Applying Chemistry and Engineering Expertise to Continuous Processing

There is ongoing discussion in the pharmaceutical industry today about the potential benefits of flow chemistry and continuous processing. This approach to chemicals manufacturing is not new; it has been widely applied for decades in the chemical process industries for the consistent, economical production of high- volume products.

However, continuous processing is a relatively new concept in the pharma industry, which was founded using a batch production approach. It is also being contemplated at a time when the demand for large-volume manufacturing is shrinking because blockbuster drugs are being replaced by small-volume, highly potent, complex drug substances that make effective use of continuous processing more challenging. In this conservative industry, new technologies are often slow to be adopted because the safety and quality of the drugs produced can be assured using established processing knowledge and techniques.

Flow Chemistry and Small-Molecule APIs

Despite these challenges, there are many benefits of continuous processing (or flow chemistry) for small molecule API production. Regulatory agencies like the U.S. Food and Drug Administration and the European Medicines Agency now encourage using continuous processes to achieve more consistent quality, potentially lower costs, and accelerate drug development.

For API manufacturing, one of the greatest benefits of continuous processing is alleviation of process safety hazards associated with reactions involving toxic or highly exothermic reagents. In some cases, flow chemistry enables the development of processes that cannot safely be performed under batch conditions, creating the opportunity to discover and apply new molecular structures.

Continuous processing also typically involves a much smaller physical footprint. Reduced equipment sizes, consumption of smaller quantities of solvent, generation of fewer unwanted side products, and reduced waste streams all result in greater process efficiencies and improved environmental profiles. Automation and online, real-time monitoring of process conditions also provide greater process control, often leading to improved product yields and quality. When reactor geometries and designs remain the same, scale-up of flow chemistry processes is also simpler than scale-up of conventional batch reactions, leading to a reduction of development times.

How Flow Chemistry Drives Process Safety

Grace Fine Chemical Manufacturing Services (FCMS) has been employing flow chemistry for decades, often incorporating it into semi-continuous, multi-step synthetic routes. Process safety has been a primary driver. Flow chemistry involves the reaction of minimal quantities of reagents at any given time, preventing the buildup of excess reactants and allowing precise control of reaction conditions –– pressure, temperature, flow rate, and stoichiometric ratios.

The latter is important not only for preventing the buildup of hazardous reactants, but also for the prevention of unwanted side reactions that can lead to undesirable impurities and lower yields. Control of reactant ratios is much easier to accomplish in a continuous process than under batch conditions. This control also simplifies reactions that would have to be run under very dilute conditions in a batch scenario. Incorporating continuous distillation for recycling of the solvent can also significantly reduce the quantity of solvent and the size and number of storage tanks required.

Finally, flow chemistry is generally more efficient than batch operations, particularly when large quantities of product must be produced. More material can be generated using equipment of similar size (or the same quantity in much smaller equipment) due to the greater productivity of continuous processes.

Typical Components of a Continuous Process

Grace FCMS performs continuous production processes in continuous stirred-tank reactors (CSTRs). These reactors are designed to operate under continuous flow conditions and regularly make it possible to perform processes in a 200-GALLON reactor that would require 2000-GALLON tanks under batch conditions.

Many pharma companies and contract manufacturers are also exploring the use of microreactors designed specifically for fine chemicals processes. With these microreactors, scale-up is achieved by numbering up (adding more of the same microreactors in parallel) rather than increasing the size of the reactor. This option has the potential to reduce capital expenditures, but typically requires additional development time up front, and it is too soon to know what impact this technology will have.

Once a reaction is complete, the product must be isolated and purified. For these activities, Grace FCMS uses various types of continuous separation technology, including liquid/liquid extraction columns,, continuous decantation, and continuous filtration or centrifugation.

In many cases, batch processes that involve approximately 10,000 gallons of material can be converted to liquid or liquid extraction systems involving a couple of 500-gallon feed tanks and a single column, producing a significant increase in volume throughput.

For pharmaceutical intermediates and APIs, continuous filtration and centrifugation are more challenging due to the very high purity required. Physical separations can be quite difficult, and with existing flow chemistry solutions it is often not possible to meet those high specifications. As a result, physical separations often are achieved through batch processing.

Manufacturers have several options for continuous distillation, including flash, wiped-film, and continuous fractionation. Unlike continuous separation technologies, continuous distillation solutions have been widely used in producing high-purity fine chemicals, including pharmaceutical intermediates and active ingredients.

Converting from Batch to Continuous

At Grace FCMS, new products are typically developed as batch processes in the lab, with most early quantities produced in a batch fashion for simplicity and cost. As processes are scaled up, conversion to continuous processing becomes more attractive in some cases. In rarecases where the process cannot be performed in batch mode, a continuous solution will be designed from the outset.

One challenge is to identify the processes that are good candidates for conversion to flow chemistry. In general, reactions involving solid reactants or that result in a solid product are less suited for continuous processing because of challenges associated with manipulating solid materials under flow conditions. Beyond that, the processes typically converted to continuous operation involve process safety or solvent handling issues or are of sufficiently large volume to permit improved process efficiencies.

The key steps involved in converting from batch to continuous operation include: Determination of which steps in a process are candidates for development as continuous processes or conversion to continuous processes; Identification of the key process variables that must be monitored and controlled during continuous flow operations. These may include temperature, pressure, stoichiometry, concentration, mixing, and intensity; Empirical quantification of the reaction rates of the desired reactions versus unwanted side reactions; And, through design of experiments, identification of how the key variables affect the yield and quality of the reaction steps.

Hybrid Solutions are Common

Some parts of a process are often suitable for continuous or semi-continuous production, while other parts are best achieved in batch mode. In other cases, the entire process can be operated under flow conditions.

For example, a peroxide oxidation process at Grace FCMS that was run under very dilute batch conditions, due to process safety concerns, was partially converted to flow chemistry. The oxidation step was converted from a 1,000-GALLON batch reactor to a 100-GALLON CSTR, with simultaneous addition of the peroxide and another key reactant. The peroxide foam was used to carry the material from the CSTR to the next vessel, where a batch step was completed. The product was then separated from the reaction mixture using continuous extraction and purified using batch crystallization, followed by continuous distillation.

In another case, the entire process was performed in continuous mode, with a specified amount of the final product collected as a lot and then analyzed. This reaction also involved very dilute conditions in batch mode, due to safety concerns.

In general, the determination of whether a process is suitable for conversion to flow chemistry depends on the economics, sensitivity, and the size and volume of each step or unit operation. Another important factor is access to installed assets. If it is necessary to invest in new equipment and engineering solutions to implement a continuous process, the costs will be more challenging to justify.

Many crucial success factors for flow chemistry also are related to engineering issues. So, it is essential for manufacturers to establish a strong, cohesive team that includes skilled organic chemists and equipment-focused chemical engineering experts. These engineering demands often make flow chemistry solutions more expensive up-front than batch processes.

A Unique Combination of Skills and Capabilities

For CDMOs like Grace FCMS, continuous processes may allow for better economics over the long term. Careful and precise determination and definition of the design space provide more consistent processes with improved productivity, yields, quality, and cost. Flow chemistry also provides CDMOs with access to novel chemistries and products that cannot practically be produced under batch conditions due to safety or selectivity issues.

During Grace FCMS’s many years pursuing continuous and semi-continuous operations, we have developed significant expertise about the engineering requirements for flow chemistry, and a deep understanding of the suitability of various processes for the continuous model.

We have strong R&D teams at our Tyrone, Pennsylvania and South Haven, Michigan sites, staffed with experienced PhD organic chemists and chemical engineers, with extensive backgrounds in continuous-processes development. These teams collaborate regularly on both development and commercial operations. This in-house strength saves Grace FCMS– and our clients – the cost of outside engineering assistance.

Grace FCMS also has the capability to perform batch and continuous processes, and to switch back and forth as appropriate for any given operation. Grace FCMS’s flexibility here helps us guide customers to optimal processing solutions based on yield, productivity, scalability, time, and cost.

Since adopting the technology, Grace FCMS  has transitioned 25-35% of our productions to continuous processing. Given that processes converted to flow chemistry usually involve large-volume products, that figure may be as high as 40-50%.