Enabling Client Success with Complementary Services Built upon a Strong Chemistry Foundation

Enabling Client Success with Complementary Services Built upon a Strong Chemistry Foundation

December 13, 2023PAO-12-23-CL-02

The most effective contract development and manufacturing organizations (CDMOs) help their clients by developing optimal, cost-efficient processes. Since its origins over 50 years ago, BIOVECTRA has operated on a foundation of synthetic organic chemistry expertise, initially focused on diagnostics but soon moving into the synthesis of small molecule pharmaceuticals. It has since expanded its capabilities to include fermentation to generate both small molecules and small proteins/peptides; production of linker molecules for bioconjugations and bioconjugation chemistry; end-to-end mRNA–LNP manufacturing, including the synthesis of proprietary lipids in a more sustainable fashion; and flow chemistry. All of these additional areas of expertise were made possible by BIOVECTRA’s strong foundation in synthetic chemistry, which continues to play a key role in enabling the company to offer reliable, efficient, and cost-effective development and manufacturing solutions across modalities to its clients today.

From Diagnostic Chemicals to CDMO Services

BIOVECTRA traces its origins back to 1970 when Regis Duffy, the Dean of Science at the University of Prince Edward Island, founded Diagnostic Chemicals Ltd. (DCL) in a makeshift lab to create summer job opportunities for students. DCL initially produced small molecules for diagnostic reagents and later expanded to offer contract development and manufacturing services for diagnostics and pharmaceuticals in 2000. In 2001, the bioscience division BioVectra DCL was established, focusing on microbial fermentation to produce small molecule active pharmaceutical ingredients (APIs). PEGylation chemistry expertise was developed, and fermentation capabilities expanded to include biologics production. The diagnostics division was sold to Genzyme in 2007, and the company renamed itself BioVectra Inc. In 2019, H.I.G. Capital acquired BioVectra, continuing investments and expansions.

Most notably, in 2021, an $80 million project was initiated to add capabilities in nucleic acid development and manufacturing, which, while representing a novel therapeutic modality for the company, will leverage BIOVECTRA’s decades of experience in fermentation and lipid manufacturing. We can produce plasmids via fermentation, use our biocatalysis expertise to manufacture mRNA, employ our synthetic chemistry capabilities to produce the lipids required for lipid nanoparticle (LNP) generation, and leverage our formulation expertise to produce final mRNA–LNP products. One truly new technology BIOVECTRA is acquiring for this integrated offering is fill/finish operations.

In essence, chemistry has always been the central anchor for BIOVECTRA and has enabled the company to expand into multiple spheres of activity, allowing it to continually build and grow throughout its history. As a result, BIOVECTRA has offered a unique combination of synthetic organic chemistry, fermentation of chemical and biologic molecules (including highly potent compounds), downstream processing, methoxy polyethylene glycol derivatives (mPEG) production, and conjugation chemistry services for more than four decades to small and large pharmaceutical, biotechnology, generic, and early-stage drug development companies.

In total, BIOVECTRA has submitted over 15 product filings, including Abbreviated New Drug Applications (ANDAs), Drug Master Files (DMFs), Veterinary Master Files (VMFs), and chemistry, manufacturing, and controls (CMC) section preparations for both the U.S. Food and Drug Administration and Health Canada. We support customers with challenging molecules, including cytotoxic active ingredients and APIs that must be semisynthesized from metabolites via highly challenging fermentations. Through strategic partnerships, the company has developed several generic products, including highly potent particulate injectable formulations and controlled-release drugs. BIOVECTRA also offers current Good Manufacturing Practice (cGMP) bioprocessing reagents, such as dithiothreitol (DTT) and tris-(2-carboxyethyl)phosphine hydrochloride (TCEP-HCI), and develops custom solutions for mPEG functionalization using proprietary, scalable chemistries.

Advantages of Combined Synthetic Chemistry and Fermentation Capabilities

The ability to synthesize complex small molecule APIs using synthetic organic chemistry and/or fermentation processes provides tremendous advantages for BIOVECTRA's clients. Many small and emerging biopharma companies at early stages of development have not yet established optimized manufacturing processes. The ability to explore both traditional chemistry and fermentation routes provides them the opportunity to truly identify the most cost-effective approach for obtaining the highest-quality material.

This combined expertise in fermentation and synthetic chemistry is unique in the contract manufacturing sector. Moreover, its benefits are not limited to clients requiring production of complex cytotoxic compounds. Customers also come to BIOVECTRA for manufacturing of bioconjugates, as we can provide end-to-end support, including fermentation of proteins, synthesis of mPEGs, and the chemistry enabling bioconjugation. As an example, one customer that used to rely on four separate service providers (one for each protein, one for mPEG synthesis, and one for bioconjugation) had its entire bioconjugate molecule manufactured at BIOVECTRA, dramatically simplifying the supply chain and thus reducing the time and cost required to produce the product.

In a similar manner, the company’s capabilities in fermentation and synthetic chemistry will benefit mRNA vaccine and therapeutic developers. BIOVECTRA can provide end-to-end support, with plasmid DNA, bioreagent (dithiothreitol and other expensive enzymes), mRNA, lipid, mRNA–LNP drug product, and fill/finish capabilities all provided under one roof.

Focus on Sustainability

The overall goal for any CDMO should be to develop the most efficient, optimized route for each client molecule. With its ability to offer synthetic chemistry methods that include both chemo- and biocatalytic reactions, as well as fermentation, BIOVECTRA offers more opportunities for achieving that goal. The company has also developed expertise in flow chemistry, a manufacturing approach that reduces resource consumption and by-product, waste, and emissions production, leading to more cost-effective production of higher-quality products.

Efforts focusing on reducing costs and complexity necessarily involve increasing the sustainability of drug manufacturing. Access to a wide range of production technologies and strategies also increases the ability to develop more sustainable solutions. Flow chemistry, batch chemocatalysis, biocatalysis, and fermentation will each be appropriate for some molecules but not for others. Having expertise in all of these technologies allows BIOVECTRA to develop the most sustainable process to produce each compound.

Lipid and LNP production present a prime example. Lipids are very large, greasy molecules that are challenging to purify and generally require numerous chromatography steps. Rapid development of production processes for proprietary cationic lipids during the COVID-19 pandemic often resulted in processes that used large quantities of hazardous materials, including chlorinated solvents. Leveraging our decades of expertise, BIOVECTRA has modernized these processes and now offers clients an improved manufacturing solution that generates highly pure products with minimal negative impacts on operator safety and the environment.

Highlighting Flow Chemistry

Flow chemistry is a truly enabling technology that offers the opportunity to produce products that are not possible to manufacture in batch mode. This includes reactions involving strong exotherms and hazardous reagents, such as reactive gases, for which storage and handling of large quantities is undesirable. It also allows for smaller manufacturing footprints and more efficient use of materials and often provides higher yields of purer products, reducing purification needs as well. In essence, flow chemistry enables reactions to be performed quickly in a small volume in a continuous fashion. This process intensification enables replication of the throughput of larger vessels over time.

BIOVECTRA is working toward a future where this mode of manufacturing is considered from the outset of every client project. The goal is to avoid the need to transfer batch processes into flow, which is an expensive endeavor that is particularly difficult to achieve in later development phases owing to restrictions on process changes. Flow chemistry also makes it possible to reshore some processes, such as fluorinations and reactions that involve nitro compounds, and to allow hazardous chemistry to be performed safely.

Another example of a reaction being explored at BIOVECTRA using flow chemistry that would not be possible in batch mode is hydrogenation. This process is fairly dangerous at large scale, as it involves large reactors under high hydrogen pressures. In flow mode, the process volumes are very small, and the reaction time is seconds or less, making it possible to safely reach pressures not possible on a large scale. Just as important, it is also possible to generate hydrogen via the cleavage of water molecules using electrolysis, which eliminates the need to store hydrogen. BIOVECTRA is evaluating a system that fits in a traditional lab fume hood and can provide the throughput of a large, two-story reactor.

This is also true for photochemistry, which is simply not practical at commercial scale due to the inability to achieve homogeneous exposure of large-scale, batch reaction mixtures to the light source. Radical photochemistry, in particular, is a process that opens many doors for the synthesis of complex small molecules. For instance, one client had struggled with a batch-based process that had the potential to produce a side product that can etch glass and involved significant off-gassing. Radical photochemistry in flow mode eliminates these issues, providing a much safer and higher-yielding process.

In addition to these applications, BIOVECTRA is exploring the use of flow chemistry in peptide synthesis. Traditionally, peptide synthesis has relied on solid-phase techniques, which, while effective, produce significant amounts of solvent waste. Flow chemistry presents an opportunity to revolutionize this area by minimizing solvent use and waste, further strengthening our commitment to environmentally conscious manufacturing practices.

Some of the efforts at BIOVECTRA involving the development of flow-based processes are occurring in partnership with Professor André Charette at the University of Montreal’s Flow Chemistry Centre. Professor Charette has extensive expertise in flow chemistry, and the Centre’s facilities have many different types of flow reactors that complement the equipment at BIOVECTRA.

The academic view of scientific problems is often very different from that in industry, and working with the Flow Chemistry Centre enables BIOVECTRA to gain access to that unique problem-solving approach and apply it to industry-relevant problems. We bring our academic colleagues a problem and, using their infrastructure and expertise, we together develop a solution and demonstrate the proof of concept. On the basis of those results, it is often possible to build a case for implementing the process at larger scale within BIOVECTRA.

One recent outcome of this collaboration was the conversion of a 50-year-old process for the production of dithiothreito (DTT), a key bioreagent, to a flow-based process that is much safer and greener. The results were published in Organic Process Research & Development in early 2023.

Academic/industry collaboration also helps BIOVECTRA build the next generation of chemists and retain this specialized expertise within Canada. In addition, it gives us exposure to the wider academic world.

Overall, we have found that the key to successful use of flow chemistry is the identification of molecules whose synthesis can benefit from the use of the technology and the development of solutions early on in the life cycle of a project. Fortunately, the issuance of regulatory guidance on flow chemistry several years ago and the continued extolling of the importance of continuous manufacturing by process chemists has led to much greater appreciation of the technology by clients in recent years.

The introduction of more process analytical technologies (PATs) and the continued evolution of inline analysis techniques for real-time, continuous monitoring is also having an impact on the adoption rate of flow chemistry. Appropriate PAT solutions have helped alleviate regulatory concerns by providing tools to assure that flow-based processes continuously perform in the expected manner.

A Natural Move into Lipids

BIOVECTRA's experience with mPEGs set the stage for a natural entry into lipid manufacturing. Like lipids, mPEGs have no chromophore and require highly specific analytical methods designed to overcome this limitation. One of the main solutions has been to use charged aerosol detection (CAD) in combination with high-performance liquid chromatography (HPLC).

BIOVECTRA has been developing these analytical tools since the early 2000s, and not exclusively for mPEGs. In 2012, we implemented a large-scale commercial process to make omega-3 oil for an API application using natural lipids for which we leveraged these analytical tools. We also developed extensive expertise in handling large, greasy lipidic molecules. Separately, many formulations developed by BIOVECTRA over the years have included liposomes, which further extended our capabilities with respect to lipid production and handling.

With 15 years of analytical experience and complementary expertise in process chemistry and formulation, BIOVECTRA was very well positioned to move into the lipid production space and make significant improvements with respect to process efficiency and sustainability. Because typical lipid purification processes require large amounts of silica compared with the amount of lipid produced, the gains were significant. For example, for just one of the lipids used to produce one of the COVID-19 vaccines, this equates to several metric tons of silica gel.

There are also opportunities to leverage flow chemistry for the production of proprietary cationic lipids, such as for reductive amination steps. The reaction in flow mode is cleaner, making the lipid easier to purify and eliminating the need for chromatography.

Unique Location and Culture
Atlantic Canada may seem like an unusual location for a world-class CDMO, but it presents many advantages. In addition to the coastal vibes and welcoming ambiance, BIOVECTRA has access to a large talent pool from local universities. Canada’s flexible immigration policies, meanwhile, make us attractive to highly skilled individuals from across the globe. In fact, approximately 40% of BIOVECTRA's personnel represent immigrant or minority cultural backgrounds, and that diversity helps drive real innovation within the company. Indeed, BIOVECTRA has purposely built young, diverse, and gender-balanced teams of individuals that appreciate both the local environment and the company culture and create a wonderful place to perform impactful science.
In addition, each and every employee is proud of the work that we have done and the fact that we impact patient lives in a Canadian province that has 150,000 people in it. One of the company’s core principles is caring, and this philosophy drives all other aspects of BIOVECTRA’s operations. That sense of community and commitment may not be tangible nor part of our equipment or capabilities but is readily apparent and makes a measurable difference.

The Power of a Culture of Innovation

BIOVECTRA stands at the forefront of biopharmaceutical innovation, bringing together unparalleled expertise, cutting-edge technologies, and a deep-seated commitment to improving patient lives. By continuously advancing in areas such as flow chemistry and lipid production and by fostering invaluable academic collaborations, the company is setting a new benchmark in sustainable and efficient pharmaceutical manufacturing. BIOVECTRA’s strong sense of community and diversity, rooted in its unique Atlantic Canadian locale, serves not just as an emblem of its ethos but also as a catalyst for ongoing innovation and optimization, underscoring the power of harmonizing technological prowess with a caring, community-driven spirit to drive the industry into the future.

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