Technical Potential for Energy and GWP Reduction in Chemical–Pharmaceutical Industry in Germany and EU—Focused on Biologics and Botanicals Manufacturing

: European policy demands climate neutrality by the year 2050. Therefore, any manufacturing optimization needs to be achieved in the well-known pareto of global warming potential (GWP) reduction combined with cost of goods (COG) reduction at increasing product amounts, while still being able to compete in the world market. The chemical–pharmaceutical industry is one of the most energy-intensive industries. The pharmaceutical industry operates with low batch sizes, but high margins. This study analyzes, based on the literature and Bundesministerium für Wirtschaft und Energie (BMWi; English: Federal Ministry for Economic A ﬀ airs and Energy)-funded project results, the technical potentials for energy and GWP reduction, while focusing on biologics and botanicals, because those are already widely based on natural raw material resources. The potential impact for green technologies is pointed out in relation to climate-neutral manufacturing.


Introduction
Germany contributes about 2% to the worldwide CO 2 eq emissions [1]. Industrial manufacturing contributes about 30% [2], whereas the chemical-pharmaceutical industry contributes about 14% [3], being third in the rankings after the iron and steel and cement industries. These energy-intensive industries have therefore founded a consortium [4]. German industry accounts for about 5.6 million employees and EUR two trillion turnover per year, being the fourth largest industrial nation [5]. The chemical-pharmaceutical industry in Germany is, after automotive and civil engineering, the third largest in terms of sales and employees [1,3].
Apart from energy consumption, all natural chemical material conversions have to be taken into account due to the chemical nature of these industries. The pharmaceutical industry is a small part of the chemical-pharmaceutical industry due to the low metric tons per year products compared to petro and bulk chemicals, and even to fine chemicals manufacturing [6,7].
Biologics manufacturing has been improved drastically in terms of COGs (five to 10) and GWP (five to 10) [34]. Consequently, as a final step, only needed before broad industrialization, any prototype operation has to be proven valid for industrial decision makers who have a natural tendency towards a conservative modest technical imagination ability and total risk avoidance in such strictly regulated industries [35]. In this study, the potential for a reduction in energy and GWP has been analyzed by assessing the status quo and using data from the literature, as well as BMWi-funded project results, in order to identify the most important activities needed in research and industry to reach the goal of climate neutrality.

Overview and Current State of Biologics
The effort to reduce greenhouse gas (GHG) emissions has been steadily gaining momentum in recent decades. A major milestone was reached in 2015 by the Paris Agreement [36] to stop global warming, which was then adopted worldwide, e.g., by the Obama administration's Clean Power Plan [37] and Germany's Federal Climate Change Act (Bundes-Klimaschutzgesetz) [2], which forces the government to take action to ensure CO 2 neutralilty by the year 2050.
Germany's GHG emissions accounted for a total of 805 million tons in 2019 (down from 1251 million tons in 1990; see Figure 1), which was about 2% of the worldwide emissions [1]. The German industry directly contributed 23.3% to the overall emissions in 2019 [2]. It is also the largest end energy consumer with 736 TWh or 29.5% (total end energy demand in 2019 was 2499 TWh) [38]. Including these indirect emissions, the contribution of the industry sector to Germany's overall emissions was estimated by VCI to be 36.3% in 2017 [3]. The energy demand of the chemical-pharmaceutical sector is about 20% [3]. To reach the goal of climate neutrality by 2050, Germany must reduce its emissions by 54-56% compared to 1990, down to 543 million tons in 2030, as can be seen in Figure 1. Biologics manufacturing has been improved drastically in terms of COGs (five to 10) and GWP (five to 10) [34]. Consequently, as a final step, only needed before broad industrialization, any prototype operation has to be proven valid for industrial decision makers who have a natural tendency towards a conservative modest technical imagination ability and total risk avoidance in such strictly regulated industries [35]. In this study, the potential for a reduction in energy and GWP has been analyzed by assessing the status quo and using data from the literature, as well as BMWifunded project results, in order to identify the most important activities needed in research and industry to reach the goal of climate neutrality.

Overview and Current State of Biologics
The effort to reduce greenhouse gas (GHG) emissions has been steadily gaining momentum in recent decades. A major milestone was reached in 2015 by the Paris Agreement [36] to stop global warming, which was then adopted worldwide, e.g., by the Obama administration's Clean Power Plan [37] and Germany's Federal Climate Change Act (Bundes-Klimaschutzgesetz) [2], which forces the government to take action to ensure CO2 neutralilty by the year 2050.
Germany's GHG emissions accounted for a total of 805 million tons in 2019 (down from 1251 million tons in 1990; see Figure 1), which was about 2% of the worldwide emissions [1]. The German industry directly contributed 23.3% to the overall emissions in 2019 [2]. It is also the largest end energy consumer with 736 TWh or 29.5% (total end energy demand in 2019 was 2499 TWh) [38]. Including these indirect emissions, the contribution of the industry sector to Germany's overall emissions was estimated by VCI to be 36.3% in 2017 [3]. The energy demand of the chemicalpharmaceutical sector is about 20% [3]. To reach the goal of climate neutrality by 2050, Germany must reduce its emissions by 54-56% compared to 1990, down to 543 million tons in 2030, as can be seen in Figure 1.  368  366  377  379  359  347  344  322  305  254  175   188  185  179  180  180  187  191  198  195  188   140   149  128  131  140  119  125  125  123  117  122   70   153  155  154  158  159  162  165  168  162  163   95   70  71  71  72  73  74  73  73  70  68   58   942  919  924  942  902  906  909  894  858  However, in the past decade there was neither a decrease in emissions nor energy demand in this sector. The development of CO 2 emissions and the energy demand of the pharma sector alone is shown in Figure 2. Approximately 1.9 Mt CO 2 was emitted by pharmaceutical production in 2017, not counting other GHG emissions [6], while the pharma sector's energy demand stayed constant overall at 6.57 TWh in 2017 [7]. However, in the past decade there was neither a decrease in emissions nor energy demand in this sector. The development of CO2 emissions and the energy demand of the pharma sector alone is shown in Figure 2. Approximately 1.9 Mt CO2 was emitted by pharmaceutical production in 2017, not counting other GHG emissions [6], while the pharma sector's energy demand stayed constant overall at 6.57 TWh in 2017 [7]. These numbers are in good agreement with global GHG emissions by the pharma industry, estimated to be about 52 Mt CO2eq globally [39]. Extending the scope by accounting for indirect energy related emissions [40], the total GHG emission of the pharma industry is much higher and has recently been highlighted by China's pharma industry GHG emissions alone, which were calculated as 55.34 Mt CO2 in 2016 [41]. All data sets suggest that the pharmaceutical industries' GHG emissions are actually increasing rather than decreasing due to increasing drug demands worldwide.
Biologics make up about 30% of the pharmaceutical industry market. The world pharmaceutical market is estimated to be EUR 1.2 billion in 2018, with about 44% US market and 24% Germany sales [42]. The industry is dominated by global players, so-called big pharma, due to high investments and high risks of failure in costly clinical trials [43].
Technical trends are transferred from traditional batches to continuous manufacturing [42], Green Chemistry [44] and biotechnological drugs. Societal needs for innovative medicines and sufficient supplies at moderate costs due to healthcare system limitations are accepted without discussion [45]. Recent studies perpetuating the belief that there is no need for improvement in such a small industry do not benefit the global situation and are wrong, for example:


Single-use plastic items are forbidden and reduced in daily life; in biotech manufacturing, however, they are booming due to single-use technology, advantages in cleaning efforts, personal resources and flexibility in various batches and products, as well as costs [46].  Other studies point out that the pharmaceutical industry is inefficient compared to automotive manufacturing [47]:  These numbers are in good agreement with global GHG emissions by the pharma industry, estimated to be about 52 Mt CO 2 eq globally [39]. Extending the scope by accounting for indirect energy related emissions [40], the total GHG emission of the pharma industry is much higher and has recently been highlighted by China's pharma industry GHG emissions alone, which were calculated as 55.34 Mt CO 2 in 2016 [41]. All data sets suggest that the pharmaceutical industries' GHG emissions are actually increasing rather than decreasing due to increasing drug demands worldwide.
Biologics make up about 30% of the pharmaceutical industry market. The world pharmaceutical market is estimated to be EUR 1.2 billion in 2018, with about 44% US market and 24% Germany sales [42]. The industry is dominated by global players, so-called big pharma, due to high investments and high risks of failure in costly clinical trials [43].
Technical trends are transferred from traditional batches to continuous manufacturing [42], Green Chemistry [44] and biotechnological drugs. Societal needs for innovative medicines and sufficient supplies at moderate costs due to healthcare system limitations are accepted without discussion [45]. Recent studies perpetuating the belief that there is no need for improvement in such a small industry do not benefit the global situation and are wrong, for example:

•
Single-use plastic items are forbidden and reduced in daily life; in biotech manufacturing, however, they are booming due to single-use technology, advantages in cleaning efforts, personal resources and flexibility in various batches and products, as well as costs [46].

•
Other studies point out that the pharmaceutical industry is inefficient compared to automotive manufacturing [47]: "The total global emissions of the pharma sector amounts to about 52 megatonnes of CO 2 e in 2015, more than the 46.4 megatonnes of CO 2 e generated by the automotive sector in the same year. The value of the pharma market, however, is smaller than the automotive market. By our calculations, the pharma market is 28 percent smaller yet 13 percent more polluting than the automotive sector".
Biologics manufacturing is most often characterized by the monoclonal antibody (mAb) production platform process, as mAbs make up about 50% of all biologics. In many studies, the energy demand and environmental impact of biologics manufacturing have been evaluated by life cycle assessment; water for injection (WFI) has consistently been identified as a key factor [47][48][49][50][51][52][53][54]. While they are mostly used for chromatographic steps, typical product-specific volumes of cleaning-in-place (CIP) and sterilizing-in-place (SIP) are in the range of 4-20 m 3 WFI /kg mAb [48,50,[55][56][57][58]. Idris et al. showed that, for a large-scale 20 m 3 mAb process (titer 2 g/L), 1.9 m 3 WFI /kg mAb is used just for Protein A chromatography [50]. Overall process WFI usage accumulated to a total of about 4 m 3 WFI /kg mAb , so Protein A chromatography usage was about 47%, marking it, by far, the most GHG emission-intensive unit operation. In addition, the subsequent ion-exchange (IEX) and hydrophobic interaction chromatography (HIC) accumulates to a total of 3 m 3 WFI /kg mAb . However, in batch processes, the chromatographic steps can make up about 75% of the total WFI usage. Sinclair et al. also investigated the environmental impact of biologics manufacturing in detail with the example of mAb platform processes [47]. Again, Protein A chromatography had the biggest environmental footprint of all unit operations, though CIP/SIP (globally, across all unit operations) was the biggest contributor to GHG emissions and energy demand. When assessing all known studies in the literature, we found that the production of 1 kg mAb is estimated to cause between 3500 and 5000 kg of CO 2 eq, accompanied by a specific cumulative energy demand (CED) between 10 and 20 MWh/kg mAb . To put these numbers into perspective, we can look at the most common products made by the chemical industry. Table 1 summarizes the GWP and energy demands of different production methods for hydrogen, ammonia, urea, and methanol. Their emissions, as well as energy usage, are about 1000 times smaller compared to mAb production. Even if the economy of scale and larger quantities must be considered in this context, it cannot be denied that the pharma sector, especially in the case of biologics manufacturing, is in urgent need of improving its process efficiency, as every sector in Germany is obliged to contribute to the goal of climate neutrality. To evaluate the potential in reducing GHG emission and energy demand, the status quo needs to be assessed. Then, a test model can be developed, which must be validated in terms of its sensibility regarding the input of estimated data. Table 1. Emissions and energy demand of chemical products. Global warming potential (GWP) and energy demand (ED) are derived from electricity demand. The data source used to construct the table can be found in [14]. Abbreviations: water electrolysis (WE), methanol pyrolysis (MP), electrolysis hydrogen (EH), electrolysis hydrogen and carbon dioxide (EHC). With a return of EUR 4500 million just for biotech-dedicated enterprises and EUR 11,400 million for biopharmaceuticals in Germany (2018), biologics make up about 10-20% of the pharma market returns in Germany [59]; therefore, emissions related to biologics manufacturing in Germany can be estimated to be about 0.2-0.4 Mt CO 2 eq/a, while the energy demand can be estimated to be 0.6-1.2 TWh/a (based on data in Figure 2). Then, by considering the European and global pharma market share, 1-2 Mt CO 2 eq/a and 3-6 TWh/a in EU-28, respectively, 5-10 Mt CO 2 eq/a and 15-30 TWh/a can be extrapolated globally. Reverse calculating the GHG emissions of the total pharma sector globally by the initially introduced factor of five to 10 leads to 50-100 Mt CO 2 eq/a, which is in very good agreement with the reported data we discussed in the introduction [40,42].

Technical Project Results for Biologics
After assessing the status quo of biologics manufacturing in Germany and EU-28, it is important to extensively investigate the effect of uncertainty regarding key assumptions in order to analyze sensitivity. Process improvements in terms of yield and WFI strongly influence the footprint of biologics manufacturing. The studied range of process improvements as well as their assumed contribution to GWP and CED are summarized in Table 2. The rationale for the reference parameters as well as a comparison to reported data were already described in the sections above. Here, the rationale for choosing the range of process improvements and their contribution to impact categories are given. Table 2. Reference monoclonal antibody (mAb) process impact factors, possible process improvements and their effect on impact factors investigated in this study. Improvement factor (IF), global warming potential (GWP), cumulative energy demand (CED), water for injection (WFI). Process improvements, e.g., upstream titer, separation efficiency downstream, as well as by substituting a single or several standard unit operations by innovative technologies, such as aqueous two-phase extraction, have been shown extensively in the literature. The authors showed that process yields can be increased by at least 10-30%. By shifting from traditional fed-batch processing to a complete continuous process will remove most of the need for CIP/SIP, and in combination with more efficient buffer usage, will at least result in a decrease in WFI consumption in the range of 50-70%. Regarding the impact of WFI on GWP and CED, it has already been pointed out that this has been shown to be at least 50%, and considering that WFI is used in every process step, it can be safely assumed that it can contribute up to 90% of overall GWP and CED.

Range GWP (t/kg) CED (MWh/kg) IF yield (%) IF WFI (%) GWP WFI (%) CED WFI (%)
To have the best compatibility with the literature and reported data, we decided to assess the potential for GWP and energy reduction by using the mAb platform process as a representative model system as well. First, the status quo (2020) is compared as discussed above, with model predicted emissions. Model inputs are the range of reference GWP and CED as well as product titer (6 g/L), batch size (12 m 3 , 6 in parallel), overall process yield (60%), and the number of batches per year (40). The production size is not meant to represent the production of a single product, but rather to cover the biological production volume at a typical representative single-enterprise level. Impact categories from this single-enterprise level were therefore scaled with a factor of 10 to obtain the number of total biologics manufactured in Germany.
The project results for the technical solution are visualized in Figure 3. Improvements in terms of lower COGs by a factor of five to 10, combined with GWP reductions of two to five, were achieved.
Comparing this range to the calculated emissions and energy demand for the year 2020, as shown in Table 3, reveals a very good match for GWP and CED. As model prediction accuracy and precision is given, the development of environmental impact factors over time can be calculated.

Industrialization of Biologics
In Figure 4 (GWP) and Figure   Comparing this range to the calculated emissions and energy demand for the year 2020, as shown in Table 3, reveals a very good match for GWP and CED. As model prediction accuracy and precision is given, the development of environmental impact factors over time can be calculated.

Industrialization of Biologics
In Figure 4 (GWP) and Figure   Comparing this range to the calculated emissions and energy demand for the year 2020, as shown in Table 3, reveals a very good match for GWP and CED. As model prediction accuracy and precision is given, the development of environmental impact factors over time can be calculated.     To analyze the potential GWP and energy saving in biologics manufacturing, three scenarios are discussed, which cover the complete range of possible impact factors and process improvements. GHG emissions in the year 2020 were assessed to be at least 0.3 Mt CO2eq. When discussing the bestcase scenario, it is assumed, for the year 2030, that the goal of cutting down emissions by 50% (as stated in the Climate Change Act) will be reached, which will in fact only be possible if the biologics industry immediately starts to adapt to the presented technology potential. When considering 2030-2050 to be the industrialization period needed by the pharma sector to complete implementations, by the year 2050, biologicals manufacturing could cut down its GHG emissions by 74.4% (0.078 Mt CO2eq/a) compared to the reference year 2020. The cumulative reduction in GHG emissions from 2030 to 2050 in this scenario is 1.056 Mt CO2eq.
When considering what lies between the best-and worst-case scenarios, it is assumed that GHG emissions in 2030 will only be reduced by 25%, due to implementation at a slower pace. Only major improvements will find their way into the industry by the year 2050. Even so, the utilization will reduce GHG emissions by 52.4% compared to 2020. The cumulative emission reduction over the course of industrialization (2030 to 2050) is 0.773 Mt CO2eq.
In the worst-case scenario, we assume that no reduction in emissions will be achieved by the year 2030, which is given for the development shown in Figure 2, and is unfortunately very realistic. In this case, the industry will not have shifted to continuous production and has ignored technological innovations like alternative unit operations, process modeling to operate at optimal conditions, etc. Due to this delay in technology adaption, by the year 2050, biologics manufacturing's carbon footprint would only be reduced to about 9% compared to 2020. Therefore, the cumulative emission reduction over the course of 2030 to 2050 due to minor efficiency improvements is 0.412 Mt CO2eq.
The last scenario is unacceptable. Industry, as well as the government, need to promote the development and industrialization of process achievements, as shown in academia, if there is to be Energy Demand (TWh) Figure 5. Calculation of energy demand (lines) and reduction compared to 2020 (bars) for biologics manufacturing in Germany. Three process improvement scenarios are considered: red = worst case (low impact and slow industrialization); orange = realistic (impact as discussed, normal industrialization time) and green = best case (highest impact and fast industrialization).
To analyze the potential GWP and energy saving in biologics manufacturing, three scenarios are discussed, which cover the complete range of possible impact factors and process improvements. GHG emissions in the year 2020 were assessed to be at least 0.3 Mt CO 2 eq. When discussing the best-case scenario, it is assumed, for the year 2030, that the goal of cutting down emissions by 50% (as stated in the Climate Change Act) will be reached, which will in fact only be possible if the biologics industry immediately starts to adapt to the presented technology potential. When considering 2030-2050 to be the industrialization period needed by the pharma sector to complete implementations, by the year 2050, biologicals manufacturing could cut down its GHG emissions by 74.4% (0.078 Mt CO 2 eq/a) compared to the reference year 2020. The cumulative reduction in GHG emissions from 2030 to 2050 in this scenario is 1.056 Mt CO 2 eq. When considering what lies between the best-and worst-case scenarios, it is assumed that GHG emissions in 2030 will only be reduced by 25%, due to implementation at a slower pace. Only major improvements will find their way into the industry by the year 2050. Even so, the utilization will reduce GHG emissions by 52.4% compared to 2020. The cumulative emission reduction over the course of industrialization (2030 to 2050) is 0.773 Mt CO 2 eq.
In the worst-case scenario, we assume that no reduction in emissions will be achieved by the year 2030, which is given for the development shown in Figure 2, and is unfortunately very realistic. In this case, the industry will not have shifted to continuous production and has ignored technological innovations like alternative unit operations, process modeling to operate at optimal conditions, etc. Due to this delay in technology adaption, by the year 2050, biologics manufacturing's carbon footprint would only be reduced to about 9% compared to 2020. Therefore, the cumulative emission reduction over the course of 2030 to 2050 due to minor efficiency improvements is 0.412 Mt CO 2 eq. The last scenario is unacceptable. Industry, as well as the government, need to promote the development and industrialization of process achievements, as shown in academia, if there is to be any hope to fully achieve the Climate Change Act goals. Great progress has already been made in the chemical industry; now the pharma industry needs to catch up.
The roadmap for achieving climate-neutral biologics manufacturing is shown in Figure 6. Staring with the demonstration of proof-of-principle and then validation (EProMit 2012-2015 as well as TPTP from 2016-2019), the next necessary project phases prior to industrialization will be to present pilot studies for biologicals (Total Traceless Biologics Plant (TTBP)) as well as botanicals (Total Traceless Phyto Plant (T2P2)). chemical industry; now the pharma industry needs to catch up.
The roadmap for achieving climate-neutral biologics manufacturing is shown in Figure 6. Staring with the demonstration of proof-of-principle and then validation (EProMit 2012-2015 as well as TPTP from 2016-2019), the next necessary project phases prior to industrialization will be to present pilot studies for biologicals (Total Traceless Biologics Plant (TTBP)) as well as botanicals (Total Traceless Phyto Plant (T2P2)).

Overview and Current State of Botanicals
The annual global herbal medicine market is estimated to be EUR 130 billion with a share of 55% belonging to herbal pharmaceuticals. Japan and China share about 50% of the market. The annual growth rates are still about 5-7% due to the common trend in natural products [43,60]. Even so, about 5% of active pharmaceutical ingredients are natural and about 23% are of natural origin with synthetic modifications [61]. Germany has about 12,000 ha of medicinal plant cultivation areas, which need to be increased towards 20,000 ha as 80% of the country's raw material is imported with about 750 companies involved [62,63].
There are two scenarios for the reduction in CO2 emissions from plant material, either dried or fresh (Figure 7). Currently, dried plant parts are used for the extraction of plant ingredients. After harvesting, these parts are dried for storage up to a maximum residual moisture of 7%.

Overview and Current State of Botanicals
The annual global herbal medicine market is estimated to be EUR 130 billion with a share of 55% belonging to herbal pharmaceuticals. Japan and China share about 50% of the market. The annual growth rates are still about 5-7% due to the common trend in natural products [43,60]. Even so, about 5% of active pharmaceutical ingredients are natural and about 23% are of natural origin with synthetic modifications [61]. Germany has about 12,000 ha of medicinal plant cultivation areas, which need to be increased towards 20,000 ha as 80% of the country's raw material is imported with about 750 companies involved [62,63].
There are two scenarios for the reduction in CO 2 emissions from plant material, either dried or fresh ( Figure 7). Currently, dried plant parts are used for the extraction of plant ingredients. After harvesting, these parts are dried for storage up to a maximum residual moisture of 7%.
The supply chain for herbal raw materials has a major influence on the CO 2 footprint of the process, which must be balanced (Figure 8).

Technical Project Results for Botanicals
The comparison of cultivation and processing methods, which started immediately before extraction, reveals a large savings potential in the drying of the material (Figure 9). By using fresh, undried plant material, 90% of the GWP in carbon dioxide equivalents can be saved [67]. This approach is supported by the development of new business models and the technologies required to achieve them [68].
The industrial manufacturing processes of the extraction industry are strongly influenced by traditional recipes (pharmacopeia), which have a high potential for optimization, as can be seen in Figure 10. The optimization of the shown process results in a saving potential of 55% for the required solvent. It also shows that maceration, as a simple process with a dependence on diffusion, requires large quantities of solvent. The supply chain for herbal raw materials has a major influence on the CO2 footprint of the process, which must be balanced (Figure 8).

Technical Project Results for Botanicals
The comparison of cultivation and processing methods, which started immediately before extraction, reveals a large savings potential in the drying of the material (Figure 9).  The supply chain for herbal raw materials has a major influence on the CO2 footprint of the process, which must be balanced (Figure 8).

Technical Project Results for Botanicals
The comparison of cultivation and processing methods, which started immediately before extraction, reveals a large savings potential in the drying of the material (Figure 9). By using fresh, undried plant material, 90% of the GWP in carbon dioxide equivalents can be saved [67]. This approach is supported by the development of new business models and the technologies required to achieve them [68].
The industrial manufacturing processes of the extraction industry are strongly influenced by traditional recipes (pharmacopeia), which have a high potential for optimization, as can be seen in Figure 10. The optimization of the shown process results in a saving potential of 55% for the required For this reason, the comparison of different manufacturing technologies within the framework of process development is an important tool for increasing efficiency.
technologies required to achieve them [68].
The industrial manufacturing processes of the extraction industry are strongly influenced by traditional recipes (pharmacopeia), which have a high potential for optimization, as can be seen in Figure 10. The optimization of the shown process results in a saving potential of 55% for the required solvent. It also shows that maceration, as a simple process with a dependence on diffusion, requires large quantities of solvent. For this reason, the comparison of different manufacturing technologies within the framework of process development is an important tool for increasing efficiency.
The comparison of extraction processes shows a clear potential for significant improvements. The comparison of extraction processes shows a clear potential for significant improvements. The GWP of the analyzed process is 99%, caused by the cultivation (1 kg CO 2 eq/kg DM) and drying (7 kg CO 2 eq/kg DM) of the raw materials. As a direct consequence, every increase in yield reduces the total footprint of the process directly ( Figure 11). A change from traditional macerations towards exhaustive percolations increases yields by up to 80%, as has been proven in recent projects. The GWP of the analyzed process is 99%, caused by the cultivation (1 kg CO2eq/kg DM) and drying (7 kg CO2eq/kg DM) of the raw materials. As a direct consequence, every increase in yield reduces the total footprint of the process directly ( Figure 11). A change from traditional macerations towards exhaustive percolations increases yields by up to 80%, as has been proven in recent projects. Processing times that are multiple days long and solvent volumes ≥10 L per kilogram extracted from raw material are not uncommon and are part of traditional recipes. This process is defined as an industrial reference process and is compared to common approaches for optimization. The comparison of different extraction methods (Figure 12), i.e., percolation, maceration, PHWE or steam distillation, enables 30-80% higher yields in the extraction process [69]. Additionally, the correct choice of particle size and temperature allows for fast extractions, decreasing the required solvent drastically by a factor of two [70] (see Table 4). +50% Yield + 50% Yield -50% Solvent reference undried material GWP (t CO 2 eq/ kg dry extract*a) Figure 11. Impact of yield improvements on specific global warming potential (GWP) of extraction processes.
Processing times that are multiple days long and solvent volumes ≥10 L per kilogram extracted from raw material are not uncommon and are part of traditional recipes. This process is defined as an industrial reference process and is compared to common approaches for optimization. The comparison of different extraction methods (Figure 12), i.e., percolation, maceration, PHWE or steam distillation, enables 30-80% higher yields in the extraction process [69]. Additionally, the correct choice of particle size and temperature allows for fast extractions, decreasing the required solvent drastically by a factor of two [70] (see Table 4). Figure 11. Impact of yield improvements on specific global warming potential (GWP) of extraction processes.
Processing times that are multiple days long and solvent volumes ≥10 L per kilogram extracted from raw material are not uncommon and are part of traditional recipes. This process is defined as an industrial reference process and is compared to common approaches for optimization. The comparison of different extraction methods (Figure 12), i.e., percolation, maceration, PHWE or steam distillation, enables 30-80% higher yields in the extraction process [69]. Additionally, the correct choice of particle size and temperature allows for fast extractions, decreasing the required solvent drastically by a factor of two [70] (see Table 4).    Pressurized hot water extraction utilizes the properties of water up to 200 • C for rapid and exhaustive extractions [28,71]. This allows us to substitute ethanol or other organic solvents with water and energy. This concept can be optimized further by implementing energy integration strategies or low-cost water recovery, based on nanofiltration. In total, this enables an overall reduction of 70% in total specific CO 2 emissions, as can be seen in Figure 13. Pressurized hot water extraction utilizes the properties of water up to 200 °C for rapid and exhaustive extractions [28,71]. This allows us to substitute ethanol or other organic solvents with water and energy. This concept can be optimized further by implementing energy integration strategies or low-cost water recovery, based on nanofiltration. In total, this enables an overall reduction of 70% in total specific CO2 emissions, as can be seen in Figure 13. A further benefit is the possibility of the integration of PHWE into a low-carbon power grid. This pushes PHWE towards a 90% reduction in CO2 emissions.
The substitution of organic solvents with water has the added benefit of reducing the secondary emissions caused by solvent production (Figure 14).  A further benefit is the possibility of the integration of PHWE into a low-carbon power grid. This pushes PHWE towards a 90% reduction in CO 2 emissions.
The substitution of organic solvents with water has the added benefit of reducing the secondary emissions caused by solvent production (Figure 14). A further benefit is the possibility of the integration of PHWE into a low-carbon power grid. This pushes PHWE towards a 90% reduction in CO2 emissions.
The substitution of organic solvents with water has the added benefit of reducing the secondary emissions caused by solvent production (Figure 14). The project results for the technical solution are visualized in Figure 15. Improvements in terms of lower COGs by a factor of five to 10, combined with GWP reductions of three to five, and 70% of 1000 kWh/kg product/a could be achieved. The project results for the technical solution are visualized in Figure 15. Improvements in terms of lower COGs by a factor of five to 10, combined with GWP reductions of three to five, and 70% of 1000 kWh/kg product/a could be achieved.

Industrialization Potential of Botanicals
The roadmap towards climate neutral industry is shown in Figure 16 and discusses three scenarios towards climate neutrality for the German extraction industry of about 100 companies. The production of 150 t of dry extract results in 0.03 Mt CO2eq annually, which is caused by extraction.

Industrialization Potential of Botanicals
The roadmap towards climate neutral industry is shown in Figure 16 and discusses three scenarios towards climate neutrality for the German extraction industry of about 100 companies. The production of 150 t of dry extract results in 0.03 Mt CO 2 eq annually, which is caused by extraction. Figure 15. Botanicals global warming potential (GWP) vs. COGs portfolio.

Industrialization Potential of Botanicals
The roadmap towards climate neutral industry is shown in Figure 16 and discusses three scenarios towards climate neutrality for the German extraction industry of about 100 companies. The production of 150 t of dry extract results in 0.03 Mt CO2eq annually, which is caused by extraction. Figure 16. Calculation of GHG emissions (lines) and reduction compared to 2020 (bars) for botanicals manufacturing in Germany. Three process improvement scenarios are considered: red = worst case (low impact and slow industrialization); orange = realistic (impact as discussed, normal industrialization time) and green = best case (highest impact and fast industrialization).
If the available technical solutions are implemented immediately and successfully, the best-case scenario results in a total reduction in emissions of over 90%, which is equivalent to a total GWP  Figure 16. Calculation of GHG emissions (lines) and reduction compared to 2020 (bars) for botanicals manufacturing in Germany. Three process improvement scenarios are considered: red = worst case (low impact and slow industrialization); orange = realistic (impact as discussed, normal industrialization time) and green = best case (highest impact and fast industrialization).
If the available technical solutions are implemented immediately and successfully, the best-case scenario results in a total reduction in emissions of over 90%, which is equivalent to a total GWP reduction of 0.5 Mt CO 2 eq from 2030-2050. This scenario considers a 50% increase in yield and a total solvent reduction of 50% across the industry. Additionally, a high level of integration of renewable energy is considered, with 100 g CO 2 eq/kWh. A slow implementation, with a 30% increased yield and 30% reduced solvent consumption, can still reduce the total emissions by 66% in total.

Conclusions
This study points out the technical potential for energy and GWP reductions in biologics and botanicals manufacturing. The largest environmental impact can be attributed to WFI for CIP/SIP in the case of biologics manufacturing. The potential shift from batch to continuous production has the highest potential, as well as the adoption of process technologies that need less WFI and enable higher product yields. The political demand for climate-neutral manufacturing requires a reduction in GWP alongside increasing product amounts, combined with decreasing COGs, to be competitive in the world market. In addition, the necessary investments in innovative green technologies to be implemented in manufacturing operations must be made. The German industry is the fourth largest worldwide and needs to compete in the world market in order to provide employment for 5.6 million people and generate a turnover of about EUR two trillion.
The chemical-pharmaceutical industry is the largest in Germany, with about 500,000 employees and a EUR 200 billion turnover, accounting in 2019 for Chemical/Pharma GER: 30 Mt CO 2 eq und 163 TWh, Pharma GER: 3 Mt CO 2 eq und 16 TWh, Biologics GER: 0.3 Mt CO 2 eq and 1.6 TWh. VCI has pointed out that EUR 50 billion of additional investment and 650 TWh of additional green energy are needed to achieve climate-neutral status. Climate neutrality implies that all applications must contribute to achieve such a target.
The German industry has annual GWP of 188 Mt CO 2 eq with a 750 TWh energy demand. Biologics contribute about 1.1% to the annual industrial GWP, with a 0.5% contribution to turnover and 0.4% to employment. The share of botanicals is 0.007% of industrial GWP contribution, with 0.2% employment and 0.15% turnover contributions, leading to three times more efficient GWP manufacturing operations than biologics.
Botanicals and biologics are already sustainable because of their natural feedstock base. BMWi-funded projects on botanicals and biologics over the last 10 years prove the technical potential for any industrialization to become climate neutral. Technologies like milli-structured process intensification devices, the shift from batch operation to continuous operation and the substitution of organic solvents for water-based processing have been developed and have proven feasible in combination with process modeling based on the quality-by-design approaches demanded by regulatory authorities for autonomous processing, generating digital twins for advanced process control and analytical process technology for real-time release testing.
The last missing link for broad industrialization is any prototype operation in order to prove naturally conservative industry decisions in a strictly regulated environment the technical and economic feasible option for an innovative solution.