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

Cynthia A. Challener

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

Articles

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.

Synthetic Biology Stirs Interest in Greener, More Efficient Processes

Synthetic Biology: The Next Frontier in Chiral Chemistry for API Synthesis

With the growth in manufacturing of APIs and formulated drugs around the world, there has been increasing pressure on government agencies to ensure that all products entering the drug supply chain meet necessary safety and quality requirements. In fact, several incidents with dire consequences have brought attention to the need for increased security within the global drug supply chain. Governments and regulatory agencies have responded with the adoption and implementation of both legislated and voluntary programs designed to address many of the issues that have caused problems in the past. While some of these initiatives are focused particularly on formulated drug products or other raw materials (e.g., excipients), others target APIs and will thus have a direct impact on API manufacturers.

The US: increasing resources and streamlining operations  


  In the United States, the Drug Quality and Security Act (DQSA) was signed into law by President Obama on November 27, 2013. This law will largely impact drug manufacturers and most notably contains requirements in Title II for the identification and tracing of certain prescription drugs that are distributed in the US (1). FDA is responsible for administering this and other programs established by the DQSA. While the DQSA does not directly affect API manufacturers, John DiLoreto, executive director of the Bulk Pharmaceuticals Task Force (BPTF) of the Society of Chemical Manufacturers and Affiliates (SOCMA) is glad to see that GMPs are being expanded to compounded drugs. “We recognize that any safety problems with a drug product reflect on the entire drug industry and thus have a negative impact on all members of the supply chain,” DiLoreto notes. 

FDA has also been actively developing guidance and other materials associated with the Food and Drug Administration Safety and Innovation Act (FDASIA), which was signed into law on July 9, 2012. Most relevant to the global drug supply chain is Title VII of the statute, which includes provisions that give FDA new authorities to detain drugs of questionable origin, penalize companies for delaying, denying, limiting or refusing inspection, and increase the fines for adulterated and counterfeit drugs (2). 

The FDASIA also grants FDA the authority to establish mechanisms for more rapid approval of drugs for patients with serious or life-threatening diseases and collect user fees from various sectors of the pharmaceutical industry (e.g., prescriptions drugs, generic drugs, biosimilars, and medical devices) that will be used to fund reviews of innovator drugs, medical devices, generic drugs, and biosimilar biological products and inspections of international manufacturing facilities. 

The BPTF is particularly encouraged by this development, because it has been working closely with members of Congress, FDA staff, and industry leaders to address FDA’s lack of resources for conducting GMP inspections of foreign drug manufacturers. “Industry is eager to see FDA increase its inspections of foreign manufacturing sites, not only to increase the safety of the API supply chain, but also to level the playing field for companies that already invest in programs and processes that ensure the safety and quality of their products,” DiLoreto observes. DiLoreto is gratified to see that FDA has also been able to work with the Chinese government, which seems to be establishing an inspection protocol for Chinese sites that is similar to the one the agency uses for domestic firms. Section 705 of the FDASIA, in fact, requires FDA within its two-year drug inspectional frequency requirement to use a risk-based scheduling approach for domestic and foreign drug facilities (2). Inspection criteria include the establishment’s compliance history and the inherent risk of the drug being manufactured. The agency is currently developing risk-based methodologies for inspections to reflect the statutory criteria and is working to establish common risk principles across the various centers. 

FDA is also revising existing cGMP regulations to update and harmonize requirements and improve detection of and response to emerging product safety and quality signals (2). Finally, Section 712 of FDASIA allows FDA to enter into written agreements with foreign governments to recognize the inspection of foreign drug establishments, and the agency is currently determining how this authority can be used to advance existing efforts in this area and further FDA’s goal of relying on foreign government inspections.

Most recently, FDA began accepting applications for its voluntary Secure Supply Chain Pilot Program (SSCPP), which is intended to enable 100 qualified firms to expedite the importation of up to five APIs and/or finished drug products into the US while allowing the agency to focus its import surveillance resources on preventing the entry of high-risk drugs that are the most likely to compromise the quality and safety of the US drug supply, according to the agency. The program is related to section 713(4)(B)(i) of the FDASIA, which covers the required submission of compliance information. 

Participating firms in the SSCPP program must be the new drug application/abbreviated new drug application sponsor or the foreign manufacturer of the product, comply with cGMP regulations and be in compliance with registration and listing requirements outlined in sections 510(i) and 510(j) of the Federal Food, Drug and Cosmetic Act, and commit to securing their drug-supply chains as participants in the Customs-Trade Partnership Against Terrorism (C-TPAT). The SSCPP is jointly administered by FDA’s Center for Drug Evaluation and Research (CDER) and Office of Regulatory Affairs (ORA) and will run from February 2014 through February 2016. On Feb. 18, 

FDA announced the first 13 companies prequalified for acceptance into the pilot program

The agency will use the information gathered, such as the timeframe for passage of products through the imports entry process, the level of adherence to program requirements, and the overall impact of the program, to develop its approach to implementing the FDASIA. Janeen Skutnik-Wilkinson, vice-president of Health Sciences at NSF International explains, “FDASIA, DQSA, and SSCPP codify into law the practices and expectations that FDA has been emphasizing since 2008.  It is important to recognise that the FDASIA has far-reaching implications for the pharmaceutical industry. To date, most pharmaceutical manufacturers and the media have focused on FDASIA’s high-profile provisions related to user fees, but several provisions of the law focus on ensuring safety and quality in the increasingly global pharmaceutical supply chain. After the 2008 Heparin contamination incident and the questions it raised about pharmaceutical safety, it’s no surprise that global supply chain safety provisions found their way into the pages of the FDASIA.

Europe: refining and expanding legislation


In the European Union, the European Medicines Agency (EMA) has implemented the API import provisions of the Falsified Medicines Directive (FMD) and has revised its GMP Annex 16, which outlines the responsibilities for Qualified Persons (QPs) (3). The main new requirement of the FMD is that pharmaceutical companies can only purchase APIs from suppliers that have received GMP certificates. “The original hope was that the amount of work might be reduced, since API suppliers would all be inspected by the authorities,” says Christine Morris, an associate with ISIS Pharmaconsulting. “However, that is not the case; pharma manufacturers still must conduct their own audits. Therefore, we don’t expect any real changes in product quality, other than perhaps for material coming from manufacturing sites outside of the EU and the US.” It appears, however, that an unintended consequence of the FMD is an increase in API prices as suppliers respond to the increase in audit and compliance requirements.

Fortunately, according to Pete Gough, executive director of Health Sciences at NSF International, the impact of implementing the FMD has not been as problematic as some had feared with respect to reported shortages of medicinal products due to issues with importing APIs from outside of the EU.  However, it is possible that many companies imported and stockpiled APIs ahead of the July 2013 deadline for implementing the new import requirements, and therefore, some problems may still emerge once these stockpiles are exhausted. Many companies in the US were concerned about meeting the requirements of the FMD, according to DiLoreto. “These concerns have been addressed with an agreement between the US authorities and the EMA,” DiLoreto explains. 

The proposed changes to Annex 16 are largely welcomed, according to Gough, because there was a real need to harmonize QP responsibilities across the EU. However, there are areas that still must be addressed, such as harmonization of terms within the Annex with other parts of the GMP Guide.

China: will regulatory changes have an impact? 


In October 2010, the new version of the 

 was adopted that included new and revised drug monographs as well as newer production technologies and analytical techniques that are used internationally for drug quality control. This action was followed by the introduction of revised GMP regulations by the Chinese State Food and Drug Administration (CFDA) in March 2011 (4). These regulations are modeled after those in the US and Europe and include more specific requirements for drug manufacturing than the previous version. However, it remains to be seen if these changes will have any impact. “We still have yet to determine if these new GMP expectations can be effectively applied and if the CFDA can enforce them,” Gough comments. 


Moves to harmonize international GMP requirements continue to progress, but very slowly, and Gough believes recent moves to share inspection outcomes across various countries and regions, and particularly between the EU and US, might be of more practical interest. “Such sharing will enable authorities to focus GMP inspections on the regions that pose the highest potential risks for both GMP non-compliance and of counterfeiting, e.g., Asia,” Gough says.  SOCMA’s BPTF strongly supports the sharing of information across countries to the greatest extent feasible as a way to eliminate duplicate work and free up resources for increased inspections where they are most needed, according to DiLoreto. Morris, however, believes that while harmonization of regulatory requirements is possible, the actual acceptance of other agency inspection results won’t take place for some time, because the different authorities have very different approaches.


  Even so, Morris does believe that the global drug and API supply chains are more secure than in the past. “There is much more awareness within pharmaceutical companies of the importance of supply-chain management and the need to have greater knowledge of the supply chain,” she states. DiLoreto adds that the industry is headed in the right direction, with better regulations and more inspections across the globe. Gough points to India’s plan to increase inspections and China’s closure of alleged producers of counterfeit drugs as further good signs. Both Gough and DiLoreto, however, note that it is too soon to judge which initiatives will be effective, because many of the legislative changes are in the early stages of implementation. 

“It is imperative though,” asserts Gough, “that pharmaceutical companies comprehensively map their supply chains and then conduct a risk assessment to identify potential vulnerabilities.  It is surprising just how many companies still do not have a clear picture of their supply chains.” API manufacturers must ensure that they can demonstrate compliance with cGMP regulations for APIs and other requirements for APIs as outlined in the new and proposed legislation discussed above. 

FDA, Food and Drug Administration Safety and Innovation Act 

(FDASIA). Accessed Jan. 17, 2014.
  3.	EC, 

. Accessed 1/17/2014.
4.	Chinese Food and Drug Adminstration, 

In order to ensure a safe drug supply chain, governments have implemented both legislated and voluntary programs designed to address problem areas.

Regulatory Initiatives Spur API Supply Chain Security

The global market for pharmaceutical excipients, or inert ingredients such as fillers, binders, disintegrants, glidants, colorants, flavoring agents, and coatings, is estimated by various market research firms to be approximately $6 billion in 2013 and growing at 5-7% annually through 2018 (1,2). There are several trends driving this growth, including the increasing size of the branded pharmaceutical market, the expansion of the generics and biosimilars market as patents expire, the reformulation of other drugs to achieve patent extensions, the use of excipients to overcome the poor solubility and bioavailability of many new drugs, and the rise of coprocessing technologies to increase productivity and reduce costs. Recognition of the important role of excipients and the development by excipient manufacturers of substances with specific functionalities designed for pharmaceutical formulations is also leading to the development of more complex products. 

At the same time, however, issues regarding the safety of the supply chain have brought attention to the need for increased regulatory controls and quality specification—for example, quality by design (QbD)—while the overall drive to reduce healthcare costs is placing significant downward pressure on excipient prices. Combined with an increasingly competitive environment in this sector, these factors are all contributing to a decline in the profit margins of many excipient manufacturers.


"Today, excipients are coming to be regarded for their true importance by the pharmaceutical industry," says Paul Evers, a market research analyst with BCC Research (Wellesley, Mass.), a publisher of technology market research reports.  In the past, excipients were typically substances produced initially for other markets, such as the food or personal care industries, and then adopted for use in pharmaceuticals. With the realization that excipients can play a major role in the performance of formulated drugs, there is now growing interest in developing substances specifically for pharmaceutical applications. These products typically have the advantage of being manufactured using more robust, carefully controlled processes that provide products of consistently high quality.

The need for the use of production processes that meet high standards is in fact another consequence of the fact that regulatory agencies have also taken notice, following a number of high profile safety/quality issues, of the potential impact that excipients can have on drug quality.  "As a result, quality and safety regulations extend to deeper levels of the industry today, starting with the design of excipients and including their manufacture, distribution, and storage. Smaller businesses in the industry have been most affected, because non-compliance has resulted in severe economic losses for these players," observes an analyst from MarketsandMarkets.

Some actions that have been taken to address these issues include the publication of the European Medicines Agency Risk Assessment Guide for Excipient GMP (Good Manufacturing Practice) as part of the Falsified Medicines Directive (3) and Revision of the EU GMP Guidance of Chapter 5 (Production)– New Supplier Qualification Requirements, which includes excipient manufacturers (4). The China Food and Drug Administration also has developed a preliminary list of high-risk excipients (5) and is developing new excipient regulations. 

Industry has taken steps on its own as well. The EXCiPACT Excipient GMP program, which was developed by industry experts from the European Fine Chemical Group and several other trade groups, was launched in January 2012 and is a voluntary, international scheme for the high quality certification of excipient manufacturers and suppliers to current GMP (cGMP) and current Good Distribution Practice (cGDP) standards (6). ANSI NSF-IPEC 363: Good Manufacturing Practices for Pharmaceutical Excipients is also being developed by the International Pharmaceutical Excipients Council (IPEC) and standards company NSF International in conjunction with the US FDA and will provide a stand-alone, quality system-based GMP standard that industry and regulatory agencies can use in evaluating, auditing, and certifying excipient manufacturing and quality (7). 

Excipient suppliers desired such guidelines because currently, novel excipients must receive approval as part of the final drug formulation; therefore, excipient manufacturers must share production information, including possible proprietary data, with the drug formulator. With the ability to demonstrate compliance with GMPs, such data provision won’t be necessary.  

Even so, there will be additional compliance requirements, particularly in Europe, for both drug formulators and excipient manufacturers, according to an analyst from MarketsandMarkets. Pharmaceutical companies will need to conduct risk assessments for pharmaceutical excipients and ensure that they meet quality standards and conduct audits of their excipient suppliers. Excipient manufacturers, meanwhile, will need to implement quality management systems that meet the more detailed requirements of the pharmaceutical industry and prepare for a large number of audits. Most importantly, increased interaction between drug and excipient manufacturers is required to achieve effective quality risk assessments and the development of common control and risk mitigation strategies, the analyst notes. 

Despite the challenging regulatory environment, there is a significant desire for the development of innovative excipients, according to Evers. "It is quite possible that the level of excipient innovation will double over the next 5 years, depending on how soon the economy recovers," he  says. BCC Research points in particular to growing interest in coprocessing for efficiency and the increasing use of oleochemicals (materials derived from biological oils or fats that are lipophilic and often have a high molecular weight) for improving the delivery of poorly soluble drugs. Other technologies, such as low permeability solubilizers, absorption enhancers, stabilizers for nanoscale carriers and orally disintegrating tablets, and replacements for animal-derived substances, are also under development. Continued innovations based on microcrystalline cellulose, which BCC believes is the most important excipient introduced in the last 50 years, will also be important in the future. Coprocessed excipients consisting of more than one substance and can be prepared using a number of different processes, such as granulation, spray drying, melt extrusion, milling, and others. The method depends on the physical characteristics of the individual excipients and the desired properties of the coprocessed excipient. Both excipient manufacturers and drug formulators must keep in mind, however, that the properties and safety profiles of coprocessed excipients may not be the simple sum of the characteristics of the individual excipients alone. 


The excipient market can be broken down by product type and by functionality. There are three main categories of products: organic, inorganic, and other (largely USP water). Organic excipients, including carbohydrates, proteins, oleochemicals, petrochemicals, and other organic chemicals, account for the largest percentage of the market (85-95% depending on the market analysis). Oleochemicals are not surprisingly expected to experience the largest growth rate of all of the organic excipients. Inorganic chemicals, including calcium compounds (phosphate, calcium sulfate, and calcium carbonate), metal oxides, and halides, account for 5-10% of the excipients market, according to MarketsandMarkets. By functionality, fillers and diluents, binders, suspension and viscosity agents, and coating agents are the leading categories of pharmaceutical excipients, and all are expected to show healthy growth through 2018.

It should also be noted that the pharmaceutical excipients market is highly fragmented, in large part due to the fact that most excipients, as mentioned above, were not originally developed for pharmaceutical applications. MarketsandMarkets reports that in 2012, none of the leading excipient manufacturers, such as BASF, Ashland, The Dow Chemical Company, FMC, Roquette, and JRS Pharma held more than a 10% share, and the top 10 companies accounted for just 60% of the market. The remainder was comprised of numerous smaller companies, with many located in emerging markets such as China, India, and Brazil.

, (Wellesley, Mass., October 2013)
  2. Markets and Markets, 

Pharmaceutical Excipients Market [By Products (Carbohydrates, Oleochemicals, Petrochemicals, Polymers, Microcrystalline Cellulose, Sugar, Calcium carbonate), By Functionality (Fillers, Binders, Lubricants, Preservatives)] – Global Forecast to 201

, (November 2013).
3. European Commission Health and Consumers Directorate,

Draft Guidelines on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing practice for Excipients of Medicinal Products for Human Use

, Feb. 2, 2013. Accessed Feb. 12, 2014.
4. European Commission Health and Consumers Directorate-General, 

Proposed Draft of Chapter 5: Production in The Rules Governing Medicinal Products in the European Union (EudraLex) Volume 4: Good Manufacturing Practice: Medicinal Products for Human and Veterinary Us

, Accessed Feb. 12, 2014.
5. China Food and Drug Administration, 

Preliminary list of high-risk excipients (in Chinese)

NSF/ANSI 363 – 20xx, Issue 1, Draft 1 (April 2011) 

Draft Standard for Pharmaceutical Excipients Good Manufacturing Practices for Pharmaceutical Excipients

Drug formulators are looking for new excipients to address solubility and bioavailability issues and extend patent protection, but there are hurdles to using novel, specialized ingredients.