Second Generation Process Research Articles

Breaking barriers, cultivating sustainability: Discovering the trifecta influence of digitalization, natural resources, and globalization on eco-innovations across 27 European nations

In recent years, the convergence of digitalization, natural resources, and globalization has profoundly influenced eco-innovations in European economies, emphasizing their significance in achieving sustainable development goals (SDGs). Additionally, digitalization enables smart infrastructure and facilitates a circular economy. Furthermore, natural resources provide prospects for transitioning to renewable energy and improving resource efficiency, while globalization connects European economies to global networks, endorsing the exchange of information and best practices. This study examines the influence of digitalization, natural resources, and globalization on eco-innovations for the 27 European Union (EU-27) nations from 1990 to 2021. The estimated outcomes reveal that digitalization substantially encourages eco-innovations. After confirming the issues of cross-sectional dependence and slope heterogeneity, this study adopts the second-generation process to estimate consistent and robust outcomes. The findings from the method of moment quantile regression (MMQR) show that digitalization significantly increases eco-innovations across all quantiles. Regarding natural resources, the findings explore the asymmetric relationship, indicating that an increase in natural resources raises the level of eco-innovations in the lower and lower-middle quantiles but decreases it in the upper quantiles. This signifies the inefficient use of natural resources in EU-27 nations. Additionally, the findings report that the globalization process significantly reduces the pace of eco-innovations. The interaction between natural resources and digitalization reveals that it increases eco-innovations at lower quantiles but reduces them at higher quantiles. As for the interaction between natural resources and globalization, the findings indicate a positive association with eco-innovations in the lower and lower-middle quantiles but a negative association in higher quantiles. Based on the estimated evidences, this study suggests some feasible policy inferences to drive eco-innovations, mitigate ecological impacts, and pave the way for a greener and more resilient future in EU-27 nations.

Scale-Up Synthesis of Site-Specific Antibody–Drug Conjugates Using AJICAP Second-Generation Technology

Chemical site-specific conjugation technology utilizing immunoglobulin-G (IgG) Fc-affinity reagents is a versatile and promising tool for producing next-generation antibody–drug conjugates (ADCs). Our research group recently reported a novel Fc-affinity peptide-mediated conjugation method, termed AJICAP second-generation. This technology, based on thioester chemistry, produces site-specific ADCs with low aggregation. Herein, we report further investigations into the AJICAP second-generation technology. By varying the parameters of the peptide conjugation step, it was found that this reaction is feasible under a wide range of reaction conditions. All synthetic intermediates of the AJICAP-ADCs were sufficiently stable, indicating that each synthetic step is a possible holding point in ADC manufacturing. The Lys248- and Lys288-conjugated ADCs were prepared on a gram-scale using two different Fc-affinity peptide reagents, employing a scale-down manufacturing approach involving tangential flow filtration. The overall product yield was >80%, and ultimately, 13.2 g of trastuzumab-Lys248-MMAE and 1.26 g of trastuzumab-Lys288-MMAE were obtained with target drug to antibody ratios (DARs). Moreover, ADCs were synthesized at various scales, and it was verified that the DAR and aggregation rates could be replicated consistently across different scales. The results strongly indicate that the AJICAP second-generation process is a robust and practical approach for the manufacture of ADCs.

Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling

A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the REACH regulation in two SNAr steps. We further established a safer and faster way to oxidize the sulfanyl to the sulfonyl intermediate by dosing H2O2 at higher temperatures, reducing accumulation while minimizing uncontrolled H2O2 decomposition. The reaction conditions for the Suzuki coupling and the second SNAr were modified to increase the selectivity in these two steps. A change in the solvent for the final crystallization allowed operation at higher concentrations and delivery of a highly pure active pharmaceutical ingredient (API). The new improved process reduced the process mass intensity by approximately 40% and was successfully used to produce 150 kg of GDC-0134.

Sustainable Biodiesel Production by Transesterification of Waste Cooking Oil and Recycling of Wastewater Rich in Glycerol as a Feed to Microalgae

The amount of solid and liquid organic waste and wastewater is continuously increasing all over the world. The necessity of their reuse and recycling is, therefore, becoming more and more pressing. Furthermore, the limited fossil fuel resources, in conjunction with the need to reduce greenhouse gas emissions, advocate the production of renewable fuels. In this work, we analyze a sustainable second-generation process to produce biodiesel by transesterification of waste cooking oil, coupled with a third-generation process in cascade for recycling the incoming wastewater. Since this latter is rich in glycerol, it is used as a feed for microalgae, from which oil can be extracted and added to the waste cooking oil to further produce biodiesel and close the cycle. We studied the influence of different factors like temperature, catalyst load, and reactants ratio on the kinetics of transesterification of the waste oil and estimated the kinetic parameters by different kinetic schemes. The obtained values of activation energies and pre-exponential factors at chosen conditions of T = 60 °C and catalyst load of 0.6% w/w in methanol are: Ea,direct = 35,661 J mol−1, Ea,reverse = 72,989 J mol−1, k0,direct = 9.7708 [dm3 mol−1]3 min−1, and k0,reverse = 24,810 [dm3 mol−1]3 min−1 for the global fourth-order reversible reaction scheme and Ea = 67,348 J mol−1 and k0 = 2.157 × 109 min−1 for the simplified pseudo-first-order irreversible reaction scheme; both in strong agreement with literature data. Furthermore, we designed very efficient conditions for discontinuous and continuous operating mode, both at lab-scale and pilot-scale. The quality of the biodiesel produced from waste cooking sunflower oil is compared with that of biodiesel produced by different kinds of virgin vegetable oils, showing that the former possesses acceptable quality standards (Cetane number = 48 and LHV = 36,600 kJ kg−1). Finally, the recycling of wastewater rich in glycerol as a nutrient for mixotrophic microalgae nurturing is discussed, and microalgae growing kinetics are evaluated (k1 about 0.5 day−1), endorsing the possibility of algae extraction each 4–5 days in a semi-continuous operating mode. The experimental results at the pilot scale finally confirm the quality of biodiesel, and the obtained yields for a two-stage process prove the competitiveness of this sustainable process on the global market.

Application of electric potential improves ethanol production from xylose by active sludge

BackgroundLow-cost raw materials such as lignocellulosic materials have been utilized in second-generation ethanol production process. However, the sequential and slow conversion of xylose into target products remains one of the main challenges for realizing efficient industrial lignocellulosic biorefinery.ResultsBy applying different constant potentials to different microbial electrolysis cells with xylose as the sole carbon source, we analyzed the output of metabolites, microbial community structures, electron flow, and carbon flow in the process of xylose electro-fermentation by domesticated activated sludge. The bioreactors produced currents when applying positive potentials. The peak currents of the + 0.242 V, + 0.542 V and + 0.842 V reactors were 0.96 × 10–6 A, 3.36 × 10–6 A and 6.43 × 10–6 A, respectively. The application of potentials promoted the xylose consumption, and the maximum consumption rate in the + 0.542 V reactor was 95.5%, which was 34.8 times that of the reactor without applied potential. The potential application also promoted the production of ethanol and acetate. The maximum ethanol yield (0.652 mol mol−1 xylose) was obtained in the + 0.842 V reactor. The maximum acetate concentration (1,874 µmol L−1) was observed in the + 0.842 V reactor. The optimal potential for ethanol production was + 0.842 V with the maximum ethanol yield and energy saving. The application of positive potential caused the microorganisms to carry out ethanol fermentation, and the application of negative potential forced the microorganisms to carry out acetic fermentation. The potential application changed the diversity and community structure of microorganisms in the reactors, and the two most significantly changed families were Paenibacillaceae and Bacillaceae.ConclusionThe constructed microbial electrolysis cells with different potentials obtained better production yield and selectivity compared with the reactor without applied potential. Our work provides strategies for the subsequent fermentation processes with different needs.

Multi-objective optimization of a 1G-2G biorefinery: A tool towards economic and environmental viability

First-generation sugarcane ethanol production is a well-established technology. However, second-generation ethanol is not yet consolidated in industries. Under these circumstances, this work presents a multi-objective optimization of this process focusing on economic and environmental objectives. The impact of the Brazilian decarbonization program on an integrated biorefinery is analyzed, considering a first-generation ethanol conventional autonomous distillery and a second-generation process with hydrothermal pre-treatment, enzymatic hydrolysis and fermentation of the xylose liquor. The economic metric was the Net Present Value and the environmental assessment was based on the plant inventory considering Global Warming Potential. A multi-objective particle swarm optimization algorithm was used, considering the ratio of bagasse diverted to the second-generation process, enzyme loading and solid fraction in the hydrolysis reactor as optimization variables. The carbon credit price was estimated for each point in the Pareto set in order to make the process economically feasible. As the main conclusions, there is a trade-off between economic and environmental targets, indicating that carbon credits may be essential for second-generation ethanol economic feasibility. The optimized integrated biorefinery is able to increase ethanol production by approximately 24% compared to first-generation biorefineries, but an increase in ethanol production higher than 13% would make the process economically unfeasible, while the decarbonization credits are not being commercialized. A price of $ 15.77 for decarbonization credits would make it possible to produce 20% more ethanol, keeping the integrated biorefinery economically feasible.

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process

The development of a sustainable commercial salt formation process for gefapixant citrate (MK-7264), an investigational new P2X3 antagonist for the treatment of chronic cough, is described. Due to the low solubility of the gefapixant free base, the first-generation process for citrate salt formation was a slurry-to-slurry process with poor quality control, wherein impurities were not well rejected and unreacted free base often persisted in the citrate produced. The development of a controlled crystallization from a homogeneous solution, which overcame these deficiencies, was complicated by solubility constraints and a daunting solid form landscape. Herein, we report a novel solution to this problem where the free base is transiently converted to a highly soluble glycolate salt enabling complete dissolution, from which direct crystallization of the final citrate salt occurs in a high yield through salt metathesis. Robust crystallization control was ensured by conducting a comprehensive polymorph screen on the glycolate salt and demonstrating its metastability compared to the desired citrate salt. In addition, process-relevant solvates of the citrate salt were discovered and derisked via a thorough understanding of their stability regions. With this information, a second-generation process salt formation with robust crystalline form and purity control was achieved, utilizing a salt metathesis co-feed process that greatly reduces the amount of solvent required, the overall manufacturing time, and the energy consumption compared to the first-generation conditions.

Abstract A05: Expansion of tumor-infiltrating lymphocytes (TIL) using Iovance's Gen 2 process from advanced bladder cancer for adoptive immunotherapy

Abstract Background: Patients with advanced bladder cancer have limited therapeutic options, apart from cisplatin-based chemotherapy and use of immune checkpoint inhibitors (ICI). Median survival for patients with metastatic disease is 15 to 18 months. Hence there is a need for more effective therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has demonstrated durable and complete responses with long-term survival of > 10 years in patients with metastatic melanoma. Previous attempts to generate TIL from bladder cancer showed some success; however, the process required an extended manufacturing time (35–50+ days). Iovance has developed a second-generation GMP manufacturing process (Gen 2) with a significantly reduced time to expand functional TIL from melanoma, cervical, and head and neck tumors. The goal of this study was to determine the feasibility of generating TIL from patient-derived bladder cancer tumor specimens using the 22-day Iovance Gen 2 manufacturing process. Methods: The TIL manufacturing process for the resected bladder tumor samples includes a pre-Rapid Expansion Protocol (pre-REP) and Rapid Expansion Protocol (REP) over 22 days. Pre-REP (1/10th scale) and REP (1/100th scale) was performed to align with the Iovance Gen 2 manufacturing process. During the pre-REP 1- to 3-mm size tumor fragments are placed in media containing IL-2 for 11 days. To further stimulate TIL growth, TIL are expanded using REP that includes irradiated PBMC feeders, IL-2, and anti-CD3 for 11 days. Release testing parameters (total viable cells, % viability, TIL phenotype) were tested on the harvested final product. TIL purity, differentiation, memory, activation, and exhaustion status were extensively characterized using multicolor flow cytometry. TIL functionality was determined by measuring IFNγ and Granzyme B release after restimulation. Results: Four bladder tumor samples were obtained from Roswell Park Comprehensive Cancer Center (RPCCC). Total viable count of REP TIL harvested on Day 22 was 18.4 +/- 8.9 × 109 (numbers adjusted to full scale), with 92.7 +/- 2.5% viability at harvest. The phenotype of harvested TIL were 92.4 +/- 4.8% CD3+/CD45+ cells, and non-T cell population including B cells and NK cells were < 4%. TIL expanded from bladder cancer samples secreted IFNγ and Granzyme B in response to anti-CD3/CD28/CD137 beads at similar levels to Iovance-manufactured melanoma TIL. Conclusions: All four bladder carcinoma-derived TIL have demonstrated growth, phenotype, and function comparable to that for other tumor types (i.e., melanoma, cervical, HNSCC). TIL generation from bladder cancer samples is feasible and allows for the application of Iovance's Gen 2 manufacturing process for an autologous cellular infusion product to treat bladder cancer patients. An early-phase trial testing autologous TIL therapy in transitional cell cancer of the urothelium is being planned. Citation Format: Qiang J. LI, Khurshid Guru, Amit Lugade, Elizabeth Brese, Kunle Odunsi, Anand Veerapathran, Kenneth Onimus, Adrian Wells, Cecile Chartier, Arvind Natarajan, Maria Fardis, Gurkamal Chatta. Expansion of tumor-infiltrating lymphocytes (TIL) using Iovance's Gen 2 process from advanced bladder cancer for adoptive immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A05.

Assessment of the self-sustained energy generation of an integrated first and second generation ethanol production from sugarcane through the characterization of the hydrolysis process residues

This paper compares the physico-chemical characterization of bagasse and sugarcane straw used for second-generation ethanol process and the waste produced in a pilot plant. The bagasse was obtained from conventional ethanol process. The cane straw was pruned in a hammer mill and also sent to the second-generation process. Analysis of the bagasse and the residue after hydrolysis indicated that about 64% of the cellulose and 95% of the hemicellulose in the sample was converted to sugars during hydrolysis. Much of the cellulose therefore remains in the final residue together with the lignin. Results for the available energy from the waste generated during the production of first- and second-generation ethanol indicate considerable potential for thermal power generation. For an integrated plant, with conventional ethanol production, second generation ethanol production and a cogeneration system burning sugarcane straw and process residues, energy self-sufficiency is achieved by using only 36% of the cane straw recovery from the field. In this case, 63 kWh is the surplus electricity generated per ton of cane processed.

Pilot Plant in Dunkirk for Demonstrating the DMX TM Process

The DMXTM process developed by IFP Energies nouvelles (IFPEN) and licensed by Axens is a second-generation CO2 capture process using a phase change solvent. Experimentation on mini-pilots and techno-economic evaluation carried out within the OCTAVIUS & VALORCO projects have confirmed its potential in terms of reduction of energy penalty and operational costs for capturing CO2 respectively on coal power-station flue gases and blast furnace gas. So, DMXTM process is very promising but it needs now to be demonstrated in an industrial scale pilot plant. ArcelorMittal, IFPEN and Axens are now considering this demonstration at the steel mill operated by ArcelorMittal in Dunkirk (France). Capacity considered is 0.5 tCO2 capture/h which is sufficient to upscale CO2 capture on all the gas emitted by a blast furnace. This paper will present the process study carried out to optimise the design of the pilot plant but also the evaluation study based on this design. First experimentation plan will be also presented and explained. It will include a parametric study on absorption and regeneration pressure but also long test runs on real steel mill gas. Planning of the demonstration and expected commercialisation will be also discussed.

Sustainable Production of Food and Bioenergy: Techno- economic and Environmental Assessment of Sugarcane Ethanol and Livestock Integration

Despite their advantages when replacing fossil fuels, biofuels have faced some concerns related to their expansion within the so-called “food vs. bioenergy” debate. This debate relies on the premise that the use of food crops and/or the increase of land use for bioenergy production would affect food availability and price. Nevertheless, it is worth to mention that livestock production is the largest anthropic use of land resources worldwide. In Brazil, livestock production mainly consists of extensive management with low technology level, which results in a low average productivity. The intensification of this system would release pasture areas to expand cropland for biofuels production. In this way, the integration of sugarcane ethanol and livestock production would allow taking advantage of the synergies between both systems; for instance, using sugarcane agroindustrial residues as animal feed ingredients in feedlot systems. In addition, ethanol production from lignocellulosic feedstock (second-generation process) is also a possible solution towards a productive land use, since a larger amount of biofuels can be produced per crop area. This work focuses on the sustainability assessment of a first- and second-generation (1G2G) ethanol facility that produces animal feed using sugarcane by-products integrated to livestock production in feedlots. The Virtual Sugarcane Biorefinery (VSB) – a computer framework that simulates the entire production chain and assesses the sustainability impacts of different biorefinery alternatives/routes – was used in this work. This paper indicates that the integration of a future 1G2G sugarcane mill with intensive livestock system may be a feasible alternative. Regarding the economic performance, verticalization of a mill with intensive livestock is preferable when compared to extensive cattle production. Integrated scenarios also have environmental advantages, such as the production of more outputs using the same area, as well as more efficient technologies that may represent lower emissions. In addition, this paper revealed that it is possible to sustainably produce biofuels without displacing food crops or livestock production, which otherwise could advance, for example, in forest areas.

Integrating Design of Experiments and Principal Component Analysis to Reduce Downstream Cost of Goods in Monoclonal Antibody Production

We present a framework to prioritize strategies for monoclonal antibody (mAb) second-generation process development, or post-approval optimization. Design of experiments (DoE), in conjunction with principal component analysis (PCA), were employed to identify process parameters that had the most impact on downstream purification cost of goods. Statistically significant parameters were identified through a DoE study, while the PCA characterization was applied as an independent tool to further elucidate the relative importance of these parameters. A stochastic approach incorporating process uncertainties was used to illustrate the distribution of downstream cost of goods under different process conditions. This framework offered insights on the relative contribution of each parameter to downstream cost of goods, and generated frequency distribution of the downstream cost of goods by incorporating process uncertainty. Such systematic approach to prioritize development strategies under compressed timelines could be useful for biopharmaceutical companies to achieve a competitive advantage.

Environmental impacts of technology learning curve for cellulosic ethanol in Brazil

This study presents a Life Cycle Assessment of second-generation ethanol production in Brazil considering current and future technologies to represent its technology evolution, compared to the first-generation process. With the start of the learning curve of the cellulosic ethanol production, improvements are expected on both biomass industrial conversion and agricultural production phases. Increased sugarcane yields and gradual introduction of more productive varieties, such as energy cane, are expected, affecting both first- and second-generation ethanol production processes. In environmental impact categories very relevant in the biofuel production debate, such as climate change, fossil depletion and agricultural land occupation, scenarios with second-generation process present lower impacts than first-generation process for the same time horizon. There is a trend of reduction of environmental impacts over time, reflecting the environmental advantages due to advances on the learning curve of second-generation ethanol technology and on biomass production system. The contribution of second-generation ethanol production will be extremely relevant to help Brazil to meet its targets in the international environmental agreements.

Techno-economic evaluation of integrated first- and second-generation ethanol production from grain and straw

BackgroundIntegration of first- and second-generation ethanol production can facilitate the introduction of second-generation lignocellulosic ethanol production. Consolidation of the second-generation with the first-generation process can potentially reduce the downstream processing cost for the second-generation process as well as providing the first-generation process with energy. This study presents novel experimental results from integrated first- and second-generation ethanol production from grain and wheat straw in a process development unit. The results were used in techno-economic evaluations to investigate the feasibility of the plant, in which the main co-products were distiller’s dried grains with solubles and biogas.ResultsAn overall glucose to ethanol yield, of 81 % of the theoretical, based on glucose available in the raw material, was achieved in the experiments. A positive net present value was found for all the base case scenarios and the minimal ethanol selling price varied between 0.45 and 0.53 EUR/L ethanol. The revenue increased with combined xylose and glucose fermentation and biogas upgrading to vehicle fuel quality. A decrease in the biogas yield from 80 to 60 % also largely affects the net present value. The energy efficiency for the energy content in products available for sale compared with the incoming energy content varied from 74 to 80 %.ConclusionsOne of the two main configurations can be chosen when designing an integrated first- and second-generation ethanol production plant from grain and straw: that producing biogas or that producing distiller’s dried grains with solubles from the xylose sugars. The choice depends mainly on the local market and prices for distiller’s dried grains with solubles and biogas, since the prices for both co-products have fluctuated a great deal in recent years. In the current study, however, distiller’s dried grains with solubles were found to be a more promising co-product than biogas, if the biogas was not upgraded to vehicle fuel quality. It was also concluded that additional experimental data from biogas production using first- and second-generation substrates are required to obtain improved economic evaluations.

Development of a Second-Generation Process to Antibacterial Candidate Sulopenem

The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with the first-generation synthesis were partially addressed in an improved second-generation synthesis of the target molecule where the penem ring is constructed via a modified Eschenmoser sulfide contraction sequence. Other highlights of the second-generation process include an improved synthesis of an important trithiocarbonate intermediate and a superior process for Pd-catalyzed deallylation of the penultimate ester to obtain low levels of residual palladium.

Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool

With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here explains how a biopharmaceutical process FMEA can be conducted. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. With the help of this guideline, different details of the manufacturing process can be ranked according to their potential risks, and this can help pharmaceutical companies to identify aspects with high potential risks and to react accordingly to improve the safety of medicines.

Second-Generation Process Research Towards Eletriptan: A Fischer Indole Approach

The development of a second-generation process for the synthesis of eletriptan via a Fischer indole cyclisation is described. The finalised process offers several potential advantages over the current route of manufacture including cost, throughput, and safety.

Second-Generation Process for the HCV Protease Inhibitor BILN 2061: A Greener Approach to Ru-Catalyzed Ring-Closing Metathesis

The ring-closing metathesis (RCM) step, a key reaction in our process to BILN 2061, was dramatically improved from the first-generation process by the selection of a more appropriate substrate as well as the use of a more effective catalyst. The two RCM reactions are compared in detail using criteria that are of high significance to the process chemist.

Recent Advances in Developing Chemoenzymatic Processes for Active Pharmaceutical Ingredients

Biocatalysis is becoming a transformational technology for chemical synthesis as a result of recent advances in large-scale DNA sequencing, structural biology, protein expression, high throughput screening, and enzyme evolution technologies. To truly impact chemical synthesis at the industrial scale, enzyme discovery, biocatalyst optimization, process design, and development must be integrated in order to deliver cost-effective and green chemistry solutions for drug manufacture. In this article, some recent applications of biocatalysis in developing chemoenzymatic processes were selected to illustrate the principle of this integrated approach. The emphasis will be directed to those examples where the chemoenzymatic route represents a second-generation process developed to replace the existing chemical one.

BIOETHANOL R&D

TWO NEW R&D AGREEMENTS have been signed between enzymes companies and ethanol producers, both with the goal of economically converting cellulose into fuel ethanol. One collaboration links Novozymes, the world's largest enzymes company, with Broin Companies, the largest dry-mill ethanol producer in the U.S. The agreement builds on an earlier R& D pact that yielded an amylase enzyme that Broin now uses to break down cornstarch in its BPX ethanol production process. BPX also will be the foundation for a second-generation process that produces ethanol from corn stalks and other cellulosic biomass, according to Broin GEO Jeffrey S. Broin. He says he's optimistic about our ability to continue developing the technology to make cellulose-to-ethanol conversion a reality in the next four to six years. The second agreement is between a smaller enzymes company, Dyadic, and Abengoa Bioenergy, a Spanish firm that calls itself the world's second-largest ethanol producer. Under the deal, Abengoa is buying $10 million ...