Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Researchers from the University of Cambridge in England have developed injectable, reformable, and spreadable hydrogels that can be loaded with proteins or other therapeutics. The hydrogels contain up to 99.7% water by weight, with the remainder primarily made up of cellulose polymers held together with cucurbiturils or barrel-shaped molecules that act as miniature “handcuffs,” according to an Aug. 15, 2012, University of Cambridge press release. 

“The hydrogels protect the proteins so that they remain bioactive for long periods, and allow the proteins to remain in their native state,” said Oren Scherman, professor in the Department of Chemistry at the University of Cambridge, in the university release and who also led the research. “Importantly, all the components can be incorporated at room temperature, which is key when dealing with proteins that denature when exposed to high heat.”

The researchers prepared the self-assembled hydrogels with high water content (up to 99.5%) and tuned mechanical properties. The protein-release characteristics were investigated to determine the effect of both the protein molecular weight and polymer loadings of the hydrogels on the protein-release rate. Sustained release of bovine serum albumin was observed over the course of 160 days from supramolecular hydrogels containing only 1.5% (by weight) polymeric constituents (1). 

The hydrogels were capable of delivering sustained release of the proteins they contain for up to six months compared with the current maximum of three months, according to the university release. The rate of release can be controlled according to the ratio of materials in the hydrogel. In addition to broadening the time for content release, the hydrogels use less non-water material than current technology. “The extra material serves as a type of scaffolding holding the hydrogel together, but it can affect performance of the cargo contained within it, so the less structure-forming material contained within the hydrogel, the more effectively it will perform,” according to the university release. 

Potential applications for the hydrogels are protein-based drugs for chronic diseases, such as hormone therapy, wound healing, and insulin treatment. The team is currently working with researchers from the Brain Repair Center in the Department of Clinical Medicine on how the technology might be used as a possible treatment for brain cancer.

Additionally, the long-term sustained release would be beneficial for administering drugs in geographic areas where access to medicines and daily drug administration may be difficult or as a means to increase patient compliance. “There’s been a lot of research that shows patients who need to take a pill each day for the rest of their lives, especially HIV patients in Africa who do not show any obvious symptoms, will take the pills for a maximum of six months before they stop, negating the point of taking the medication in the first place,” said Eric Appel, doctoral student and co-author of the recent research article, in the university release (1). “If patients only have to take one shot that will give them six month’s worth of medication, we’ll have a much greater chance of affecting an entire population and slowing or stopping the progression of a disease.”

Articles

Researchers have developed injectable, reformable, and spreadable hydrogels capable of delivering sustained release of the proteins they contain for up to six months.

Formulation Development Forum: Hydrogels for Long-Sustained Release

What will be the future innovation in drug delivery? To gain a perspective, 

asked leading experts for their views. Participating in the industry roundtable were Anthony Recupero, PhD, senior director, licensing, Aptalis Pharmaceutical Technologies; Linda A. Felton, PhD, chair of the Department of Pharmaceutical Sciences and associate professor of pharmaceutics, the College of Pharmacy at the University of New Mexico, Health Sciences Center, and member of the Steering Committee of the Modified Release Focus Group of the American Association of Pharmaceutical Scientists; and Louise Righton, global divisional marketing manager for 3M Drug Delivery Systems.  

Andrew Douglas/Radius Images/Getty Images			

Looking ahead over the next 5 to 10 years, in what areas do you see the opportunity for the greatest innovation in drug delivery? How may factors, such as increased development of specialty medicines for targeted patient populations and personalized medicines, affect approaches in drug delivery or influence specific drug-delivery technology?

Recupero (Aptalis Pharmaceutical Technologies):

 In the next 5 to 10 years, we see a great opportunity for innovation in drug delivery by designing novel formulations that target particular pharmacokinetic (PK) profiles needed for the corresponding patient populations that are underserved by current drug formulations on the market. Whether these drugs use oral or parenteral formulations, the key focus will be on customized drug release that provides for a novel PK profile that leads to greater efficacy and/or reduced safety risks for specific patient populations within particular therapeutic areas. These patients may be identified by characteristics, such as age, co-morbidities, or a variety of potential biomarkers that indicate a favorable response to the drug of interest, if dosed under the appropriate conditions. Central nervous system is a general therapeutic area where these strategies are likely to pay off significantly, given the variability in patient responses based on a variety of personal factors.   

Drug delivery insights: Nanotechnology			

The customized drug-release profiles required will necessitate the use of multiple types of technologies, including extended-release, sustained- release, and timed-pulsatile release. Much of the innovation will come from developing a better understanding of the patient rather than the identification of new molecules.  

From a business perspective, it will be key to have proprietary technologies available with strong patent estates behind them for these applications. This will allow companies to develop a protected pathway to market exclusivity in a manner that can be protected not only by technology and formulation patents, but also by new use patents that are the result of novel clinical findings based on the enablement of the delivery system. This will allow companies and investors to maximize their return on investment and encourage further innovation in drug delivery. 

): The next decade will continue to be an exciting time to be a formulation scientist as the industry moves away from incremental innovations and 'me-too' drugs in favor of more significant advances. As we look toward the future of pharmacy, I see many opportunities for improvements in drug delivery and patient safety. With a better understanding of diseases and anatomy and physiology, I expect to see more targeted drug-delivery systems being developed. These systems will include targeting specific sites in the body as well as targeting chemicals to specific cells in the body. A great deal of effort is currently being expended on targeting at the cellular level to improve therapeutic outcomes and reduce systemic toxicities. These new chemical entities, however, are likely to create additional delivery challenges for formulation scientists. Such challenges will likely be resolved using innovative approaches. 

Significant research effort is currently focused on identifying new indications for existing drugs. Such repurposing will further contribute to the need for alternative delivery routes as well as targeted drug release. I expect to see improvements in vaccine delivery, including needle-free technologies, delivery by the inhaled route, and enhanced product stability. There are also opportunities for improved therapies in the management of chronic pain, where premature drug release (dose dumping) is minimized. Such systems would also reduce the potential for abuse. Further development and implementation of anticounterfeiting technologies is expected and would also contribute to patient safety, especially as the global marketplace continues to grow.  

Industry roundtable participants, from left to right: Anthony Recupero, PhD, senior director, licensing, Aptalis Pharmaceutical Technologies; Louise Righton, global divisional marketing manager for 3M Drug Delivery Systems. Not pictured: Linda A. Felton, PhD, chair of the Department of Pharmaceutical Sciences and associate professor of pharmaceutics, the College of Pharmacy at the University of New Mexico, Health Sciences Center, and member of the Steering Committee of the Modified Release Focus Group of the American Association of Pharmaceutical Scientists.			

The aging population will also create opportunities for the development of new and novel drug delivery systems. In addition to improvements in taste-masking technologies and alternative delivery routes, there is a growing need for combination products to reduce total daily doses of medication. While there has been much discussion about personalized medicine, creating combination products unique for individual patients has potential to greatly impact patient adherence to therapeutic regimens, improve disease state management, and enhance quality of life and could be easily implemented in community pharmacies.  

Drug delivery insights: Calcium carbonate microspheres			

 Consideration of the user's experience and interface with drug-delivery devices is on the rise and will continue to have a significant impact on the success of a product. Throughout the next decade, companies will continue to seek efficient and user-friendly ways to deliver drugs, which build patient preference while still meeting the needs of healthcare providers and regulatory agencies. In this increasingly patient-driven marketplace, companies are observing that the integration of patient-friendly features, such as adding a dose counter to meter-dose inhaler devices, can not only serve as an asset in the regulatory process, but can also build patient preference and loyalty. Furthermore, the increased patient convenience found in needle-free drug delivery devices can offer companies an important life-cycle management tool that can differentiate their product and provide a competitive edge.  

Advances in targeted drug delivery and customized release profiles are key industry goals.

Future Innovation in Drug Delivery

When FDA first announced in 2002 a new initiative, 

Pharmaceutical Current Good Manufacturing Practices (CGMPs) 

Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach

, in 2004, it put into motion an effort to enhance product quality and modernize pharmaceutical manufacturing through a science- and risk-based approach under quality-by-design (QbD) principles (1). That effort was further encouraged by the issuance of guidance on process analytical technology (PAT) in 2004 to facilitate the introduction of new technologies that would enhance process understanding and assist in identifying and controlling critical points in a process (2). These technologies include: appropriate measurements devices, which can be placed at-, in-, or on-line; statistical and information technology tools; and a scientific-systems approach for data analysis to control processes to ensure production of in-process materials and final products of desired quality (3). 

So how far has the industry come in advancing PAT and where may future innovation lie?

 conducted an industry roundtable to gain perspective on advances in analytical instrumentation and methods development. Participating are: Tim Freeman, managing director of Freeman Technology and past chair of the Process Analytical Technology Focus Group of the American Association of Pharmaceutical Scientists; Kevin Aumiller, TOC product manager at GE Analytical Instruments; Andy Salamon, senior staff scientist and customer advocate at PerkinElmer; Chris Heil, product specialist, Antaris NIR analyzers at Thermo Fisher Scientific; and Scott Samojla, senior director of PATROL process systems at Waters.  

 What would you identify as the most significant advances in PAT used in the pharmaceutical industry during the past five years?  

Before focusing on specific technologies, I'd like to highlight what I believe is an important shift in the perception of PAT over the last five years. Initially introduced by the regulators in 2004 to support efficiency in development, manufacturing, and quality assurance, PAT has, in the intervening years, progressively proven its potential value. Collective and individual experience has led to a widespread appreciation of the integral role that PAT will play in achieving new levels of manufacturing efficiency and product quality, and as a result, the uptake of PAT is now increasing significantly, most notably for the information-gathering needed to support the development of more efficient processes.  

Industry roundtable participants, from left to right: Tim Freeman, managing director of Freeman Technology and past chair of the AAPS Process Analytical Technology Focus Group; Kevin Aumiller, TOC product manager, GE Analytical Instruments; Andy Salamon, senior staff scientist and customer advocate at PerkinElmer; Scott Samojla, senior director of PATROL process systems, Waters; and Chris Heil (not pictured), product specialist, Antaris NIR analyzers, Thermo Fisher Scientific 

This focus on information-gathering and process monitoring is reflected in the technologies that have advanced most during the past five years. The use of on- or in-line systems with a proven track record has increased considerably but so too has the application of at-line methods that provide unique information and insight.  

In- and on-line systems deliver value by enabling the real-time tracking of process behavior and the changing properties of in-process materials. Today, the pharmaceutical industry is making greater use of some traditional on-line techniques, such as pH measurement, and also newer real-time technologies, such as particle sizing, and, of course the spectroscopic methods such as NIR. In the at-line arena, I'd recognize particle-imaging and bulk powder characterization systems, as examples of technology that are really advancing understanding. By providing the information needed to rationalize particle and powder behavior, these technologies support the attainment of better powder processing performance, which is vital for greater manufacturing efficiency. 

NIR spectroscopy has matured into a common technique for PAT analysis across the whole pharmaceutical manufacturing life cycle from raw material identification to granulation and drying to blending and tablet production.  The advent of fit-for-purpose and total solution NIR analyzers has unlocked the full potential of NIR spectroscopy as a process analytical technology for monitoring and controlling pharmaceutical production processes. We have witnessed the development of dedicated PAT NIR analyzers during the past five years, which offer total process analysis solutions. The evolution in design was witnessed not only in the NIR analyzers but also in the software, accessories, and probes required for a total analysis solution. Software integration and process communication also are key aspects of a total analyzer package.   

Experience has shown that the most challenging and often most important facet to a successful process analysis is representative sampling. The interface of the analyzer to the sampling point is critical since this is where the NIR spectrometer interrogates the sample for analysis. A perfect example is the challenge in getting a representative sample on a probe installed in a fluid-bed dryer when the product is being fluidized and the moisture level dictates whether the product will coat or foul the probe window. Advances in fiber-optic probe design have led to self-cleaning probes with purge air or retraction mechanisms to prevent probe fouling. In addition, probes that use side-view windows, angled tips, and curved, cupped design have been developed to ensure that representative samples are in contact with the probe window. These advances in NIR analyzers, software, and accessories have furthered the application of  PAT for production process optimization, reduction in production costs, and improved product quality through timely measurements of critical quality attributes.    

 The need for an improved scientifically based understanding of the manufacturing process has been and will continue to be key to future success in the pharmaceutical industry.  The advent of ultra-performance liquid chromatography provided the power to not only meet these needs within the laboratory, but enables on-line chromatographic use for process monitoring and control. The benefits of this approach reduce process variability and risk while adding automation and information not previously available on-line. 

 A prime example of PAT advancement has been associated with equipment cleaning and release. Clean-in-place (CIP) systems, which have historically been used in the biopharmaceutical space, have gained traction within traditional pharmaceutical facilities and contract manufacturing organizations. This has been promoted by the unprecedented merger and acquisition activity seen in the past three to five  years. With an industry focus on increasing plant capacity and reducing overall operating costs, facilities are taking on more products, which in turn, spawns the need for rapid equipment changeover. The implementation of CIP to replace manual cleaning has provided significant opportunities for efficiency in this area. 

Offering the benefits of automated, predictable, and repeatable cleaning cycles, CIP systems satisfy the main objectives of PAT by building quality into the process and providing real-time assurance of quality. The critical quality and performance attributes associated with cleaning can be monitored and controlled continuously. For example, the temperature and concentration of cleaning solutions can be monitored with in-line conductivity probes and temperature sensors. The agitation of the vessels can be actively controlled with flow meters and pressure transducers.  With the use of process logic control (PLC) systems, sequences can be timed to provide consistent exposure to the cleaning agents and rinse water.   

Once cleaning is complete, indirect sampling of final rinse water can be performed in near real-time with at-line total organic carbon (TOC) analyzers and in-line conductivity sensors. Direct swab samples can also be analyzed with at-line TOC instrumentation.  TOC instruments provide detection of residual product and other non-ionic species present in the process. The conductivity sensors can detect the presence of ionic contaminants, such as cleaning agents in the rinse water. The combination of test methods provides expedient feedback to release the equipment for use. 

 Looking ahead five years, how do you see PAT evolving in the pharmaceutical industry? 

While the use of PAT for information gathering and process monitoring, particularly in development, has grown substantially during the past five years, there is still some way to go in terms of optimizing its application across the whole manufacturing cycle and its utilization as a mechanism for process control. In the next five years, I expect PAT to penetrate further into commercial manufacture as confidence in its use and capabilities expand.  

The automation of process control is an ongoing trend and will continue to motivate suppliers to bring new technologies on line. On the other hand, experience from other sectors would suggest that the sophisticated application of the most relevant at-line techniques is an extremely complementary and productive approach. It, therefore, seems likely that the focus should and will remain on technologies that truly deliver in terms of relevant information whether at-, on- or in-line. Parameters, such as particle morphology, and powder flowability, compressibility, shear strength, and surface area are all likely to remain pertinent for powder processes. 

 In the pharmaceutical industry, PAT is well adopted among the largest pharmaceutical companies, especially in the more developed countries.  In the next  five years, I see the evolution of PAT into smaller pharmaceutical companies, contract manufacturing organizations, dietary supplement manufacturers, and companies in the less-developed world. Companies in these regions and industries have seen the progress that the larger pharmaceutical companies have made and see the value of PAT tools, such as NIR spectroscopy, for monitoring and controlling their processes to improve quality and lower production costs. 

Advances in data analysis and data management are critical to the future success of PAT. Managing the sheer volume of real-time, multivariate data generated from a production process so it can be used for real-time process adjustments or off-line production analysis is a challenge. During the last 10 years, significant knowledge has been gained on how to properly implement process instrumentation for on-line analysis.  

For many companies,  the starting point for implementing PAT tools was moving familiar laboratory spectroscopy techniques from laboratory to line. The value of PAT is built around real-time analysis of critical quality and performance attributes to improve process quality. For a pharmaceutical process, this means combining data from multiple sources to get a complete picture of the overall quality of raw, in-process, and final products. This approach requires advanced data-management systems capable of receiving information of various formats from multiple analyzers and production automation systems. Take for example, the data management required when applying PAT to the pharmaceutical hot-melt extrusion process. Real-time data of multiple formats and sources from a NIR analyzer, barrel temperature probe, pressure sensor, extruder-screw speed, and ingredient feed rates would need to be archived in a common location for real-time, multivariate data analysis as well as off-line post processing analysis. 

With future advances in data-analysis and data-management software, companies will be able to focus their PAT efforts on optimizing their sampling at point of analysis, chemometric models, and multivariate analysis tools, thereby allowing them to apply PAT to more challenging production processes. 

 Real-time chromatographic analysis will increasingly enhance manufacturing  processes—development, transfer, monitoring, and control. Integrating these enhancements within a unified information access model capable of very high-speed analytics will yield improved decision management, predictive analytics, and comprehensive analysis—without the paper. This integration can be achieved by deploying real-time analytics while eliminating the time delays, analytic, and process variability associated with traditional off-line analysis.   

 In the next five years, the adoption of PAT will likely be very evolutionary in nature. Existing processes will be incrementally changed to provide for better efficiency. It is unlikely that a disruptive technology will be readily adopted that totally replaces an existing process. 

Within the context of cleaning systems, we will likely see the development of better tools and analytics that allow for more optimal control of the processes. As indicated earlier, many cleaning processes currently employ the use of conductivity and TOC measurements as a check of equipment cleanliness. This testing is most often performed in the laboratory but also can be performed at-line to speed the time to result. With the use of robust and fast-responding on-line instrumentation, CIP cycles could be designed to run until contaminants drop below a predefined threshold rather than running for fixed periods of time. With the immediate feedback afforded by integrated conductivity and TOC monitors, processes could become quicker and require lower utility costs to achieve the same or better quality. This transition will require the use of instrumentation that can reliably detect the contaminants of interest within the complex matrix of a cleaning process.  

 To consider the potential advancements in analytical instrumentation, I would look at other significant advances in pharmaceutical development and not just at PAT advances. Nanotechnology drug delivery is the biggest advancement in the past five years and will be the biggest advancement in the future five years. Currently proven scaled-up developed manufacturing practices and processes do not exist to consistently produce, on a large scale, nanopharmaceuticals. In the development laboratory, single particle-inductively coupled plasma

mass spectrometry (SP–ICP–MS) of nanomaterials is the most significant improvement. This is not in-line, on-line, or at-line testing, but is a significant advance in analytical testing.  

Pharmaceutical cGMPs for the 21st Century—Risk-Based Approach: Final Report 

 Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance 

Progress Report on Process Analytical Technology,  

www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/ucm072006.htm

Industry experts share perspectives on analytical instrumentation, methods, and data analysis.

Process Analytical Technology: Charting Progress in Data Analysis

Chiral chemistry plays a significant role in the development of pharmaceutical intermediates and APIs, and as such, advances in asymmetric synthesis are of value to pharmaceutical companies. Researchers in academia and industry continue to develop new routes for achieving desired enantioselectivity. Some recent approaches include a more efficient route to prostaglandins, a biocatalytic route for making a key intermediate in the production of boceprevir, the API in Merck & Co.'s Victrelis, and a bifunctional catalyst derived from BINOL ligands for producing highly enantioselective bromolactonizations of unsaturated carboxylic acids.  

The global market for chiral technology, inclusive of applications in pharmaceuticals, is expected to show moderate growth during the next five years. The global chiral technology market was worth nearly $5.3 billion in 2011, according to a recent analysis by BCC Research. This market is expected to increase at a compound annual growth rate (CAGR) of 6.5% from 2011 to 2016 and will approach $7.2 billion by the end of the forecast period. Chiral synthesis products accounted for the majority of the chiral technology market in 2010, with an 80.0% share (i.e., $3.9 billion in revenues). This market segment was estimated at $4.2 billion in 2011 and is exepected to be $5.7 billion by 2016, a five-year CAGR of 6.4%, according to BCC. The chiral analysis market was valued at $785.7 million in 2010 and grew to $839.4 million in 2011. This market is projected to reach nearly $1.1 billion by 2016, a CAGR of 5.8% over the five-year period, according to BCC.  

Researchers at the University of Bristol in England recently reported on an improved method for making prostaglandins, natural, hormone-like chemicals that have pharmaceutical applications. The prostaglandin analog latanoprost, which is used to treat glaucoma and ocular hypertension, is a well-known prostaglandin. It is the active ingredient in Pfizer's Xalatan, which generated 2011 sales of $1.25 billion; the patent for the drug expired in 2011 (1).  

Due to prostaglandins' biological activity, but difficulty in synthesizing them, strategies for better synthetic routes for prostaglandins are an active area of research. For example, the current synthesis of latanoprost requires 20 steps and uses the methodology and strategy developed by E.J. Corey, winner of the 1990 Nobel Prize in Chemistry, according to an Aug. 15, 2012, University of Bristol press release.    

The University of Bristol researchers reported on a synthesis of prostaglandin PGF

, which relies on the use of an organocatalyst, a small organic molecule, to catalyze a key step in the process, which produced high levels of control of relative and absolute stereochemistry and fewer steps, according to the university press release and recent article detailing the research (2). The new process uses a new disconnection that enabled the researchers to complete the synthesis in only seven steps, according to the university release. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step with enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups (1). The route to the bicyclic enal is important for a more efficient and potentially cost-effective route but also serves as a basis for examining related chemical structures of prostaglandin analogs (1, 2).  

"Despite the long syntheses and the resulting huge effort that is required for the preparation of these molecules, they are still used in the clinic because of their important biological activity, said Varinder K. Aggarwal, professor in the School of Chemistry, University of Bristol, in the university release. "Being able to make complex pharmaceuticals in a shorter number of steps and, therefore, more effectively, would mean that many more people could be treated for the same cost." 

Researchers at the School of Chemical and Biomolecular Engineering at the Georgia Institute of Technology and Merck & Co. recently developed an amine dehydrogenase for the synthesis of chiral amines. Specifically, the researchers successfully altered a leucine dehydrogenase through protein engineering to an enantioselective amine dehydrogenase. Instead of the wild-type α-keto acid, the new amine dehydrogenase accepted the analogous ketone, methyl isobutyl ketone, which corresponded to exchange of the carboxy group by a methyl group to produce chiral (

Earlier this year, Codexis, a biocatalysis company, reported on its work with Merck & Co. for developing an enzyme-based production method for a key intermediate in the production of boceprevir, the API in Merck's Victrelis, a drug to treat hepatitis C. The companies reported on a chemoenzymatic process for manufacturing the boceprevir bicyclic proline intermediate based on amine oxidase-catalyzed desymmetrization. The key structural feature in boceprevir is the bicyclic proline moiety, which during development stages, was produced by a classical resolution. As the drug candidate advanced, Codexis and Schering–Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis where the net reaction was an oxidative Strecker reaction. The key part of the reaction sequence is an enzymatic oxidative desymmetrization of a prochiral amine substrate (4, 5).  

According to Codexis, the new method increased chemical intermediate yield 150% over the previous process. It also reduced raw material use by 60%, water use by 61%, and overall process waste by 63%. Codexis used its proprietary CodeEvolver directed evolution technology to develop the custom enzyme for use in the commercial-scale manufacturing of the boceprevir intermediate (5). 

Codexis had earlier partnered with Merck & Co. for another biocatalytic route. The companies developed a biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the API in Merck's antidiabetes drug Januvia (5). In May 2012, Merck extended its pact for biocatalysis with Codexis for another three years to 2015. The initial agreement was announced in April 2007.   

Heterocyclic compounds are important in pharmaceutical applications, and researchers at the California Institute of Technology (Caltech) recently reported on an advance in the synthesis of such compounds. They reported on their work in the enantioselective construction of quaternary 

-heterocycles by palladium-catalyzed decarboxylative allylic alkylation of lactams (5, 6). 

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," said Brian Stoltz, professor of chemistry at Caltech, in a Jan. 13, 2012, university press release. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access." 

Specifically, the researchers reported on the highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams, and structurally related lactams. The researchers asserted that the synthesis provides a new approach for the asymmetric synthesis of such structures, an important development given the prevalence of quaternary 

-heterocycles in biologically active alkaloids and pharmaceutical agents. The researchers reported that the catalysis provided enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the 

 alkaloids, quebrachamine and rhazinilam, but that were previously produced by chiral auxiliary approaches or as racemic mixtures (5, 6). 

BINOL and its derivatives are widely used classes of ligands in asymmetric synthesis, such as in Diels–Alder reactions, carbonyl addition, and reductions (7). Researchers at the University of Texas, Austin, recently developed a bifunctional catalyst derived from BINOL for producing highly enantioselective bromolactonizations of unsaturated carboxylic acids (8, 9). Specifically, the catalyst promoted highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzed the highly enantioselective bromolactonizations of 5-alkyl-4(Z)-pentenoic acids. The researchers assert that these reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceeded by means of 5-exo mode cyclizations to give lactones in which new carbon–bromine bonds are formed at a stereogenic center with high enantioselectivity. The researchers also reported on what they say is the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization (8, 9). 

 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, 

 2. G. Coulthard, W. Erb, and K. Aggarwal, "Stereocontrolled Organocatalytic Synthesis of Prostagladin PGF

, online DOI10.1038/nature11411, Aug. 15, 2012.  

Industry and academia advance novel approaches for achieving enanioselectivity.

Meeting Challenges in Asymmetric Synthesis

Can you explain how the Freiburg and Illertissen facilities complement each other in terms of scale and capabilities?  

Holger Weyhers, director of pharmaceutical operations, Pfizer Illertissen

: Pfizer has two Centers of High Containment (HC) Excellence in Germany. The Product and Process Development  (PPD) facility in Freiburg focuses on product development, scale-up, and clinical supply. The Illertissen facility is focused on commercial-scale manufacture and packaging. Pfizer CentreSource (PCS), a commercial unit of Pfizer Global Supply, provides contract manufacturing and development-stage outsourcing services through these facilities. PCS recently expanded its suite of HC services to support earlier stage development in addition to commercial supply. Services and support available through PCS include drug-product formulation development, excipient studies, material characterization, compatibility studies, analytical method development, process analytical technology, product enhancement, ICH stability studies, and clinical supply. 

A weighing isolator in the Pfizer facility in Freiburg, Germany, is used for dispensing highly potent compounds. (Image Courtesy of Pfizer)  

Bernd Schuemmelfeder, director, PPD business development, Pfizer Freiburg

: At PPD Freiburg, the focus is on highly potent solid dosage form development to ensure a smooth process transfer from laboratory (5–15 kg) 

 pilot (70 g) to commercial scale (150 kg). Our DevCon (Development Containment) facility was designed as a multiple module facility to provide flexibility during product development at scales of  5–150 kg. Pfizer's strategy is to have capacities in place to support early-stage candidates when limited tox data are available. Pfizer handles such early-phase compounds by default as Occupational Exposure Band (OEB ) 4 compounds. According to the Pfizer nomenclature, OEB 4 refers to compounds with an occupational exposure limit of smaller than 10 µg/m

: The Illertissen site focuses on HC manufacturing and specialized packaging operations; the facility can handle compound classes,  including highly active compounds, cytotoxics, and hormones. Our three containment suites accommodate a portfolio of medium- to large-volume products, with batch sizes of 80–700 kg. Containment facilities are highly automated, and follow the "engineered containment" philosophy (i.e.,  a best-in-class environmental health and safety approach in line with current regulatory requirements). The processes in the NEWCON facility and our smaller scale ICON facility are fully automated and remotely controlled, thus there is no contact whatsoever between operator and product.   

The Illertissen facility received ISPE's 2008 "Facility of the Year Award" for process innovation and garnered the overall ISPE 2008 "Facility of the Year Award." The facility's innovative "cell concept" layout (in contrast to the more traditional modular design) and the automated remotely run production processes previously described incorporate the current aspects of process visualization, manufacturing execution systems, process visualization, masterbatch recording, and electronic batch recording.  

: Can you describe the containment approach at the Freiburg facility and its sustainability features?   

: DevCon has been designed as a multiple module facility to provide best flexibility during product development ranging from 1 to 150 kg. Our PPD group, and its facilities are an integral part of Pfizer's manufacturing site in Freiburg, which received the ISPE 2011 Facility of the year Award for Sustainability. The design of the Freiburg facility incorporates a range of eco-friendly technologies, such as geothermal energy for cooling and heating, adiabatic cooling , and other sustainable building design elements (photovoltaics, energy monitoring, and performance windows, for example.) We also introduced greener laboratory techniques. Subsequently, we have achieved notable improvements in HVAC (heating, ventilation, air conditioning) energy consumption levels. As a result, we are now generating some 93% of total plant energy from renewable energy technologies.

Pfizer has two manufacturing facilities in Germany for high-potency manufacturing, respectively in Freiburg and Illertissen. Pharmaceutical Technology's Executive Editor Patricia Van Arnum visited the facilities and spoke to the company about the design and operation of these facilities.

Plant Focus: High-Potency Manufacturing and Sustainability at Pfizer

High-potency manufacturing is a niche, but specialised area that requires proper facility design, equipment selection, production processes and operator knowledge to safely handle and produce highly potent APIs (HPAPIs) and finished drug products containing HPAPIs. 

 conducted an industry roundtable to gain a perspective of these issues. Participating were: Joe Cascone, director of potent product pharmaceutical development at Metrics; Joe Nettleton, vice-president and director of operations at Cambrex's Charles City, Iowa (US), facility; Peter Müller, delegate of the Dishman board and member of the Carbogen Amcis management team; Theodore Iliopoulos, chief scientific officer at Euticals; Paul Doherty, chemical engineer, Sigma Black Belt, and plant manager at Ferro Pfanstiehl Laboratories; and David Bormett director of operations at SAFC.  

A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process. What are the key considerations in designing a high-potency manufacturing facility and in selecting equipment?  

 High-potency containment structures address both cross-contamination requirements targeting patient safety and, at the same time, worker safety by maintaining occupational exposure limits (OELs) below 10 mcg (Band III) or 10 ng (Band IV) per cubic meter of air for an eight-hour weighted average. Exposure to just a small quantity of a HPAPI or highly potent compound can pose significant health risks.  

The challenge in designing a high-potency containment facility is to find the appropriate level of containment that should manage the exposure risk at a reasonable cost. It is also crucial that the operators and the production staff understand the need and proper use of engineering controls. Enclosed reactors, centrifuges, dryers and highly dusty mills are key manufacturing assets in an API production line and, together with product-transfer systems, are key elements in a high-containment design. The most crucial issues in selecting the proper equipment are the containment of the process itself. In other words, one must ensure that no airborne particles are released to the ambient air and that product remains in the process piping used. Equipment and facility-engineering controls apply to all areas handling such compounds, not just manufacturing. It also refers to process-development and quality-control laboratories. 

Proper initial design and engineering of a potent-compound handling facility is crucial to achieve the desired levels of containment. Consideration must be given for containment of the entire process, from weighing and charging of raw materials, to packaging of the final material. Key facility-design criteria include single-pass heating, ventilation and air-conditioning (HVAC) systems, controlled access to areas, airlocks around potent-compound handling rooms for segregated gowning/degowning, proper room-pressure differentials for containment, degown misting showers, bag-in/bag-out filtration components, sufficient support utilities (such as supplied air) and proper waste-handling capabilities. 

SAFC uses an overall potent-compound handling system that incorporates five levels of cascading protection, with the first two being the primary methods of material isolation/containment:  					

: using closed-system glassware and reactors and alpha-beta/split butterfly valves.

: glovebox isolators, ventilated laminar-flow enclosures, rapid-transfer ports, local exhaust ventilation and closed-system cleaning through clean-in-place (CIP) systems.

: proper air pressurisation, high number of air changes, single-pass air, restricted room access, airlocks, safe-change filters and misting showers. 

: As a secondary precaution, Saranex coveralls and hoods, powered air respirators or supplied air, proper glove selection, and chemical suits when needed for solvents/reagents.

: training, written procedures/policies, education and employee-health monitoring.

When designing and selecting equipment, it is important to partner with vendors that understand isolation/containment and the requirements for potent-compound handling. In many cases, the equipment vendors can provide data from previous containment testing conducted using surrogate products. The equipment selected should be fit-for-purpose and provide the necessary flexibility to accommodate process changes, especially for multipurpose facilities. 

 In pharmaceutical manufacturing, there are two primary objectives for containment: to protect product quality and prevent worker exposure. There are underlying design principles that apply to all pharmaceutical manufacturing and analytical facilities at Cambrex. The operational goal is to maintain process isolation using isolators, sealed process vessels, dedicated piping, and single-pass, high-efficiency particulate air (HEPA)-filtered airflow. It also is crucial to design the ventilation system so that potentially contaminated air will flow downstream and away from the process area. Ingress and egress also are controlled to ensure both air and worker traffic moves in a single direction with minimal turbulence. Gowning/degowning vestibules, material pass-throughs and misting showers also are integrated into the flow. Upon ingress, disposable garments are donned, and upon egress, workers are misted with water to tack particulates to disposable garments, which are then discarded before exiting. 

With respect to exposure prevention, in many instances, the design strategy for quality protection is the same as exposure prevention. Process isolation using isolators, sealed reactors and dryers and HEPA-filtered airflows are all important. In some cases, however, pressure differentials that protect pharmaceutical quality may not be protective of worker exposure. For example, when opening an isolator, positive pressure in the isolator will prevent cross-contamination, but the pressure release will potentially expel particulate material toward the worker. In these cases, the engineering strategy may include a bag in/out system. It also may be appropriate to include extra personal protective equipment when transferring toxic or potent compounds. 

Mockups, training and verification also are key. Because all manufacturing process are different, it is important to verify that a given process design will function correctly and that operators are familiar with the process before a pharmaceutical product is actually manufactured. At Cambrex, it is common for the manufacturing team to develop and conduct mock handling exercises. These mock exercises may include the handling of surrogate pharmaceutical compounds followed by an assessment of potential releases and cross-contamination using wipes, air sampling and appropriate analytical detection. Naproxen is typically used as a surrogate because it has an extremely low detection limit and is easy to clean. At completion, mock exercises will demonstrate that process and containment equipment performs as expected, provide process ownership and training for operators, and identify potential need for design modifications to prevent cross-contamination or worker exposure. Cambrex routinely conducts equipment maintenance and equipment performance verification to ensure isolators, hoods, balance enclosures, airlocks and HEPA systems are working properly. 

 Carbogen Amcis has more than one site and has more than one production facility at its headquarters site in Bubendorf, Switzerland, but the concepts pursued with regard to containment are governed by one common philosophy regarding the handling of HPAPIs: the risks to be controlled regard the patient, the worker, and the environment. Therefore, we are analysing the whole lifecycle from the purchasing of raw materials (which may eventually be highly potent compounds) to the delivery of products and to the creation of waste, the whole set of buildings and installations involved and the whole series of applicable procedures and measures.  

The containment requirements are defined in view of the toxicological category (performance-based exposure limit [PBECL], OEL, or acceptable daily exposure [ADE], respectively), whereby Carbogen Amcis is working with a four-categories approach, and strict requirements are applied in case of Categories 3 and 4. They particularly involve with regard to production, separation of the ventilation (room and/or reactor exhaust, i.e., systems), HEPA-filtration of exhaust air, separation of the room (airlocks), pressure cascades, partial dedication of specific equipment to HPAPIs, completely closed processing and separation of the wastestreams. Thus, the focus is on avoiding carryover as well as contamination of the workers and the environment through production equipment (cleaning), through space and through infrastructure systems. 

The respective considerations are applied along the whole sequence of activities (i.e., the lifecycle). The details cannot be outlined here, but it can be said in a summary that they include gloveboxes or isolators, respectively, barrier isolation benches, laminar flows and flexible containment with all the activities subjected to their specific risk analysis. Personal protective equipment is eventually used as a safety backup during critical operations.  

The facility and equipment constitute the barriers between the high-potent active agents and their surroundings. A facility designed with one-pass air and multiple airlocks with cascading negative pressure differentials will, in conjunction with other controls, mitigate cross-contamination. Hard- and soft-wall isolation technology demonstrates sufficient containment for the manufacture of solid-oral dosage forms containing compounds deemed to fall within an occupational exposure band of 10 mcg /m

  (TWA). These systems may be verified by recognised industrial hygiene practices, such as the

 ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment 

Enclosing a particular process or unit operation is reasonably well-established by most equipment manufacturers and isolation specialists. A key challenge is linking the unit operations together with the proper conveyance technology. This is particularly daunting if there is a wide variety of equipment makes and models. It is generally easy to contain powders within a bowl or vessel. Charging and discharging those powders and transporting them to other pieces of equipment is more complex. Examples of conveyance technology that may offer solutions include vacuum conveyance and continuous-liner 'bag-out' systems. 

Another challenge related to isolation and containment centres on powder sampling. Process intermediates (e.g., blends and granules) need to be sampled to characterise in-process attributes and/or comply with prescribed regulations. Access to the product 

 properly designed and contained sample ports is essential. 

 First and foremost is the principle to not rely on 'moon suits' for the operators and instead have a strategy and philosophy to use engineering controls to provide proper containment. The key considerations are the OEL of the substance to be handled and, particularly for a CRO/CMO, the stage of the API and the scale of operation. The organisation should have a system in place that uses the OEL to establish the acceptable options available for facility design and equipment selection. For a CRO/CMO, the best and most economical means to handle a potent substance depend significantly on the stage (preclinical, clinical or commercial) and scale. For example, the best means of producing a preclinical small-scale API might be a combination of dedicated laboratory-scale equipment, disposables and a small isolator. In contrast, a commercial product produced at a 50-kg scale might require plant-scale equipment with validated cleaning procedures and test methods.  

Risk assessment, evaluation and mitigation

On an operational basis, what are key best practices to achieve the desired level of containment? What are key considerations for making the appropriate risk assessment, risk evaluation and risk mitigation? What types of metrics are used to monitor risk during operation? 

 Conducting a thorough risk assessment is the best practice to achieve a desired level of containment. It is important to note that 'more' containment may not be a 'desired level' of containment. Rather, the desired level of containment is derived from the need to protect employees and mitigate cross-contamination of drug products. The level of containment required in any instance should be technical and quantifiable. It is not speculative or derived from interpretation or opinion. 

A comprehensive risk assessment will determine what engineering, facility and administrative controls are required. A risk matrix may be developed for each step of the process. Each matrix will identify associated potential adverse events. Each potential adverse event should be quantified by calculating the product of its probability of occurrence by its severity. Risks cannot be monitored during a process, but actual events and exposures can. Proper feedback tools are essential to ensure the 'desired level' is appropriate and effective. 

Utilisation of properly designed engineering controls is the primary means for achieving the desired level of containment. It is important to understand the OELs or potential OELs of developmental compounds, for the product to be handled in the facility, and then design and test to meet 50% of the lowest OEL. Planning for containment at 50% of the OEL allows for variability that may occur due to different operators, process scales, material densities and/or equipment use. Proper containment should be confirmed by obtaining industrial hygiene air/surface samples and conducting testing for the specific compound being handled, or using a representative surrogate product. Data generated during industrial hygiene testing should be used to assess areas of greatest potential risk for exposure to allow for improvements and changes to be implemented to minimise the risk. Testing must be repeated over time to evaluate containment systems and processes and to ensure that equipment continues to operate at expected levels.  

Another key area for consideration is equipment cleaning following use with potent compounds. An effective and verified cleaning programme is critical to prevent potential cross-contamination, especially in a multiuse facility. Equipment cleaning also can be an activity for potential employee exposure. Therefore, CIP systems should be employed when possible, and monitoring should be performed during cleaning activities to verify that the OEL requirements are being met.  

Facilities handling highly potent compounds should have a compound evaluation and categorisation system in place in order to conduct appropriate risk assessments and communicate hazards. This is especially critical when working on developmental compounds that may not have an established OEL. The categorisation can be used to determine proper handling and containment requirements for the compound based on the systems in place within the facility.  

 A proper facility to handle HPAPIs should be designed considering technologies such as isolators, laminar flow hoods and local exhaust ventilation systems with air filtered before released to the ambient air. The air supplied to the rooms should be single-pass with proper air-pressure differentials to keep product-exposed areas negative to all adjacent areas or airlocks. Appropriately validated cleaning procedures should secure no cross-contamination with the next compound to be produced using same equipment or piping. ISPE launched the 

Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) Baseline Guide

, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross- contamination (2, 3). EMA followed with a concept paper, published in Oct. 2011, and suggests using "a more scientific approach...to establish threshold values" (4).  

In instances when the toxicity of a compound is not known, it must be treated as Band IV compound. Obviously, the best would be to determine the toxicity of a given compound prior to embarking in high-cost production set-ups. To minimise the risk and for extra safety purposes even if engineering controls are in place, personnel working with highly potent compounds should wear suitable personal protective equipment, including respiration equipment.  

Best practices in dealing with HAPIs are the availability and checking of material safety data sheet (MSDS) data for any compound used in the process, process hazard analysis, start-up, safety review, training, change control, emergency planning and response. Measurement of the dust during operation in the production areas is a key parameter in defining and checking the safety level at the operational level.  

 Risk management at Cambrex begins with training. All Cambrex employees granted access to areas that manufacture potent or toxic APIs must participate in training and become certified. Training follows a detailed risk assessment and risk-management framework that was developed in collaboration with the Cambrex toxicologist who is board certified and has extensive experience in risk assessment and with the Cambrex occupational nurse. Project-specific risk management recommendations are formalised by the toxicologist into a document known as a Project Safety Dossier (PSD). PSDs are formally reviewed by the manufacturing team before beginning work. In high-containment areas, new process designs are evaluated by certified Cambrex manufacturing teams in mock exercises that verify and document containment. Cambrex is guided by a four-band occupational exposure band (OEB) framework. Every molecule used to synthesise the API is evaluated separately and assigned an OEB. In some cases, where data is unavailable for a particular synthetic intermediate, Cambrex may conduct 

When making risk-management recommendations and decisions, Cambrex is cognizant that safeguards must balance the conflicting goals of mitigating exposure risk, minimising the ergonomic hazards imposed by unnecessarily conservative exposure controls, and quality considerations. Safeguards include integration of API-specific toxicodynamic factors into risk-management decisions, appropriate use of personal protective equipment and containment verification with good hygiene practices. 

 The best practices to be applied depend on the category and amount of the material handled and on the frequency and complexity of the operation in question. For Carbogen Amcis, we are working with dedicated equipment that is firmly installed in many instances and working with flexible containment approaches in others (e.g., when having to dismantle equipment in the context of cleaning or when having to be sure that eventual leakage could be controlled). A realistic assessment of the risk in question is important.  

Key practices in analytically monitoring involve swabbing surfaces (e.g., in the laboratory) as well as air-sampling during critical operations. Thereby, we are normally working with a combination of IOM samplers carried by the worker and of stationary samplers adequately placed to provide an idea of the eventual emission's distribution in space. We use surrogates right after installing new equipment and periodically perform analogous sampling and analysing (i.e, high-performance liquid chromatography) of the true highly potent materials to control routine operations later on. The key parameter to be realistically determined is the exposed person's potential daily up-take in mcg.  

 Before moving forward with any project work, a process hazard analysis (PHA) should be conducted. This PHA will evaluate all aspects of the technical challenge and incorporate information, such as safety data sheets, product use, OELs, short-term exposure limits, odor threshold, industrial-hygiene monitoring method and analysis, irritant or sensitiser, toxicological data, primary toxic effect, route/mechanism of exposure, warning signs of exposure, treatment for exposure, cleaning procedures, acceptable surface residual levels, deactivation procedures, flammability/combustability, applicability of transportation regulations, waste disposal consideration and other regulatory impacts.  

Even with the best facility design and equipment selection, the level of containment can be largely determined by operational practices. Therefore, a considerable amount of effort needs to be devoted to writing solid operating procedures, and providing operator training. The organisation should have a system in place that uses the OEL to establish the acceptable options for handling procedures and practices. In addition, industrial-hygiene monitoring should be used to verify that the combination of facility design, equipment selection and operational practices is providing the expected level of containment. Medical monitoring of employees should be included as a verification of the adequacy of the industrial-hygiene sampling programme.  

 What are some recent technological advances in facility and equipment design for high-potency manufacturing? 

 Many equipment vendors are pre-engineering their equipment to be contained whereas in the past this was considered an optional upgrade. New equipment is more modular in nature. Product-contact modules can be cleanly removed from drive units and disassembled and cleaned in remote washing areas. This reduces downtime and exposure risks.  

 There has been an increasing interest in the use of disposable containment options for potent-compound handling, especially for larger-scale operations. Disposable systems reduce the time for cleaning and can eliminate the potential for cross-contamination. They also may be used as secondary isolation around fixed equipment to improve overall containment of the process to meet lower OELs. Improvements in local exhaust systems, with proper filtration for potent-compound capture, also have been implemented to further reduce potential exposure to employees or the facility.  

The integration of two types of equipment, in some instances by two different equipment vendors, is also an area that has seen improvement. This could include engineering glovebox isolation equipment onto Nutsche filter/dryers or lyophilisers to allow for containment during discharge of potent compounds. 

 There is a growing trend in powder processing. Closed systems for powder handling and special valves are being developed along with engineering advances in the equipment used to contain the highly potent APIs or hazardous compounds. The term containment itself directs engineers in developing methodologies and structures to isolate the highly potent compounds. Charging materials to reactors, discharging a centrifuge, charging of a mill and packaging in closed systems are becoming popular practices in dealing with highly hazardous substances produced in multipurpose facilities. Traditional technologies are not easy to clean, and the risk of material remaining on the surfaces is too high. Disposables used in the use of closed system solve these problems, but have limitations with some solvents. Some examples of currently used isolation technologies using disposables are drum-sampling, dispensing, transfer sleeves, filter-change containment, decontamination and cleaning containment. The benefit is that with low investment, one can achieve the desired containment level. I am sure that the future development will be focused in the development of isolation technologies at the level of dust generation. 

With improved awareness and hazard recognition related to high-potency API development and manufacturing, there is a greater appreciation of proper risk management associated with HPAPI handling in general. Industry leaders are working to move away from administrative containment strategies to more robust engineering controls. Specifically in regards to micronisation of HPAPIs, Cambrex maintains GMP micronisation suites equipped with high-level containment engineering controls. These containment systems units have demonstrated performance to 1 ng/m

What I am seeing is a lot of small improvements to potent-handling equipment, such as better means of cleaning split butterfly valves that are providing continuous improvement in containment. These small improvements should not be underestimated in their beneficial impact.  

Experts share insight on facility design and operations for high-potency manufacturing.