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

Cynthia A. Challener

Continuous manufacturing, regardless of the application, can result in more consistent processes and products. Advantages include reduced energy, water, raw material consumption, waste generation, product losses, and downtime, in addition to lower capital and operating expenses. For the pharmaceutical industry, additional benefits include reduced human intervention. The biopharmaceutical industry is taking steps towards the realization of integrated, continuous manufacturing of biologic drugs with two changes. First, perfusion has moved from concentrations of 10–15 million cells/ml a decade ago to a now well-established upstream process at concentrations of 50-80 million cells/ml. Second, simulated moving-bed chromatography is in the adoption phase for downstream separation and purification. Some of the challenges include the large existing batch-based infrastructure, the traditional separation of upstream and downstream operations, and the need to develop new technologies for downstream processing steps.


  “At Genzyme, we envision an integrated system in which media enters the system at the front end and purified drug substance comes out the other,” states Timothy Johnson, associate director of commercial cell culture development at Genzyme. “It will take numerous steps to get there,” he adds, “but we are moving one unit operation at a time towards continuous biopharmaceutical production, and there are no issues that are so technologically complex that we won’t be able to develop appropriate solutions.”

 The biggest notable achievements, according to John Bonham-Carter, vice-president of business development with Refine Technology, come from CMO companies such as Gallus and Rentschler and from end users such as Genzyme, who have shown that continuous processing is possible today using existing equipment in a reliable setting. “It is the integration of different technologies that is novel, rather than any new technology itself,” he notes. 

a senior scientist with Novo Nordisk’s Biopharm Research Unit, adds that the work done at companies like GE Healthcare, Genzyme, and Novo Nordisk has helped demonstrate that continuous processing is not overly complex. “We have shown that going from batch to continuous is achievable and manufacturable. The technologies are available today; what is required is a fresh approach (and some guts) to switch to continuous processing.” 


  In small-molecule manufacturing, the switch to continuous processing is hindered in part by the vast batch-based infrastructure (and associated skill/knowledge base) in the biopharmaceutical industry that is cost efficient and familiar. “Many companies have invested significant time and money in batch processes, and are thus understandably unwilling to make major investments in new techniques,” notes Tiainen. In addition to the need to convince the decision-makers at biopharmaceutical manufacturers of the advantages and cost savings, it is also necessary to overcome user “fears” about unknown processes, particularly linking upstream and downstream operations, according to Stéphanie Dubois, cell culture lab manager and application specialist with Pall Life Sciences. 

 With respect to technology on the upstream side, Genzyme has come to appreciate the crucial importance of media formulations and has invested in finding optimal solutions, according to Johnson. The perception of increased process complexity is another issue, but as the number of companies exploring continuous processing increases and wider application of this knowledge occurs, this issue is gradually diminishing, according to Bonham-Carter. Tiainen adds, however, that there is not enough down-scaled and laboratory-sized equipment to enable wider exploration of continuous processing, particularly with respect to downstream processes.

Once the needed technology is developed on the downstream side, the issue of integration of upstream and downstream operations for fully continuous production lines will need to be addressed, which will involve managing the impacts that changes in one process step have on other steps down the line, according to Bonham-Carter. Tianen agrees that the interdependency of unit operations is currently a potential issue for product quality.

This particular hurdle leads to another key challenge–overcoming the divide between upstream and downstream groups within biopharmaceutical companies. “Implementation of integrated continuous manufacturing projects requires collaboration between groups. There is definitely much more communication internally at Genzyme than previously existed, and the traditional boundaries of the organization are beginning to subside,” Johnson comments. He also notes that two-way collaboration with supplier of materials, equipment, sensors, and automation and control systems is necessary for achieving effective solutions for continuous processing. 

— Cynthia A. Challener, PhD, is a contributing editor for 

.  Further discussion on this topic will appear in 

 May 2014 Bioprocessing & Sterile Manufacturing e-book. 

Articles

Both upstream and downstream processes can benefit from continuous manufacturing advantages.

Advances in Continuous Biopharmaceutical Manufacturing

Lifecycle management opportunities including clinical and compliance benefits coupled with the need for patent extensions are impacting the development of controlled-release technologies for solid-dosage drugs.

Lifecycle management opportunities are impacting the development of controlled-release technologies for solid-dosage drugs.

Controlled-Release Technologies Create Opportunities for Solid-Dosage Drug Formulators

The majority of highly potent APIs (HPAPIs) to date have been developed for the treatment of cancer (cytotoxics and cytostatics), particularly tyrosine kinase inhibitors and derivatives. There are, however, other therapeutics, including hormones, narcotics, and retinoids, which are also highly potent. In addition, while HPAPIs are generally thought of as small-molecule drugs, many biopharmaceuticals have occupational exposure limits  (OELs) of 10 μg/m3·8 h or less, a general guideline for classifying APIs as highly potent, according to Srinivas Achanta, regulatory affairs manager with Hetero. Of particular interest are antibody drug conjugates (ADCs), drugs that include a small molecule, cytotoxic payload, and an antibody connected with a linker. These therapies are designed to deliver the highly potent payload to targeted cells, reducing the likelihood of harm to normal cells. The number of ADCs in development has grown in recent years, and this growth is a key driver of the HPAPI market. The increasing number of ADCs and HPAPIs in general is creating challenges with respect to the prevention of cross-contamination in large manufacturing facilities with multi-use equipment and maintaining containment during larger-scale purifications.


  Because ADCs enable the targeted delivery of HPAPIs to the specific cancer cells (or other problematic cells), they have attracted significant attention, and the number of ADCs in development has increased dramatically. “The toxin that is conjugated to the antibody in ADCs has been the fastest growing segment of the HPAPI market, with demand quickly increasing in recent years,” says Dave Bormett, director of operations for SAFC. With three components to manufacture and combine together under containment conditions, the production of ADCs can be a complex process, adds Achanta. In addition, Bormett notes that certain new types of ADC compounds, which may be considered the next generation of ADCs, are considered to be even more potent than existing products and are pushing the limits on current capabilities with respect to the handling of low OEL materials.


  Single-use manufacturing technologies are on the rise for small-scale highly potent products such as ADCs, according to Jeff Marcoux, technical business development manager at Novasep. “Another important trend is the widespread acceptance of portable dedicated equipment, including both single-use and permanent systems for small-scale production of very highly potent compounds such as ADC payloads, which often have OELs lower than 0.1 µg/m3·8 h,” he notes. “Dedication of equipment and the adoption of single-use technologies can play an important role in controlling cross-contamination and maximum carry-over limits after cleaning (MACO) when implemented as part of a risk-based approach,” adds Marcoux. 

At SAFC, on the other hand, single-use, disposable technologies have thus far been used in certain limited applications, but they are being considered for HPAPI manufacturing where they can improve containment, particularly for larger-scale manufacturing activities, according to Bormett.

“All high-potency APIs must be produced under conditions that not only protect the operators from exposure to the compounds, but also prevent contamination and the inadvertent carryover of a different product that was previously produced or is simultaneously being manufactured. While modern HPAPI facilities are meeting today’s requirements, there is a continual need to improve these technologies going forward. To accomplish this task, we need to focus on the development of production and handling methods including single-use systems and/or new technologies that can provide increased protection of the API from cross-contamination. Such protection systems must focus on the cleaning and removal steps,” observes Achanta. “The development of such new technologies is of increasing importance as the number of multiproduct facilities, which pose the greatest risk of contamination of HPAPIs, are growing around the world in order to meet the greater demand for these products,” he adds.


  ADC payloads are small molecules containing complex chemical structures. As such, the purification of these molecules is challenging from a safety, health, and environmental point of view, as well as with respect to the technological aspects, according to Marcoux. “The chemical structures of the impurities obtained from chemical processes used for the synthesis of ADC payloads are often closely related to the desired HPAPI. As a result, traditional purification processes, such as crystallization or low-pressure silica gel chromatography, are often inadequate or lead to unacceptable loss levels,” he explains.  Novasep has found that HPLC purification technologies are particularly well suited for this class of compounds, ensuring robust, scalable, and reproducible purification under contained operational conditions. 

Marcoux also notes that because tracking of impurities is a challenge at the ADC stage after conjugation of the payloads with the antibody, much of the purity control for ADCs occurs at the payload stage. Both conjugatable and non-conjugatable impurities are increasingly controlled at this stage of the manufacturing process.

Maintaining containment around large-scale purification steps, such as chromatography, can also be challenging, according to Bormett. “It is important, therefore, to implement appropriate facility and equipment controls to ensure that these operations are handled appropriately,” he comments.


  Appropriate process design is in fact crucial for the entire HPAPI production operation. “Most very highly potent APIs and ADC payloads require small clinical and commercial quantities, and the production of gram-scale GMP APIs and payloads can be challenging. The control of containment using flexible and small equipment, including glass equipment, is always a challenge and requires a tailored approach for each process and each unit operation,” Marcoux says.  The appropriate process design at the development scale is also necessary to ensure that the process will fit the equipment and capabilities of the facility upon scale-up, according to Bormett. “The technical issues that must be addressed for scale-up of a manufacturing process are the same for an HPAPI or non-HPAPI. The challenge is ensuring that the proper engineering controls are in place for the process upon scale-up, and ensuring any limitations are considered when developing the process,” he notes.

One of the biggest challenges at large scale is the handling of powders and solids, according to Achanta. “Up to a scale of a few kilos, it is relatively straightforward to manage solids, because bottles with alpha-beta split butterfly valve connectors can be used for charging reactors to maintain containment. On a larger scale, however, this approach is impractical,” he explains. 

Bormett also notes that appropriate cleaning methods must be implemented to achieve the required limits for residue levels in multi-use equipment. “The use of analytical methods that provide very low detection limits is necessary in order to confirm that the required residue levels have been achieved,” he says. Bormett further notes that there is certainly an interest in continually achieving lower detection limits when handling HPAPIs.

Finally, Achanta points to the ambiguity surrounding the classification of HAPAIs given that different pharmaceutical companies often use proprietary systems is an issue. In addition, he notes that because the classifications for new APIs are often unknown due to a lack of data, they must be carefully managed with appropriate process design and containment controls.


  There has been an increase in investment in HPAPI capacity by both contract manufacturing organizations and large pharmaceutical companies, particularly to support ADC development and manufacturing, according to Bormett. SAFC, for example, has two major expansion projects under way to support HPAPI manufacturing. At the company’s Verona, WI facility, three HPAPI-capable GMP manufacturing areas are being added, including a plant with 400 L and 800 L reactors. In addition, Bormett says that SAFC is building a commercial antibody drug conjugation facility in St. Louis, MO to meet growing market demand beyond the current clinical-scale facility. 

Novasep, meanwhile, recently invested $4 million to expand its HPAPI manufacturing capabilities at its site in Le Mans, France. In the expanded cGMP facility, which has been commissioned, the company manufactures highly potent compounds with OELs lower than 0.03 µg/m3·8 h at the kg-scale, according to Marcoux. The investment features cryogenic chemistry at -60°C in Hastelloy reactors, as well as large-scale HPLC chromatography and drying in contained areas to manufacture ADC payloads at commercial scale. 


Cynthia A. Challener is a contributing editor to 

Increasing potency and growing interest in antibody-drug conjugates are creating challenges for manufacturers of HPAPIs.

Appropriate Process Design Critical for Commercial Manufacture of Highly Potent APIs

Changes in the biopharmaceuticals market are affecting all aspects of manufacturing, particularly downstream processes. The expected launch of numerous biosimilar monoclonal antibodies (mAbs) will create cost pressures for existing products, while increases in antibody titers are rapidly outpacing improvements in the productivity of downstream processes. At the same time, there is a shift toward smaller-volume, flexible manufacturing to meet local market needs, for which the cost equation is different than that of the conventional large-scale approach. In addition, many drug candidates are highly potent because they are designed for targeted delivery, and thus smaller doses are required, which equates to lower product volumes needed. To be competitive in this environment, manufacturers of both established products and new types of therapies must find ways to lower the cost of downstream processing while simultaneously increasing productivity.

Downstream processing of established products


Improvements in cell-culture techniques and widespread adoption of single-use technologies for upstream operations have led to dramatic increases in titers for mAbs, which represent the largest class of existing drugs (and drugs in development). As a result, chromatography unit operations are the largest bottleneck in the downstream processing of mAbs, according to Kimo Sanderson, vice-president of client services for Asahi Kasei Bioprocess. “Increased mAb titers are placing pressure on downstream processing time and cost, with Protein A resins and viral filtration membranes representing a significant portion of the cost,” says Sylvio Bengio, PhD Pall Life Sciences, Chromatography Group. They are, however, also resulting in increased contaminant levels (higher host-cell protein concentrations, aggregates), which further increases the downstream processing challenges, observes Matthias Jöhnck, head of Merck Millipore chromatography R&D. Jöhnck also notes that cost pressure from biosimilars entering the market is an issue for branded biologics manufacturers. 

Advanced technologies required for many candidate drugs


The development of many new classes of therapeutics will have a significant impact on downstream biopharmaceutical processing operations, according to Bengio. “A significant number of new drug candidates are not full-length antibodies, but antibody fragments, engineered antibodies (diabodies, tribodies, multi-specific antibodies, and antibody-drug conjugates), and non-antibody scaffolds, and there are no ‘platform purification technologies’ (such as Protein A for mAbs), thus new purification methods using conventional or nonconventional tools must be found. Affinity chromatography with specific ligands could be an elegant capture solution,  but the design of new protein-specific ligands and their immobilization on appropriate and scalable chromatography resins at a ‘reasonable’ cost  is a challenge,” Bengio says.  

Jöhnck adds that the driving forces for these new templates are the need to reduce side effects and achieve higher efficiencies by targeting more than one aspect of a disease simultaneously using one molecule. Generally, these new molecules also aim to achieve higher potency, which results in reduced processing volumes in manufacturing and lower manufacturing costs. “Most importantly,” asserts Uwe Gottschalk, vice-president of purification technologies at Sartorius Stedim Biotech, “the new candidates being developed are characterized by technical differentiation. The same can be said for biosimilars. Only those manufacturers that can develop a modern process will be able to compete and reach the commercialization stage. As a result, the biopharmaceutical companies developing new therapeutics and biosimilars are very interested in evaluating innovative technologies and prepared to take on the risk associated with adopting newer standards.”


Downstream processing technologies must also be adjusted to meet the needs of smaller, more flexible production facilities with adaptable capacities. “There is a real trend toward local manufacturing, so all aspects of the production process need to be competitive at smaller scales,” Gottschalk says. There is also the need for increased flexibility and the capability to adapt to multiple production lines in a single facility, according to Bengio. “Biopharmaceutical manufacturers are fundamentally trying to grapple with unknown demand expectations and how to run their operations at maximum efficiency while meeting variable demand,” observes Sanderson. He adds that plant capacity management is crucial, and as a result, there is increasing use of sophisticated scheduling and planning software that is designed to identify bottlenecks in the manufacturing process and determine the most effective way to mitigate then.


One aspect of biopharmaceutical manufacturing that is often overlooked, and in some cases considered part of upstream rather than downstream processing, is the harvesting step, according to Gottschalk. Centrifugation is typically used for large-scale processes, but it is not practical for smaller volumes. Depth filters are also not applicable. Sartorius Stedim has found that dynamic body feed (DBF), which is used in the blood, plasma, and food industries, is an effective solution. “DBF is similar to depth filtration, but diatomaceous earth (DE) is used with cell material to form a cake that acts as a very efficient filter layer that provides high productivity, even with high biomass,” says Gottschalk. To address concerns about dust handling associated with DE, Sartorius has developed a self-contained filter, which the company is currently beta testing.


Virus filtration is an expensive downstream processing step that has been a focus of technology development. Much improvement has been made since virus filtration was first used approximately 15 years ago, according to Gottschalk. “Initial virus filters suffered from breakthrough and were very susceptible to blockage by aggregates if the feed was not ultrapure. The devices available today have 10 times greater productivity as a result of changes in the morphology of the filters and the use of surface modification to increase the hydrophilicity. I expect even further advances given that we are still in the very early stages of using this technology,” comments Gottschalk.


New chromatography media are enabling higher flow-rates of up to 1000 cm/h and higher protein binding capacities, thus contributing to higher productivities and lower manufacturing costs, according to Jöhnck. Matrices have been introduced for the capture phase that can tolerate more impurities and higher salt concentrations, as well as provide much greater pressure resistance. Mixed-mode resins also represent a powerful solution, as a “low-salt or no-salt” alternative to hydrophobic interaction chromatography (HIC) and offer unique selectivities for challenging purification steps, according to Bengio. 

With so many choices today, Bengio adds that high throughput chromatography screening tools in 96-well plates or small prepacked columns are enabling the rapid screening of multiple chromatography resins with minimal sample consumption, and when conducted in conjunction with a design of experiment approach allow the determination of appropriate separation conditions (e.g., load, pH, and conductivity).
  
  In-line dilution is also an important technique for boosting the productivity of chromatography processes, both for next-generation purification technologies and existing systems, according to Sanderson. “Most new chromatography equipment has built-in in-line dilution capability, but biologics manufacturers with legacy systems don’t have access to this technology. Asahi Kasei Bioprocess has addressed this gap by designing a plug-and-play system that produces buffer on-demand for existing equipment,” he says. The company has also taken into consideration the needs of smaller-volume manufacturers and offers a flexible in-line buffer solution with a very small footprint and a capacity of up to 1000 L/hr.


  With respect to chromatography advances, improvements in protein A capacities for mAb purification cannot be neglected. “With Protein A, it is really a cost issue,” says Sanderson. There are efforts to make it cheaper. Jöhnck points to Protein A resins launched in the last few years that provide not only higher flow rates of up to 500 cm/h and higher dynamic binding capacities exceeding 50 g/l, but also high cycle stabilities. “Cycle numbers of 200 are achievable, which has dramatically reduced the antibody capture costs per cycle down to $3-5 g of antibody. Therefore, I do not expect any change regarding the dominant role of Protein A resin used in antibody manfacturing,” he observes. Gottschalk adds that alternative technologies to Protein A purification, such as precipitation and extraction, are being investigated, but he doubts they will replace Protein A in the near future.
  


  Membranes an ideal alternative for small-volume processes


Not surprisingly, the use of classical resin-based chromatography is expected to remain dominant for large-scale processing. For smaller volumes, however, Jöhnck notes that membranes can be advantageous, because they are ready-to-use devices (no qualification work) that can handle high flow rates and are potentially lower cost at small scale. The polishing step, according to Gottschalk, is where membrane separations have had a significant impact. “These membranes look like filters and are operated like filters, and they can remove many different impurities. Yet they are very small devices that use approximately 5% of the buffer volume of a traditional column and are disposable, making them very easy to use,” he explains. Bengio adds that such membrane tools can be used either in flowthrough mode to remove DNA or impurities (host cell proteins) or even in capture mode to purify large molecular weights species (e.g., factor VIII, plasmids, viruses, and virus-like particles).


Such membrane filters are just one example of single-use technologies being employed for downstream processing. Others include disposable bags for buffer preparation, single-use devices for clarification, and even prepacked columns and new chromatography systems, according to Jöhnck. “Resin manufacturers are introducing new disposable chromatography columns that are available in different formats up to 32 cm iD or larger,” he notes. “There is a lot of interest in disposable technologies for downstream processing because of the growing need for flexibility and the ability to adapt to changing capacity demands,” agrees Gottschalk. “Single-use technologies won’t be the solution for all issues, but they will be advantageous for many downstream unit operations,” Gottschalk adds.


Another trend in downstream processing is the establishment of more continuous operations. “Continuous processing in many other industrial areas has been the key to dramatically reducing the manufacturing cost of products,” says Jöhnck. For antibody processing, for example, he notes that the combination of a continuous operating capture step using a multi-column Protein A resin approach combined with anionic and cationic columns/devices has already been reported. “These approaches certainly will be introduced in drug manufacturing in the coming years in order to meet the necessary requirements for many of the new materials that are under development. One example in this context is the development of disposable chromatography devices that do not utilize classical membranes or resins, but rather other types of new cost-effective supports, theoretically enabling true single-use chromatography,” he explains.

Bengio agrees that continuous chromatography systems and tools may reduce operational costs due to the use of smaller disposable systems, less chromatography resin, and increases in productivity. “Continuous processing approaches are changing the rules and the definition of a batch, and continuous chromatography streamlines operations and decreases purification costs,” he says.


  Reorganization of processes is also being pursued, and may be achieved in advance of true continuous processing, according to Gottschalk. Such reorganization will involve the elimination of the holding steps that typically exist between downstream processing unit operations. The result will be a smaller overall process train that will be compensated for by running the process repeatedly. Such processes may also include alternative technologies, such as simulated moving bed chromatography. Bengio suggests that non-chromatography methods, such as aqueous two-phase separation and crystallization, may allow in some cases for further cost reductions in downstream processing. 

Separately, Bengio believes that in-silico and modeling approaches to evaluating mixed-mode chromatography will also be powerful tools for effectively evaluating the complex interactions involved in these types of powerful but sometimes difficult to optimize systems. 


Cynthia A. Challener is a  contributing editor to

Higher antibody titers and a growing demand for smaller-volume, flexible processes are creating the need for more cost-effective downstream processing.

Increased Efficiency Key to Competitiveness in Downstream Bioprocessing

While clearly the active pharmaceutical ingredient is the primary component of any formulated drug, the mechanism of drug delivery plays a critical role in determining the safety and efficacy of therapeutics. Access to novel drug delivery mechanisms and devices can have a significant impact for drug manufacturers. In fact, drug delivery technologies can help drug manufacturers in differentiating new therapeutics from existing products, provide a means for extending patent protection, and enable novel treatments. While the majority of drug delivery devices are related to oral delivery, however, it is not surprising given the growth of the biopharmaceutical market that the fastest growing segments of the drug delivery market address the delivery of biologic drugs. Different models for development, including outsourcing, partnering, collaboration, and licensing have resulted.

The novel peptides, protein, nucleic acid, growth factor, cytokine, interferon, and antibody-based drugs available today provide new mechanisms for treating diseases, but also pose challenges with respect to successful drug delivery. "The large size of most biopharmaceuticals, combined with their other molecular properties, lead to poor physical and chemical stability within the body and limited membrane permeability, and severe toxicity when applied systematically. Therefore researchers are developing a range of new delivery technologies and materials to enable these new drugs to be delivered intact to their target sites," says Rajveer Singh Rathor, a senior research analyst for healthcare with MarketsandMarkets. 


  One of the key drivers for growth in the drug delivery market for biologic drugs is the growth of the biopharmaceutical market itself. Another major driver of the drug delivery market in general (for both large and small molecule therapies) is the expiry of patents for certain blockbuster drugs, according to Shalini Dewan, a senior research analyst with BCC Research, a publisher of technology market research reports based in Wellesley, Mass. She adds that growing demand for self-administration and home healthcare devices; the rising incidence of chronic diseases such as cardiovascular diseases, diabetes, and cancer; the growing focus on pediatric and geriatric patients; and the increasing demand for minimally invasive surgeries are other factors contributing to growth in the drug delivery market. In addition, pharmaceutical companies are increasingly adopting drug delivery technologies to differentiate their products in the highly competitive environment, according to Rathor.

At the same time, both analysts point to recent drug failures and recalls, stringent regulatory processes, various technical barriers, and the difficulty in striking the right partnership deals to the development of drug delivery platforms as negative factors affecting the growth of the drug delivery market. 
  Thus in 2012 BCC Research estimates the overall market for drug delivery systems including both large and small molecule drugs was $147 billion and expects it will reach $175.1 billion by 2018, growing at a compound annual growth rate (CAGR) of 3%. MarketsandMarkets has higher expectations, and believes that the market will grow at a CAGR of 9.5% from 2012 to reach $224 billion by 2017. 

North America, which has a well-established healthcare infrastructure and a large number of leading pharmaceutical and biopharmaceutical companies (around 80% of the world’s research and development in biopharmaceutical is conducted by US-based firms), is the largest market for drug delivery, accounting for 45-50% followed by Europe with 25-30%, according to MarketsandMarkets. North America and Europe are expected to grow at a slower pace (8-9%/year) than emerging markets, primarily due to a certain amount of saturation in the market, but also due to increasing competition from drug delivery firms in emerging countries and unstable and uneven reimbursement policies for innovative drug delivery devices. The Asian region however, and particularly India and China, is expected to grow at a double-digit CAGR from 2012 to 2017 due to the expansion of the Asian economy, an increase in disposable income, the development of healthcare infrastructures, increasing penetration of health insurance, and the rising prevalence of chronic diseases, according to Rathor.


Advanced drug delivery systems offer several advantages over conventional delivery systems, such as improved therapy through increased efficacy and duration of drug activity, decreased dosing frequency, more convenient routes of administration, and improved targeting of a specific site in order to reduce unwanted side effects, according to Dewan. "The challenge for both drug and drug delivery companies is to deliver both existing and emerging drug technologies in a manner that will improve drug administration for patients," she observes. "Drug delivery technologies have grown phenomenally from plain drug reformulation and release technologies to innovative platforms that hold huge potential for the effective delivery of biological and novel drugs." adds Rathor.


  MarketsandMarkets divides the global drug delivery market into nine segments based on the route of drug administration, including oral, pulmonary, transdermal, injectable, ocular, nasal, topical, implantable, and transmucosal. While oral drug delivery technologies represent the largest share (close to 40%) of the overall market, pulmonary, transdermal, and injectable technologies are growing the fastest with estimated double-digit growth rates. "A growing number of companies are investing in technologies including orally disintegrating tablets (ODT), dry powder inhalers (DPIs), pen injectors, auto injectors, buccal films, nasal sprays, intraocular implants, and infusion pumps, many of which are designed for use with biologic drugs. The developments in these areas are a result of their proven technology, high dose efficacy, and their ability to offer enhanced patient convenience and compliance," Rathor explains.

For biopharmaceuticals, pegylation is currently the leading drug delivery technology and is used with products such as interferon. Pen injectors, which are used for insulin delivery in the treatment of diabetes mellitus, are the leading device for biopharmaceuticals. The rising incidence of diabetes will continue to drive the growth of this drug delivery technology, according to Rathor. He also notes that pen injectors offer the simplest and safest way of delivering biopharmaceuticals such as peptides, hormones, and monoclonal antibodies that cannot be taken orally. Liposomal delivery is another very popular method for the delivery of biologic drugs. 


Polymers, including pegylated drugs, have played an important role in the advancement of drug delivery technology by providing opportunities for controlled release of therapeutic agents in constant doses over long periods, according to Dewan. Research is ongoing to develop controlled-release systems for biopharmaceuticals. New transdermal technologies have created opportunities for developing delivery mechanisms for existing molecules with no viable delivery systems and existing drugs that can benefit from additional delivery systems, such as compounds that previously were unable to be delivered through the skin, according to Dewan. One such example is WEDD (Wearable Electronic Disposable Drug Delivery) developed by Travanti Pharma, a Teikoku Pharma affiliate company, is a proprietary drug delivery technology platform for electronic transdermal (iontophoretic) delivery of therapeutic agents using an applied electromotive force. Targeted technologies based on loaded nano-carriers (nano-shells or nanoparticles) are also attracting increasing interest, with gold nano-carriers leading growth in revenue. "Targeted drug delivery is a more personalized approach based on an individua's unique genome and immune response.

The more scientists learn about the molecular causes for disease, the better targeted and effective nanotechnology-enabled drug delivery therapies will become,” Dewan says. Finally, she notes that increasing interest in prodrugs is due to their ability to overcome formulation, delivery, and toxicity barriers for better drug utilization.


There are several different models for the procurement of drug delivery technology in the biopharmaceuticals industry, including in-house development, co-development, and licensing, depending on the need of the biopharmaceutical manufacturer, Rathor notes. For example, Caisson Biotech signed a development and license agreement with Novo Nordisk in 2012 giving Novo Nordisk exclusive rights to use Caisson’s proprietary heparosan-based drug delivery technology for engineering and developing compounds within undisclosed therapeutic areas. On the other hand, Novo Nordisk has an in-house manufacturing facility for pen injectors.

Nectar Therapeutics has also worked with many biopharmaceutical companies, such as Roche, Astrazeneca, Amgen, Baxter, Novartis, and Pfizer, to develop biological products (i.e., Pegasys, Neulasta, Omontys, Cimzia, Mircera, PEG-Interon) based on Nectar’s patente PEGylation technology. These products have been developed by their respective companies using PEGylation technology of Nector Therapeutics, according to Rathor.

In a third representative collaboration, Radius Health and 3M Drug Delivery Systems formed a exclusive partnership for the development and commercialization of BA058-transdermal in December 2012. BA058 is a novel, synthetic proprietary peptide analog of human parathyroid hormone related protein which is used to treat patients with osteoporosis that are at high risk of fracture. This agreement updates the general development agreement announced in May 2011 by the two companies for BA058-TD.

Advanced drug delivery technologies can increase efficacy and safety, extend patent lives, and provide competitive differentiation for biopharmaceuticals.

Drug Delivery Technologies Provide Growth Opportunities for Biopharmaceuticals

The complexity of both small-molecule and large-molecule drugs is increasing as pharmaceutical companies seek therapeutics with new mechanisms of action. In small-molecule therapeutics, increasing complexity often translates to larger numbers of stereocenters. Because only the isomer of a chiral drug that exhibits activity must be produced in high purity, much effort has been invested over the past 20 to 30 years in the development of tools for the asymmetric synthesis of pharmaceutical intermediates. Classical resolution and other methods for the separation of isomers, including large-scale chiral chromatography, and advanced chemocatalysts that mediate a wide variety of enantioselective transformations and enable more rapid and efficient synthesis of complex pharmaceutical intermediates and APIs are widely used today. More recently, technology for the development and commercialization of a diverse array of enzymes that can catalyze stereoselective reactions has led to their increasing use for pharmaceutical synthesis. While advances continue to be made in chemocatalysis, the area of chiral chemistry generating the most excitement is synthetic biology, or the use of multiple enzymes in one-pot reactions (and ultimately in a single organism) to carry out sequential reactions that result in the production of an advanced intermediate or even an API.

While there haven’t been any major new breakthrough chemical or biological transformations reported in recent years, there continue to be incremental improvements in existing technologies. For the pharmaceutical industry, these advancements include improvements in processing capabilities, such as flow chemistry, that make large-scale implementation of these technologies possible, according to John Caldwell, editor-in-chief of

and professor emeritus at the University of Liverpool. He also notes that the development of effective chiral transformations that are “greener” and proceed at large scale in water, use low levels of catalysts that can be recycled, require lower temperatures and pressures, reduce the number of steps through carefully designed cascade sequences, are more atom economical, and use less hazardous materials has become important in the pharmaceutical industry. “We now have a lot of choices of methods for obtaining pharmaceutical intermediates with extremely high enantioselectivities in the range of 99.9%, and part of the challenge now is choosing the best method for a given API,” he notes.

Route development based on good process chemistry is in fact crucial and should be addressed prior to choosing a chiral technology, according to Garrett Hoge, chiral technology manager at the ChiroTech Technology Center, part of Dr. Reddy’s Custom Pharmaceutical Services business. “It is important not to use chiral technology just for the sake of it. Chiral chemistry must be implemented in an effective manner. It is as important to have an efficient route to the prochiral substrate as it is to have a highly effective chiral catalyst,”  Hoge says.


The “greening” of chemical manufacturing is one trend that has led to the growing use of biocatalysts for asymmetric synthesis, because these reactions often proceed in water under mild conditions, produce less waste, and are highly selective. Biocatalysis has also passed the proof-of-concept stage, according to Hoge. In addition, Tom Moody, head of biocatalysis and isotope chemistry with Almac and a professor of chemistry at the University of Belfast, notes that a diverse array of enzymes are now commercially available in quantities suitable for pharmaceutical manufacturing. There are a large number of transaminases and dehydrogenases, for example, available for commercial-scale use that enable the enantioselective production of key building blocks and intermediates needed for API synthesis, according to Stefan Mix, Almac’s biocatalysis team leader.


The increased availability of enzymes can be traced back to significant advances that have been achieved in molecular biology, metabolic engineering, and bioinformatics, according to Moody. “The design and engineering of enzymes for highly selective chiral transformations is now possible under tight timelines,” Mix notes. “In fact, a customized enzyme for a specific application can be developed in a few months rather than with extended periods of time and cost,” Mix explains. In many cases today, the cost of chiral ligands is greater than the cost of the enzyme that can provide the same product,” he adds. Hoge also points out that the identification of the gene of interest within a specific organism is also much easier today, and genes can be synthesized for just s few $100.


The availability of large quantities of enzymes at reasonable cost, combined with the greater sustainability of processes based on biocatalysts, has led to their use at earlier stages of the drug development process. “There is definitely a growing acceptance of the use of enzymes for the synthesis of APIs according to GMP,” Moody says. However, unlike for chemocatalysis, for which there are established procedures and guidelines for GMP manufacturing, a scientific approach has been undertaken for biocatalysis. Selected industrial specialists are now getting together to prepare a detailed document for the application of enzymes under GMP that will be published in 2014, he notes. Mix adds that, even though medicinal chemists are slow to adopt novel technologies, where once it was common to use enzyme catalysis only in second-generation synthetic routes, today biocatalysts are being considered from the earliest phases of new product development because of the benefits they provide in terms of cost, productivity, and efficiency.

One leading example of the implementation of a second-generation biocatalytic route was achieved by Merck & Co. A highly active and stable immobilized transaminase catalyst for the reduction of ketones to chiral amines created using directed evolution techniques served as a replacement for a rhodium-catalyst used for asymmetric enamine hydrogenation in the production of the antidiabetic drug Januvia (sitagliptin) (1). Development of the enzyme was accomplished in 10 months through cooperation with Codexis. The process demonstrated the potential to improve productivity by 56%, increase yield by 10-13%, and reduce overall waste generation by 19%, according to Merck. A pilot plant process was completed in 2009, and FDA granted approval for the new route in April 2012 (2). 

The work that Frances Arnold, the Dick and Barbara Dickinson professor of chemical engineering, bioengineering, and biochemistry at the California Institute of Technology, demonstrates the versatility and potential of enzyme catalysis. Arnold has engineered a bacterial cytochrome P450 enzyme to catalyze highly diastereo and enantioselective carbene transfers from diazoester reagents to aryl-substituted olefins, enabling cyclopropanation through a route not observed in nature (3).


  More recently, the idea of synthetic biology has taken hold, according to all three scientists. “Pharmaceutical companies, contract manufacturers, and academic researchers are all investigating the possibility of engineering systems that consist of multiple enzymes that work in tandem and/or in sequence to generate complex chiral molecules with high selectivity,” Hoge explains. Further down the road, Moody says the ultimate goal is to engineer whole cells that switch on and off genes for different enzymes and can take basic raw materials and convert them into isomerically pure, complex, highly value added pharmaceutical intermediates, and ideally APIs themselves. “Investigations are still at the very early stages, but the interest in biomimetic synthesis is very high, and there is a wealth of transformations possible given the biological complexity of nature,” Mix observes.

ChiroTech, for example, has developed a two-enzyme system for the dynamic kinetic resolution of nonnatural α-amino acids. The company engineered N-acetyl amino acid racemase (NAAAR) to catalyze the racemization of many N-Acetyl amino acids, which when used in combination with an L- or D- acylase enzyme, enables their dynamic kinetic resolution. “Because the NAAAR enzyme is general in its ability to racemize many N-Acyl amino acids, we have found many applications for this system and typically achieve an enantiomeric purity of 99%,” Hoge comments.


  Chemocatalysts will always have a place in API manufacturing, even though much of the excitement today is centered around biocatalysis. “Asymmetric hydrogenation in particular is a very important reaction in the pharmaceutical industry and will continue to be so,” Hoge asserts. He adds that there are still many new applications yet to be discovered. The fact that many chiral ligands are coming off patent will also promote the use of chemocatalysis because the cost of catalyst systems will decline significantly. In addition, chemocatalysts are very attractive for generics manufacturers, who can capitalize on asymmetric hydrogenation technology by improving on innovator routes that might not access a chiral technology. “These new and improved routes are enabled with technology allowing for more efficient implementation and a lower cost of goods than the originals,” Hoge notes.


  Organocatalysts also show potential for use in chiral transformations, particularly when used in cascade reactions, such as those being developed by David MacMillan, the James S. McDonnell distinguished university professor of chemistry at Princeton University. “We have a much greater understanding of the molecular environment required for catalysts, and therefore there is greater potential to design effective organocatalysts,” Caldwell says. In fact, ChiroTech has found that industrial application of this technology is possible and plans to bring an organocatalytic route to the plant within the next several months, according to Hoge.

Fitting the theme of synthetic biology, MacMillan’s approach to organocascade catalysis is based on the biochemical blueprints of biosynthesis. According to MacMillan, it includes the successful merger of different reactivity platforms, allowing access to intricate structural motifs directly applicable to natural product synthesis and enabling the straightforward generation of multiple stereocenters in a single operation. His group is using this strategy to construct the chiral frameworks of several complex natural products. Most recently, they achieved the enantioselective total synthesis of (−)-minovincine in nine chemical steps (4).

Caldwell believes that the design of cascade reactions through the assembly of known chemistry--whether involving organo-, chemo-, or biocatalysis--in unique sequences that leverage the best properties of each provides tremendous opportunities for advancing asymmetric synthesis in general and developing practical, efficient, and more sustainable commercial-scale routes to enantiomerically pure pharmaceutical intermediates and APIs.


  1.	C. K. Savile et al., Science, 329 (5989), 305-309, (2010).
  2.	Merck, Case Study: A Journey To Revolutionize Drug Manufacturing. In an industry charged with helping the world’s populations be well, green chemistry is a critical tool. http://www.merckresponsibility.com/wp-content/uploads/2013/07/green_chemistry.pdf . Accessed 1/30/2014.
  3.	P. S. Coelho et al., Science 339 (6117), 307-310, (2013).
  4.	B.N. Laforteza et al., Angew. Chem. Int. Ed. 52 (43), 11269 -112, (2013).


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

The commercial availability of an increasing diversity of enzymes has led to the growing use of biocatalysts for API synthesis.