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Demystifying Synthetic Biology Part V: The Product is Key in Downstream Processing

Dive into DSP in the final edition of our Demystifying SynBio series. If you’re just joining us, be sure to catch up on parts I, II, III, and IV.

Upstream bioprocessing – better known in biomanufacturing as fermentation – is directly followed by downstream bioprocessing (DSP). Just as fermentation is all about maximizing the production of a target compound, DSP focuses on capturing and purifying as much as possible, as cost effectively as possible. Distillation is a well-known example of downstream processing whereby alcohol from industrial fermentation is concentrated and purified to make whisk(e)y, gin, and other beverages. The role of DSP in synthetic biology product manufacturing is critical for commercial viability as it ensures the product meets quality and market standards, setting it up for long term success. Thus, developing a DSP strategy is often the first port of call when embarking on a biomanufacturing venture to ensure the technology and infrastructure exists to capture and purify the compound of interest.

In this fifth and final installment of our Demystifying Synthetic Biology series, we explain why DSP should be introduced as early as possible in the product development process, and we look at the range of processing techniques for large-scale fermentations. We also share the considerations and concerns in processing synthetic biology products, how synthetic biology and chemistry can work together for difficult-to-engineer compounds, and insights on integrating synthetic biology-enabled compounds into commercial product pathways.

The critical role of downstream processing

The ability to separate and process compounds to specific yields and purity levels can make or break the commercial viability of a synthetic biology product. The DSP phase focuses on separating and purifying a compound of interest, often from a complex fermentation broth. This process must ensure that the level of purification is both a high enough yield for commercial viability and within specifications for its final application, whether that is formulation into a food, therapeutic, or substance for another manufacturing process.

A successful downstream process ideally starts before product development has even begun. Knowing the physical and chemical properties of a target compound and the anticipated fermentation methods allows the DSP team to predict how it can most effectively be purified and – critically – how much it will cost. Understanding this cost is important for determining the viability of a product and process.

Modeling and small scale data is crucial to estimating these costs. It is far too expensive to test and troubleshoot fermentation and DSP methods at a manufacturing scale of thousands of liters. Instead, we’ve developed methods to test at the benchtop scale and capture data on the compound and the fermentation broth. An expensive DSP cycle, or one that results in poor yields or quality, will ultimately result in a commercially non-viable product and wasted resources and time.

The philosophy of “Begin with the end process in mind” lies behind every successful DSP. Constant communication between the DSP team, the upstream fermentation team, and the strain engineering team is critical in implementing this philosophy and bringing a product to market. For example, the DSP team must know if any additional solvents have been added to the fermentation broth in the development phase – solvents such as DMSO may help fermentation broth ingredients dissolve in the culture media, but can also make product purification more difficult for the DSP team.

Once the downstream process is defined and demonstrated to work, it is deployed at the manufacturing scale. Refinements to the process are required frequently for cost-cutting and for adapting to changes in the fermentation process, such as different media components or even newly improved strains of the engineered organism. These changes are conducted at the benchtop scale prior to implementation in manufacturing.

Product is key in DSP

The chosen method of DSP depends largely on the target compound and how it is produced. During upstream fermentation, engineered organisms typically excrete the product extracellularly into the fermentation broth, which is composed of a complex mixture of off-target metabolites and media components.

The DSP strategy required to extract and purify the product is driven by the fundamental physical properties of the target compound itself. The separation process for extracellular products begins with separating the solid biomass from the liquid fermentation broth. Centrifugation separates the dense biomass from the culture supernatant containing the product – in other words, separates the solids from the liquids. This remains quite dilute in terms of volume-to-product, so the following step involves reducing the volume. This is where three fundamental properties of the product – size, solubility, and polarity – come into play.

Considerations for DSP of synbio products

Synthetic biology offers a fast, cost-effective route to a wide array of chemical and biological compounds. Like all technologies, synthetic biology has its own unique challenges and limitations that must be accounted for in DSP:

1. Compounds may not be fully excreted by the cell

In cases where the organism retains the target compound intracellularly, cell lysis – the breaking down or disruption of the cell membrane chemically or mechanically – may be necessary for the DSP. Cell lysis often complicates the process by adding more contaminants to the mix, making purification more difficult. Fortunately, synthetic biology allows for improved strain iterations, and researchers can also engineer solutions to improve product excretion and overall titer in the fermentation broth.

2. Compounds may be toxic to the production organism

In some cases, the target product may be toxic to the organism producing it. Bioprocessing solutions, such as overlaying the fermentation culture with an oil that absorbs the target compound, can mitigate the toxic effects but may significantly add to the cost of DSP depending on the methods required. Synthetic biologists may work around this by engineering an organism with an additional chemical group that blocks the toxic group on the target compound. An enzymatic or synthetic chemistry step can alter this group and convert the fermentation product into the desired final product during the downstream process.

3. Finding a clear, integrated to-customer route

A longstanding hurdle for synthetic biology products is integrating them into existing process engineering infrastructures. In the late 1990s and early 2000s, the algae biofuel boom fell apart when the complex downstream processing steps required to make these products usable for cars became so costly at scale – coinciding with a drop in oil prices at the time – that these products became economically non-viable. Ensuring that fermentation and downstream processes fit existing infrastructures helps clear a route to customer application, making synthetic biology-designed products commercially achievable and feasible. This is exemplified by Amyris’ squalane and Genomatica’s nylon building block, hexamethylenediamine, both produced via fermentation.

Synthetic biology demystified

Synthetic biology – building with the power of biology – is not a new idea. The misconception and myth that the technology cannot scale are perhaps the most commonly misunderstood things about synthetic biology. Throughout this blog series, we have demonstrated that synthetic biology is like any other field of science – built on the shoulders of giants – in what is simply the next iteration of the field of biology. The field combines a rational, engineering approach to research and product development with refinements on decades-old molecular biology tools (as well as more recent ones). These tools are further enabled by modern technologies like automation, software, and computational biology to rapidly scale experimental design and execution in R&D.

Successful synthetic biology products on the market today rely on integrating into the existing infrastructure of upstream fermentation bioprocesses and downstream purification processes. These products – present in industries as diverse as fuel, food, pharmaceuticals, cosmetics, textiles, and more – are no longer a whispered myth among researchers or a hyped-up presentation at industry conferences.

Synthetic biology is here now. The field is advancing steadily, delivering on its potential to develop effective, sustainable, and economical bio-based alternatives for essential chemical and biological compounds.

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Richard Sherwin

Head of Commercialization

Richard is an industry veteran with more than 30 years of experience in the KSM, API, and intermediate markets. He is responsible for leading the commercialization and revenue generation for Antheia’s robust pipeline of products. Richard brings an exceptional track record of leading international sales teams, driving revenue growth, building strategic partnerships, and delivering innovative products to market, including ANDA and NDA developments. Richard led commercial efforts at some of the leading global pharmaceutical companies and most recently, built his own consultancy business advising a range of clients, including $1B divisions of major multinationals.

Appropriate regulatory submissions will be prepared and submitted to support Antheia’s customers who need to reference and access necessary process-related information.

Yihui Zhu, PhD

Head of Fermentation

Yihui leads the fermentation team at Antheia. With over 25 years of hands-on experience in the field, he brings in-depth knowledge and expertise in microbial metabolism and fermentation process development. He is also skilled in developing comprehensive fermentation data collection, analysis, and visualization systems. Prior to joining Antheia, he served as a fermentation lead at Intrexon and Codexis where he successfully built fermentation labs and teams and led multiple biofuel and biochemical projects to reach stretch milestones and tech transfer. Yihui is passionate about the potential of fermentation and is dedicated to advancing the field through innovative research and development.

Yen-Hsiang Wang, PhD

Head of Strategy, Partnerships, and Finance

Yen-Hsiang leads strategy, partnerships and finance at Antheia. He completed his M.S. and Ph.D. in Bioengineering at Stanford, with extensive research experience in synthetic biology, metabolic engineering and computational modeling. Before joining Antheia, he worked at McKinsey and Tencent with a strong focus in corporate strategy and big data/advanced analytics. At Tencent, he served as Director of Strategy and Business Development for the AI Lab, leading corporate initiatives in healthcare AI/ML applications and commercialization. He also served in AI4H (Artificial Intelligence for Health), a collaboration between WHO and ITU, to establish global standards for AI in healthcare.

Audrey Wang

Head of Financial Planning and Analysis

Audrey leads financial planning and analysis at Antheia. With an MBA from Washington University in St. Louis, Audrey is passionate about leveraging financial analysis, digital technology, and data analytics to guide companies in making optimal investments and strategic business decisions. Audrey has a decade of experience in helping companies solve unique problems and creating long-term impact with unconventional approaches. Before joining Antheia, she was at Vir Biotechnology and Merck where she led various FP&A workstreams, including investment valuation, asset prioritization, and manufacturing sites operation finance support. Audrey completed CFA Level II and passed the U.S. CPA exam in 2011.

Antonij Tjahjadi, CPA

Head of Accounting

Antonij Tjahjadi leads accounting at Antheia and holds active CPA license. He joined Antheia with more than 20 years of experience in corporate accounting, bringing deep expertise in ramping up accounting operations for start-up companies, SEC reporting/technical accounting, and SOX implementation efforts. Before joining Antheia, he held various leading roles in both public and private company settings, including directing accounting functions at Ambys Medicines, where he successfully implemented Netsuite with Point Purchasing integration and set up various accounting policies and processes, and played a key role in the initial public offering of Nutanix, Inc.

Ken Takeoka

Head of Biology

Ken leads the Biology team at Antheia, which incorporates both strain and protein engineering functions. He has more than 16 years of experience in the synthetic biology field, working with leading companies, including Amyris and Novartis. One of his passions is molecular biology tool development and he previously worked to build the foundation for the automated strain engineering pipeline at Amyris. At Novartis, he modernized the molecular biology techniques and established a platform to model mechanisms of antibiotic resistance in a range of organisms.

Suzanne Sato

Head of Downstream Processing

Suzy leads downstream chemistry processes at Antheia. She has 19 years of experience in process development, including route development through synthetic chemistry and scale-up of small molecule APIs for GPCR targets under cGMP for Phase I-III trials. Before joining Antheia, Suzy led a full DSP team at Amyris where she successfully pivoted developments from biofuels hydrocarbon products to pharmaceutical intermediate, flavor, fragrance and nutraceutical products. She led a team that scaled 11 products and took five products to commercial manufacturing.

Farrah Pulce, PMP

Head of Project Management

Farrah leads program and project management at Antheia. She has over 20 years of experience leading program and project management, operations, and engineering for companies across the CPG, aerospace, and automotive industries. Prior to joining Antheia, Farrah implemented and led the sustaining program management team at Impossible Foods. She also led product operations, project management, and cost optimization at Blue Bottle Coffee and Tyson Foods to develop and commercialize new products. As a certified project management professional (PMP), Farrah has a proven record of successful project delivery, improving project management practices, and building collaborative teams.

Jordyn Lee

Head of Communications

Jordyn leads communications and external affairs at Antheia. She brings a decade of multidisciplinary communications experience in helping companies make complex science and technology accessible to broad audiences, all while maintaining technical accuracy and integrity. She has a passion for visionary storytelling and translating impact across the entire communications ecosystem – her work has spanned from public relations to corporate communications to marketing. Jordyn has served as an advisor to a number of different life sciences companies and most recently led corporate communications at Amyris.

Ben Kotopka, PhD

Head of Data Science

As Head of Data Science at Antheia, Ben manages in-house software development and external partnerships for storing and interpreting research data, executing bioinformatics analyses, and streamlining business processes. Prior to Antheia, Ben worked as an academic researcher at the intersection of machine learning, bioinformatics, and synthetic biology. Following this, as an entrepreneur and consultant, he developed and deployed data science solutions for biotechnology applications ranging from metabolomics-driven compound discovery to MRI segmentation.

Guerin Kob

Head of Supply Chain

Guerin is responsible for leading the design, development, management and improvement of Antheia’s end-to-end global supply chain. He has over 15 years of experience leading high-performing supply chain and procurement teams at leading biotechnology and specialty chemical companies, with extensive experience in process development and end-to-end supply chain optimization. Prior to joining Antheia, Guerin served as Senior Director of Global Supply Chain for Sumitomo Chemical’s biotechnology division with Valent Biosciences, where he led the end-to end supply chain including procurement, logistics and distribution, integrated business planning, materials management, customer service, and supply planning functions globally.

Pavel Aronov, PhD

Head of Bioanalytics

Pavel leads the Bioanalytics team at Antheia. He has 20 years of experience in analytical and clinical chemistry, mass spectrometry, chromatography, and metabolomics. Pavel built and led the original Chemistry and Analytics team at Impossible Foods enabling strain development, fermentation, DSP, regulatory, QC, and scale-up of leghemoglobin biomanufacturing. During his academic career at UC Davis and Stanford University Pavel developed a vitamin D assay used by all major clinical diagnostics laboratories and pioneered metabolomics studies to investigate kidney disease and microbiome.

Jesse Ahrendt

Head of Quality Assurance and Regulatory Affairs

Jesse has more than 25 years of experience in regulatory affairs, quality systems, manufacturing quality, and regulated industries, ranging from early- to late-stage pharmaceuticals, biomanufacturing, consumer care, and medical devices. He has supported global product launches and the underlying quality supply chain components in industries that require strict adherence to internationally accepted quality standards. Before Antheia, he led quality efforts at Zymergen and Sandoz, and supported many global pharmaceutical companies during his time in Biotech Consulting at NSF International, all to bring quality to the forefront in manufacturing, standardize global processes, and support customer regulatory requirements.

Heidi Pucel

Chief People Officer

Heidi is a results-driven human resources executive and HR business partner who leverages decades of experience in empowering, motivating, and inspiring to drive transformation within high-performing and rapidly-growing workforces. A certified executive coach and passionate advocate for people-oriented solutions, Pucel serves as a partner to executive teams to design programs that support employee development, engagement, and recruitment and retention. Pucel most recently served as Chief People Officer for Countsy, where she worked as an interim HR executive for clients in the biotechnology and software industries, such as Ceribell and Tune Therapeutics.

Zack McGahey

Chief Operating Officer

Zack is a leading executive in operations management, specializing in bioprocess engineering and manufacturing management. He has over 20 years of experience leading manufacturing functions for companies across the pharmaceutical, synthetic biology, diagnostics, and automotive industries. Before joining Antheia, Zack was VP of manufacturing and capex project management at Zymergen. He also gained experience managing commercial scale facilities operations for Tesla, where he was responsible for managing 10 million square feet of factory, lab and warehouse space during the Model 3 ramp.

Kristy Hawkins, PhD

Co-Founder & CSO

Kristy has over 20 years of experience in the field of synthetic biology, focusing on yeast metabolic engineering for the production of small molecules. She did the founding work on the benzylisoquinoline alkaloid pathway during her graduate studies and gained valuable industry experience at Amyris and Lygos. Kristy is an expert in tool development, high-throughput screening, and host strain and heterologous pathway engineering.

Christina Smolke, PhD

Co-Founder & CEO

Christina is a pioneer in synthetic biology and metabolic engineering, where she has over 20 years of experience. As Professor of Bioengineering and Chemical Engineering at Stanford University, her laboratory led the breakthrough research to engineer baker’s yeast to produce some of the most complex and valuable medicines known. Under her leadership, Antheia’s synthetic biology platform enables new possibilities for drug discovery and efficient, sustainable, transparent, and on-demand drug manufacturing at scale. Her vision and accomplishments have garnered numerous awards, including the Chan-Zuckerberg Biohub Investigator, NIH Director’s Pioneer Award, Nature’s 10, Novozymes Award for Excellence in Biochemical Engineering, and TR35 Award.

U.S. Secretary of State Antony J. Blinken visits Antheia to discuss biotechnology innovation

Appropriate regulatory submissions will be prepared and submitted to support Antheia’s customers who need to reference and access necessary process-related information.