September 13, 2022 PAO-09-022-CL-01
To be truly successful, contract development and manufacturing organizations (CDMOs) must do more than provide the same services that pharmaceutical companies can implement on their own. It is not sufficient merely to be capable of transferring in CMC technology that is developed by pharma partners and implement it somewhere.
That is why the mission of Asymchem is preparation for vision. As a CDMO, we collaborate with our clients while simultaneously focusing on future needs, thereby collaborating for vision. We are driven to be the reliable partner of choice for the global pharmaceutical industry, providing superior service and solutions throughout the full drug life cycle from development to commercialization.
To achieve that vision, Asymchem applies new technologies, and, if a needed technology does not exist, we develop it. By taking this approach, Asymchem always remains in a position to solve problems for our customers, including problems that initially are not obvious or that anyone has yet begun to address. Our ongoing prophetic investment strategy ultimately makes it possible for Asymchem to provide solutions that help our clients bring their challenging compounds to market as quickly and cost-effectively as possible.
A technology-focused mission and vision cannot be realized without a strong culture of innovation and collaboration. At Asymchem, innovation is at the forefront of the company’s vision and is emphasized from the leadership downward throughout the entire company. This focus on innovation is readily apparent in the company’s guiding principles, financing practices, and everyday activities.
One reflection of Asymchem’s culture of innovation is our centers of excellence in various technologies, including biocatalysis, flow chemistry, and macromolecular development. These centers of excellence are at the cutting edge of the industry and are staffed by teams that are highly knowledgeable, have extensive industry experience, and are dedicated to innovation.
Some of the centers’ leaders may not be classically trained in the particular fields for which they are responsible but have experience in other areas of the company and bring new insights to these important fields that can catalyze the development of novel solutions.
This cross-pollination of experience and collaboration between the different centers is also encouraged by locating most of them near one another, in many cases on the same campus or within a short drive. Fostering an environment that facilitates cross-pollination of ideas while maintaining a focus on specific technology areas really helps spur innovation.
As a CDMO, Asymchem is in the business of solving problems. We see many different problems across a wider spectrum and seek solutions from all possible sources. While Asymchem primarily operates in the pharmaceutical space, we are always looking to other areas for new ideas. Doing so opens the possibility of solutions that may be commonplace elsewhere but less leveraged in the pharma industry.
With such a broad vision of the entire market, our experts are able to pull experiences and knowledge from one area and apply it to another more readily than biotech or pharma companies — and other CDMOs — that are very specialized in a particular modality or indication. That makes Asymchem unique in the CDMO world. Over the last 20 years, we have invested in many new technologies, such as flow chemistry and biotransformation.
Our CEO Dr. Hao Hong is a very passionate chemist with many great ideas and a major driving force and role model when it comes to innovation. He challenges all employees to make sure that they spend time considering new ideas. This type of culture is very important. It sets the foundation for how we work and who we work with and constantly pushes the company to develop really differentiating technologies that can help solve customer problems, both those that exist today and those that might develop in the future.
Biocatalysis has been a core area for Asymchem for nearly a decade. Our expertise in enzyme evolution enables the development of specialized enzymes optimized to perform highly specific chemical transformations. Supporting this expertise is our capability in fermentation, which makes it possible for Asymchem to produce these engineered enzymes cost-effectively at large scale.
What is unique about Asymchem is that these technologies do not operate as a standalone business that is operated in a vacuum, unlike companies that focus solely on providing designer enzymes. We integrate that biocatalytic step with many other chemistries to manufacture complex drug molecules. More importantly, biocatalytic and chemistry solutions are brought together under one roof in a seamless approach to process development and manufacturing.
Currently, Asymchem is expanding these core capabilities in biotransformation and fermentation to synthetic biology. While this investment is still in the early stages, there is real excitement within the company about the opportunities this move presents, because these tools can be applied to the production of many types of molecules using green processes.
Asymchem began investing in flow chemistry, particularly for ozonolysis to generate carbapenems, in the early 2000s, long before the rest of the industry, including other CDMOs, realized its true benefits. It became an important focus after the U.S. FDA issued a position paper advocating for advanced technologies in pharmaceutical manufacturing — one of which was flow chemistry — to bring down costs and ensure quality, among other reasons. With regulatory agencies pushing this new paradigm, it was clear that the pharma industry would ultimately move in that direction, and Asymchem intended to be at the head of that movement.
To that end, the company made multiple investments ahead of any specific business opportunities, many of which turned out to be prophetic in nature. The focus was primarily on implementation of flow chemistry on a large scale. While there are thousands of reports on flow chemistry coming out of academic labs, Asymchem is interested in leveraging the technology to produce materials that are best for human use at the clinical and commercial scale.
More recently, Asymchem has begun to focus on innovation around equipment design for flow chemistry. The company holds a number of patents in the areas of photochemistry, electrochemistry, and other chemistries that do not lend themselves well to traditional batch processing but fit well with flow paradigms. Our goal is to ultimately execute at least 30% of all manufacturing activities in flow mode, supporting the production of tons or even hundreds of tons of throughput in a year, including for molecules that would not be possible to produce at such large scales using batch technologies.
One of the key benefits of flow chemistry is that it allows the safe implementation of processes involving hazardous materials and/or that are highly energetic and as a consequence not really safe and green in a commercial manufacturing setting. Flow chemistry makes it possible to perform these reactions safely, because it essentially involves the continuous operation of very small-scale reactions within a higher degree of containment.
Examples of chemistries with rapid reaction kinetics that operate within the timeframes typical of flow processes include strong base-driven reactions, such as organometallic chemistry; high-energy reactions, such as nitrations; and reactions that must be run at cryogenic or very high temperatures. Flow chemistry has also been invaluable in overcoming challenges posed by the COVID-19 pandemic, because it has enabled rapid implementation of these types of solutions.
Of course, flow chemistry does not always provide advantages over batch processing, and as such Asymchem is pragmatic about its use. There are cases where flow mode affords advantages both for the upstream chemistry and the downstream purification. There are others where the chemistry is best performed in batch mode, but the post-reaction processing is more efficient in flow mode. Such downstream operations tend to be more uniform from one type of chemistry to another and include, for example, extractive workups and distillations.
An initiative is currently underway at Asymchem to expand the application of flow chemistry beyond the production of clinical trial materials to improve the safety of hazardous large-scale commercial processes. We are collaborating with pharmaceutical customers to design efficient flow solutions that allow the safe implementation of these processes in a manner that also reduces cost and increases manufacturing capacity.
Being a “green” company is important and can be challenging for CDMOs working simultaneously on many projects that involve synthetic organic chemistry. An additional advantage of both biocatalysis and flow chemistry is their greater sustainability compared with traditional chemocatalytic processes and batch operations. Much of the efforts at Asymchem in the area of flow chemistry are driven by a strong culture of sustainability and environmental compliance, because flow mode enables reduction of emissions and waste generation.
There are many requirements with respect to sustainability and environmental protection. Some come from customers; large pharma companies in particular conduct due diligence regarding vendor compliance with environment, health, safety, and sustainability expectations. Western regulatory bodies have their own expectations in these areas, as well as with respect to importation of intermediates, APIs, and drug products. Domestic Chinese requirements also exist, and in many cases are more stringent than those of both customers and Western regulatory authorities.
The result at Asymchem is a culture and history of compliance that meets and often exceeds the expectations of any one party, because the highest expectations of each are the minimum internal expectations. The company has also made many investments in technologies focused on improving sustainability, such as flow solutions for treating and recycling solvent waste and biocatalytic solutions for onsite bioremediation of wastewater. These investments help to not only protect Asymchem workers and the environment but also contribute to reduced operating costs and decreased risk.
Another key capability at Asymchem is highly potent drug substance manufacturing. While many CDMOs have added capacity for HPAPIs and highly potent drug product production, we are able to combine our strengths in fermentation and synthetic chemistry with our HPAPIs capabilities and apply them to the manufacture of antibody–drug conjugates (ADCs) and other modalities being investigated as targeted therapies.
ADCs comprise a monoclonal antibody (mAb) tethered to a small molecule cytotoxic molecule referred to as the payload or warhead. The antibody is designed to bind to a specific type of cell in the body — most often a tumor cell, but applications are expanding beyond oncology. Asymchem’s experience in small molecule chemistry and our mAb manufacturing expertise allow us to provide end-to-end support for ADC development and manufacturing. We are able to produce the antibody, the linker, and the small molecule payload, attach the linker and payload together, perform the conjugation step, and generate the final, formulated drug product.
Providing all of these services in one location is highly advantageous for pharmaceutical customers pursuing ADC projects. Rather than spend resources managing multiple CDMOs for the different ADC components and production steps, their efforts can be focused on further drug discovery. In addition, only one quality service agreement is needed to cover all aspects of an ADC project. Asymchem is currently working with several clients with ADCs in the clinic and are well positioned to support them as these candidates advance to later stages and hopefully commercialization.
The experience Asymchem has developed handling highly potent compounds has also been leveraged in the area of antibiotic intermediates and APIs. Many of the same containment technologies required when working with highly potent molecules must also be used when working with antibiotics. This transfer of expertise is a concrete example of how working across a broad number of modalities and technologies enables us to apply insights and learning from one area to another.
Photochemistry is another technology that often serves as a greener alternative to traditional synthetic organic chemistry. Asymchem has two fundamentally different types of photoreactors that can be brought to bear on synthetic problems, each of which typically work better for certain reactions. The exposure that Asymchem has to a broad range of problems from multiple customers gives us insight into which technology will provide the optimum solution for each new project.
Recently, the American Chemical Society recognized Asymchem with the inaugural CMO Excellence in Green Chemistry Award, which recognizes achievements in support of pharmaceutical research, development, and manufacturing that demonstrate compelling environmental, safety, and/or efficiency improvements. The award was earned specifically for a production-scale continuous [2 + 2] photocycloaddition reaction to prepare a key raw material.
To be most effective, partnerships must be based on mutual respect. A track record of accomplishments is an excellent foundation for establishing that respect. Asymchem highly values partnerships with pharma companies that acknowledge the company’s history of demonstrated achievements and seek our assistance because they believe we are ideally positioned to provide assistance and support.
Indeed, where appropriate, Asymchem is willing to co-invest in new technologies with clients that have highly specific needs and where it is anticipated that the new technologies will benefit many customers and research initiatives. This type of investment is particularly valuable when it comes to the different types of analytical instruments that can be leveraged for advanced analytical techniques. It is also common in formulation, for which it is necessary to build up an enabling technology to deliver a specific project. Often combinations of technologies are required in formulation projects, and expanding our capabilities is therefore always highly beneficial.
In addition to traditional partnerships with customers, Asymchem has also been involved in numerous nontraditional collaborations with academic groups and with other service providers. A number of papers have been published with academic partners in fields such as electrochemistry. This type of relationship allows both parties to mutually learn about how technology and the challenges inherent in its practical implementation for manufacturing.
A future focus on innovation and investment must be implemented within the context of customer development programs and the risks and budget they are comfortable working within. It is the responsibility of CDMOs like Asymchem to apply the entire breadth and background of their experiences toward identifying new technologies with the potential to meet future customer needs. In some cases, investments will be milestone-driven, but others reach further.
The key is to invest at the right point on the innovation S-curve: at the bottom of that first curve and not at the top when it can be too late to benefit. It is better from a business perspective to be too early than too late when it comes to investing in new technologies. It is always possible to invest in technology and wait for the business case to materialize after committing a certain level of investment. If investments are made too late, however, the money is generally wasted.
One recent investment at Asymchem was in mRNA. Capabilities in mRNA were built up soon after the emergence of the COVID-19 pandemic to enable the company to support early-stage development projects. A team was quickly formed to manage the buildout of mRNA technology, and several projects were underway within just six months.
Asymchem is currently exploring the potential advantages of moving away from solid phase synthesis toward the use of in-house developed liquid-phase synthesis for large chemical molecules, such as oligonucleotides.
Another area of interest is drug delivery. Many APIs today have limited solubility and bioavailability and require modulation and/or enhancement of their activity via the use of various excipients. The delivery of COVID-19 mRNA vaccines, for instance, is made possible through the formation of lipid nanoparticles (LNPs) by using cationic lipids. Asymchem has begun investing in developing and manufacturing various excipients, including not only lipid-based excipients but other types that are anticipated to have a significant impact on drug delivery going forward.
Dr. Hong has also organized several brainstorming sessions to identify technologies with potential future applications. The strategy at Asymchem is quite clear: technological investment is not solely driven by client projects and to meet customer needs but is much more proactive. New technologies are developed and applied, and the results are used to convince clients of their value — and to attract new customers as well.
Although the pharmaceutical industry is conservative by nature, innovation forms its foundation, and as the understanding of the human genome, human biology, and disease mechanisms advances, the pharmaceutical sciences evolve. To remain successful, therefore, it is essential for CDMOs to constantly educate themselves about relevant scientific and technological advances.
Asymchem is a learning company. Our scientists and researchers keep up to date through review of the literature and participation in industry conferences, initiatives, and consortia. Collaborations with academic groups and other innovators further contribute to our continual development. The knowledge we gain through these activities enables Asymchem to approach each problem with an open mind and ultimately to be an early technology adopter.
Authors: Mark McLaws, Ph.D., Vice President of Process Chemistry and CMC; James Gage, Ph.D., Chief Scientific Officer; and Stephen Hu, Ph.D., Chief Technical Officer and Chief Business Officer, Asymchem
Dr. McLaws obtained his Ph.D. from the University of Utah and has over 19 years of process chemistry experience in the pharmaceutical manufacturing industry. During his career, he has supported process development and manufacturing of clinical-phase and commercial small molecule APIs in a variety of therapeutic areas. At Asymchem, Dr. McLaws leads a team of technical experts to support CMC activities, with a particular focus on late-stage development, validation, and commercialization.