Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

The pharmaceutical industry is currently challenged to accelerate the development of new drugs while reducing the cost of these efforts. Drug repositioning is an effective approach for achieving these goals. Evaluating existing compounds that have been proven safe-whether approved, still in clinical trials, or previously found to be ineffective for the diseases they were originally targeting-takes less time and money. The challenge is to identify the right existing compounds to investigate for a given disease.

	Drug repositioning today is currently pursued using one of five key approaches, according to Aris Persidis, co-founder and president of Biovista, which is developing a pipeline of repositioned drug candidates in neurodegenerative diseases, epilepsy, oncology, and orphan diseases. Phenotypic screening is the one method that involves laboratory testing. In this approach, a drug substance is tested in parallel against a small set (10–50) of animal models or cell lines. “This approach is neither comprehensive nor systematic by any means, but if one is lucky and gets a hit, then a potential new use of a drug in a specific new disease has been identified with some initial experimental proof,” Persidis says.

	To achieve systematic or comprehensive repositioning, computer-based approaches must be used. There is no single preferred digital tool or technology for accomplishing drug repositioning because different tools are optimally suited for different strategies, according to Hermann Mucke, CEO of H.M. Pharma Consultancy, a firm that provides drug development services, including support for drug repositioning activities. “Many pharmaceutical companies use their own in-house algorithmic solutions or leverage technology platforms developed by specialists in repositioning, such as Biovista, Excelra, etc.,” he notes.

	In addition to in-silico modeling and target docking using algorithmical solutions beyond medicinal chemistry, Mucke points to data mining of side effects and drug interactions as a way to find valuable clues for APIs formulated into marketed drugs. “Crucial information can also be extracted from the peer-reviewed and patent literature by creative pharmacologists who can think out of the box and ‘connect the dots’,” he adds.

	The other four approaches identified by Persidis overlap somewhat with these strategies and include literature mining, pathway mining, adverse-event matching, and gene-regulation mining. “Pathway mining involves the use of pathway keywords to search the literature and other gene/protein pathway databases where a specific pathway is linked to different diseases, and then match drugs known to hit that pathway across the different diseases,” he explains.

	Similarly, in adverse-event matching, lists of adverse events are used to mine the labels of drugs for the same adverse events. “If different drugs that work in different diseases have the same adverse events, then maybe they can work in the same diseases,” Persidis observes. Gene regulation mining uses data from microarrays to find genes that may be up/down-regulated in a disease microarray, and then the literature is searched to find drugs known to have the opposite effect.

	Unfortunately, there are few data sources that are specifically tuned to the needs of drug repurposers, according to Mucke. In addition, analysis tools are not yet sufficiently advanced to assist without extensive training in pathway and systems medicine.

	The existing approaches have all yielded some successes and failures, adds Persidis. They fall into the “quick/easy/cheap category,” however, and are limited in their applicability. “To do repositioning is easy, to do it well is hard. The key limitation of these existing computational approaches is that they are focused on reducing repositioning to one parameter (gene up/down, common side effects, etc). As a result, they do not take into account the complexity of diseases and their mechanisms of action, or the complexity of patient populations,” he said.

	Going forward, both Persidis and Mucke believe that the application of artificial intelligence (AI) to drug repositioning will take the field much further than it can go today. “AI is emerging as the best tool to do repositioning well. New AI-driven technology shows the best promise, because AI is able to integrate and use many different types of data much more effectively than before,” Persidis explains.

	Adds Mucke: “Advanced AI technologies that can look for connections they have not been specifically trained to identify will revolutionize drug repositioning within the next few years, taking us beyond mere expert systems.”

	It is not just existing compounds that have potential for drug repositioning; their derivatives can also be explored for therapeutic activity. “Once you have a repositioning candidate compound identified for your disease target (or vice versa), you can let loose all the medicinal chemistry and pharmacology tools that are out there,” says Mucke. Derivatives can be generated using known quantitative structure-activity relationship approaches that have been widely employed in drug discovery for many years, according to Persidis.

	Of course, the parent compound must be identified first, which is a repositioning exercise. “The real challenge is not the derivatives, but the starting points. Once you have a drug, then deriving different versions can be done, but you can’t derive a different version unless you know where to start from. The difficulty is finding a good starting point,” says Persidis.

	H.M. Pharma Consultancy maintains the Discontinued Drug and Candidate Database (DDCD), a comprehensive machine-readable database of information on compounds that might be suitable for drug repositioning. The DDCD is regularly updated with information on approved drugs and drug candidates that might be available for repositioning efforts taken from peer-reviewed papers, patent documents, and chemistry, pharmacology, and development information in various public sources, according to Mucke.

	The company uses the DDCD as an internal resource for drug development projects and for repositioning projects that it is completing as part of the European Union Research and Innovation program, Horizon 2020. “The DDCD has been constructed over the past 20 years and goes beyond any single public source in defining the pool of compounds that are potentially available for drug repositioning,” Mucke comments.

	Over the past 10 years, Biovista has been developing an AI solution called Project Prodigy. “A major challenge in drug repositioning is to balance the insights into a new use with equivalent insights into potential side effects,” Persidis says. “Biovista’s AI program is one of very few equally able to identify both potential new uses and the specific subpopulations to include or avoid, based on a full understanding of the benefit/risk balance,” he notes.

	The Project Prodigy AI is also one of few systems that does not limit itself to machine learning (ML), says Persidis. That is important because ML only affords ‘hits’ that are basically already known from training sets, even if hard to find. “Biovista’s Project Prodigy AI is capable of building entirely new clinical scenarios that have never been seen before and can be evaluated as truly novel. No training sets are needed or used. This ability provides a key advantage over typical ML-based approaches,” he states.

	Project Prodigy, according to Persidis, has already been used in a number of projects. Internal efforts at Biovista have led to repositioned drugs with animal model/cell line validation and issued or granted patents in multiple sclerosis, epilepsy, anti-glomerular basement membrane disease, and some rare diseases such as Friedreich’s ataxia and Leber’s hereditary optic neuropathy. The company has also used the AI system in collaborations with major pharmaceutical companies, patient advocacy groups, and FDA.

	Developing a drug is a long, expensive process. Repositioning is the most efficient way to get to a valid starting point. “Drug repositioning should be a standard operating procedure at any stage of development, especially early on. Its ‘right way’ systematic use also reduces development and investor risk across different phases of the portfolio,” said Persidis.

	While none of the current digital tools available for repositioning are capable of providing anything beyond assistance for pharmacologists who know how to use them and who can interpret their results properly, according to Mucke, this situation will change soon with the application of continually improved AI technology.

	“AI has already shown its promise, with actual results achieved much more efficiently than other approaches. Now, it is beginning to be understood as one of the most powerful ways forward for drug development and healthcare cost containment,” Persidis concludes.

Vol. 42, No. 9
	September 2018
	Page: 22Â­–26

	When referring to this article, please cite it as C. Challener, “Can Artificial Intelligence Take the Next Step for Drug Repositioning?" 

Articles

Existing software tools cannot take into account the complexity of disease.

Can Artificial Intelligence Take the Next Step for Drug Repositioning?

As the pharmaceutical industry matures, the complexity of new drug candidates is increasing. More complex molecules are more challenging to synthesize, often requiring advanced chemistry techniques to ensure both high yields and high selectivity. Sophisticated chemistry such as exotic catalytic transformations are used more widely as a result. Many of these reactions are highly sensitive to temperature and pressure, with control of one or both of these reaction conditions improving the selectivity and yields of desired products, particularly in cases where undesired impurities have similar structures and physical characteristics. Low-temperature chemistry, and in particular cryogenic chemistry at temperatures down to -80 °C, can facilitate transformations that cannot be achieved at higher temperatures.

	In the past few years, there has been an increase in the number of new API projects being brought to contract development and manufacturing organizations that require low-temperature chemistry. New routes to existing products that are designed to improve efficiency and productivity also more often involve cryogenic processes, according to Jean-Pierre Pilleux, site director at Novasep’s Chasse-sur-Rhône facility in France. “As novel APIs become more and more complex, cryogenic conditions are often mandatory to obtain the required selectivity. For example, processes employing organometallic chemistry can be critical in API synthesis,” adds Jean-Baptiste Guillermin, head of process development at the Chasse-sur-Rhône plant.

	Use of low temperature can influence the reaction pathway, particularly for reactions in which desired and undesired products differ only slightly from an energetic standpoint, whether with respect to stereo-, regio-, or chemoselectivity. Reactions involving unstable intermediates, notably organometallic reagents, that cannot be conducted at or near room temperature are often possible at much lower temperatures. In addition, processing involving gaseous reagents can be easier to implement at low temperature.

	“Cryogenic chemistry is an enabling technology that can allow the limiting of impurities, performance of processes with highly reactive compounds, improvement of reaction selectivity, elimination or reduction of unwanted side reactions, prevention of ice crystal formation, and reduction of the volatility of compounds for greater safety,” notes Ed Price, president and CEO of PCI Synthesis.

	Running large-scale cryogenic processes is an entirely different proposition than performing low-temperature chemistry in the lab, according to Price. “In the lab, glassware can be placed in an acetone/dry ice bath. For commercial production, heat transfer fluids must be pumped through jacketed vessels using sophisticated pump technology (costing five to six times that of conventional pumps) and complex control systems,” he explains.

	In addition, specialized analytical tools are required; measuring cryogenic temperatures cannot be achieved with normal mercury or alcohol thermometers because they freeze. Platinum resistance thermometers that exhibit well-defined electrical resistance behavior as a function of temperature must be employed instead.

	“The need for specific and expensive equipment means that the capex [capital expenditure] for newcomers can be significant,” observes Pilleux. He adds that greater energy consumption and handling of unstable intermediates also must be considered. In addition, while there are always challenges going from small to large scale, scaling cryogenic chemistry and processing is significantly more complicated because extreme temperatures must be delivered and maintained, according to Price.

	“Running processes under such cold conditions is as much an art as a science. These reactions are very touchy and sensitive. They have to be run very specifically, which involves controlling an entire system of pumps and heat exchangers to reach, maintain, and control the temperature as the reaction progresses,” he notes. For that reason and based on 40 years of experience running cGMP cryogenic processes, Pilleux considers process robustness to be key. “Understanding the impact of reaction parameters using a quality-by-design approach during development, coupled with close interactions between chemists and chemical engineers using thermal modeling allows the efficient prediction of scale-up parameters for such highly demanding processes,” he states.

	The need for strict control of the reaction temperature throughout the entire reaction mixture can pose challenges as well. The addition of reactive reagents to such processes may lead to the generation of local exotherms that must be removed via efficient mixing and good heat exchange properties of the reactors, according to Pilleux.

	In addition, the low surface area-to-volume ratio of batch reactors restrains the size of vessels for production. In fact, it is not just the need to achieve and maintain low temperatures that is challenging. It is the fact that batch processing has not changed dramatically from a technology standpoint for decades, according to Price. “Pharmaceutical plants today look similar to those in operation 20–30 years ago,” he says.

	For certain chemistries, there is no other option than to perform them at low temperature. “It goes back to the perennial organic chemistry battle between yield, cycle time, and impurities. Achieving the required purity levels is always the first priority. In early development phases, the goal is to deliver high-purity products, and the economics of the process are not as important. That comes into play if a candidate progresses to later clinical stages. If the process cannot be performed economically at low temperature, another route will need to be identified,” Price comments.

	It is important during development, he notes, to gain an extensive understanding of the process and determine the warmest reaction temperature that won’t cause significant problems and the potential benefits that can be gained if the reaction is performed at the lowest possible temperature.

	In many cases, gains in yield and selectivity can overcome the additional costs of running a process at cryogenic temperatures. For instance, Prices notes that a product that is produced in multiple small batches can cost significantly more and take more time to manufacture than if that product is produced in one or two large-scale cryogenic runs.

									Some reactions that are most often performed under extreme low temperature conditions, according to Ed Price, president and CEO of PCI Synthesis, include:

	As drug candidates continue to become more sophisticated, demand for processing under extreme conditions, including cryogenic temperatures, will continue to grow. “The question then becomes, how do we incorporate novel engineering/processing solutions that really move the needle for drug manufacturing?” according to Price. Manufacturing on a smaller scale in a continuous manner to obtain the same yields and throughputs of larger equipment could be one answer, he notes.

	Guillermin agrees. “Reactors having a higher surface-to-volume ratio and more efficient mixing can be used to increase the productivity of low-temperature processes and avoid the potential for high-temperature hot spots,” he says. “Continuous flow reactors are a breakthrough solution.”

	Novasep is, in fact, focusing on the development of flow-chemistry solutions at production scale in order to offer alternatives to batch processes. “This technology generally enables the use of less extreme temperature conditions and control of very short reaction times, even at production scale, allowing the production of unstable intermediates that cannot be obtained under batch conditions-and with a reduced energy cost. These technologies are rapidly expending and Novasep has built a strong expertise in this domain,” says Guillermin.

	Late in 2017, Novasep also initiated a €4-million ($4.7-million) investment to expand its low temperature capability at its Chasse-sur-Rhône facility and address the increasing market demand for cryogenic processes. The company now has a total low-temperature capacity of 35 m3. The investment includes the installation of a new cGMP cryogenic production line capable of operating at temperatures as low as -80 °C and is equipped with a 4000L Hastelloy reactor, filter drier, and cleanroom. The cGMP pilot-plant capabilities were also expanded with the addition of a new stream comprising a 400L Hastelloy reactor, filter drier, and cleanroom.

	PCI Synthesis, meanwhile, added a 1000L jacketed reactor specifically designed for cryogenic chemistry to meet the needs of two recent projects including a new chemical entity moving from Phase I to Phase II and a generic API for which its client wished to de-risk the supply chain by adding PCI as an approved alternate supplier with in-house cryogenic capacity.

	In addition to the 1000-gallon Hastelloy C reaction vessel, the system comprises three separate heat exchangers for liquid nitrogen, steam, and glycol; a specially designed pump; and control valves and control logic. The reactor is housed in a special suite and is paired with a 50-gallon glass-lined reactor for workups and additional processing and a 3-m2 Hastelloy pressure drier.

Vol. 42, No. 8
	August 2018
	Pages: 22–25

	When referring to this article, please cite it as C. Challener, “Increasing API Complexity Drives Demand for Cryogenic Capabilities" 

Low-temperature chemistry enables performance of more challenging and selective chemistry.

Increasing API Complexity Drives Demand for Cryogenic Capabilities

Regulatory agencies have significant interest in the implementation of more advanced methods for the detection of adventitious agents. This interest, according to Horst Ruppach, director of viral clearance and virology at Charles River Laboratories, comes from recent experiences in which adventitious viruses were found in a marketed rotavirus vaccine in 2010 and in an insect production cell line (SF9) in 2014. In both cases, the standard testing methods failed to detect these contaminants. Concerns about more advanced methods still remain to be addressed.

	Overall, the methods used in adventitious agent testing have not changed dramatically in recent years and are performed as recommended and described in guidances and regulations. Antibody detection assays and nucleic acid amplification techniques are used to screen source materials for specific viral contaminants in the plasma product industry, according to Ruppach. A panel of cell-based 

 assays combined with antibody detection, and quantitative polymerase chain reaction (qPCR) assays for specific viruses is used in the vaccine and recombinant protein industry.

	Protocols have been, in some cases, partly modified or complemented when necessary, such as prolonging incubation times for some in-vitro assays to detect slow-growing viruses like Vesivirus, according to Ruppach. In the plasma-product industry, he notes that screening for emerging viruses such as Zika and Hepatitis E has also partly been added to meet country-specific recommendations. A shift from culturing and

 assays to qPCR-based assays for mycoplasma testing of recombinant products has also occurred to some extent.

	In general, however, release testing is still performed using slow, but long-accepted culture-based tests, according to Michael Brewer, head of pharma analytics with Thermo Fisher Scientific. The exception, he adds, is the much broader use of qPCR for in-process testing during cell-culture processes (e.g., mycoplasma, mouse minute virus [MMV], and Vesivirus for Chinese hamster ovary [CHO] culture) and even for conditional release to downstream processing while waiting for results of the culture-based tests.

	There are real issues with existing cell-based methods that are driving interest in the development of alternative techniques. “Cell based 

 assays can detect a broad range of viruses, and even unknown viruses, but the methods are not standardized and can be run in different ways, which significantly impacts the assay specificity and sensitivity,” Ruppach says. In addition, some potential contaminating viruses don’t grow in the detector cells, while others do grow but cannot be detected. “On top of these issues is the fact that positive results cannot be assigned to a virus type or even virus family; subsequent identification assays are necessary,” he observes.

 assays encounter the same challenges and limitations, and there is a high failure rate due to the route for test sample administration. Studies have also shown a low detection rate for these tests compared to 

 assays, according to Ruppach. Ethical reasons are an additional concern, with growing emphasis placed on minimizing animal testing. One of the biggest issues with both 

 testing, however, is the time it takes to obtain results, which can be as long as five to six or even more weeks. “An additional complicating factor is the fact these assays cannot be validated following International Council for Harmonization (ICH) Q2 due to the undefined specificity and sensitivity,” he states.

	While these limitations are overcome with qPCR, Brewer points out that, at the moment, available assays exist only for a small set of viruses that represent the biggest threat to CHO cell culture. “Rapid testing for viruses and mycoplasma remains a critical need for the industry to achieve the goal of rapid, real-time or near-real-time lot release. For continuous processing, time to result is even more important,” he asserts.

	There have been some advances in instrumentation for adventitious agent testing that have the potential to impact testing in the near future. Ultra-high multiplex PCR is enabling rapid workflows when combined with high-recovery nucleic acid extraction, automated sample prep, and high-throughput DNA sequencing technologies, according to Brewer.

	There is much discussion in the industry and among regulators about the potential advantages of new nucleic acid-based technologies and other high-throughput sequencing (HTS) methods, also known as massive parallel sequencing or next-generation sequencing (NGS). “These technologies have the power to detect any virus with a level of sensitivity comparable to virus-specific qPCR and, unlike 

 assays, deliver sequence data that can identify the contaminant,” says Ruppach.

	There are other benefits as well. “Replacing traditional adventitious agent tests with NGS-based tests would provide the highest level of confidence in negative and positive results,” states Brewer. “In addition, time to result for such tests is aimed to be less than two days, and the ability to automate much of the workflow could reduce hands-on time to less than three-and-a-half hours. Furthermore, while traditional culture testing is limited to sampling points in cell banks and harvest media only, rapid molecular testing enables sampling, testing, and decision-making throughout cell-culture processes,” he continues.

	There are major concerns about this technology, however, that must be addressed. The presence of virus-specific nucleic acid does not necessarily indicate a replication-competent contamination, and thus most current nucleic acid assays cannot differentiate viable from non-viable contaminations, which is the case for both in-vitro and in-vivo assays, according to Ruppach. “Some HTS-based methods have been recently developed that can differentiate replication-competent and non-replication-competent viruses, which will help eliminate this important drawback,” he notes.

	For instance, Brewer notes that qPCR and NGS techniques that offer quantitative values or target enumeration capability can be applied to assess viability by measuring changes in target nucleic acid levels at multiple time points in the case of a positive initial test.

	Managing the large amounts of data produced when using HTS technologies presents another challenge. “Data processing becomes an important factor in results evaluation. The algorithm used can lead to both false-negative or false-positive results and significantly impact the outcome of the analysis,” Ruppach explains. No regulations or standards have yet been established regarding the data-processing process.

	Brewer notes that qPCR has been improved by the inclusion of controls that help reduce the risk of false positives due to inadvertent cross contamination of test samples with positive controls.  He does agree that a full solution will require designed-for-purpose software to enable data analysis and results reporting, including enabling compliance with 21 

	The concept of nucleic-acid testing has been well received by industry and regulators, and solutions are in development. “The goal is to supplement or replace the traditional adventitious agent tests with rapid NGS-based detection and identification of a predefined panel of viruses and broad range of bacteria, including mycoplasma,” says Brewer.

	Initiatives are underway to grow regulatory understanding of the capabilities of these new technologies that are supported by various regulatory agencies. For instance, Ruppach points to the Advanced Virus Detection Technologies Interest Group, which was established by the industry and FDA to address specific challenges and provide solutions to make these technologies ready for use under GMP conditions.

	The Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB), established by the Massachusetts Institute of Technology Center for Biomedical Innovation, has also had a positive impact. “The CAACB allows for open communication on contamination events that have impacted the industry and provides a forum for experts to discuss how viral testing can be improved and the overall risk of viral contamination reduced,” according to Brewer. The consortium has also helped to develop a more comprehensive understanding of the adventitious agents that are encountered.

	“More advanced NGS-based techniques are in development and offer the potential to supplement or replace the 28- or 14-day culture-based test following validation and regulatory review and acceptance,” asserts Brewer. “Given that a stated goal of the pharmaceutical industry is to move to real-time or near-real-time lot release in the future, replacement of the 28- or 14-day culture-based adventitious agent test with a rapid test will be required,” he adds. 

	It is worth noting that following validation, regulatory filing, and review, regulators have accepted qPCR-based mycoplasma testing for lot-release testing applications across multiple therapeutic modalities (e.g., manufacturing cell culture, cellular therapy, tissue therapy), according to Brewer.

For more advanced NGS-based methods, regulatory acceptance and validation are still needed.

Improvements Needed for Adventitious Agent Testing

Mammalian cell lines, particularly Chinese hamster ovary (CHO) cell lines, have become the standard expression systems for the production of biologic drug substances from recombinant proteins to more complex monoclonal antibodies (mAbs). CHO cells have played a significant role in the manufacture of revolutionary drugs for the treatment of many diseases, and their use is still the focus of major investment among biopharma companies worldwide, according to Barry Holtz, president of iBio. Although the standard, they do possess limitations that need to be addressed as the biopharmaceutical industry evolves to meet government, payer, and patient expectations for cost-effective, safe, and efficacious medicines. In addition, conventional mammalian cell lines may be inappropriate for the production of next-generation medicines such as bi/multi-specific antibodies and gene and cell therapies.

	High cost and long development timelines are two major drawbacks of conventional expression systems, according to Mike Laird, senior director and principal scientist for process development at Genentech. These systems also have the potential for low expression levels for some novel protein structures.

	The biggest issue, asserts Holtz, is the time involved in the development of mammalian expression systems. “Traditional mammalian cell-based systems require the development of stable cell lines that perform well, which requires the completion of multiple evaluations in small reactors over several months. While the product is well-characterized at that point, scale up to larger reactors is often needed, and the environmental changes in bigger vessels, whether single use or stainless steel, can impact the post-translational modification of the protein, which can cause problems and delays in the business timeline. At each step, the protein must be extensively characterized to assure efficacy and potency. All of this effort adds significant expense as well.”

	Therapeutic protein production using CHO is expensive, agrees Mark Emalfarb, founder, CEO, president, and director of Dyadic International. “Mammalian expression systems require costly upfront investments in manufacturing facilities and high material and production costs. In addition, CHO expression entails a relatively low mAb yield (low-single-digit g/L/d) and a long cycle time. Furthermore, CHO cell lines typically require two viral purification steps, which are not necessary for some alternative systems, such as the 

 (C1) fungal system we are developing. C1 has no viruses and thus the need for those purification steps is eliminated,” he observes.

	Another important issue relates to the fact that the current generation of mammalian expression systems has not seen the complex, non-natural protein formats currently found in discovery and thus their synthesis, folding, and secretion machinery has not evolved to handle such proteins, according to Andy Racher, associate director of future technologies at Lonza Pharma & Biotech. “These systems have limited ability to produce these new proteins with clinically relevant attributes and in clinically relevant amounts,” he notes. In addition, many new proteins contain three or four rather than one or two different polypeptides, and current expression vector formats are challenged by these new protein heteromers.

	“It is time to realize the limitations of CHO and look beyond it to explore newer and potentially more efficient drug development and production methods,” asserts Emalfarb.

	As the need to make biologic drugs more accessible and affordable to patients increases, the industry is ramping up its investigation of other manufacturing methods. The drawbacks of mammalian expression systems are also driving the exploration of new and alternative technologies to move many next-generation biologic drug candidates through later development stages.

	A number of “new” technologies will become more routine as the demands for new “designed” proteins strain the capabilities of conventional CHO cell systems, according to Holtz. One important approach is the engineering of new mammalian cell lines using new genetic editing technologies and the innovative design of gene constructs to optimize yields. He also notes that techniques to evaluate libraries of cell lines will help optimize expression and yield.

	Lonza, for instance, has developed a suite of multigene vectors where three, four, and possibly more different genes can be easily inserted into a single expression vector. “By putting all the genes into a single vector, all genes are ensured of being inserted into a transcriptionally active locus in the genome and being transcribed at high levels,” Racher says.

	There are also efforts to develop entirely different expression systems based on plants, baculovirus, bacteria (such as 

 in the Phoenix system), and yeast, many of which have already been demonstrated to get proteins to the clinic and licensure, according to Holtz.

	“In the not-too-distant future, it is likely that drug companies will evaluate two or more expression systems simultaneously as a routine best-practices approach in early stage development,” he comments.

	iBio’s plant-based system offers rapid evaluation of protein expression at a very low cost, according to Holtz. Because vectors are used to transfect the plant leaf cells, multiple constructs can be evaluated in parallel. Once infected, the plants produce the required proteins in less than seven days. At that point they are harvested, homogenized, and a clarified protein extract is ready for traditional protein separation and purification. In addition, scale-up is seamless and reproducible; each 10-g plant is an individual bioreactor, so it is only a matter of growing more plants and there are no issues around changes in protein structure or posttranslational modification, according to Holtz. He also notes that plant bioreactors are grown with no human or animal-derived materials and are not handled at any time by humans, which eliminates the chance that mammalian adventitious viruses will be present.

	Production of plant-made biologics been scaled-up by several companies in new facilities that can produce hundreds of kilos of mAbs and other therapeutic proteins per year. Successful antibodies (cancer vaccines and others) and other therapeutic proteins such as enzyme replacement therapies have been successfully taken to advanced clinical trials and some to licensure. In all cases, there have been no reports of adverse events associated with production of therapies in plants,” Holtz states.

	iBio grows 2.2 million plants continuously at its Texas facility and has worked with a variety of clients to produce mAbs, fusion proteins, antibody-drug conjugates, and vaccines, including virus-like particles (VLPs). “We have invested in increased product and process facilities and a cGMP-compliant pilot plant that-coupled with our large-scale manufacturing facility-assures clients that they can develop their protein through clinical trials and then be supported for the commercial launch of their products,” says Holtz. iBio will also transfer the technology to clients if they want to build and operate their own facilities.

	Emalfarb believes that the C1 fungal expression system may one day be a safe and efficient approach to speeding up the development, lowering the production costs, and improving the performance of vaccines and biologic drugs at flexible commercial scales.

	Dyadic’s Cl gene expression platform is based on technology originally developed for industrial biotech applications, such as biofuel and enzyme production, and sold to DuPont for $75 million in December 2015. The genetically modified strain of 

 is designed to produce enzymes and other proteins at a rapid rate. The company retained the rights to apply C1 to human and animal biopharma applications and has been investigating its use for the production of mAbs with humanized glycostructures; non-glycosylated mAbs, antibody fragments, FC fusion proteins, next-generation biologics, and other therapeutic proteins for which glycosylation structures are undesirable; and antigens, vaccines, and VLPs.

	“We are applying the power of an industrially proven gene-expression system that has been used by the likes of Abengoa, BASF, Dyadic, DuPont, and Shell Oil, among others, to produce industrial enzymes and proteins at greater than 100 g/L of total protein at up to 80% purity (80 g/L) at commercial scales greater by 25 times (500,000-L scale) or more than some of the largest CHO bioreactors (12,000-L scale) in one-half to one-third the time,” Emalfarb explains, noting that there is still room for yield improvement with C1. He adds that Dyadic has to date achieved a productivity for mAbs of 9 g/L in 90 hours or a 2.4 g/L/d production rate, which can be compared to 4 g/L in 336 hours or a 0.30 g/L/d for typical CHO processes, an eight-fold improvement.

	Emalfarb notes that the media cost for C1 is a fraction of that for CHO, there is no need for viral inactivation, and C1-expressed proteins are secreted from the cells in a purer form than those produced by CHO cells so are likely to be quicker and easier to purify.

	Dyadic is currently working with pharmaceutical companies that are researching its C1 platform to speed up the development and lower the cost of biologics, enable the development and commercialization of genes that are difficult to express at reasonable yields in CHO and other cell lines, and apply C1 for the production of larger quantities of proteins earlier in discovery and development. The company and its partners are also investigating the possibility of getting difficult-to-express genes that have potential as new and novel cures-but have been shelved due to lack of expression into the clinic-in a commercializable and affordable way, according to Emalfarb.

	In late 2017, Lonza introduced a new yeast-based expression system for the production of next-generation biologics. Its XS Pichia 2.0 Expression and Manufacturing Platform, based on 

, was designed to combine the best features of bacterial and mammalian systems in one system: fast and easy strain development and robust and rapid fermentation combined with a highly pure secreted product for a simple downstream processing, according to Christoph Kiziak, research and technology lead for microbial technology at Lonza Pharma & Biotech.

	“The driving force was to rethink the whole production strategy for producing proteins to circumvent the main bottlenecks of bacterial systems (e.g., intracellular production, endotoxin), CHO systems (e.g., time-consuming, viral clearance), and yeast systems (e.g., use of methanol, hyperglycosylation), while maintaining the use of 

 due to the general advantages and regulatory acceptance of this yeast cell,” Kiziak says.

	The “auto-inducible” setup of the new system makes it convenient for high-throughput clone screening, which results in highly pure material for preliminary quality analysis of the product at an early time point.

	In addition, fermentation development follows a product-specific model-based approach, which allows yeast fermentations to be performed in two to three days with a high volumetric productivity, according to Kiziak. It can also be expanded by an 

 model for process productivities over a wide production window. “This predictive model allows us to take into account production plant and process-specific limitations at any stage of development and provides high flexibility and quality for later production,” he explains.

	The methanol-free process also avoids the negative impact on cell viability and product quality of the commonly used AOX1 system, according to Kiziak. There is no need for explosion-proof facilities and the lower oxygen transfer rates compared to the AOX1 system provide additional flexibility regarding production plant requirements. There is also no need for endotoxin or viral clearance testing.

	Furthermore, the product is secreted into the culture supernatant, where the minimal medium together with the low host-cell protein background provides an ideal starting point for an efficient downstream process.

	To date, Lonza has focused on producing multi-specific novel antibody mimetics from various sources using the XS Pichia 2.0 and has achieved productivities of more than 2 g/L per day. The company is working to make the system even more customer friendly and easy to apply and to refine the model-based approach in order to improve the accuracy of the prediction of fermentation processes. Additional promoters with different strengths and induction profiles are also being developed to allow the tuned expression of helper factors, auxiliary proteins, heteromeric products, enzyme cascades, etc., which will expand the applicability of the XS Pichia 2.0 in the future, according to Kiziak.

	Regardless of the technology, there is a general acceptance that existing mammalian expression technology can no longer meet the needs of the biopharmaceutical industry. “One way to make healthcare more accessible and affordable to patients could be changing the cell lines we use for manufacturing,” Emalfarb observes. “Our goal is to bring affordable medicines to more patients, in addition to improving processes to develop new treatments,” he adds.

	The industry isn’t there just yet, however, according to Laird. “At this time, we are not aware of novel expression technologies appropriate for commercialization of next-gen biologics with significantly reduced costs, timelines, or complexity that can also ensure consistent post-translational modifications such as glycosylation. Although some new complex molecules could be harder to express using current or conventional mammalian expression systems, we think these systems are and will be the best approaches to express proteins for therapeutic purposes for the foreseeable future, especially given the vast knowledge from current advances in genome sequencing and CRISPR [clustered regularly interspaced short palindromic repeats] gene-editing technology that can be used to modify these conventional mammalian expression systems,” he explains.

	“With that said, we are very open to evaluating novel expression systems and will feverishly pursue new technologies as they become available,” Laird asserts. “We all have the same goal of delivering medicines to patients as quickly and efficiently as possible,” he concludes.

	Genentech is currently focused on the development of targeted integration mammalian cell lines to enable faster, more consistent medicine development with higher productivities. To date, engineered host-cell lines to optimize performance, increase productivity, ensure product quality, increase the ability to produce complex formats, and decrease timelines have been achieved, according to Laird.


	Vol. 42, No. 7
	July 2018
	Page: 28–31

	When referring to this article, please cite it as C. Challener, “The Search for Next-Gen Expression Systems" 

Biopharma seeks alternatives that meet the needs for next-gen biologic drug production.

The Search for Next-Gen Expression Systems

Demand for controlled-release formulations is expanding as patients’ expectations for greater convenience are increasing. Extended-release products have reduced dosing frequencies, which are particularly beneficial for pediatric and geriatric patients, but are appreciated by most patients and in general lead to improved medication adherence (1). Reformulation of branded drugs in controlled-release formats is one of the most common methods for extending the product lifecycle. Generic drugs are also often formulated with controlled-release properties (2).

	Controlled-release behavior can be achieved using polymer coatings on solid dosage forms or by the incorporation of various types of polymer matrix systems, enzyme-activated systems, or systems that respond to changes in physical conditions within the formulation. Mechanisms include dissolution, diffusion, osmotic pressure, maintaining a hydrologic or hydrodynamic balance, and ion exchange. Newer approaches are currently being developed based on nanotechnology and novel matrix technologies and include gastro-retentive drug delivery for controlled release, buoyant systems, and mucoadhesive systems for regulated release of antiviral medications (1,2).

	Excipients are key ingredients in controlled-release formulations. They act as matrix formers in matrix delivery systems and as polymeric membranes for drug powders and multi-particulate systems in oral solid dosage (OSD) forms, according to Bujar Muça, technical product manager, IMCD. Plasticizers and pore formers impact drug release in coated products, and, often, two-polymer chemistries are used to provide tailored drug release. In oral liquid products, excipients can also provide taste masking and protection for the gastric mucosa, he adds. In specific cases, excipients can provide abuse deterrence and aid in the avoidance of alcohol-induced dose dumping, according to Evonne Brennan, technical marketing manager at IMCD.

	“Ultimately,” says Shawn Branning, strategic marketing leader for controlled release at DuPont Nutrition & Health, “excipients that provide controlled-release characteristics to oral solid dosage forms allow not only control of the rate of the API release, but also targeting of where that release occurs.” He adds that when considering OSD forms, controlled-release formulations can refer to various types of sustained-release or targeted-(delayed) release profiles.

	Several factors must be considered when selecting specific excipients for controlled-release formulations, according to Chhanda Kapadia, technical manager, IMCD. Dosage form type and design need to be considered along with the solubility of the API to ensure that the desired dissolution profile can be achieved with a given excipient, and/or that a good 

 correlation is obtainable. Issues that relate to patient compliance and safety should also be considered, according to True Rogers, technologies leader at Dow Pharma Solutions.

	Ethylcellulose remains the polymer of choice in multi-particulate drug delivery systems with or without an additional coating platform, the use of which is dependent on the characteristics and dosage form type of the drug, according to Brennan. Methacrylate polymers are broadly used in delayed-release dosage forms and also provide gastro-resistant functionality. In monolithic delivery systems, hydroxypropyl methylcellulose (HPMC) continues to be the excipient of choice, although the use of two-polymer matrix systems is growing. “This approach can provide unique synergies and enable fine-tuning of the drug release pattern via modification of polymer entanglement and matrix texture,” Muça explains.

	The key for pharmaceutical formula tors, concludes Rogers, is to have proven and flexible polymers such as cellulosics along with knowledgeable partners that can help provide solutions to formulation challenges.

	Many APIs with unique formulating challenges

	Formulators can, in fact, face many challenges-from achieving desirable dissolution and release profiles for poorly soluble drugs to risk management of dose dumping to the selection of biocompatible materials with the desired controlled-release properties (1). Controlled-release products also require high API dosages, which can in some cases be difficult to formulate into the desired dosage forms with acceptable properties (2).

	Newer APIs present some unique formulating difficulties, according to Rogers, such as small therapeutic windows or sensitivity to certain pH environments. On the other hand, formulating controlled-release alternatives to already-marketed products can be challenging if it is necessary to select different polymer chemistries and excipients to avoid patent infringement issues, according to Lies d’Olieslager, technical product manager, IMCD. Consistently matching the drug release profile, the scale-up of controlled-release coating processes (which requires extensive process knowledge), the curing of aqueous coating systems-particularly under dynamic conditions-and resistance to ethanol-induced dose dumping are additional challenges, she adds.

	“Controlled-release excipients are excellent solutions to these particular challenges,” Rogers asserts. For instance, he notes that some excipients can now offer dual functionality, both controlling the release of the API and providing increased solubility to poorly soluble APIs. Understanding polymer chemistry and exploring synergies are also important to overcoming these difficulties, according to Brennan. “Formulator experience is crucial; with movement of personnel, the loss of expertise can impact development times in an already costly process,” she says.

	Given that excipients are key ingredients in controlled-release formulations, it may seem surprising that excipient choices are somewhat limited, particularly for certain patient populations, notably children. Suppliers are developing “novel” excipients that may provide solutions and support to move existing formulations into new areas, according to Mary Tanenbaum, technical manager, IMCD, but excipients do not have their own approval pathway. “Pharmaceutical companies are hesitant to take on the responsibility of toxicology and clinical trials with an untested material and run the risk of jeopardizing approval of their new drug applications,” Tanenbaum observes.

	Most new excipients, therefore, are modifications or combinations of previously approved excipients. For instance, Muça points to granular Carbopol developed by Lubrizol to address flowability issues in direct-compression processing of matrix delivery systems. The Dow Chemical Company has also developed and commercialized Methocel DC2, a more flowable morphology of HPMC for streamlined direct-compression manufacture of modified-release matrix tablets, according to Rogers. In addition, custom grades of Benecel HPMC from Ashland fill a gap in HPMC polymer choice for matrix systems, providing formulators with more predictable release profiles and reducing batch-to-batch variability previously observed due to HPMC blending, according to Brennan.

	Meanwhile, FMC Health & Nutrition, now part of DuPont Nutrition & Health, has promoted the use of surfactants for in-situ curing while coating with Aquacoat ECD, a 30% by weight aqueous dispersion of ethylcellulose polymer. “This pseudolatex dispersion has advantages over solvent systems because it has a high-solids content with low viscosity, and thus a shorter processing time,” notes Engin Sari, technical product manager, IMCD. DuPont has also developed a coating with a robust sustained-release profile in the presence of alcohol that helps formulators create products with resistance to alcohol-induced dose dumping, he adds. Aquacoat ARC is a blend of Aquacoat ECD and guar gum in an aqueous system for multi-particulate drug delivery systems.

	Collaboration is essential to finding solutions

	IMCD represents a wide portfolio of products and continually pursues a training program covering excipient functionality to ensure ongoing knowledge transfer, according to Brennan. “Engaging with formulators to review any challenges they face is key to successful development of solutions. Continued education is also fundamental; excipient manufacturers regularly provide information on product functionality, product consistency, and product variability, and we need to stay up-to-date,” she comments.

	As an industry group, the Controlled Release Society provides a forum for networking and the development of connections within other formulation groups. It does not provide an avenue for the discussion of intimate formulation details, however, which remains challenging, according to Brennan. “Using confidentiality agreements is one approach, but these take time. Good relationships with development teams, therefore, continue to be of primary importance,” she says.

	Excipient manufacturers need to work side-by-side with drug product manufacturers as early as possible in the drug product development process in order to not only identify the issues, but to mitigate the impact of the issues proactively, agrees Rogers. He adds that excipient manufacturers must understand every detail of their processes and polymers in order to achieve the best solutions for their customers.

	“Dow Pharma Solutions works closely with our customers to understand their specific needs, and, over time, we have developed new solutions to meet controlled release formulation challenges as they have arisen,” Branning remarks. “Partnering with our customers not only helps us in suggesting the right solutions for their formulations, but also helps drive our development of new excipients to meet the ever-changing needs of the market. We have found this type of partnership to be the best strategy for addressing the challenges faced by the pharmaceutical market today,” he concludes.

	The Dow Chemical Company has also been busy combining different businesses to expand its excipient offerings to the broader market. The excipient portfolios of The Dow Chemical Company, DuPont, and FMC’s Health & Nutrition division will be combined when the three businesses are merged to form DuPont Nutrition and Health. “The new company will have the expert teams from all three businesses working together and with customers and channel partners to understand their needs and unresolved challenges as well as provide unique combination solutions,” Branning says.

	1. Future Market Insights, “Controlled-Release Drug Delivery Technology Market: Global Industry Analysis and Opportunity Assessment 2017–2027,” Report Description (to be published July 2018).
	2. Future Market Insights, “Oral Controlled Release Drug Delivery Technology Market: Diffusion Controlled Release System Anticipated to be the Most Attractive Segment During the Forecast Period: Global Industry Analysis 2012–2016 and Opportunity Assessment 2017–2027,” Press Release, July 20, 2017.


	Vol. 42, No. 7
	July 2018
	Page: 24–26

	When referring to this article, please cite it as C.Challener, “Selecting Excipients for Controlled Release" 

With the right excipients, formulators can control when, where, and how an API is released.

Selecting Excipients for Controlled Release

Flow chemistry for the production of small-molecule APIs is recognized to offer significant benefits, particularly for processes that involve hazardous reagents or that are highly exothermic. The ability to provide greater process control combined with the use of minimal quantities of reagents at any one time increases the safety of such processes, in many cases enabling the production at commercial scale of valuable compounds that cannot be manufactured practically in batch mode. Continuous processing is new to API manufacturing, however, and additional tools and technologies must still be developed to make this promising approach a practical, widespread reality.

	A few solutions that have been recently introduced or are under development to facilitate the adoption of flow chemistry for API manufacturing are described as follows.

	Continuous processes are required not only for the reactions used in the synthesis of small-molecule APIs, but also for the unit operations connecting reactions. The development of continuous work-up solutions is one area that has been lagging.

	Zaiput Flow Technologies was founded at the end of 2012 to commercialize liquid-liquid separation/extraction technology suitable for continuous processing that was developed by Andrea Adamo while working at the Massachusetts Institute of Technology. The company’s core capability, according to Adamo, is engineering innovation in the context of fluid-related operations.

	Zaiput’s membrane-based separation technology exploits the concepts of hydrophobicity and hydrophilicity and unlike traditional devices does not require gravity to achieve separation. Differences in the wetting properties of two liquids (or a gas and a liquid) on the porous membrane allow for separation of immiscible solutions, even for solutions with compounds that have the same density. One material wets the membrane, filling all of the pores (the wetting phase). Application of a controlled-pressure differential “pushes” the wetting phase through the pores while leaving the not-wetting phase behind.

	“This technology is the only solution available for continuous manufacturing because these devices can be operated in a pressurized line to enable multistep synthesis without interruptions,” Adamo, who is the CEO of the company, asserts. He adds that the systems have excellent scalability and thus provide a single solution from the bench to the plant, reducing the time and money needed for optimization and scale up.

	Zaiput has sold its technology to pharmaceutical companies around the world, and even sent devices into space on the International Space Station. The technology was included in the CRS-13 Mission in December 2017 to confirm its ability to perform in zero-gravity conditions. The devices were found to successfully separate immiscible liquids in space while under remote operation and observation.

	The company has an ongoing collaboration with Snapdragon Chemistry, a contract-development company focused on facilitating the adoption of flow chemistry and is starting one with the “Medicines 4 All” program operated by Virginia Commonwealth University (VCU) with support from the Gates Foundation. “Zaiput has innovation at its heart, and we are always looking for new additions and new ideas,” Adamo asserts.

	For continuous manufacturing, where many of pieces of equipment have to be operated, monitored, and adjusted simultaneously, automation is essential. Automation has long been available on plant-scale but is now coming into the pilot plant and laboratory, according to Matthew M. Bio, president and CEO of Snapdragon Chemistry. “With laboratory automation enabled, flow chemical process development is accelerated through automated experimentation. At the pilot scale, automation is being applied to ensuring safety and consistent product quality,” he explains.

	In-line process analytical technologies (PATs) such as infrared (IR) spectroscopy, Raman spectroscopy, and bench-top nuclear magnetic resonance are also being developed specifically for flow chemistry applications, according to Bio. “In the lab, in-line PATs are providing rich data sets that can be mined for process understanding, while in the pilot plant, they provide real-time process monitoring and enable feedback control of continuous processes.”

	Automated flow systems, coupled with embedded in-line PAT, are being used at Snapdragon to automate the discovery and development of continuous manufacturing processes. “We are able to rapidly define process design spaces through automated process characterization,” says Bio. The company is also developing autonomous process development tools where optimization algorithms are used to discover optimal reaction conditions. The data derived from these flow systems can be used for machine learning applications.

	Flow chemistry is often performed in microreactors, small reactors with small volumes and high throughputs. Anton Paar, in conjunction with pharmaceutical companies such as Janssen, Patheon, Astra Zeneca, and Lonza, has used additive manufacturing to produce a microreactor as part of the international research project “CC Flow.” Initial research and simulations were performed by Professor Oliver Kappe and his team at the University of Graz.

	The reactor was designed for the difluoromethylation of a lithiated nitrile with fluoroform (CHF3), a known greenhouse gas. “Three prototypes were developed before the final design and the perfect internal and external dimensions were determined,” explains Stefan Pfanner, specialist for additive manufacturing and direct metal laser sintering at Anton Paar.

	The reactor was produced via direct metal laser sintering using 316L stainless-steel powder with dimensions of 164 mm by 93 mm by 3 cm (thickness). Stainless-steel was chosen based on the chemical, mechanical, and thermal stability and thermal conductivity required for the reaction, according to Pfanner. A serpentine cooling core is surrounded by reaction channels that have an inner diameter of 0.8 mm and a total length of four meters. There are four inlets, two defined reaction zones, and one outlet.

	Anton Paar plans to develop various tailor-made reactor types for different industrial requirements, according to Gunter Kole, business area manager for analytical and synthetic chemistry at the company. “One of the advantages of 3-D printing is that any type of design can be produced, which has not been possible in the past with conventional manufacturing technologies,” he notes.

	In November 2017, Corning and the University of Liège in Belgium announced the establishment of the first lab in Europe qualified for use of the Corning Advanced Flow reactor (AFR) (1).

	The lab is located in the university’s Center for Integrated Technology and Organic Synthesis (CiTOS), which provides customers with continuous-flow demonstrations, experimental trials, feasibility testing, and chemical reaction process development services. Other labs have previously been qualified in the United States and China.

	Earlier in 2017, Angelini Pharma installed Corning’s AFR technology at its Aprilia facility for use in API manufacturing (2). The company started with a pilot line (G1 glass and G1 silicon carbide) in 2015 and decided to switch to the G4 production reactor shortly afterwards. The production reactor meets pharmaceutical quality and FDA requirements. The company uses flow chemistry to perform reactions it could not do previously on a commercial scale in batch mode (2).

	The AFR technology is specially designed to enable the conversion of batch chemical processes to continuous processes. The reactors consist of engineered fluidic modules that integrate heat-transfer and mass-transfer into a single piece of equipment. As a result, they offer at least 100 times enhancement in mixing, 1000 times improvement in heat transfer performance, and efficient scale-up from the lab to full-scale production, according to the company (1). Processes, therefore, can benefit from increased efficiency, scalability, yields, and quality with reduced performance variability and cost.

	Another change in technology that is impacting continuous manufacturing today, according to Bio, is the approach to scale up and the design of production facilities for continuous manufacturing. He points to Eli Lilly’s Kinsale plant in Ireland as an example of a new approach to pharmaceutical drug-substance manufacturing in which the use of small-footprint modular components in fume hoods results in a flexible facility where process trains can be easily reconfigured for multi-product applications. “The reduced size and cost of continuous manufacturing equipment together with the ability to adjust output by numbering out and numbering up will enable responsive supply chains for pharmaceutical API,” Bio states.

	Snapdragon has developed a scalable-by-design approach to flow chemical process development. “We have invested in the development and characterization of laboratory reactors that mirror the performance of production-scale reactors. Our custom software platform FlowChem WebApp continuously logs data from these reactors and interacts with a suite of [Internet-of-Things] IoT-enabled flow components for automated experimentation and even autonomous, algorithm-driven, reaction optimization. These tools allow for rapid translation of laboratory results to production scale,” says Bio.

	Snapdragon has also invested in the development and scaling of photochemical processes, recently completing the design and construction of a production-scale 5 kW flow photoreactor that is built to work with a range of different wavelengths and is able to operate under pressure for gas/liquid photoreactions.

	Pumping technologies for flow chemical applications, particularly at lab and pilot scale, are still inadequate, according to Bio. “The syringe pumps typically used in laboratory flow demonstrations don’t accurately mirror the performance of plant-scale pumping technologies, but to develop plant-ready processes, pump performance characteristics must be taken into account,” he explains. Some manufacturers are beginning to look at this issue, though. The Tacmina Smoothflow technology is particularly useful for developing flow processes with organometallic reagents, according to Bio. Snapdragon has been working with Tacmina to evaluate this pump in flow chemistry applications. The company is also evaluating microannular gear pumps as another scalable pump technology for flow chemistry.

	1. Corning, “Corning and University of Liège Announce First Advanced-Flow Reactor Qualified Lab in Europe,” Press Release, Nov. 3, 2017.
	2. Corning, “First Industrial Use of AFR Technology in Italy,” Press Release, March 2017.


	Vol. 42, No. 6
	June 2018
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, “New Tools Outline Advances for Continuous API Processing" 

From separation systems to reactor technology, new tools are increasing the feasibility of continuous API production.