Category: Continuous Processing

Flow chemistry for the continuous production of small molecule active pharmaceutical ingredients (APIs) can provide significant safety, environmental, cost and quality benefits. Effective development and implementation of continuous manufacturing solutions requires a combination of chemistry and engineering expertise and the knowledge and experience to determine which processes are suitable for conversion from batch to continuous operations.

Old Approach, but New to Pharma

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 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 the 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.

Many Potential Benefits

Despite these challenges, there are many benefits of continuous processing — flow chemistry for small molecule API production — that can be realized. Regulatory agencies, such as the U.S. Food and Drug Administration and the European Medicines Agency now encourage the adoption of continuous processes to achieve more consistent quality and potentially lower costs and to accelerate drug development.

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

Continuous processing also typically involves a much smaller physical footprint, reduced equipment sizes, the consumption of small quantities of solvent and the generation of fewer unwanted side products and reduced waste streams, resulting in greater processes 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.

Drivers at Albemarle Fine Chemistry Services

Albemarle Fine Chemistry Services has been employing continuous processing and flow chemistry — often incorporated into semi-continuous, multi-step synthetic routes — for decades. 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 size/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

Albemarle FCS performs continuous production processes in continuous stirred-tank reactors (CSTRs). These reactors are designed to operate under continuous flow conditions and make it possible, typically, to perform processes in a 200-gallon reactor that under batch conditions require 2000-gallon tanks.

Many pharma companies and contract manufacturers are also exploring the use of microreactors designed specifically for fine chemistry 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 shows significant promise to reduce capital expenditures, but typically requires additional development time up front. It is presently too soon to know what impact this technology will ultimately have.

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

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

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

Continuous distillations include flash, wiped-film and continuous fractionation, providing manufacturers with several options. Unlike continuous separation technologies, continuous distillation solutions have been widely used for the production of high-purity fine chemicals, including pharmaceutical intermediates and active ingredients.

Converting from Batch to Continuous

At FCS, new products are typically developed as batch processes in the lab, with most early quantities produced in a batch fashion owing to simplicity and cost. As processes are scaled up, conversion to continuous processing becomes more attractive in some cases. In rare cases 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 that involve solid reactants or that result in the production of a solid product are less suited for continuous processing, owing to the challenges associated with manipulating solid materials under flow conditions. Beyond that, the processes that are typically converted to continuous operation involve process safety or solvent handling issues or are of sufficiently large volume to enable realization of improved process efficiencies.

The key steps involved in converting from batch to continuous operation include:

1. Determination of which steps in a process are candidates for development as continuous processes or conversion to continuous processes;
2. Identification of the key process variables that must be monitored and controlled during continuous flow operations, which may include temperature, pressure, stoichiometry, concentration, mixing intensity, and other variables;
3. Empirical quantification of the reaction rates of the desired reactions versus unwanted side reactions; and
4. Through design of experiments, identification of how the key variables affect the yield and quality of the reaction steps.

Hybrid Solutions are Common

Often, part of a process is suitable for continuous or semi-continuous production, while other parts of the process 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 Albemarle FCS 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 foaming of the peroxide 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 continuous mode depends on the economics, the sensitivity and the size/volume of each step/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.

Engineering Intensive

An equally important consideration to weigh when exploring the adoption of continuous processing is the fact that often flow chemistry solutions are more expensive to implement up front than batch processes, because they are significantly more engineering-intensive.

It is essential to implement a team approach that involves chemists skilled in organic chemistry along with the equipment-focused expertise of chemical engineers. For manufacturers who are largely chemistry-focused, it is important to intentionally establish a strong team of chemists and chemical engineers, because many of the crucial success factors for flow chemistry relate to engineering issues.

A Unique Combination of Skills and Capabilities

For contract development and manufacturing organizations (CDMOs) like Albemarle FCS, continuous processes may enable the provision of 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.

The key to successful development and implementation of continuous manufacturing for small molecule pharmaceutical intermediates and APIs is recognition of the processes that are suitable for flow chemistry and appropriate process design.

Albemarle FCS has been pursuing continuous and semi-continuous operations for many years, and during that time we have gained significant knowledge and expertise with respect to the engineering requirements for flow chemistry and a deep understanding regarding the suitability of processes for the continuous model.

We have strong R&D teams staffed with experienced PhD organic chemists and chemical engineers with extensive backgrounds in the development of continuous processes at our Tyrone, Pennsylvania and South Haven, Michigan sites. These groups collaborate on a regular basis, and their efforts are integrated into both development and commercial operations. With this strong internal capability, Albemarle FCS has no need to seek engineering assistance from outside service providers.

Furthermore, we have the ability to perform batchwise and continuous processes and the capability to switch back and forth as appropriate for any given unit operation. Access to this toolbox of production paradigms enables Albemarle FCS to provide our customers with the ability to identify the optimal processing solution from the perspective of yield, productivity, scalability, time and cost.

Over the years, approximately 25–35% of our processes have been implemented in a continuous manner. When considered from a volume perspective, that portion increases to 40–50%, owing to the fact that the process that are converted to flow chemistry are typically associated with the largest-volume products.

Originally published on PharmasAlmanac.com on August 12, 2019.

Messenger RNA (mRNA) therapeutic and vaccine actives require a specialized delivery vehicle to protect these fragile molecules from degradation and enable them to enter target cells. Encapsulation in lipid nanoparticles (LNPs) is the most common approach pursued to date. Manufacturing of mRNA–LNPs using traditional batch processes is challenging, however, due to the sensitivity of the mRNA and the need for control over nanoparticle formation. DIANT Pharma’s unique system for continuous production of pharmaceutical-grade nanoparticles, including mRNA–LNPs, overcomes these challenges while providing the range of benefits offered by continuous manufacturing in the biopharmaceutical industry, including speed, throughput, inline feedback, and simplified scale-up.

Barriers to Transitioning from Batch to Continuous Pharma Manufacturing

In the heavily regulated pharmaceutical industry, it takes many years for molecules with promising biological/therapeutic activity to become approved and marketed drug products. In addition, once a product is commercialized, it is very difficult to change the approved manufacturing process. Since batch processing was the conventional and established method, this approach is widely accepted from the perspectives of both drug developers and regulators, and the pharmaceutical/biopharmaceutical industry has been slower to widely adopt continuous processes compared with other manufacturing industries.

Transitioning to continuous manufacturing processes has been difficult for drug developers given concerns over regulatory acceptance and impacts on timelines. In the view of many drug developers and manufacturers, it is far less risky to use proven and well-understood technologies and strategies that do not carry the potential for delays in new drug approvals or, in the worst case, rejection by regulatory authorities.

In addition, continuous processing requires real-time collection of analytical data and sophisticated systems for immediate analysis of that data to continuously provide monitoring of critical process parameters and feedback for ongoing process control. The development of more advanced inline and online process analytical technologies (PATs) and hardware/software data management and processing solutions that were previously unavailable or not sufficiently robust for large-scale manufacturing has thus been a recent and transformative driver of the adoption of continuous manufacturing.

Better Control and Scalability

Real-time monitoring of continuous processes ultimately allows for considerably greater control of manufacturing processes than is possible in batch manufacturing mode. Typically, continuous processes involve much smaller volumes that interact for much shorter periods of time. These attributes — combined with real-time monitoring via PATs — results in a higher degree of control that minimizes undesired reactions and many of the complications.

Greater control, in turn, avoids most of the inherent complications associated with scale-up of batch processes and leads to more efficient and straightforward process scalability. Unlike batch processes, for which scale is achieved by increasing volumes within a reactor, a continuous process can provide more product if run for a longer period of time or if the volumetric flowrate is increased without changing the volume in reaction. Because of the high level of process control, consistent product quality is achieved throughout longer runs. For continuous processes involving ultra-small volumes, such as those implemented using tiny microfluidic devices with restricted volumetric throughput, scale can be achieved by running multiple processes in parallel.

Combined Industry/Regulator Push for Adoption

Another recent driver for the adoption of continuous manufacturing in the pharmaceutical industry has been the Food and Drug Administration (FDA). The agency has been pushing for the introduction and adoption of advanced manufacturing technologies that improve quality and consistency while reducing costs, notably including an emphasis on continuous processing. Through various advanced manufacturing initiatives, grants and awards have been established for the development of transformative continuous manufacturing solutions. In the end, therefore, the combined efforts of industry and regulators have led to the recent emergence of a range of continuous manufacturing approaches, including the technology that DIANT Pharma has developed for the production of many types of nanoparticles, such as lipid nanoparticles (LNPs) encapsulating oligonucleotide (e.g., messenger RNA (mRNA)) therapeutic and vaccine actives, which have recently seen significant growth in demand across the industry.

Successful Process Intensification Realized

Current continuous processing solutions allow for a significant reduction in the number of unit operations needed for drug substance and drug product manufacturing. When deployed in combination with advanced automation technologies and platforms, the personnel (and associated training time) required to operate these continuous processes is much less than that needed for batch processes, and fewer touchpoints of human interaction additionally reduces risks of human error and contamination of the processes. Hold and storage times are eliminated, leading to smaller plant footprints. The smaller volumes and dramatically shorter residence times also enable the production of molecules that cannot be safely manufactured in batch mode, creating opportunities for the development of truly novel drug substances not previously possible.

End-to-End Continuous Processing Remains the Goal

The ultimate — still aspirational — goal for the future of biopharmaceutical manufacturing is true end-to-end, integrated continuous processes in which raw materials are fed into the process on one end and the final, formulated drug product is generated at the other, with all intermediate operations linked together. For mRNA–LNP products, that would mean production of the mRNA (including plasmid manufacture linked to in vitro transcription and purification steps) using a continuous process that is then directly linked to the LNP processing stream, which would be connected to continuous lipid production streams as well and would include all downstream operations through final drug product formulation and fill/finish. The concept could be taken even further, with raw materials from petroleum plants connected into the upstream side, where appropriate.

At this stage, however, most continuous processes involve linkage of a limited number of unit operations because the technology is still lacking for full implementation of end-to-end solutions. For mRNA–LNP production, one bottleneck is sterility and endotoxin testing, as there is no inline/online analytical method currently available, and testing must be performed offline. That limitation presently prevents implementation of an integrated, end-to-end process through final formulation and fill/finish but points the way toward forthcoming innovation that can help realize that vision.

Batch versus Continuous Nanoparticle Production

Top-down and bottom-up approaches have both been used to generate nanoparticles. In the top-down approach, the material is generated in bulk by some means, such as extrusion. It is then subjected to a process (e.g., nanomilling) that reduces the particle size of the material to the nanoscale, which is followed by particle-size analysis.

The bottom-up approach typically involves solvent (usually ethanol) injection into an aqueous solution of the material. For LNPs, the ethanol is injected into an aqueous solution containing the relevant lipids. A second step involves concentration and removal of the solvent. 

From this point forward, the two approaches converge. Depending on the ultimate product formulation, further manipulation of the nanoparticles may or may not be required, potentially along with a subsequent purification step. The need to test the material after each unit operation requires not only time but also holding/storage tanks. The final step for pharmaceutical applications involves sterile filtration and bioburden reduction.

Overall, typical batch processes therefore comprise anywhere from six to nine unit operations. With continuous nanoparticle generation, it is possible to fold all of those unit operations into a single process within a closed system.

Revolutionary Technology Built on a Basic, Bottom-Up Approach

The goal at DIANT Pharma has been to integrate the separate unit operations required for nanoparticle generation into one continuous process or at least a single closed system. The successfully established process builds on the basic bottom-up ethanol injection strategy through use of single-pass tangential-flow filtration (SPTFF). This technology does not include any recirculation of the process solution and thus enables truly continuous operation for extended periods of time.  

As with other continuous manufacturing solutions, DIANT Pharma’s technology for the production of mRNA–LNPs and other pharmaceutical-grade nanoparticles offers the benefits of a smaller production footprint complemented by reduced facility and storage requirements, ready scalability, reduced human intervention, elimination of holding tanks/times, and — specifically for this process — greater particle size control. In addition, only one set of operators is required to run the entire process, saving time and money on personnel and personnel training. Furthermore, because the system is fully closed, cleanroom requirements are also reduced. 

We view our approach as truly revolutionary rather than evolutionary. It represents a unique solution for nanoparticle generation and has the potential to change the way in which this process is implemented in the pharma industry, including but not limited to the production of mRNA–LNPs with therapeutic and vaccine applications.

Continuous Process with High-Quality Outputs

DIANT Pharma’s continuous nanoparticle generation system not only eliminates numerous batch-based unit operations, it also generates very high-quality nanoparticles with improved properties compared with those typically obtained from batch processes. The inline/atline sensors incorporated into the system provide real-time process data (e.g., temperature, pressure) throughout the entire process. As a result, users have extensive insight regarding process performance and the ability to understand what is happening during the continuous flow of material, which allows a high level of process control. 

Flexible Production Capability

DIANT’s system, which is based on a single injection site for formation of the nanoparticles, is designed to enable easy process scaling. Nanoparticles generated over a range of volumetric flow rates have similar characteristics, making this solution highly desirable from a risk-mitigation perspective. In addition, the lab and research unit (LARU) uses the same technology and geometry as the large-scale system, eliminating the need for extensive process optimization when scaling up from R&D to clinical and commercial production.

As importantly, the technology can be used to produce a variety of nanoparticles. In addition to LNPs and other lipid-based nanoparticles, polymeric nanoparticles, polymeric micelles, and other polymer conjugates, DIANT’s system can also generate polymer/lipid particles, nanosuspensions, and nanoemulsions. All but the nanoemulsions can be produced using the exact same system setup used for the production of LNPs. The only changes required would be due to chemical compatibility issues. For the production of nanoemulsions, some front-end modifications are required to accommodate oil-based (rather than alcohol-based) solvents and their different viscosities and required operating temperatures. Both options are currently commercially available.

Continuous Technology and Support

Given that the continuous production of nanoparticles is a new concept in the pharmaceutical industry, DIANT Pharma is committed to working closely with our customers — and potential customers — to explain and demonstrate how our technology works and the numerous benefits it provides. We are not interested in simply selling equipment — we want to be involved with our customers to the greatest extent possible to help enable further innovation on their part.

Companies interested in learning more about DIANT’s continuous production solution often first send us material to be processed so that they can evaluate the properties of the products generated using the system. We welcome the opportunity to build those relationships and help them better understand and appreciate the technology.

Once a company acquires the DIANT Pharma system, we collaborate with the customer’s technical experts to provide as much support as they require, including assisting with the performance of feasibility studies, product development, and process scale-up. We are ready to help further develop customer products, as well as manufacturing and/or commercialization strategies. Our efforts may include integration of new sensors or algorithms to meet their specific needs. We want customers, regardless of size, to get to know and trust us and truly understand who we are and the value we provide through not only our unique manufacturing system but our expertise and collaborative culture.

Originally published on PharmasAlmanac.com on May 6, 2023.

A number of trends in the pharmaceutical industry are placing pressure on drug manufacturers to reduce both development times and costs. Clinical trials have been typically on the critical path, and the CMC section had less time pressure and moved forward according to clinical trial results; new regulatory avenues have changed this. New manufacturing strategies are needed to overcome these issues.

Continuous processing of both drug substances and formulated drug products is championed by the U.S. Food and Drug Administration (FDA) as an effective approach to addressing the need for increased efficiency and quality, and some may be better suited to changing paradigms.

Clinical trials have been typically on the critical path, and the CMC section had less time pressure and moved forward according to clinical trial results; new regulatory avenues have changed this. New manufacturing strategies are needed to overcome these issues. Continuous processing of both drug substances and formulated drug products is championed by the U.S. Food and Drug Administration (FDA) as an effective approach to addressing the need for increased efficiency and quality, and some may be better suited to changing paradigms.

A confluence of factors is driving the need for a paradigm shift in pharmaceutical manufacturing strategies. Movement towards evidence-based medicine, rising generics competition, dramatically higher clinical trial costs and timelines, the shift away from blockbusters to niche products, and the growing number of candidates with accelerated development designations (Fast Track, Breakthrough Therapy, Orphan Drug) are all placing pressure on drug manufacturers to eliminate inefficiencies and increase productivity in order to reduce development costs and get new therapies to the market more rapidly.

Continuous processing, which has been utilized in numerous industries for many decades, is attracting significant attention as a plausible solution. Even the FDA reviewed the use of continuous processes as a way to improve efficiency and quality, and now a handful of technology and market leaders are taking the lead. Not surprisingly, given the conservative nature of the pharmaceutical industry, the transition to continuous manufacturing is occurring slowly.

We at Hovione are convinced, however, that as more branded drug companies and contract manufacturers begin to recognize the value provided by continuous processing, and any remaining questions about regulatory compliance and quality assurance are addressed, this manufacturing approach will be more widely adopted.

Flowing in the Right Direction

There are a host of benefits associated with the use of flow chemistry for the production of active pharmaceutical ingredients (APIs); reduced operating costs, smaller manufacturing footprints, lower capital expenditures and operating costs, and improved process efficiencies, control, and product quality are at the top of the list. Additional advantages include increased development speeds, greater process safety when employing hazardous chemistries, and the opportunity to perform reactions that cannot be run under batch methods.

In general, reactions conducted in flow reactors are more selective, providing higher yields of the desired products and fewer impurities. As a result, purification processes are often much simpler and may even be eliminated in some cases. Solvent use can often be significantly reduced compared to that needed for batch reactions, and energy consumption is reduced, given the smaller reaction volumes. As a result, flow chemistry often enables greener chemistry with reduced raw material and resource consumption combined with shorter production times.

Scale-up with flow chemistry is also typically much simpler, leading to much shorter commercialization times. In some cases, commercial-scale production is achieved in the same reactor used for development work by performing longer runs. In others, additional reactors are used in parallel — “numbering up” — which also requires no further development work. Even if flow reactors must be scaled up, there are often few difficulties given the design characteristics of these systems.

Many of these benefits can be attributed to the fact that continuous processes are operated at a steady state. Processes at steady state conditions are easier to maintain than processes in which an end point needs to be achieved through a transient state. Process conditions are also more consistent, and therefore product quality is more consistent. The batch-to-batch variability observed in traditional manufacturing processes is eliminated. In addition, continuous processes are much more homogeneous as the result of improved mixing, so the “hot spots” and variability observed during a single batch run are also largely avoided.

Equipment for flow chemistry has advanced significantly in recent years as well. For instance, where initially it was impossible to conduct flow chemistry with solid reactants or products, many of the reactors available today are designed to allow these more complex transformations without plugging. Solutions of continuous solids handling during downstream purification and separation processes — filtration and, particularly, crystallization — are also under development, with significant accomplishments being made by groups such as the Center for Continuous Manufacturing and Crystallization (CMAC) and the Novartis-MIT Center for Continuous Manufacturing, both partnerships between industry and academia.

Towards Continuous Drug Product Manufacturing

Continuous manufacturing has also been demonstrated to be advantageous for the manufacture of final drug products. Here again, the key advantages are reduced development times due to simpler scale-up (often using the same equipment for development and commercial-scale production) and more consistent and higher product quality. For small-molecule drugs, continuous tableting is in fact increasingly common for the production of oral solid dosage forms, and we believe at Hovione that in the future, continuous processing of tableted products will become a growing trend.

Equipment manufacturers have invested significantly in the development of effective systems for continuous tableting operations, from feeders to tableting machines to coaters. Advances in process analytical technology (PAT) have also increased confidence in the ability to adequately monitor and control continuous operations. Access to these reliable and high-performing equipment and analytical tools is contributing to the adoption of continuous processing for tablet production. Pharmaceutical companies are also realizing how such continuous processes can help them improve productivity and flexibility to meet changing market needs.

Monitoring and control are, indeed, at the heart of successful continuous manufacturing operations. Continuous processing is not possible without PAT; immediate and ongoing feedback of critical process parameters is vital if optimum processing conditions are to be maintained. Advances in PAT have been significant in recent years, and today there is a wide range of tools applicable for the real-time monitoring of manufacturing processes for both drug substances and drug products. Ultimately continuous process is ready to succeed because of the maturing of a combination of advanced technologies: improved equipment, precise monitoring, automation, and software.

Regulatory Backing

Another impetus for increasing adoption of continuous manufacturing strategies has come from FDA. The agency has encouraged the adoption of continuous manufacturing since 2004, and has been increasingly more vocal about the issue, speaking at various conferences and workshops.^1,2 Congress also supports this innovation; the 21st Century Cures Act, proposed in 2015, would require FDA to support the development and implementation of continuous manufacturing for drugs and biologicals as one of several approaches to speeding up drug development and commercialization.³ Industry should take the lead and propose solutions for the new regulatory environment that will need to address this field. Industry is the common denominator to all the regulators; therefore, if we want clear, harmonized guidelines, it is up to us to take a greater role in the standard-setting process and to present constructive solutions to real problems.

Adding Value

As with any new technology, deployment of continuous processing must bring value. For API synthesis, continuous manufacturing is most likely to add value when it enables the use of process chemistry that cannot be performed under batch manufacturing conditions, or performs better continuously. Criteria to argue for a continuous process typically include: safety, yield, purity, and waste, as well as investment for the installed capacity for large volumes.

Continuous manufacturing of tablets has been the object of more innovation across many dimensions. Advances in processing equipment are overcoming many of the challenges posed by ingredients with physical properties that can cause difficulties with handling and processing. As a result, the percentage of APIs that can be reliably and consistently processed into highquality tablets using continuous manufacturing equipment is expanding.

Continuous tableting can be a game changer when development time is highly compressed. When FDA grants Breakthrough Therapy designation, the CMC section becomes immediately critical to project success, and compliance. In these situations FDA may approve the NDA based on Phase II data alone; however, FDA has been crystal clear that they will not compromise on the sponsor being able to demonstrate complete understanding and control over the manufacturing process.

Continuous tableting may be a preferred route in this case, as minimal amounts of API will suffice to define and validate a single-scale production; that can work continuously for a few hours to prepare clinical trial materials and generate validation data. The same production solution is then operated for 1,000 hours to deliver commercial quantities. In breakthrough therapies there may not be time to scale up drug product multiple times as the API may simply not be available in the given time frame. When an API costs ten thousand to tens of thousands of dollars per kilogram, there may well be considerable savings in API costs by opting for continuous dosage form manufacture.

A Natural Evolution

Hovione has been producing small-molecule APIs for decades. In response to customer needs for assistance with overcoming formulation challenges posed by increasingly complex drug substances, we developed expertise in particle engineering. We are now responding to their needs for more integrated manufacturing support, including the production of final products using state-of-the-art technologies.

Implementing PAT at a CDMO

Hovione is committed to supporting an increased number of NDA programs, providing integrated solutions to CMC challenges and delivering a robust process for “right-first-time” commercial launch of much-needed medicines. Understanding the needs of fast-moving clinical candidates, we have as an organization decided to develop know-how and installed capabilities for continuous manufacturing for the production of both APIs and solid dosage drug products, particularly tableting. Throughout its history, Hovione has been a pioneer in technologies, and an early adopter. As early as 1982, patents were issued for Hovione claiming higher chiral purity when reactions were performed below -45ºC; for example, a commercial process was inspected by FDA where liquid nitrogen was introduced into the jacket of a 2,000- liter vessel that same year.

Indeed, Hovione has, since 1997, made all new reactor capacity fully automated with distributed control systems (DCS) approaches, and all control strategies have been designed in-house and applied in a standardized way at all sites. PAT was implemented in 2005 with extensive expertise in its use for productivity and quality improvement. In other examples, Hovione has multiple installations in industrial processes (described in FDA filings) in drying operations, in controlling completion of reactions, and in the control of particle formation — in some cases in large-scale commercial continuous processes.

We also have been deploying advanced PAT solutions in our development and analytical labs. This experience makes Hovione ideally positioned to face the challenges of continuous manufacturing and be a CDMO that enables our clients to realize the maximum benefits of this revolution. To do so, we focus on utilizing continuous processes where they add value for the company, for our customers, and for our patients.

A Continuous Future

The pharmaceutical industry is in a period of rapid change and innovation. Those companies — both brand manufacturers and contract service providers — that are able to adopt new technologies into their operations that result in better understanding, better control, and lower cost will come out winners during the turbulent times ahead. New manufacturing strategies will be essential, and we at Hovione believe that continuous manufacturing capabilities are part of the kit of the best partner CDMO for tomorrow’s innovators. Many large pharmaceutical companies have, or are already investing in, continuous manufacturing systems for both small-molecule and biologic APIs as well as drug products.⁴ Most have at least created internal groups focused on evaluating its potential. A few leading contract development and manufacturing organizations, such as Hovione, have also focused on the development and implementation of capabilities for continuous processing.

Adopting continuous manufacturing is a challenge in an industry that is risk averse and where for over 100 years everything has been done in batch production. This requires a change in mind-set, a whole reeducation of our scientists, and a re-kitting of our facilities at every scale — a big ask in a world of tightened budgets. Hovione is convinced that our industry requires CDMOs that believe in this new paradigm and are prepared to invest, hire, and develop the right talent, and take on projects that have this extra dimension of risk. When a CDMO offers services in the area of continuous process, a wider range of pharmaceutical manufacturers will be able to discover the benefits of continuous processing without having to make significant up-front investments.

It is an exciting time for our industry; never has there been an environment where regulatory and manufacturing innovation combined to find ways for new drugs to go forward to approval in shorter time frames. We expect continuous processing to serve as fertile ground for further innovation.

References

1. Rockoff J.D., “Drug Making Breaks Away From Its Old Ways,” The Wall Street Journal, February 8, 2015, www.wsj.com/articles/drug-making-breaks-away-fromits-old-ways-1423444049accessed June 2, 2015.
2. Wechsler J., “Congress Encourages Modern Drug Manufacturing.” Pharmaceutical Technology website, May 1, 2015, www.pharmtech.com/congressencourages-modern-drug-manufacturing,accessed June 2, 2015.
3. Energy & Commerce Committee, United States House of Representatives, “Full Committee Vote on the 21st Century Cures Act,” May 19, 2015, http:// energycommerce.house.gov/markup/full-committee-vote-21st-century-cures-act, accessed June 2, 2015.
4. Poechlauer P. et al., Org. Proc. Res. Dev., 17 (12), 1472–1478 (2013).

Originally published on PharmasAlmanac.com on February 1, 2016

The Importance of Virus Inactivation

Viral clearance strategies are essential for the production of safe biologic drug substances and drug products. Holistic approaches that include avoidance through careful selection and testing of raw materials and appropriate upstream process conditions, combined with multiple, orthogonal downstream virus removal mechanisms, such as virus inactivation and filtration, are required by regulatory authorities to ensure that biopharmaceuticals are free of endogenous or adventitious agents.

Virus Inactivation via Low-pH

In a monoclonal antibody (mAb) templated process, viral inactivation typically follows protein A capture and is prior to polishing chromatography. This order of unit operations is attractive since viral inactivation is usually achieved through a 30-60 minute product hold step at low pH (~pH 3.5) and takes advantage of the low pH conditions required for Protein A elution, minimizing the amount of pH adjustment needed.   

While pH, inactivation time, buffer, and temperature are important parameters for viral inactivation and can vary between different mAb processes, in traditional batch manufacturing the implementation of this unit operation remains fairly consistent across the industry and is performed in large stainless steel tanks. The protein A elution pool is captured in the first tank, where the pH is adjusted to the inactivation setpoint as needed. This low-pH bioprocess fluid is often transferred to a second tank where it is held for a predetermined, validated inactivation time to achieve the specified level of viral clearance. The pH of the bioprocess pool is then adjusted up to a pH suitable for the subsequent process step.

The harvest from a single bioreactor is generally purified over protein A in multiple cycles, resulting in several large-scale tanks dedicated for virus inactivation of the entire batch. As a result, the overall viral inactivation process is capital and plant footprint intensive, in addition to being relatively slow.

Inline Virus Inactivation: Enabling Next-Generation mAb Processing

The biopharmaceutical industry is moving towards intensified and continuous processing to realize gains in cost, speed, flexibility, and product quality with the ambition to improve access to lifesaving therapeutics.  

To date, the most signifcant progress has been in upstream operations with advances in perfusion processing. There have also been noteworthy developments in downstream, including continuous multicolumn chromatography for protein A capture and flow-through technologies for polishing rather than traditional bind-and-elute approaches.

This shift toward connected and continuous mAb processing, in particular the chromatography steps that precede and follow viral inactivation, necessitate the development of novel approaches to improve or replace this step as well. Continuous viral inactivation solutions are expected to have numerous benefits including: elimination of large hold tanks for inactivation, reduction of facility footprint requirements, reduced processing time, facilitated conversion to single use, and perhaps most importantly, potential improvement in product quality. 

Therefore, inline technology that replaces traditional batch operation while enabling effective virus inactivation is expected to play an important role in the development of next-generation mAb processing solutions.

Robust Understanding of Process Parameters Essential 

Viral inactivation is a well-understood process and relies on a number of parameters. Two critical parameters are pH and exposure time, with acid selection, protein concentration, and temperature also of high importance. While lower pH setpoints can reduce the time needed for inactivation, this typically incurs greater risk of protein damage. 

Strategies to ensure critical parameters are well-controlled in traditional batch viral inactivation processes have been long established. As the industry moves to inline viral inactivation, it will be essential to develop very robust understanding and control of these critical parameters in the new processes, as well.

Continuous Designs

Design considerations for continuous inline viral inactivation are different than traditional batch operation. In a continuous flow design, the incoming solution requires inline acidification and complete mixing prior to the inactivation chamber, followed by inline pH adjustment and thorough mixing before moving to the next unit operation. In addition to efficient static mixers, pH sensor and control strategies will have increased importance.  The pH probes need to be stable over the duration of the process, up to many weeks, while having the ability to rapidly detect and report changes in pH. Should the pH not meet the requirements of the process, control strategies such as diversion to waste are critical to ensure that only solutions that meet the criteria are used for further processing.   

Fluid dynamics are also an important consideration when designing a continuous, inline chamber for inactivation.  If we consider the simplest continuous incubation chamber, a straight pipe, we can see the immediate impacts of fluid dynamics, with fluid in the middle of the pipe flowing faster than the fluid near the edges or walls of the pipe. This will result in a broad residence time distribution, with shorter residence times potentially correlating to insufficient virus inactivation and longer residence times resulting in increased levels of protein damage. 

In consideration of these challenges, significant effort has been invested in developing an effective incubation chamber design that provides a narrow distribution of residence times with an end goal of getting as close as possible to plug flow through the entire chamber. To this end, different designs have been built and evaluated to tighten the flow distribution profile, including a coil flow inverter, packed-bed reactors and serpentine flow designs.

In each case, an understanding of residence time distribution is necessary before robust claims can be made for chambers at manufacturing scale. A key question must be answered: What is the minimum incubation time that your protein is experiencing for the virus inactivation?

MilliporeSigma’s Solution

MilliporeSigma is developing an inline virus inactivation process leveraging an incubation chamber with a coiled-flow inverter design. In this design, the number of turns, number of 90° bends, and coil radius in the chamber have a direct impact on fluid dynamics and residence time distribution.

To gain a robust understanding of all operating and design parameters, we are conducting extensive testing using both small scale models and manufacturing scale chambers. As part of this effort, we are pursuing a design of experiments (DOE) approach at small scale to evaluate the impact of turns and 90° bends in chamber designs. Residence time distribution is determined for each chamber at a range of operating flowrates by introducing pulses of protein into the chamber and then pushing them through with buffer.  The effluent is then monitored with UV and integrated to obtain cumulative distribution curves.   

Though this DOE approach, we are able to develop efficient manufacturing-scale chamber designs that offer narrow residence time distributions. This efficiency reduces the need to use oversized chambers to ensure that even the fastest fluid existing the chamber will have met the minimum incubation time. In turn this efficiency also reduces the maximum residence time of the slowest fluid which minimizes the potential for degradation of pH sensitive mAbs. 

In addition to the residence time characterization, evaluation of inactivation is important.  We have evaluated an enveloped model bacteriophage and observed equivalent inactivation performance when comparing an inline viral inactivation process to a traditional batch process (static incubation) under equivalent conditions (pH and time), and in future work will evaluate mammalian viruses.   

The Regulatory Perspective

Regulatory authorities recognize the societal benefits of continuous processing to reduce cost and expand therapeutic access and are broadly supportive of these efforts.  Patient safety will remain the key priority for regulatory authorities, biomanufacturers and suppliers.

Virus inactivation is a well-understood step. The key parameters (pH, time, and temperature) needed to achieve inactivation have been well characterized. As the biopharma industry evolves to inline viral inactivation, regulators are likely to scrutinize system implementation and the means for demonstrating inactivation. Manufacturers will need to validate their process parameter setpoints through small-scale virus spiking studies and then demonstrate that the mAb solution flowing through the viral inactivation system at manufacturing scale consistently remains at those setpoints throughout the course of the continuous run.

By characterizing chamber residence time distribution and system performance within a recommended operating window, the equipment vendor can streamline industry efforts to adopt and implement inline virus inactivation systems.

Other Potential Applications and Solutions

Solvent detergent inactivation is another batch viral inactivation technique that is commonly used in the plasma industry. This method utilizes a solution comprising an organic solvent and a detergent (surfactant) instead of low pH to inactivate enveloped viruses.

As with inline activation at low pH, it is essential to ensure the correct solvent and detergent concentrations are reached and to achieve the correct incubation time of the treated process solution in the incubation chamber. While less common in recombinant protein processes, this method – or sometimes a detergent-only method (no solvent) – has been evaluated for therapies that are significantly degraded under low-pH conditions. 

Future prospects

The Biopharma industry has expressed strong interest in connected and continuous manufacturing in response to market trends and to expand access to lifesaving therapies. This evolution in Biomanufacturing understandably will take time, and will exist alongside legacy processes where investments in existing infrastructure and regulatory approval have been completed. Over time, the industry will transform since the benefits of speed and higher quality are important for all therapeutic proteins. The full promise of next generation processing will require the convergence of process technologies, digital solutions and analytics. This evolution will require advancements in process analytical technologies, sensors, and adaptive process controls. These future technologies will drive a reduction in process deviations and streamline batch release for continuous processes. 

Mindful of these future needs, new facilities are being designed with considerations for perfusion bioreactors and connected or continuous downstream solutions such as multi-column capture and flow through polishing operations.  These solutions, coupled with advanced approaches to buffer preparation and management, result in more efficient facility utlilization and footprint reduction. 

Inline viral inactivation is a key contributor to the future of connected and continuous processing as the integral step between capture chromatography and flow through polishing.

Originally published on PharmasAlmanac.com on May 28, 2021