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

Cynthia A. Challener

Continuous manufacturing has been common practice in many industries for decades, but it is just now entering the early phases of adoption in the pharmaceutical industry. With effective online analytical capabilities available, equipment suppliers have been able to develop systems for various aspects of the tableting process, and drug manufacturers are beginning to realize the many benefits of continuous processes. Although challenges remain, expectations are high for the eventual fuller use of integrated continuous processes for solid-dosage manufacturing.


There are several benefits associated with effective continuous production systems. Increased safety and lower costs are on top of the list. “Continuous processes are more integrated with fewer steps, which leads to less manual handling and increased safety,” says Kris Schoeters, product manager continuous processing for GEA Pharma Systems. “In addition, the equipment and facilities are much smaller, allowing flexible operation at lower capital costs, with less work-in-progress materials.” Along with the monitoring and tracking, which are a fundamental aspect of continuous manufacturing, there also is better control of the process than is possible with batch processes, so both the consistency and quality of tablets are improved, according to Stephen Boswell, director of S3 Process, a provider of process equipment.  

Additionally, the development time and costs for continuous processes are often less than those for conventional batch-manufacturing operations. “Inherent R&D advantages include quicker capabilities to test a variety of process conditions and the use of smaller quantities of expensive API,” notes Sharon Nowak, global business development manager for food and pharmaceuticals with K-Tron Pitman. Adds Ivo Backx, manager of business and project development for the pharmaceutical industry with Siemens: “The time is shrunk at the development stage and during the move from development to production, in part, because process analytical technology (PAT) tools are an integral part of the development process and also because there is no need for scale-up to different equipment. Commercial-scale quantities can be produced on the same continuous tableting equipment used during the development stage.”

Benefits continue to accrue after product launch as well. Capacity can be dynamically adjusted to meet market requirements by running a process for longer or shorter periods, according to Backx. Boswell adds that with smaller equipment and less capital investment, it is also possible to locate continuous tableting lines in a greater number of geographic locations so that transportation costs are lower and drugs can be formulated for the local market. “Such advantages are particularly critical for US and European manufacturers to remain competitive,” he notes.

Overall, companies that implement continuous manufacturing processes expect a fast return on investment and cost savings from 10-20% compared to batch operations, according to Backx. Furthermore, with the reduced waste generation, greater product recovery, lower energy consumption, and overall improved operation efficiency, continuous processes enable “greener” manufacturing.


Even with these benefits, pharmaceutical companies have been unwilling until recently to make a move toward continuous tableting. “There has been a hesitancy to make investments in continuous manufacturing. It is quite a big step for drug manufacturers to take,” says Boswell. Some of that hesitancy, according to Schoeters, has been related to the need to establish that each batch of product, ultimately released following sampling and testing of finished product, is homogeneous. “Traditionally, this characteristic is established by blending the batch immediately prior to compression, but in a continuous process, the batch is never assembled in one place. Previously, the available on-line monitoring tools were not efficient enough.” 

Recent developments in the use of PAT for on-line and at-line monitoring to prove the quality of product and process continuously as well as the design and engineering of continuous process components in pharmaceutical execution, have helped pave the way for continuous processing consideration, according to Nowak.  

The introduction of equipment for flexible, compact, quasi-gram-scale continuous manufacturing has also been critical, according to Schoeters. GEA focused on integrating the entire process cycle from weighing, blending, granulation, and drying up to tablet compression in its systems. “Also important is a steady-state controllable flow of ingredients into the granulator, even in the face of often-challenging powder flow properties, and to ensure plug flow so that tracing of ingredients for specific ‘batches’ can be established.” Adds Boswell: “A substantial derisking of R&D scale-up is possible with certain continuous technologies, such as that from Gerteis, where process parameters are the same between clinical-trial to large-scale manufacturing, [thereby], saving substantial scale-up cost and risk.”

K-Tron also has addressed the need for equipment that can process smaller quantities of material for both development and pilot-plant continuous processes and for poorly flowing APIs and excipients. It has systems designed to deliver as little as 20 grams per hour with high accuracy, according to Nowak, and its latest feeder, which will be introduced at Interphex in April, functions effectively with difficult cohesive powders.

FDA’s support of continuous processing is also causing many pharmaceutical companies to seriously pursue this option in development and manufacture. Still, Backx warns that companies need to have a clear understanding of their business goals when implementing continuous tableting or any other continuing manufacturing operation. “For some companies, continuous manufacturing might provide a new approach to improving a problematic process through increased process understanding and control while others may be looking to first implement continuous manufacturing for drug-development efforts rather than changing existing processes.”


Of course, there are challenges still to be faced before continuous tableting will be widely adopted in the pharmaceutical industry. Nowak points to two major issues that are currently being addressed: the integration of the complete continuous process and defining both the actual lot size being produced and the size and frequency of sampling measurements.  

Schoeters agrees that full integration of all of the different PAT measurements is critical, as is intelligent feed-forward and feed-back loops and control systems to ensure the most efficient performance. 

K-Tron, which has experience with these types of online feed-loop controls in equipment for the plastics and food industries, expects that they can easily be modified for utilization in a continuous blending or granulation process to assist in the overall quality of the product and process, according to Nowak.  “The ability to monitor material feed properties and integrate this data into a sophisticated overall data management tool will not only provide for enhanced process understanding, but also enable end-users to specifically understand the process impacts of different lots of raw materials.” 

There are also implications for facility design that must be considered. “The workflow within facilities must change with the adoption of complete continuous tableting processes,” says Boswell. “Those changes won’t happen overnight, but they will happen over time.”

Regulatory-related issues are causing some companies to remain cautious. The uncertainty regarding how regulators will formalize the approval of continuous manufacturing and real-time release strategies is a concern, notes Backx. He points out, though, that the uncertainty is largely due to the lack of experience rather than any actual regulatory impediments. Some are also worried about continued emphasis on the term “batch” in regulations. “This concern is unfounded, however; regulatory definitions for the term ‘batch’ already include those batches produced through continuous methods—the mode of manufacturing is not mentioned. Companies establish the ‘specific quantity’ of output that will count as one batch for tracking and tracing and potential recall purposes,” Backx explains.


As pharmaceutical companies begin to realize the significant potential for cost savings and quality improvements, many of these issues and concerns will be addressed. Companies, such as Siemens, GEA Pharma Systems, K-Tron, and S3 Process, are working closely with customers in the pharmaceutical industry, software platform manufacturers, and universities to gain greater process understanding and develop fully integrated continuous tableting systems that will ultimately include data-driven quality verification for in-line assurance and real-time product release.  

Articles

Equipment suppliers are helping the pharmaceutical industry move towards adoption of continuous tablet production.

Making Strides in Continuous Tableting

Biopharmaceutical manufacturers are looking to their raw-material suppliers to provide them with the support of a secure supply chain. To gain a perspective, Cynthia Challener, PhD and editor of the 

Pharmaceutical Sciences, Manufacturing, and Marketplace Report

, recently spoke to Beth Ann McLane, SAFC’s product manager for enhanced quality, of the importance of ensuring supply-chain transparency and quality for raw materials. SAFC recently introduced a line of PharmaGrade products for raw materials for biopharmaceutical applications. 

Public demand for increased supply chain security

Pharmaceutical Sciences, Manufacturing and Marketplace Report: 

What situation led to the decision to develop your new PharmaGrade raw materials for the biopharmaceutical industry?

 Biopharmaceutical manufacturers are faced, now more than ever, with the reality of global events that have threatened and breached supply-chain security. These occurrences have caused a public outcry, and regulatory bodies have demanded higher levels of compliance. Manufacturers are now being held fully responsible for the raw materials that go into their products, and they simply do not have enough capacity to test for all of the possible contaminants that could find their way into the materials. 

In response, the industry is moving towards risk assessment and risk mitigation of raw materials from the early stages; in essence, manufacturers are looking to their raw-material suppliers to provide them with the support of a secure supply chain. The more that biopharmaceutical manufacturers know about their suppliers and the raw-material supply chain, the more confident they can then be about the safety of those raw materials.

Pharmaceutical Sciences, Manufacturing and Marketplace Report:

 How is the introduction of a new grade of pharmaceutical raw materials anticipated to fill these market needs?

 PharmaGrade products were developed to provide better supply-chain transparency and manufacturing controls; they are a lower-risk option to use in manufacturing than many currently available raw materials. The portfolio was created in response to urgent demand from customers for products they can count on to be consistent and that are from a source where the production is controlled and changes are limited. These types of customers are not only looking for a guaranteed level of quality, but they also want to know what is happening with the raw materials and to be notified if/when any changes occur.

When we started to build the product line, we anticipated that customers would be looking for a higher level of documentation and support than ever before. In response to this expectation, we have put a great amount of resources into identifying and qualifying products for the line. In addition, SAFC has a strong change control notification system and offers robust support, especially for our GMP and Elite quality-level products.The Elite products provide an option for customers that are looking for highly controlled products, but do not necessarily need them to meet the same level of validation as required by GMP guidelines.

Ensuring audit-worthiness of key ingredients

 What are the specifications/requirements for the new grade of raw materials? How were these determined? How are they different from existing raw materials?

 SAFC’s goal is to hit seven key criteria for the new materials that were directly based off of customer requests. The first six are:

Manufactured under GMP (or SAFC’s Elite) quality guidelines

Quality assurance review and release of each lot

Readily available quality documentation (laid out in an easy-to-use format)

The challenge for raw-material suppliers has been to produce and sell raw materials that can stand up to an audit. As such, one of our key goals is to make sure customers know what they are buying and are satisfied that the products meet their expectations for quality and documentation when they audit. The seventh, and perhaps, the most important criterion, is to have these products available as catalog items in inventory, so customers can have access to them when they need them.

Which types of materials is SAFC looking to offer at this new grade? How/why were they selected? 

 SAFC is offering a broad range of amino acids, buffers, and specialty chemicals as PharmaGrade materials. These chemicals were selected because they are components with known usage in biopharmaceutical manufacturing. We knew they would appeal to a broad number of customers.An example of a product we offer is L-methionine sulfoximine, which is used as a selection agent. Until SAFC introduced the PharmaGrade version of the product, the other products available in the market were not made at the same high quality level, under controlled processes, and with the same supply-chain transparency. Additionally, we wanted to be sure to offer commonly used chemicals, such as sodium butyrate, L-tyrosine, and disodium salt. 

 How has the introduction of the new grade of raw materials affected SAFC’s suppliers and customers? What feedback have you received?

 Many of our customers have been eagerly looking forward to the introduction of new PharmaGrade products, and the feedback has been very positive. They have been extremely pleased with the readily available inventory of each of our products as well as the enhanced quality product documentation that comes with them.

Each product has a complete dossier of information about it, including the site of manufacture and quality systems associated with the product. We are directly responding to customer requests for products that are available when they need them and in the format they need them. Customers have clearly expressed that they want us to expand the offering as quickly as possible.

The only real issue we have had is delays in adding new products to the line due to requirements we expect from suppliers. This line of products requires that our suppliers provide us the detailed information about raw materials and procured products so that we can offer the full level of supply-chain transparency expected with the PharmaGrade portfolio. If we realize that a product cannot meet the standards, then we will not move forward in adding it to the line. Or if we realize that we need longer to verify the standards, then we will take the time to make sure that happens.

 What can be expected in the short-term and long-term with respect to the PharmaGrade products for biopharmaceutical manufacturing?

 SAFC offers PharmaGrade products globally, and we will continue to launch new products globally each quarter. Our immediate plan is to double the size of the PharmaGrade portfolio by the end of 2013. Our long-term goal is to create a full line of products for biopharmaceutical manufacturing with the right supply-chain transparency and control to help customers reduce the risk in their raw materials and, ultimately, their final products.

Ensuring the quality of raw materials is a crucial component of achieving product quality of APIs and finished drug products.

Strategies for Achieving Biopharmaceutical Supply-Chain Security

As the demand for larger amounts of stem cells and other fragile cells grows, biopharmaceutical companies are struggling with how to effectively produce these specialized biological materials in larger quantities. ATMI LifeSciences has developed a new reactor to meet that need. Product Director Matthieu Egloff spoke with the 

Pharmaceutical Sciences, Manufacturing & Marketplace Report

 about the special conditions required for the larger-scale production of fragile cells and how its new Xpansion reactor was designed to provide them.

A podcast version of the interview also may be found 

Pharmaceutical Sciences, Manufacturing & Marketplace Report:

 Why is there is a need for special reactors that are suitable for the growth of cells and particularly for fragile cells. Also, what are the trends in biologic API manufacturing that have led your company to develop a special reactor system?

 First, I will start by dividing or categorizing the cell-therapy market. There is a lot of noise today in the cell-therapy and emerging field, and it is a promising new therapeutic area. In these markets, you have different kinds of applications, but you have also different kinds of sources for cells and so have different products based on these cells.  

From all of these kinds of cells, one that is today making a lot of noise is stem cells. You have different sources of stem cells, adherent stem cells and pluripotent stem cells. All of these stem cells are very fragile cells to grow and use, and the technology to cultivate these cells doesn’t really exist today, or at least in the last year, there were not many technologies able to grow these cells.

Because cell therapy is an emerging market, I think the main companies developing the biotechnology didn’t have the time to really get involved into this market and to develop the right technology. But, today, this dawn is changing, and biotech companies, such as ATMI, are now developing this specific bioreactor.

And I will say why we have to develop a new bioreactor. Before, most of the biotech production was based on cell lines, mammalian cell lines, for adherent cells, for example, and these cells were used for vaccine production or for protein production. In this case, you just need to grow the cells and you will use what will be secreted by the cells. There is not really a need to harvest the cells at the end of the process.

But with cell therapy, it’s completely different. Now, you will have to harvest the cells because the cells are the product. You have to grow the cells and then make sure to be able to get them. That’s the tricky point from a technology perspective, and from a biology perspective, these cells, the stem cells, for example, are very fragile cells, meaning that they are very sensitive to what we call the niche microenvironment. You really have to control this niche microenvironment to be sure that the stem cells that you will grow will behave as you want.

So that’s the reason that you have to develop a very specific bioreactor that will support the right growth for these cells.

 What exactly makes the cells fragile, and what are the special requirements that are needed to be able to work with those cells?

 The main reason that these cells are fragile is because they are very sensitive to what I mentioned before, to the niche microenvironment, meaning they are very sensitive to the physiochemical parameters of pH and dissolved oxygen, and they are very sensitive to shear stress. Also, different factors and parameters can, in fact, affect the differentiation of the cells. That’s something very specific to stem cells. The stem cells can differentiate into different lineages, so according to different factors, they can differentiate into one type of cell or another one. And that’s why it’s very complicated to cultivate these cells because you really need to [not only] grow them, but to drive them on the right path. You have to avoid differentiation, or at least avoid the differentiation you don’t want to have. That’s why you really need a system that will be able to control these niche microenvironments.

 What are some of the special requirements that allow you to do that then in a reactor system?

  The first one, if we are talking mainly about adherent stem cells, is to control the environment of the cells, so you will have to control the pH and you will have to control the dissolved oxygen level into your bioreactor. You will have also to control and to minimize the shear stress, meaning that you can’t use a bioreactor with high mixing and shear stress. You will have to protect the cells; that’s the main requirement you need.

And, of course, for the stem cells growing in adherence, you will have to provide a surface to help the cells to adhere to something, to the surface or the scaffold needed to preserve the stem cells and not leave the cells to differentiate into another type of cell you don’t want to have.

 Can you describe your Xpansion Bioreactor system and how you’ve incorporated these requirements? How it is different from a conventional reactor as far as the design and operation, and how does it fit in with the rest of the manufacturing operation?

 Today, most of the cell-therapy companies, or the companies developing products based on stem cells and adjuvant stem cells, are using tissue-culture flasks or multi-tray vessels to grow these cells. And these companies, because they are in the early R&D phase, or in clinical and early clinical trials, are using multi-tray stacks. These technologies have been used in the market for a very long time. They are robust, and these technologies—the tissue culture flask and the 2D and multi-tray stacks—are what we can call planar technology, meaning a 2D surface, a plate surface, and plastic. A cell-therapy company has to scale up the process, but it’s just impossible to have a commercialization process based on a tissue-culture flask or multi-tray stack technology because with this system, for the controls, you have to operate the system with manual operation and you have to operate the system under very aseptic conditions. There is a lot of risk to continue to use these technologies for high-volume manufacturing at the commercialization stage. Most of these cell-therapy companies have to develop and to scale up these small scale processes. For them, the main requirement, of course, is to be able to preserve the cell’s integrity, identity, and potency.

Because the stem cells are very fragile, and because these companies have developed the cells onto a 2D surface, a plastic 2D surface, they have to keep the same kind of microenvironment. Again, still for the same purpose, to preserve the sensitivity.That’s why, at ATMI, we developed something very similar to what people are used to using. We developed a multi-plate bioreactor, and that is unique on the market today. There is no other multi-plate bioreactor. We have really compacted the design of a multi-tray stack to keep the same philosophy. We continue to use a 2D surface and with plastic. We are using the same polystyrene material as in multi-tray stacks or tissue-culture flasks, and we are using the same kind of surface treatment. Thanks to that, we are really providing to the cells the same kind of environment as in a tissue-culture flask or in a multi-tray stack.

That is the first innovation we brought—to really compare the design.  In a typical multi-tray stack, you have a lot of space between two plates, and with the design of Xpansion, we really succeeded in avoiding the space between two plates. Turning to a multi-tray stack, you have a space between two plates of about 16 mm; with Xpansion, we have only 1.6 mm between two plates. We also succeeded in reducing the thickness of the plate; it is about 3 mm in the multi-tray stack, and with Xpansion, we have only 1 mm of thickness for the plate. Thanks to that, we really compacted the design, and with one Xpansion bioreactor, that’s the name of the bioreactor, Xpansion, with the Xpansion bioreactor with 200 plates in only one device, it is equivalent to 20 multi-tray stacks.

To give you an idea, a 10 multi-tray stack is about 4 meters high, and the Xpansion with 200 plates is below 1 meter high. It has really decreased the footprint, but it’s also decreased the number of operations because you don’t have to manipulate 20 devices; you only have to manipulate one device.

That was the first innovation—to keep the same kind of material, to preserve the niche microenvironment, and to compare the design.  The second point was to add all the advantages of a bioreactor, meaning the capacity to control pH, to control the dissolved oxygen, inside the bioreactor. We also have another feature, the capacity to observe the cells inside the bioreactor. We have a specific microscope that helps us to observe the cell density and the cell confluency inside the bioreactor.

The main value of this bioreactor is to help our customers to switch easily from multi-tray stacks or tissue-culture flasks into a bioreactor system. Thanks to that, they are able to scale up the process. Then, of course, they are able to improve the safety of the process because it’s a closed system. They also are able to decrease the cost of goods because you minimize the number of operations. You need less operators to operate the system, and they are able also to decrease the investment cost. Because, thanks to the system with the bioreactor, you will minimize the number of incubators that are required, and you will minimize the number of laminar flow hoods that are required with the previous technologies.

Because the bioreactor can be operated in a closed system, you will be able to work in a Class C environment, so you will definitely minimize the size of your facility, and the class form environment of your facility. Again, you will decrease the investment cost.

 Are you working on further developments for fragile-cell manufacturing? Are you looking to improve the reactor or introduce any other technologies that would be of benefit?

  Yes, definitely, because we think that Xpansion is a great technology to help our customers to move from the R&D process to clinical production, and then to start to have early commercialization or mixed-scale commercialization of production and sales. But, some companies will have to produce a huge number of cells per cell batch, and for this kind of process, we are evaluating what can be the next generation of bioreactors for stem-cell production of very, very large numbers of cells.

For that, there are two main options today that we are evaluating. The first one is microcarriers, and it’s very difficult to grow stem cells on microcarriers for different reasons, but one of them is mainly the shear stress on the cells and how to guarantee seeding of the microcarrier and so on, and how to scale up a microcarrier-based process.

For that, we have a specific bioreactor at ATMI that has a specific and very low shear stress, thanks to a very high mixing efficiency.  It’s a PadReactor, and it’s based on a patented mixing technology. That’s one method we are exploring—the use of microcarriers and this bioreactor. The second option we are evaluating is to use what we call a 3D scaffold that provides a lot of surface for the cells into a small volume, and thanks to the 3D technology, we may be able to produce a very high number of cells in a very small bioreactor. Those are the kinds of technologies that we are today evaluating for the future.

 Do you have any estimation on a time frame for when these technologies would be available?

 Today, we have the PadReactor technology available. We have already a lot of data using this technology and microcarriers for viral production. We are working with the top vaccine producers in the world with these technologies, so this technology is used a lot. We now have to adapt the microcarriers for fragile cells, and we are now starting to assemble some partnerships to explore how to grow stem cells with the PadReactor technology. So, hopefully, in the next year, we will have good data to show to our customers regarding this technology. And for the 3D technology, it really depends on how we will push forward the development; the ongoing development is quite confidential today, so it is difficult to give you an answer on the second option.

Matthieu Egloff, product director with ATMI LifeSciences, discusses the need for larger, special reactors that can provide the necessary conditions for the production of fragile cells on a larger scale.

New Reactor Technology Enables Larger Scale Manufacture of Fragile Cells


Catalysis is critical to the synthesis of pharmaceutical intermediates and APIs. Catalysts make important synthetic reactions proceed more rapidly and often enable the formation of complex structures in fewer steps with greater selectivity. Biocatalysts, typically enzymes, offer additional advantages. They catalyze reactions under mild conditions and thus consume less energy. They do not require the use of heavy or toxic metals, and in some cases enable the avoidance of hazardous raw materials. In addition, such reactions can often be carried out in water rather than organic solvents, and they tend to generate less waste.

Until recently, pharmaceutical companies tended to consider biocatalytic routes only in later development stages. “Biocatalysts have not frequently been considered in the design of manufacturing processes for drug candidates in early stage development, such as candidate selection in preclinical development, according to Daniel Mink, corporate scientist, biocatalysis, from DSM. “Generally, biocatalysis has been treated as a viable cost-saving alternative only in late-phase clinical stages (i.e., Phase II and III).

Biocatalysis is now being applied throughout the pharmaceutical development process, beginning with the synthesis of compounds for structure activity relationship studies through initial route development and for commercial scale production, according to Tom Moody, head of biocatalysis with the Almac Group. 


Recognizing the growing need for biocatalytic expertise, Almac established a biocatalysis group in 2007 that has since doubled in size. The company recently invested £2.5 million ($3.75 million) in biocatalyst R&D and launched its own selectAZyme biocatalyst technology platform. “The biocatalysis group is now an integral part of the Almac Sciences’ business unit, which focuses on the development phase. Furthermore, Almac has successfully introduced biocatalysis in manufacturing processes for candidates in preclinical development that immediately resulted in substantial savings in terms of processing time, quantity of starting materials required, and quality of end product, with no impact on the development time, according to Moody.

DSM, meanwhile, has a proven track record with over 30 commercial bioprocesses run on a multiton scale with experience in the manufacturing of intermediates, APIs, and enzymes, according to Mink. “As a result, this collaboration on biocatalysis fits strategically and technically for both companies. Our manufacturing assets are complementary, and together we can offer a true one-stop-shop for biocatalytic solutions.” 

 As importantly for Moody, with the partnership in place, Almac now has the opportunity to screen the collection of DSM enzymes at Almac, while DSM has access to Almac’s proprietary enzymes. “Together, we now offer the pharma industry the largest enzyme platform for structural diversification and commercial scale production,” he explains. Each company has the entire platform of enzymes in house and available for screening but will continue to handle the sale of enzymes or transformations individually. “With such a large platform that offers many complementary enzyme chemistries, we have a much higher chance of finding a hit as the result of our enzyme screens,” Moody states.

Specific enzyme technologies of note include pig liver esterase (PharmaPLE) for sterically demanding esters, aldolases for carbon–carbon bond formation, and epimerases and oxidoreductases that make it possible to investigate different chiral spaces, which is critically important in pharmaceutical synthesis.


The goal of this partnership is to increase the services that both companies can offer to their customers. “Via this agreement, we maintain our commitment to the future of pharma manufacturing, adding to our green-chemistry toolbox. Working with the Almac Group marks further advancement of DSM's stated strategy towards strategic partnerships to excel in providing new customer solutions,” says Alexander Wessels, president and CEO of DSM Pharmaceutical Products.Notably, the agreement is nonexclusive. “The relationship with the customer is very open, and it is the customer who drives the entire process,” Moody says. Almac will always discuss manufacturing options in good faith with the client. If the process fits within Almac’s scale of manufacture, Almac will likely keep the project. If it exceeds Almac’s capacity, Almac will and recommend DSM where appropriate. 

In addition, customers can choose from several different business models. “From the earliest stage of discussions, the clients’ strategy for commercial supply will be discussed and defined, and a range of options will be offered to them,” notes Mink. 

If a customer is only interested in material delivery, Almac or DSM, as appropriate, will develop the process and supply the product at an agreed price. Alternatively, customers can pay for the process development work and own the process intellectual property, but still have Almac or DSM manufacture the product. Clients can also choose to have full control over the process, own the enzyme for the particular transformation (such as one that has been evolved at the behest of the customer to perform specific chemistry using the customer’s substrate), and transfer the manufacture to an external third party. Customers that choose to scale up their processes with DSM will benefit from a seamless transition. “Almac has an experienced and dedicated technical transfer team that has already transferred multiton scale manufacturing processes to commercial facilities in Europe and the Far East,” Moody observes. “Furthermore,” he adds, “Almac and DSM share the same approach to process development and have complementary production capacities, which should make the transition even smoother.”


The collaboration, announced in the fall of 2012, has already born fruit. The first project, for which Almac developed the process and has proven it at the pilot scale, will shortly be transferred to DSM for commercial-scale production. While the companies cannot provide details of the API due to confidentiality agreements, Moody has indicated that the compound is a natural product, and the process involves a multistep synthesis.

“We are excited about this collaboration and the fact that it will help increase our chances of finding the right enzymes for our customers and make it possible to access new and varied structures,” says Moody. “Both Almac and DSM are and will remain very active in the discovery and development of new enzymes that will further widen the spectrum of bioreactions possible and offer even more diversity to the pharma industry, adds Mink.”

Collaboration provides pharmaceutical industry customers with access to enzyme expertise and assets resulting in cost-effective, green processing at all phases of development, from preclinical to commercial manufacturing scale.

DSM, Almac Partner in Biocatalysis

Pharmaceutical laboratories are under pressure to increase productivity in order to speed up product development. The growing interest in process analytical technology has increased demand for more rapid analytical techniques that are appropriate for use in the manufacturing environment. More rapid analysis of production batches is needed to get material to market faster. Ultra high-pressure liquid chromatography (UHPLC), introduced in 2004, has become an important analytical tool for meeting these varied needs for higher throughput. Analytical instrument makers believe that further advances in the technology will enable UHPLC to have an even bigger impact on the pharmaceutical industry.


“The field of separation science was revolutionized with the introduction of the first commercially available UHPLC system,” asserts Eric Grumbach, senior product marketing manager for separations technologies with Waters Corporation.  “Today, there are tens of thousands of these systems in use, clearly indicating that the inherent business and scientific benefits of UHPLC technology are being realized,” he continues.Many factors are contributing to the demand for UHPLC. First, according to Grumbach, is the fact that the pharmaceutical and other industries, are under increasing pressure to improve overall profitability, from research and development through manufacturing and distribution, all the while facing the challenge of diversifying their product portfolio into new and unfamiliar territory. “One avenue towards improving profitability is to increase the throughput of their laboratory and manufacturing operations in an effort to decrease product development timelines and bring their products to market faster,” he notes.

The need for quicker results, but with moderate sample sizes, is another driving force behind the implementation of high throughput UHPLC, according to Michael Frank, marketing manager for HPLC at Agilent Technologies. “For the release of a production batch, not only the one sample has to be analyzed, but easily up to 20 if counting blanks, standards, repeated analyses, etc. The approval process using conventional HPLC, with typical run times of 20 minutes, can take nearly 7 hours. UHPLC, which is often 5 to 10 times faster, allows a significant reduction in the analysis time, and thus, production batches can be released in much less time. As a result, produced goods can be packaged and shipped sooner, streamlining the complete process and saving money.”

The online monitoring of products directly in the manufacturing facility is also much more feasible when using UHPLC compared to HPLC, according to Rainer Bauder, HPLC solutions manager for Thermo Fisher Scientific. “With UHPLC, the results are available within a few minutes rather than 30 or 45 minutes, which enables an immediate response to any undesired condition within the production cycle. Similar benefits can also be applied to process development and cleaning validation.”

	Multiresidue methods, including UHPLC, are also becoming the preferred way to monitor for drug residue contamination as the number of contaminants that are monitored increases, according to April DeAtley, LC product planner from PerkinElmer. “The combination of more complex analyses and a growing number of samples means that longer runs cannot be tolerated in high throughput labs, where the emphasis is put on achieving the maximum chromatographic resolution in dramatically reduced times.”


UHPLC is based on stationary phases using smaller particles. While conventional HPLC assays use 2.5–5 µm separation media, UHPLC assays use smaller 1.7–1.8 µm column chemistries that offer up to a three-fold higher separation efficiency. Thus, the same exact separation can be achieved in a column that is threefold shorter, which directly translates into higher throughput due to shorter analysis times. Alternatively, better chromatographic resolution can be achieved with UHPLC compared to conventional HPLC if the same method conditions are used. Bauder adds that in addition to faster results, the power of UHPLC as a technique lies in its extreme versatility, the opportunity to reduce operation costs and solvent consumption, and the ability to develop higher resolving methods for new products, which mitigates the risk of missing problematic impurities during drug development or production. Nearly all instrument suppliers offer online calculators for establishing equivalent conditions for UHPLC and HPLC. Thus, the analytical chemist now has the flexibility to decide between the same resolution and higher speed or the same speed and higher resolution, according to Frank.


While it may seem contradictory, one recent advance in UHPLC technology has been the introduction of the ability to run conventional HPLC methods on UHPLC systems. “Pharmaceutical customers need to be able to run legacy HPLC methods because these methods have been validated for approved drugs, and any change in the QC method requires revalidation, a halt in production, and an interruption of the revenue stream,” explains Grumbach.

There have also been a number of developments with respect to separation column technologies, according to Bauder. “New sub-2 micron particle and core-enhanced column technologies boost separation efficiencies and are triggering the development of new generations of column chemistries that offer improved selectivity for previously problematic target molecules, such as small, highly charged ions and mixtures of acidic, neutral and basic analytes. Grumbach points to the development of alternatives to U(H)PLC  systems based on supercritical fluid chromatography (SFC), which he believes has enabled the development of a truly exceptional selectivity tool that is orthogonal to traditional reversed-phase methodologies. “This mode of chromatography has proven to be a clear replacement for normal-phase chromatography for most applications, and one that is ideally suited for chiral analysis. As an added benefit, the reduced solvent usage has significantly reduced assay cost and allows organizations to meet sustainability initiatives.”

The ability of the instrumentation to withstand increasingly higher pressures is also critical to the advancement of UHPLC technology. “Entire systems are now able to tolerate greater pressures, including pump backpressures and detector flowcells. As a result, UHPLC systems are increasing in their overall performance,” notes DeAtley. Bauder adds that the development of novel detection techniques fully supporting UHPLC-type separation deliver additional leverage for faster and more in-depth sample assaying. Thermo Fisher Scientific has also focused on improving workflows around and within UHPLC instruments, including the introduction of automation tools, such as its x2 dual gradient UHPLC pumps and autosamplers that perform sample injection and fraction collection.


 Workflow, in fact, is one of the factors limiting the ability of pharmaceutical companies to fully leverage UHPLC technology. “A consistent theme we have heard from many of our customers is that the bottleneck of their workflow has moved from analyzing their samples, to preparing those samples prior to analysis. There is a need to make sample preparation workflows more efficient such that they can keep pace with the higher throughput analysis that UHPLC technology inherently provides,” Grumbach observes. Frank believes, however, that automated liquid-handling systems and the ability to make automated changes with different ultra high-pressure valve solutions for rapid switching to different solvents and columns is increasing the flexibility of UHPLC systems.

	Other limitations of UHPLC are being addressed with column technology, according to DeAtley.  “Solid core column technology is allowing for very fast runs, incredible resolution, and lower pressures, which takes much of the stress off of the system,” he comments. Bauder believes that, in addition to needed advances in system control and sample management, there remains significant improvement potential with respect to data processing and detection technologies, and that new and exciting column technologies are also showing great promise.


 Clearly, much more can be expected from UHPLC in the future. DeAtley believes that column technology coupled with UHPLC capabilities will work together for lower pressure UHPLC applications with the benefit of fast run times and overall cost of ownership benefits. “We are definitely continuing to explore the boundaries of UHPLC technology. Further advances, however, may not come in the form of smaller particles (e.g. 1-µm particles) and higher pressures, but rather through the use of miniaturization, microfluidics, and different particle technologies,” says Grumbach. Concludes Bauder, “The ultimate goal for UHPLC is to reduce the variety of separation methods required by end users while optimizing run time and sample throughput. Near-universal separation methods, as well as near-universal or (alternatively), highly selective detection technologies, have the potential to transform the chromatography lab and make UHPLC the methodology of choice.”

Ultra high-pressure liquid chromatography (UHPLC) is enabling faster product development and production batch approvals with increased sensitivity.

Increasing Productivity with UHPLC

Increasing numbers of drug candidates suffer from poor solubility issues. Various amorphous dispersion techniques have been developed that increase solubility. Much work remains to be done, however, to improve the performance of such methods. Enhancement of amorphous dispersions prepared using spray-drying is the focus of an exclusive collaboration between excipient producer The Dow Chemical Company (Dow) and CDMO Bend Research. The two companies are developing fully characterized polymers supported by complete quality-by-design (QbD) principles that can be tailored to meet the performance needs of specific drugs.

David Lyon, senior vice-president of research with Bend Research and Karen Coppens, senior R&D manager, Bob Schmitt, R&D fellow, and Brian Koblinski, strategic marketing manager at Dow, shared details about the new partnership with 

 What specific capabilities does each company bring to the partnership?

Dow brings over 50 years of experience as one of the leading polymeric excipient suppliers worldwide. This materials-science experience is supported by high-throughput synthesis capabilities with API/polymer screening, laboratory-scale product development and structure/property optimization, a fully cGMP market development plant capable of supporting the clinical development of optimized solutions, and world-scale manufacturing capabilities. 

 As one of the recognized leaders in spray-dried dispersions (SDDs), Bend Research brings proven feasibility screening, SDD formulation expertise, cGMP clinical manufacturing capabilities, and experience in successful technology transfer.

 Why did choose to partner specifically with each other?

 We understand that successful solubility enhancement requires optimization of both the polymer and the formulation. In addition, it is imperative that QbD evaluations be incorporated early in the development cycle in order to facilitate robust formulations. Working jointly, we can seamlessly offer customers complete science-based support of their product development programs.

 How will the solid dosage industry benefit from the formation of this partnership?

The collaboration between Bend Research and Dow reduces drug-development risk by seamlessly combining materials development and optimization early in the formulation development process for spray-dried dispersions (SDDs) to achieve optimal clinical outcomes and robustness in drug-product manufacturability.

Our two companies use rigorous science that is grounded in fundamentals to develop new excipients and processes that improve the performance of solubilization technologies. This collaboration further extends that effort to use cutting-edge research to enhance existing technologies and ensures that our clients have access to a reliable supply of solubilization excipients that meet the critical-to-quality properties that are key to the performance of their compounds.

Pharmaceutical Sciences, Manufacturing & Marketplace Report: 

What does the collaboration enable you to do together that you could not each do on your own?

The collaboration allows Dow and Bend Research to offer a complete SDD solution to the market. Dow’s ability to design, synthesize, and characterize polymers is coupled with Bend’s ability to formulate and manufacture SDDs. These complementary skills distinctly position the collaboration to rapidly develop robust formulations that meet the clients’ clinical requirements.

 Can you explain further why you believe that incorporating QbD into the collaborative effort is so important?

 A properly designed and executed QbD study is the best way to develop a robust SDD product. QbD should be included in formulation development as well as in process development. Studies presented by Dow and Bend Research demonstrate that some SDD performance attributes show a high sensitivity to variations in polymer substitution while others can tolerate a wider variability. 

 Dow is able to produce and characterize QbD samples in a design space broader than the currently available commercial product, which helps Dow tailor the material to best meet the needs of the compound.

 Bend Research’s expertise in SDD technology addresses the variability in SDD process parameters that a formulation can tolerate. Coupling the polymer and process reduces variability in performance and leads to a robust drug product.

Specific polymer and formulation advances

 What types of polymers are you developing, and how are they differentiated from others on the market?

 Dow will provide hypromellose and hypromellose acetate succinate (HPMCAS), plus options to tailor these materials as well as next-generation cellulosic and noncellulosic polymers for enhanced performance. These new materials for SDDs will be developed and commercialized to address technology gaps in manufacturability and delivery, providing greater drug-product utility and therapeutic performance.

harmaceutical Sciences, Manufacturing & Marketplace Report:

 What new formulation processes are being investigated, and how do they advance SDD technology?

 Bend Research brings engineering solutions to SDD formation. For example, our patented hot-spray technology facilitates SDD production of API’s with low organic solubility at commercially relevant through-puts.

 What have you been able to achieve through this collaboration? Have you had initial successes?

Initial results were presented in 2012 at the annual meeting of the American Association of Pharmaceutical Scientists (AAPS) and the American Association of Chemical Engineers (AIChE). These presentations highlighted the solubilization optimization of several model drugs from SDDs using Dow’s fully characterized Affinisol HPMCAS and Bend Research’s science-based formulation approach. QbD principles were used in the studies to determine the performance sensitivity of the SDDs with respect to variations in the substitution levels of the HPMCAS. The results indicate that the sensitivity varies among drugs, and that a QbD study is one of the best ways to develop a robust formulation for each SDD drug formulation. The pharmaceutical industry has since embraced this concept, and we have several ongoing projects supported by our collaboration.

Dow Chemical and Bend Research are developing and commercializing new materials for spray-dried dispersions that address technology gaps in manufacturability and delivery.