February 3, 2021 PAO-02-21-CL-02
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.
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.
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.
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
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.
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).
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.
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.
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.
Gerhard Noessner is the Director of Process and Analytical Development API at Excella GmbH & Co. KG. He has more than 35 years of experience in organic chemistry and 20 years of experience in process development. He obtained his degree in organic chemistry from the University of Regensburg. After a postdoctoral fellowship as a medicinal chemist in Prof. Murray Goodman´s group at the University of California, San Diego, he joined ASTA Medica, the pharmaceutical branch of Degussa, as research chemist in the field of new oncology drugs. In 2001, he moved to FAREVA Excella´s process development group, which he is leading since 2004.