manufacture of mAbs, vaccines, and bacterial-based products.
This comprehensive environmental study of single-use process technology is the first to offer a comprehensive examination of environmental impacts across the full process train using life cycle assessment (LCA). LCA is an internationally recognized discipline that can be used to examine products and processes from an environmental perspective across the full lifecycle of a product or process, from raw-material extraction and refining through manufacturing, use, and end-of-life disposal or recycling. The methods involve analyzing material and energy flows from cradle-to-grave to calculate potential environmental impacts. This study was performed in accordance with the International Standards Organization ISO 14040 and ISO 14044 (8, 9). The details and quality of the study were evaluated by a third-party critical review panel as per ISO 14044 because the study involved comparative assertions. The critical review panel consisted of an independent LCA expert and two domain experts from the biopharmaceutical manufacturing industry (10).
The results reported here focus on global warming potential (i.e., greenhouse gas emissions), cumulative energy demand (i.e., embodied energy), and water usage. The study also examined a range of additional environmental impact categories, such as ozone depletion, acidification, eutrophication, resource depletion, particulate matter formation, photochemical oxidant formation, as well as others. A companion article describing the results of the more comprehensive set of environmental impact categories is in preparation and will be published separately.
The goal of this study was to compare the potential environmental impacts associated with the production of mAbs using either single-use or traditional durable process technologies. The full process trains were evaluated at 100-L, 500-L, and 2000-L scales. Calculations were based on a 10-batch campaign assuming 6 g/L titres. The study did not account for any potential difference in product yield resulting from choice of process technology. Any such issues are product- or process-specific and beyond the scope of this study.
The results of this LCA will be used to communicate potential environmental impacts to interested stakeholders and to identify key areas for potential improvement in terms of supply chain, product design, manufacturing, or end-of-life as appropriate.
The scope of this study included both upstream and downstream processes involved in the production of mAbs. Figure 1 shows a process schematic of the full process train categorized into fourteen unit operations. A 15th category included the clean-in-place/steam-in-place (CIP/SIP) infrastructure and common support activities, such as process water and HVAC requirements (collectively termed "Support CIP/SIP System").
Figure 1: Process diagram of full process train for the production of monoclonal antibodies (mAbs). For this study, the process train was categorized into 14 unit operations and a 15th category, "Support CIP/SIP System," that included the clean-in-place/steam-in-place infrastructure and common support activities, such as process water and HVAC requirements. IEX is ion-exchange chromatography, UF/DF is ultrafiltration/diafiltration.
The potential for a smaller production facility enabled by the choice of single-use technology was not specifically included in the scope of this study. However, the floor space used per HVAC class for each technology was scaled to the required facility footprint. This approach assumed that a traditional technology facility is in place and single-use technology is adapted to the existing facility.
A variety of single-use technology from different manufacturers is available. This study systematically used GE technology (i.e., WAVE Bioreactor system and ReadyToProcess components) wherever appropriate due to the greater availability of internal data, and to support an effort to identify opportunities for environmentally conscious product design.
This study did not address any potential differences in labor requirements.
Life-cycle inventory analysis
The main body of data used in this study was derived in collaboration with BioPharm Services and can be considered industry average based on a combination of primary and secondary sources. Data on production of single-use components were obtained primarily from GE Healthcare. Data on transportation, packaging, and end-of-life were gathered through a combination of supplier data (GE Healthcare) and expert interviews. Additional secondary data were obtained from the ecoinvent 2.2 life-cycle inventory database (11).
The life-cycle assessment models were developed in SimaPro Analyst version 7.2.4 life-cycle assessment software (12). The inventory data were analyzed using several impact assessment methodologies. Cumulative energy demand (CED) was calculated using the Cumulative Energy Demand v1.07 method and includes the total life cycle energy requirements including production and distribution of energy that is consumed across the life cycle, reported in units of megajoule-equivalents (MJ-eq). Lifecycle global warming potential (GWP) was calculated using the IPCC 2007 100a method and is reported as CO2-equivalents (CO2-eq), including all greenhouse gases specified in the Kyoto Protocol using 100-year time horizon global warming potentials from the Intergovernmental Panel on Climate Change 4th Assessment Report (13). Water usage (withdrawal) is reported in kilograms (kg) and was calculated using a custom impact assessment method that evaluates the withdrawal of freshwater (and saltwater, if any) across the lifecycle of the system being studied.
To maintain sterility, traditional durable equipment must be cleaned and steamed in place (CIP/SIP) between each batch. This requires a large amount of process water, water for injection (WFI), acids, and bases. The energy and supporting equipment required are all considered in this analysis. Single-use components that contact media do not require rigorous cleaning and sterilization, but instead are pre-sterilized by off-site Cobalt-60 irradiation. The transport of single-use components to and from the facility is included as well as the facility's operating energy, the Co-60 source, and the concrete required for the irradiation cell. These impacts are allocated to each irradiated component as a mass fraction of irradiation facility throughput.
The traditional durable equipment is nominally assumed to have 10-year lifetimes, after which 25% of the equipment is re-used while the remainder is either recycled (90%) or landfilled (10%). The single-use process trains contain components that are designed to be used once and then discarded. The exceptions are the replacement of single-use chromatography columns, which are typically reused for several batches depending on the number of cycles per batch. In this case, a recommended usable life for a ReadyToProcess Capto S 2.5 chromatography column is 20–50 cycles. The LCA model assumed 7 cycles per batch for Protein A and 5 cycles per batch for ion exchange chromatography (at 2000-L scale). The number of cycles for traditional chromatography is assumed to be two cycles per batch for both Protein A and ion exchange chromatography.
Several assumptions were made regarding treatment at end-of-life. For single-use components such as cellbags, filters, and connectors, disposal was assumed to occur by hazardous waste incineration without waste heat recovery. Non-hazardous waste was sent to landfill or wastewater treatment. Process water was assumed to be used once without recovery.
Use-phase electricity was assumed to be from an average US grid mix. Selection of an average European electricity grid mix exhibits lower environmental impacts but does not lead to any discernable shift of relative magnitudes between single-use and traditional process technology.
The fuel mix for generation of WFI was composed of different ratios of fuel oil, natural gas and electricity. The default mixture was equally weighted for fuel oil and natural gas at 45% each while electricity was weighted at 10%.
Sensitivity and uncertainty analyses
The sensitivity of the LCA results to variations in key assumptions was extensively analyzed using a Plackett-Burman experimental design. Lifetime of durable equipment was varied from 5–25 years. Chromatography column lifetimes were varied from 10–100 cycles. Transportation distances were varied from 5–25 miles (local), 1000–5000 miles (domestic), and 1500–7500 miles (international). Different ratios of WFI fuel mixes were examined. Equipment reuse was varied from 0–25%. Equipment recycling was varied from 50–100%. Co-60 irradiation facility parameters were varied as well. None of the variations in key assumptions had a significant effect on the study conclusions. The detailed results of the sensitivity and uncertainty analyses will be reported in a subsequent publication.
Figure 2 shows the cumulative energy demand (CED) and global warming potential (GWP) for single-use versus traditional durable process technology for the full process train with a 2000-L working volume. The results are categorized by life-cycle stage. The supply chain phase includes materials and manufacturing of all process equipment and consumables required to support a 10-batch mAb production campaign. The use phase includes all impacts that occur during mAb production, including cleaning and sterilization of traditional durable equipment between batches. The end-of-life phase includes the disposal of consumables and the disposal, re-use, or recycling of allocated portions of durable components.
Figure 2: Cumulative energy demand (CED) and global warming potential (GWP) for the production of a monoclonal antibody in a full process train at 2000-L scale with assumed mAb titre of 6 g/L. Impacts grouped by life cycle stage (supply chain, use phase, and end-of-life).
A substantial majority of the life cycle environmental impacts occur during the use phase. Note that the comparative CED and GWP results are very similar because almost all of the GWP is related to energy production and consumption. The single-use process train exhibits 38% lower GWP during use phase (and 34% lower GWP across all life-cycle stages) compared to a traditional durable process train. The corresponding reduction in CED is 38% during use phase and 32% across all life-cycle stages. Supply chain GWP and CED impacts are slightly higher for single-use compared with traditional process technology due to the increased manufacturing required to provide the consumable components used in a single-use approach. However, supply-chain impacts represent <11% of the life-cycle CED impact and <5% of the life GWP impact. Environmental impacts from the end-of-life stage represent <1% of overall life cycle impacts.
Figure 3: Cumulative energy demand (CED) and global warming potential (GWP) for the production of a monoclonal antibody in a full process train at 2000-L scale with assumed mAb titre of 6 g/L. Impacts displayed by unit operation.
Figure 3 shows the CED and GWP impacts for single-use vs. traditional process technology categorized by unit operation. The most substantial impacts (38–40% of both GWP and CED) are related to the support CIP/SIP system, which includes the CIP/SIP infrastructure and common support activities such as process water and HVAC requirements (the main difference between process approaches in this category is the amount of energy required to generate WFI and steam). The use of single-use process technology exhibits lower CED and GWP impacts compared to traditional durable technology in all unit operations except Protein A and ion-exchange chromatography, which are higher for single-use since several single-use columns must be used in parallel to reach this scale.
Figure 4: Water usage for the production of a monoclonal antibody in a full process train at 2000-L scale with assumed mAb titre of 6 g/L. Impacts grouped by life cycle stage (supply chain, use phase, and end-of-life).
Figure 4 shows water usage categorized by life cycle stage. Substantial water savings are realized during the use phase for single-use process technology due to the reduction or elimination of cleaning and sterilization between batches. Figure 5 shows water usage categorized by unit operation. As expected, water usage is dominated by activities related to the support CIP/SIP system. Single-use process technology exhibits lower water usage in all unit operations except Protein A and ion exchange chromatography, again due to the need for parallel chromatography columns at this scale. Note also that the majority of water usage in the UP 03 Bioreactor is for media, so the primary water usage savings of single-use process technology is due to the shift from steam heating to electrical heating. The negative water usage during the end-of-life stage reflects credit related to the re-use and recycling of durable components.
Figure 5: Water usage for the production of a monoclonal antibody in a full process train at 2000-L scale with assumed mAb titre of 6 g/L. Impacts displayed by unit operation.
The results in Figures 2–5 focus on the 2000-L working volume scale. Similar results were obtained at 100-L and 500-L scales, and the process technology comparisons discussed in this section apply to all three scales.
The study has shown that a shift from traditional durable process technology to single-use process technology can result in substantial reductions in cumulative energy demand, global warming potential, and water usage for the production of monoclonal antibodies, in addition to improving flexibility and productivity. Although single-use process technology introduces a need for the production, distribution, and disposal of single-use components, this approach also reduces or eliminates the need for large quantities of steam, process water, and water for injection. The LCA model developed for this study is dynamic and offers the potential for further exploration of different bioprocess conditions and "what if" scenarios. The detailed insights gained in this comprehensive study offer the potential for further improvements in environmentally conscious product and process development for biopharmaceutical manufacturing.
Matthew Pietrzykowski is a research chemist, and William Flanagan* is the leader, both at at the Ecoassessment Center of Excellence, GE Global Research, Niskayuna, NY. Vincent Pizzi is a global product marketing leader at GE Healthcare, Westborough, MA. Andrew Brown is a bioprocess engineer, Andrew Sinclair is managing director, and Miriam Monge is vice-president, all at Biopharm Services Ltd., Chesham, UK. *firstname.lastname@example.org
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