Category: API / Intermediates

The key to successful development of safe, efficient, and cost-effective active pharmaceutical ingredient (API) production-scale processes is the application of smart chemistry and process development principles that include convergent strategies, telescoping, and open-mindedness. Over the last 40 years, FAREVA Excella has perfected this approach and is an ideal partner for pharma companies looking for a service provider that can boost productivity and reduce costs through the development of safe, reliable, robust, and efficient synthetic routes that can be practically implemented at commercial scale. 

What Makes a Good Process? 

Any commercial chemical manufacturing process must meet a number of specific criteria in order to be considered appropriate and effective. The first requirement is safety, which includes minimum use and accumulation of hazardous reagents and control of exotherms and gas evolutions. Good processes are robust and reproducible, repeatedly and reliably delivering high-quality product in an expected time cycle while operating within readily obtainable parameter ranges (e.g., temperature, pH, and starting material purity) within the optimum design space. Any intermediate (whether isolated or not) generated during the process must be stable over extended periods of time in solvent wet or dry stages and at elevated temperatures (risk assessment) with known holding points. 

All of these features are of no value if a commercial process is not economically feasible. That requires avoidance of costly reagents, highly diluted reactions or crystallizations, and extreme conditions, as well as minimization of waste generation. Convergent rather than linear synthetic strategies are also critical to minimizing the number of individual steps in an overall process and thus the cost. Convergent synthesis also reduces the risk of failure and enables the parallel synthesis of intermediates, thus decreasing production timelines. 

Overall, good commercial chemical manufacturing processes are as simple as possible, requiring the fewest steps and relying on fundamental chemistry and minimal equipment use without impacting robustness or introducing any problematic steps. As a result, they are cost-effective and bring about shortened production times. 

Choosing the Right Solvents and Reagents 

The best commercial chemical manufacturing processes are based on readily obtainable grades of solvents and reagents selected after developing a full understanding of the quality and physical properties of each. Recommended solvents include ketones, esters, alcohols, toluene, and acetonitrile, and all should be used in such a way as to meet local authority limits and requirements. Chlorinated solvents, mixed solvent systems, alkanes, ethers, and low and high boilers should be avoided where possible.

In addition, the number of solvents used throughout multistep processes should be minimized. If the same solvents can be used for sequential steps, isolating the intermediates may not be necessary. This telescoping approach can dramatically reduce the overall time required to complete multi-step processes. It also helps to avoid filter-dryer bottlenecks for solid intermediates and handling issues with low-melting intermediates. However, as no purification is performed while telescoping, it is essential to understand the composition of the intermediate solutions and the impacts any impurity may have on downstream reactions and their associated workup and isolation requirements.

Finally, combinations of solvents known to co-elute during residual solvent analysis via gas chromatography (e.g., methanol/isopropyl acetate, methanol/methyl ethyl ketone (MEK), for methods used by FAREVA Excella) should be avoided.

Following these recommendations enables the development of more efficient and cost-effective processes with lower costs of goods and faster time to market.

The automated 4-reactor SYSTAG FlexiLab is an ideal tool for parallel synthesis and DoE studies to determine the design space of chemical reactions.

Efficient Reactions 

Several factors can increase or reduce the efficiency of chemical reactions implemented on the commercial scale. Primary among them is control throughout the duration of the process, including during the addition of different reagents. It is preferable to charge the reactor with any solids first, then solvents, with liquids (neat or solutions) added last. Reactive reagents and intermediates should be added in a manner that prevents their accumulation and the occurrence of exotherms or off-gassing. Ideally, reactive solids are added in solution, and solids addition should be avoided at elevated temperatures.

Efficiency is gained by running reactions at the highest concentrations possible to facilitate productivity but without impacting safety (heat sink) and robustness. Volumes should be considered in light of the plant design and available equipment and with the goal of avoiding large volume swings. Catalytic reactions are also more efficient than those that require complete use of stoichiometric (or excess) reagents. As an example, the Friedel–Crafts reaction typically requires the use of more than stoichiometric quantities of Lewis acid, but, in some cases, it is possible to select starting materials that do not form complexes with Lewis acids, allowing for the use of much lower quantities. Leveraging this kind of experience — which can be applicable to many types of reactions — in the design of new processes can lead to significant efficiency gains. If the reagent in question is expensive, it can also lead to dramatically lower costs.

It is also worth noting that heterogeneous reactions, which may involve two immiscible liquid phases or a liquid and solid phase, can suffer from robustness and scale-up issues. It is essential to understand the nature of these heterogeneous reactions and the potential impact of changes in reactor geometry and scale effects on mass transport and mixing when moving from lab to pilot and production scales. Undesired side reactions, insufficient conversion of starting materials, and inseparable phases during the workup are examples of issues that may arise if appropriate reaction conditions at scale are not established.

There are also opportunities to increase efficiency at the workup stage. Minimizing the number of washes can reduce waste volumes and disposal costs. Selection of the most effective extraction solvents can help achieve this goal, as well as to reduce workup times. Where possible, it is preferable to avoid the need for pH adjustments, but if they are required, it is best to establish a practical target range based on an understanding of the pH profile curve and have a recovery procedure in place if the pH is overshot. Avoiding the need for solvent replacements also aids in efficiency, but, if necessary, distillation under vacuum is preferred. The reuse of any distillates should always be considered.

Isolation processes can also impact efficiency. For intermediates, avoiding isolation is optimal, as discussed above. For any product, only the minimum number of steps necessary to achieve the desired level of purification should be employed, and various processes should be evaluated to determine the most efficient and effective solution. Aqueous precipitations, which can lead to oiling out, impurity entrapment, and poor solid filtration, are best avoided if possible. Filtrations below ambient temperature are more complex and should therefore only be pursued if there is no other option.

Smart Chemistry for APIs at FAREVA 

The overall approach for API production at FAREVA Excella is based on smart chemistry. Efficient synthesis routes are designed in-house, taking into consideration the various factors outlined above. We use registered starting materials, solvents and reagents and ensure that the optimum process for commercial-scale production is moved to the plant, eliminating the need to develop second- or third-generation processes. Reactions are run at the highest possible concentration (neat when appropriate) and optimized to provide high yields for all steps in the shortest possible cycle times (by running reactions under pressure when applicable) and avoid intermediate drying.

These processes yield high-quality products, typically with < 0.1% total impurities, while being environmentally compatible due to the optimization of raw material usage, minimization of waste generation, and avoidance of dangerous and expensive reagents. 

The SYSTAG CaloCalc 2000 is used for calorimetric studies and automated synthesis,
enabling the safe scale-up of exothermic reactions

Innovative Approaches to Process Development 

At FAREVA, our goal is to develop economical, independent, tailored, and unique synthetic routes fitting to our facility and equipment. We prefer a convergent synthetic approach combined with the use of one-pot reactions and telescoping of processes. This strategy has evolved over the 40 years FAREVA Excella has been active in process development, including the production of more than 90 molecules from a wide range of structural classes.

Key to this approach is ignoring established doctrines that hamper progress. In the laboratory, all options are considered, with the exception of dangerous and hazardous reactions, regardless of what the traditional viewpoints are concerning the particular transformations involved. While in most cases the known rules apply, we have on several occasions identified exceptions that have enabled more efficient, economical approaches. 

The Value of Innovative Process Development 

In one example, FAREVA Excella was able to improve the overall volume yield of a lab-scale, multi-step synthetic route for an API from 13% to 35–41%. The process involved a total of 21 chemical operations, but — through the use of convergent synthesis and telescoping — just seven isolated intermediates. The most important improvements in the process were achieved in steps 6 and 7, for which the chemical yields were increased from 66% to 91% and 53% to ~90%, respectively. This increase provided significant value, because the lower yields for these last steps led to a significant loss of expensive material manufactured in the preceding steps.

Overall, the volume yield was increased by a little more than a factor of three. The advances were made possible by leveraging knowledge and experience gained from other projects. As a result, issues that occurred during scale-up were addressed right away, making it possible to run the process at commercial scale (currently 4,000 liters).

Applying Smart Solutions for Customer Projects 

As a contract manufacturer, FAREVA is able to apply its smart chemistry and innovative process development approach to its customers’ programs. In many cases, processes for novel APIs are developed within highly accelerated timelines in order to provide material for toxicity studies or clinical trials. Time is the critical factor in this phase, and in most cases a synthetic route is scaled directly from the lab without consideration of efficiency or optimization. When it is time to launch a product, however, a second-generation process is regularly required that is optimized for efficiency and cost-effectiveness at commercial scale.

At this point, there may be significant room for improvement through the application of FAREVA’s process development principles. First, we run the process as provided to become familiar with the chemistry. The experience gained is then used to adapt the process so that it can be scaled in FAREVA Excella equipment. Thereafter, we can start with process optimizations like the increase of volume yields or the reduction of batch cycle times.

The scope of improvements that we can consider depends on what changes we are allowed to implement with regard to the customer’s regulatory strategy — solvents, reagents, or even the overall synthetic strategy can be part of such challenge. Discussions are held with the customer to determine which of our process development principles we are allowed/are free to apply. Once we have approval, work begins in the lab, where our decades of experience are applied to improve the process.

A Responsive Outsourcing Strategy 

FAREVA Excella does to some extent rely on service providers to support our API production activities. However, we only outsource the early steps of processes for the production of mature products, and with customer’s approval, but do not involve service providers in the process development of new products. We work with selected partners in France, Germany, Italy, Spain, and Asia, all of which are medium-sized chemical companies with high chemical expertise. For security of supply reasons, we keep FAREVA Excella as an active manufacturing option for outsourced steps. This way, we can buffer capacity or address supply issues by performing these steps in-house as well when necessary.

Differentiated Outsourcing Provider 

For pharmaceutical manufacturers looking for reliable and responsible outsourcing partners, FAREVA provides several advantages. In addition to the application of smart chemistry and our process development principles, FAREVA is innovative and creative, identifying unique and tailored solutions.

Our regulatory history includes numerous successful U.S. FDA inspections, including Prior Approval Inspections, and global commercial product launches. We have worked on over 200 molecules and have experience with a very broad range of chemical reactions. On site, we apply process analytical technology (PAT) for real-time monitoring of both chemical reactions and crystallizations and software for running design of experiments (DoE), both of which facilitate development of optimum and robust processes. In addition, we have capability in nuclear magnetic resonance imaging, mass spectrometry, X-ray crystallography, and scanning electron microscopy, all of which are key enablers of process development involving synthetic organic chemistry. 

Through what we refer to as a clarification call prior to finalizing any proposal, FAREVA seeks to understand the logic and reasoning behind an existing process. In addition, we look to determine what changes to solvents and reagents can be made, particularly if the existing process relies on hazardous or other materials that are not first choice for commercial manufacturing regarding EHS aspects. These interactions allow us to clarify the ultimate scope of the proposal, but also provide an opportunity for the customer to gain a real sense of the expertise FAREVA can bring to the project.

Originally published on PharmasAlmanac.com on February 3, 2021.

The pharmaceutical industry is on the cusp of a transformative shift, with the adoption of novel manufacturing technologies reshaping the landscape. Innovative technologies, such as flow chemistry and biocatalysis, are achieving not only sustainability goals but also unprecedented levels of quality and efficiency. As drug developers navigate the journey from preclinical development to commercialization with the support of contract development and manufacturing organization (CDMO) partners, these technologies emerge as true differentiators, opening doors to cost-effective and environmentally friendly processes. Operating at the intersection of sustainability and chemical technology, these advanced approaches enable greener drug manufacturing while delivering a host of additional benefits. Today, Asymchem is strongly differentiated as a CDMO not only by its quality track record and strong customer relationships but by its ability to develop novel and transformative manufacturing technologies.

Robust Technology Ecosystem

One effective strategy for a CDMO to distinguish itself from competitors is by cultivating expertise in innovative manufacturing technologies. The establishment of a distinctive technology portfolio opens up possibilities across various application domains. Take synthetic biology, for example, which can be harnessed for diverse industrial purposes, such as carbon capture, eco-friendly synthesis of sustainable dyes, and microbial wastewater treatment. Proficiency gained in these unique domains can subsequently serve as a source of fresh concepts and a pathway to enhance and optimize the efficiency of pharmaceutical manufacturing. Moreover, possessing proficiency across a spectrum of advanced technologies creates opportunities for new synergies that would otherwise remain untapped without a comprehensive understanding of these multifaceted novel capabilities.

Asymchem has dedicated itself to serving the pharmaceutical industry by cultivating an extensive portfolio of cutting-edge technologies over many years. The company’s very robust technology ecosystem comprises several advanced technical manufacturing solutions in which Asymchem has developed a high level of expertise.

Notably, the company stands as an industry leader in two key domains: flow chemistry and biocatalysis. The in-depth knowledge and expertise of these technologies have led to the development of an innovative manufacturing approach that synergizes both: flow biocatalysis. This novel approach, resulting from the synthesis of flow chemistry and biocatalysis, stands as a distinctive offering now accessible to Asymchem’s customers. This example underscores Asymchem’s commitment to pursuing hybrid opportunities and pushing the boundaries of technological advancement in the field.

The full potential of flow biocatalysis is not yet known, as this new solution has only arisen in the last 12 to 18 months. Also in the last year, Asymchem began leveraging biocatalysis to produce more complex architectures, including peptides and oligonucleotides, offering a compelling alternative to traditional solid-phase chemical methodologies. With biocatalysis, the integration of fragments occurs seamlessly within the liquid phase, introducing strategic control points from a regulatory perspective and facilitating the purification of intermediates.

Innovation remains at the core of Asymchem’s identity, serving as a true differentiator for the company. Asymchem’s unwavering commitment to innovation is driven by the overarching goal of delivering superior solutions to our clients as they navigate the journey from preclinical development to commercialization. Every investment in new technologies at Asymchem is deliberately geared toward the creation of practical solutions that are designed to apply seamlessly across laboratory settings, pilot plants, and clinical and commercial production facilities.

Proactive on Sustainability

The discourse surrounding green chemistry and sustainability within the pharmaceutical industry has transitioned from aspirational to imperative. CDMOs face mounting pressure to demonstrate their capacity to implement environmentally-friendly processes, aligning with their clients’ corporate sustainability objectives.

Asymchem stands as a shining example, uniquely poised to provide pharmaceutical developers with sustainable solutions. The company’s two flagship technologies, flow chemistry and biocatalysis, are inherently greener and more sustainable than traditional, resource-intensive, stepwise batch organic chemistry. Asymchem’s prowess in developing scalable solutions, from laboratory experiments to full-scale commercial production, positions it as a potential industry leader in providing authentic sustainability efforts on behalf of customers.

It also merits mention that these two cutting-edge technologies not only facilitate greener drug manufacturing but also offer a host of additional advantages over their conventional counterparts. Indeed, Asymchem has pursued expertise in both flow chemistry and biocatalysis because these technologies offer significant benefits compared with historic technologies, including higher quality; access to novel chemical structures; performance of novel transformations or reactions not practical to implement at large scale in batch mode; and resource, time, and cost savings. As such, Asymchem’s profound expertise in flow chemistry, biocatalysis, and the emerging domain of flow biocatalysis enables the company to deliver unparalleled value to clients, addressing both sustainability and chemical technology aspects of their pharmaceutical projects.

Emphasis on Risk Mitigation

Chemical manufacturing, whether geared toward drug substances, cosmetics, lubricants, or other products, invariably entails hazards that demand meticulous management to safeguard employee health and safety. Companies that ardently pursue novel technology development inherently acquire substantial engineering prowess.

For Asymchem, the extension of this engineering expertise to the realm of safety solutions was a natural progression. As such, safety engineering has evolved into a central competency of Asymchem, systematically applied throughout all facets of its operations, spanning from synthesis reactions to purification processes.

Notably, Asymchem has developed a scientific mechanism for evaluating safety risks, diligently implemented as processes move from laboratory-scale experimentation to progressively larger scales. These assessments are performed within cutting-edge, specialized non-GMP workspaces and facilities, encompassing every operational phase, including the use of raw materials procured by Asymchem.

With a focus on environmental risk management, Asymchem exclusively works with materials that can be disposed of responsibly. The company has also made substantial investments in state-of-the-art waste treatment and remediation technologies, solidifying its commitment to environmental stewardship. As a reflection of that commitment, Asymchem was the sole enterprise in its vicinity permitted to continue operations during the 2008 Beijing Olympics.

Sound Non-GMP Sourcing Strategy

While the pharmaceutical industry typically associates its greatest risks and quality concerns with noncompliance with Good Manufacturing Practice (GMP) requirements, there exists a widespread misconception. Thousands of companies offer GMP-compliant chemistry services, making it relatively accessible. In stark contrast, the landscape for non-GMP manufacturing is considerably more exclusive and poses unique challenges in conducting due diligence. Furthermore, it is not uncommon for such non-GMP-focused companies to face sudden closures due to bankruptcy or manufacturing incidents. Consequently, emphasizing risk mitigation in the context of non-GMP materials cannot be overemphasized.

Asymchem has meticulously devised a set of due diligence exercises to scrutinize prospective vendors. The company also conducts “make versus buy'”analyses to distinguish between raw materials suitable for procurement and those better suited for in-house manufacturing. This determination hinges on multiple factors, including the number of suppliers, the extent of familiarity Asymchem has with these suppliers, and their reputation for being high-quality and dependable.

Crucially, even in instances where the decision leans toward purchasing a non-GMP raw material, Asymchem takes an innovative approach by qualifying itself as a supplier. This strategic foresight ensures that Asymchem can step in to produce the material should the supply become unexpectedly disrupted, for any reason. This approach holds immense benefits for clients as these raw materials form the foundation upon which entire chemical synthesis pathways rest. They also represent a substantial proportion of the overall chemistry operations. Asymchem’s commitment to this strategy effectively shields its clients from the inherent risks associated with non-GMP supply chains.

Wringing More Value Out of Chemistry

While CDMOs offering API synthesis services may seemingly share similar chemistry fundamentals, they encounter a unique challenge when distinguishing themselves in a competitive landscape. Chemistry, in essence, follows well-established principles — transformations that involve carbon–carbon bond formation, functional group oxidation or reduction, and more. Despite continuous reports in the academic literature detailing innovative transformation methods, the practical applicability of these methods in commercial pharmaceutical intermediate and drug substance manufacturing often remains limited and poorly understood.

Once again, the differentiator is how those transformations are implemented using novel technologies. Transitioning from traditional batch-based processes like alkyl lithium and organomagnesium chemistry, which necessitate cryogenic temperatures, result in significant energy consumption, elevated carbon dioxide emissions, and substantial costs. In contrast, the adoption of flow-chemistry processes reduces costs and carbon footprint, enhances safety, and frequently improves product yield and purity. Despite the same transformation at its core, the utilization of a superior technological approach unlocks more value from the chemistry.

Harnessing the power of biocatalysis and flow chemistry, Asymchem epitomizes this paradigm shift. Furthermore, the company’s mastery of these technologies, bolstered by profound knowledge and extensive experience across diverse applications, constantly generates novel opportunities for innovation and enhancement — opportunities that might elude those with less advanced capabilities.

Consequently, Asymchem has transcended its identity as a traditional CDMO and emerged as a prominent force in developing manufacturing technologies. The company has undertaken the formidable task of bringing the value of flow chemistry to pharmaceutical manufacturing, including the handling of solids, salts, emulsions, suspensions, and more. Continuously shouldering the burden for its clients, Asymchem facilitates their access to the advantages of cutting-edge technologies without requiring exorbitant investments in time, resources, or finances.

Establishing Robust Regulatory Compliance from the Outset

For pharmaceutical CDMOs, a demonstrated track record of regulatory compliance coupled with a proven quality system is absolutely paramount. This importance becomes even more pronounced for CDMOs situated in emerging market geographies, given the skepticism stemming from numerous public failures.

Creating an effective quality assurance system that can convincingly demonstrate a CDMO’s unwavering commitment to quality assurance requires substantial effort, resources, and a culture of continual improvement. In some respects, it can be likened to possessing an additional technology.

The fundamental measure of compliance lies in adhering to GMP requirements. A CDMO is either compliant or not, a distinction readily unveiled during audits. The extent to which a CDMO rigorously implements its quality system serves as the litmus test, often best manifested through an extensive track record of outstanding regulatory performance.

Asymchem stands apart from its counterparts in China. Most other CDMOs in the country initially focused on medicinal chemistry, prioritizing the swift synthesis of compounds for early-stage studies with scant attention to process efficiency and sustainability.

In stark contrast, Asymchem’s genesis as a process R&D and manufacturing company allowed it to serve big pharma clients right from its inception. Consequently, the company operated under rigorous standards pertaining to environment, health, and safety (EHS), site engineering, documentation, and other aspects — a mindset that set it apart.

Over time, Asymchem’s clients have evolved alongside the company, with projects transitioning from early development to full-scale commercial production. This process of nurturing client relationships has significantly contributed to Asymchem’s robust track record of performance. In fact, the company’s audit history reflects the substantial efforts, resources, and diligence invested in crafting a sturdy regulatory framework — a framework that instills confidence in Asymchem’s clients and makes them feel secure in their partnership with the company.

Borderless Development and Manufacturing Partner

One of the reasons that Asymchem is so focused on technology is that technology is borderless.

The pursuit of cutting-edge technology not only yields tangible assets but also fosters the generation of invaluable knowledge. In its capacity as a CDMO, Asymchem delivers tangible drug substances — physical assets that underpin pharmaceutical development. However, the true essence lies in the processes harnessed by Asymchem to craft these assets, serving as the cornerstone of its offerings. These processes can be conceived and perfected in China, with the knowledge easily transmitted electronically to sites located anywhere in the world for seamless implementation.

This technological proficiency empowers Asymchem to undertake endeavors that many other CDMOs are simply incapable of. Fifteen years ago, collaborating with Chinese CDMOs bore fruit primarily through cost savings relative to their U.S. and European counterparts. However, the landscape has evolved, and today, the price differentials have dwindled significantly.

What sets Asymchem apart now is the sheer depth of its unique capabilities, a distinction that transcends geographical boundaries. The company has wholeheartedly embraced technology, a departure from the conventional practices within the CDMO industry. Indeed, Asymchem’s primary selling point and genuine differentiator lie in its prowess in manufacturing technology.

Originally published on PharmasAlmanac.com on January 29, 2024.

Much of the innovation occurring in the pharmaceutical industry today is achieved by smaller pharma/biotech firms with limited commercial manufacturing experience. Outsourcing partners with deep process science and process engineering expertise, extensive networks with traditional and nontraditional equipment vendors, and the ability to redesign existing systems and develop new technologies can enable scale-up and commercialization while shortening manufacturing time, simplifying the supply chain, and reducing manufacturing CoGs.

Introduction

With the pressure to reduce development times and get to the clinic as quickly as possible, many small and medium-sized pharma/biotech companies develop processes with a focus on generating initial material for preclinical and early-phase clinical testing. Often, these processes present challenges with respect to scale-up and commercialization, because they were developed without consideration for the long-term manufacturing plan, from the availability of key raw materials to control of particle size to practical purification at large scale. Complex, “boutique” release testing methods creating major development time and costs are also common. However, experienced CDMOs that have the ability to develop solutions can help these innovators improve their processes and ultimately reduce their costs. This case study presents the collaboration between an early-stage company that was struggling with the development of a realistic and economically viable commercial pathway and BioVectra, a CDMO with 50 years of experience. This collaboration led to the successful commercialization of a product that is now improving the life of millions of patients in the world.

Process Science and Process Engineering Solutions

Like many of today’s small molecule drugs, the product presented challenges from synthetic (e.g., chirality, sensitive functionality), efficacy (e.g., solubility, bioavailability, stability) and/or handling (e.g., high potency, controlled substances) perspectives. Therapeutics are often difficult to manufacture. They may require a novel route to circumvent existing patents, and/or may present issues around raw material/building block availability. Safety of both product (i.e., control of impurities) and process (i.e., control of process hazards) is paramount, followed by ensuring that the process design plan is able to meet client economic constraints. An understanding of the behavior of small molecules and the potential problems that could arise enables anticipating roadblocks and rapidly providing solutions, ensuring that even accelerated projects are successfully completed.

For this specific project, where the complex synthetic API product had unique characteristics requiring careful balancing of process conditions, the primary scale-up challenge was filtration of a solid intermediate and final API. Laboratory-scale filtrations for small molecules are typically performed in a funnel using filter paper. The collected filtrate is then washed to provide a pure product. These filtrations can be directly scaled, sometimes resulting in >2-m diameter Nutsche filters, but are simply not practical for commercial API production. Processing time is too long, and large volumes of solvents are required, adding unnecessary cost. Additionally, wet cake quality is hard to control, which creates risk of variability.

Since the customer had limited commercial experience, they requested that BioVectra take control of managing the scale-up implementation challenges. Typical pharma filter units and centrifuge operations were not options due to the need for thin cake filtration, extensive washing, and process constraints for cycle times. The filtration bottleneck created safety issues, supply chain hurdles, and unacceptable CoGs at larger scale.

A personalized, integrated approach was adopted to ensure that development was not performed in isolation, but rather was a joint effort encompassing R&D, manufacturing, quality, and procurement. Process science and process engineering resources were deployed to identify root causes and develop specialized process solutions that would be amenable to implementation at large scale. The result was a reduction in delays between development phases and the identification of optimal manufacturing processes that provided high-quality product with substantially reduced overall CoGs. However, no one knew then that the customer forecasts were vastly underestimated and that technologies that would be needed soon to supply the market did not yet exist.

Technology Development to Solve Process Roadblocks

Confident of its success in clinical development, the customer entered into agreements with larger partners and quickly saw its commercial forecasts grow beyond prior projections, with approval in several geographies.

Presented with the challenge of scaling up faster and to a much larger capacity than anticipated, the only possible avenue was to align process science, process engineering, and technology innovation capabilities to address the challenges of scaling as the project advanced through its development life cycle. This work included the redesign of certain unit operations and the development of new technology in collaboration with suppliers not typically associated with the pharma industry. Working with a leading vendor in chemical thin-cake filtration to create a novel GMP belt filter unit provided a major breakthrough in the overall process efficiency. Additionally, the redesign of a totally enclosed, solvent-capable filter press emerged, providing a safe, high-yield, and cost-efficient solution.

Planning for rapid scale-up (from 10-kg to >1000-kg batches) required unique interaction with equipment fabricators, while the custom equipment was fabricated with consultation from process engineers.

Lastly, the construction of internal capability also allowed BioVectra to concurrently and proactively plan scaled-up process trains that would accommodate the process conditions and optimal process flow for economic production at scale. The use of multiple processing suites at varying scales aided with acceleration and delivery of the whole project to commercial scale in less than three years, including the build of a new manufacturing area.

Success, Continuity, and Expansion

For this customer, the deep process science and process engineering expertise, the extensive networks, and the ability to develop new technologies that drive efficiency and value made BioVectra the partner of choice to create a pathway to commercial success. The ability to support projects from R&D to commercial scales, design specific plans, and adapt to the changing needs of the market allows customers to avoid the time and cost associated with technology transfer from one service provider to another during scale-up and after achieving commercial scale. Equally important, a low staff turnover means that a strong contingent of subject matter experts that worked on the project from inception remain employed by the company, which allows for continued oversight and training of a dedicated manufacturing team and for continued success.

In fact, the commercialization of this product was so successful that the construction of a dedicated wing was necessary to increase the annual throughput. This construction (and installation of the specialized equipment) has led to routine metric-ton level production to supply the growing demand of the market.

The flexible technologies utilized can be applied to respond to further increases in demand and to produce other highly complex therapeutic compounds. Our extensive expertise in QA and cleaning validation translates into long experience with multiproduct facilities.

Knowledge, Collaboration, Innovation. Repeat.

In this case, existing technologies were adapted to meet specific process needs. However, in many cases, a CDMO must develop new technologies to solve process scale-up challenges.

Such was the case for a product that formed a solvate with the crystallization solvent. All typical drying techniques and unit operations failed to achieve sufficient reduction of the residual solvent. BioVectra’s process development and engineering group developed a temperature and vacuum profile for drying in a mechanically fluidized dryer to produce the API with consistent residual solvent values. A fundamental understanding of physical chemistry led to the solution for this problem, and the process has proven to be scalable from 100-kg to 1300-kg batch sizes.

Having a wide breadth of process knowledge — including process science and process engineering expertise — and available technologies facilitates the development of solutions to complex process challenges. Good predictive knowledge is also a fundamental component of successful process innovation. At BioVectra, close collaboration is not limited to internal process and engineering personnel, but extends to clients, vendors, and the entire partner network who all engage in open and transparent discussions — for the benefit of patients.

Originally published on PharmasAlmanac.com on March 19, 2020