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Synthetic Chemistry in Pharma

This blog is part of an educational series about synthetic chemistry. If you missed our introductory primer, you can find it here. In this second installation of our synthetic chemistry series, we explore its critical role in small-molecule drug development, highlighting its importance in the drug development and discovery process, as well as its limitations.

Synthetic chemistry is an essential part of drug development, opening the door for scientists to create complex small molecules with specific properties. Small molecule drugs – including household staples like aspirin and acetaminophen – currently make up the bulk of approved pharmaceuticals to date. Though biologics and new modalities like cell and gene therapies are gaining ground with an increasing share of annual drug approvals, small-molecule drugs still remain in the majority.

Such small molecule drugs typically originate from chemical compounds produced in nature by plants or microorganisms. Once these compounds are identified as having potentially therapeutic properties, they can be rapidly modified using synthetic chemistry tools to produce an array of therapeutic candidates for screening in drug development.

Strength (and cost efficiency) in numbers

Synthetic chemistry plays important and distinct roles in every phase of drug development. Initially, synthetic chemistry is used to generate many drug candidates, either through a targeted synthesis of just a few compounds or, quite often in pharma, through a process called combinatorial chemistry, which yields a large number of compounds in a single process. When a lead compound is identified, the drug development team will rapidly produce a large variety of chemical derivatives on a small scale for screening, with a high-throughput combinatorial approach to assess their properties.

If small scale screening yields a compound with the desired therapeutic properties, the therapeutic candidate is chemically synthesized for pre-clinical and early-phase clinical testing, typically using a scaled-up version of the initial method. It is worth noting that 70% of the money invested in drug development goes into failed candidates, so there typically isn’t much investment in production optimization until the drug candidate has shown robust therapeutic potential in the clinic.

As the drug candidate progresses through clinical trials and toward commercialization, pharma organizations then begin looking at how to manufacture the therapeutic at commercial scale. It’s not as simple as multiplying the original, bench-scale method and optimization is key to ensuring a market-viable product. This is achieved by minimizing the number of chemical reaction steps involved, including costly chemical isolation and purification steps, as well as reducing waste and identifying the best starting materials.

Chemistry is constrained

Optimizing the critical steps of isolation and purification is no easy task. As any chemist will tell you, it is easy to add things to a flask – the hard part is getting a pure product out of it. Unfortunately, chemical reactions under laboratory conditions are not very specific because reagents interact with all of the molecules in the mixture, potentially reacting with more than just the one the chemist intends. Worse still, the number of byproducts multiplies exponentially with each step if not properly purified. The goal of process chemistry is to optimize the production of one molecular product and minimize the number of steps to get there.

For example, glucose is extremely complex to synthesize purely, despite being a simple sugar produced by plants. It has four stereocenters – points at which three atoms connect and can be arranged. Because chemical reactions cannot distinguish between the placement of atoms at these points, it results in a mixture of 16 different configurations of glucose.

Water-soluble compounds like glucose are also extremely difficult to purify. Common techniques of extracting chemical compounds into organic solvents simply don’t work and recrystallization of these products is quite difficult. More complex techniques like chromatography or lyophilisation are often needed to separate and isolate these types of compounds, but these are difficult to scale up and are prohibitively expensive.

Synthetic chemistry is naturally biased

Where synthetic chemistry struggles, biosynthesis excels. Water-soluble compounds are easily created in the aqueous environment of a living cell and stereochemically rich molecules like glucose are produced in the precise configuration required by biological systems to utilize effectively. The breadth of possibility in the natural world lays bare the limitations of synthetic chemistry.

The pharmacopeia of useful drugs mankind has identified so far is highly biased toward what we are good at making through synthetic chemistry. This is no surprise, as we use synthetic chemistry for both the initial preparation of drug candidates and their scaled-up production. Nature, however, complements our attempts at discovering and developing effective drugs. Scattered throughout the pharmacopeia, there are therapeutics we borrowed from the natural world like the antibiotic vancomycin-producing soil bacterium A. orientalis or essential pain medicines from the opium poppy.

These chemicals are not intuitive starting points for synthetic chemistry because they are big, complex molecules – we simply could not have found them by searching blindly. Thanks to synthetic biology, nature’s chemicals are now accessible as starting points where we can apply synthetic chemistry tools to create something entirely unique – such as the critical anti-cancer drugs Taxol and docetaxel that are used in chemotherapy treatments.

While there are many classes of molecules that are difficult to produce with traditional synthetic chemistry, the world of biology opens the possibility of new horizons in generating and manufacturing new (and old) therapeutic compounds. In our next blog, we look at how biology and chemistry come together to address these limitations of synthetic chemistry.

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.

Antheia Announces Continued Partnership with Olon

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