Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

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. 

Looking ahead over the next five 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 five to ten 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 of 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.   

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.  

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.  

 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.  

Articles

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

35th Anniversary Special: Future Innovation in Drug Delivery

Small-molecule APIs dominate pharmaceutical manufacturing, so where may future innovation reside? The scientific literature abounds with novel approaches to a given synthesis or refinements to existing syntheses as a means to improve product yield, process conditions, enantioselectivity, or production economics. These efforts are an integral part of process development and commercial manufacturing and will continue to be so. But what may be the game-changer in small-molecule manufacturing? As we consider the possibilities, continuous-flow technology through micreactors as an alternative to traditional batch manufacturing may be one possibility.  

Continuous-flow technology involves the continuous introduction of a stream of chemical reactants into a flow or microreactor to yield a desired reaction product on a continuous basis (1). Continuous-flow technology may offer potential advantages compared with traditional batch manufacturing of pharmaceuticals, such as greater optimization and control of the process, an improved safety and environmental profile for a given process, and a reduced manufacturing footprint compared with batch-reactor systems (1). 

In general, microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer (2). Microstructured devices operate in a continuous-flow environment, which can provide controlled process conditions, high flow rates, and high mass throughput. Continuous operations also may allow for bulk-chemistry processes to have high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment, such as pressure loss, heat-transfer characteristics, residence time, and mixing time (2, 3).  

Reflecting growing interest in microreactor technology for fine-chemical manufacturing, Lonza reported earlier this year investment in what it terms the "Factory of Tomorrow," at its facility in Visp, Switzerland. The facility will offer production of multitons of intermediates and/or APIs based on continuous-flow processing. Lonza currently operates assets that can produce several kilograms to several tons of small-molecule APIs using microreactors. The new facility will provide an integrated solution where all common unit operations in flow can be streamlined in a flexible fashion using microreactors (FlowPlate, Lonza). The facility was slated to be operational in June 2012. 

The new unit will enable the integration of complete flow processes in addition to microreactors, according to company information. It will be able to integrate a range of flow reactors, such as continuous stirrer tank reactors or ultrasounds and streamline flow processes, including work-up unit operations, such as liquid–liquid extraction, distillation (wiped-film, thin film). Higher pressure applications will be enabled as well by allowing gas–liquid reactions, such as ozone and HCN chemistries. The technology can be used for chemical reactions under severe and extreme conditions,  such as very high temperatures or cryogenic conditions. 

Effectively applying continuous-flow technology involves a multidisciplinary approach of chemistry and engineering. As an example, researchers at the Massachusetts Institute of Technology (MIT) reported on the development of a Suzuki–Miyaura cross-coupling reaction in a continuous-flow microreactor system. Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides and is an important reaction in organic chemistry in general and for pharmaceutical compounds specifically.  

The researchers developed a continuous-flow Suzuki–Miyaura cross-coupling reaction that started from phenols and produced various biaryls in good yield using a microfluidic-extraction operation and a packed-bed reactor. The project used a multidisciplinary approach with the research on microreactor technology developed by a team led by Klaus F. Jensen, department head, Warren K. Lewis professor of chemical engineering, and professor of materials science and engineering at MIT. The organic synthesis portion of the project was developed by a group led by Stephen Buchwald, Camille Dreyfus professor of chemistry at MIT (3–5). 

1. J. Hamby, "API Synthesis, Formulation Development, and Manufacturing" supp. 

2. N. Korman et al., "API Synthesis, Formulation Development, and Manufacturing" supp. 

4. T. Noel et al., "Suzuki–Miyaura Cross-Coupling Reactions in Flow: Multistep Synthesis Enabled by a Microfluidic Extraction," 

 online, DOI: 10.1002/anie.201101480, May 17, 2011. 

Flow chemistry and microreactors offer alternatives to traditional batch manufacturing.

35th Anniversary Special: What's Ahead in Chemical API Manufacturing

 the biopharmaceutical company Amylin Pharmaceuticals for a purchase price of $5.3 billion and an additional $1.7 billion for assuming Amylin’s net debt and a contractual payment obligation to Eli Lilly based on Amylin’s recently terminated agreement with Eli Lilly over the diabetes drug exenatide. After the closing of the acquisition of Amylin by Bristol-Myers Squibb, AstraZeneca will make a $3.4-billion payment to Bristol-Myers Squibb as part of the companies’ previously formed diabetes-drug collaboration. 

Amylin’s primary focus is on the research, development, and commercialization of a franchise of GLP-1 agonists for treating Type II diabetes. Amylin and Eli Lilly had partnered for developing exenatide, the active ingredient in the diabetes drug Byetta, which was approved in the United States in 2005, and for developing a once-a-week version of exenatide, Bydureon, which was approved in the European Union in June 2011 and in the US in January 2012. In November 2011, Amylin and Eli Lilly terminated their alliance for exenatide, with worldwide development and commercialization rights transitioning back to Amylin, starting with the US in 2011 and progressing to all markets by the end of 2013. As part of that termination, Amylin agreed to make a one-time, upfront payment to Eli Lilly of $250 million and pay future revenue-sharing payments to Eli Lilly based on global net sales of exenatide products. In addition to Byetta and Bydureon, Amylin also is developing exenatide suspension formulations and a pen device for Bydureon. 

Following completion of Bristol-Myers Squibb’s acquisition of Amylin, AstraZeneca will make a payment to Amylin, as a wholly owned subsidiary of Bristol-Myers Squibb, in the amount of approximately $3.4 billion as part of the diabetes-drug collaboration between Bristol-Myers Squibb and AstraZeneca. Bristol-Myers Squibb and AstraZeneca formed a collaboration in January 2007 for researching, developing, and commercializing select investigational drugs for Type II diabetes. As part of its acquisition of Amylin by Bristol-Myers Squibb, AstraZeneca also has the option, exercisable at its sole discretion following the closing of the acquisition, to establish equal governance rights over key strategic and financial decisions regarding the collaboration upon the payment to Bristol-Myers Squibb of an additional $135 million. These collaboration arrangements have been approved by the boards of directors of Bristol-Myers Squibb and AstraZeneca.

The Amylin acquisition fits strategically with Bristol-Myers Squibb’s efforts to build its diabetes franchise, which includes its diabetes collaboration with AstraZeneca. The Bristol-Myers Squibb/AstraZeneca diabetes collaboration is focused around several diabetes drugs: Onglyza (saxagliptin), Kombiglyze (saxagliptin and metformin HCI extended-release), and Forxiga (dapagliflozin), a selective and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2), a new class of diabetes drugs. In January 2012, FDA issued a Complete Response Letter regarding the companies’ new drug application for dapagliflozin and requested additional clinical data to allow a better assessment of the risk–benefit profile for dapagliflozin. In April 2012, EMA’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the approval of dapagliflozin. The CHMP positive opinion for dapagliflozin is under review by European regulatory authorities.

Bristol-Myers Squibb’s pending acquisition of Amylin has been unanimously approved by the boards of directors of Bristol-Myers Squibb and Amylin and is subject to customary closing conditions. Amylin has agreed not to solicit competing offers. The companies expect the deal to close approximately 30 days after commencement of a tender offer of $31.00 per share by Bristol-Myers Squibb for Amylin.

Bristol-Myers Squibb has agreed to acquire the biopharmaceutical company Amylin Pharmaceuticals for a purchase price of $5.3 billion and an additional $1.7 billion for assuming Amylin's net debt and a contractual payment obligation to Eli Lilly based on Amylin's recently terminated agreement with Eli Lilly over the diabetes drug exenatide.

Bristol-Myers Squibb Agrees to Acquire Amylin for $5.3 Billion

Drug-delivery approaches that better control and target delivery are important to achieve clinical efficacy. Several recent interesting approaches involve gold nanoparticles for targeting tumor sites and elastic capsules using nanosized flakes. 

Researchers at the University of Sydney in Australia, led by Nial Wheate, senior lecturer in the Faculty of Pharmacy, and researchers from the University of Strathclyde and the University of Glasgow in Scotland recently reported on delivering the anticancer drug cisplatin using gold-coated iron oxide nanoparticles for enhanced tumor targeting (1). The researchers used this approach to overcome some challenges of cisplatin, namely poor bioavailability, severe dose-limiting side effects, and rapid development of drug resistance (1). The iron oxide core was coated in a protective layer of gold before the anticancer drug cisplatin was attached to the gold coating using spaghetti-like strings of polymer, according to a May 31, University of Sydney press release.  

The technology was demonstrated when the team grew cancer cells in plates. When they placed a magnet under the plates, the drug affected and killed only those cells growing near the magnet, leaving the others unharmed, The potential benefit of this targeted drug- delivery method is reduction of side-effects due to the chemotherapeutic drug traveling to other cells.  

The iron oxide nanoparticles (FeNPs) were synthesised via a coprecipitation method before gold was reduced onto its surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH

} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterized by dynamic light scattering, scanning transmission electron microscopy, UV visible spectrophotometry, inductively coupled plasma mass spectrometry, and electron probe microanalysis. Nanoparticle drug loading was found to be 7.9 X 10

 moles of platinum per gram of gold. External magnets were used to show that the nanoparticles could be accumulated in specific regions and that cell-growth inhibition was localized to those areas (1).  

In another development, researchers at the National Institute for Material Science in Japan recently developed a new elastic capsule using an inorganic nanometer-thickness flake-shaped material (nanosheets). Tests of the new capsule demonstrated that the release duration of anticancer drugs and other drugs can be controlled freely and can also be extended by several times by using the newly developed capsule.  

The researchers were seeking to overcome some of the challenges of  inorganic and organic materials conventionally used in capsules, according to a May 9, 2012, press release of the National Institute for Material Science in Japan. Inorganic capsules are hard, strong, and durable, but their structures are not easily adjusted to adapt to conditions.  Organic capsules are flexible and structural adjustment is possible, but they have the drawback of low mechanical strength. In this research, a soft capsule was developed by creating an assembly of nanosheets of silica, which is an inorganic material. While this capsule consists of a mechanically stable inorganic material, free control of its structure is also possible. 

This capsule expands and contracts when heated and cooled, and the size of the pores in the outer wall, which are formed by the spaces between the nanosheets and serve as passages for drug release, can be controlled over a wide range by adjusting pH to various levels, according to the press release. As a result, the sustained-release time of the anticancer drug DOX was successfully extended by several times in comparison with conventional porous capsules having a simple structure. It was also possible to control the drug-release duration and drug-storage amount by changing the pore structure of the capsule, thereby changing the drug-release routes under appropriate pH conditions (2).  

 1. N. Wheate et al., "Cisplatin Drug Delivery Using Gold-Coated Iron Oxide Nanoparticles for Enhanced Tumor Targeting with External Magnetic Fields,"

, online, DOI10.1016/j.ica.2012.05.012, May 30, 2012.  

 2. Q. Ji et al.,"Flake-Shell Capsules: Adjustable Inorganic Structures," 

, online, DOI: 10.1002/chin.201223201, May 7, 2012. 

Gold nanoparticles for targeting tumor sites and elastic capsules using nanosized flakes are some recent approaches used to control and target drug delivery.

Formulation Development Forum: Nanotechnology-based Drug Delivery

When FDA first announced in 2002 a new initiative, 

Pharmaceutical Current Good Manufacturing Practices (CGMPs)

 for the 21st Century, and later issued its report, 

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 principles (QbD) (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.  

 On an industry level, 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. 

 On an industry level, looking ahead five years, how do you see PAT evolving in the pharmaceutical industry, both in terms of adoption as well potential advancements in instrumentation, data analysis, and related testing in a PAT environment. 

: 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. 

It is also my view that the extension of PAT into the manufacturing arena will prove valuable in terms of fully exploiting the processing experience that resides there. In our area, for example, the application of appropriate and relevant powder testing has unlocked real understanding about why certain plants behave as they do, providing information that can be used to further the development of more efficient processes. By closing this loop, and bringing formulation, process development, and manufacture closer together, PAT will be able to significantly accelerate progress. 

: 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. 

Process analyzer software with automated archival and industry standard process communication protocols embedded into the process analysis workflow are critical attributes when implementing a PAT analyzer. Analyzer software that supports multiple data exchange formats, process communication protocols and the ability to execute external applications further simplifies the implementation process. Current gaps in data analysis and management have required pharmaceutical companies to write, implement, and validate custom software for their PAT applications.  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.

35th Anniversary Special: The Today and Tomorrow of Process Analytical Technology

The US Department of Health and Human Services (HHS) has established three new centers to develop and manufacture medical countermeasures, such as vaccines and medicines, which can be used in health emergencies and in preparedness protection. HHS will invest $400 million in the initial phases of the centers, which include contracts to biopharmaceutical and pharmaceutical companies.

 Created as public–private partnerships, the Centers for Innovation in Advanced Development and Manufacturing, will provide the first major domestic infrastructure in the United States capable of producing medical countermeasures for protection against the health impacts of bioterrorism as well as pandemic influenza and other epidemics, according to a June 18, 2012, 

. The public–private partnerships will seek to engage the innovation from small biotechnology companies, training from academic institutions, and the development and manufacturing expertise of large pharmaceutical companies.

 Each center will be run by a consortium led by an organization experienced in developing or manufacturing medical countermeasures. HHS will invest approximately $400 million in the initial phases of the centers, using contracts with the center leads. Overseen by the Biomedical Advanced Research and Development Authority within the HHS Office of the Assistant Secretary for Preparedness and Response, each contract can be renewed for up to 25 years. Under the contracts, each consortium will retrofit existing facilities or build new ones to incorporate flexible, innovative manufacturing platforms that can be used to manufacture more than one product. The facilities will use cell- and recombinant-based vaccine technologies that have the potential to produce vaccines for not only pandemic influenza but also other threats more quickly and in a more affordable way, according to HHS.

HHS says that the centers’ use of these technologies also will allow each to develop and manufacture a variety of products quickly enough to respond to large-scale emergencies by providing needed domestic surge capacity. Together, the centers will be capable of domestically producing a quarter of the nation’s pandemic influenza vaccine within four months of the onset of a pandemic. In 2009, only one company had manufacturing facilities solely in the US to produce H1N1 pandemic vaccine, according to HHS. 

The private partners will provide approximately 35% of the total cost of the initial building phase. HHS will support the cost of operation and maintenance of the centers in subsequent years. As the facilities become operational in 2014 and 2015, the center leads will begin assisting small biotechnology companies with technology, regulatory affairs, quality systems, and manufacturing expertise to reach the goal of a licensed and readily available product for public and private use. Also at that time, center academic partners will offer advanced training for biotechnology workers.

 Emergent Manufacturing Operations Baltimore LLC, with facilities in Baltimore and Gaithersburg, Maryland, will lead one center, working with a network of partners: Michigan State University; Kettering University of Flint, Michigan; and the University of Maryland in Baltimore. This contract is for approximately $163 million over the first eight years. Novartis will head a second center, leveraging existing public–private investments by HHS in its facilities in Holly Springs, North Carolina, and work with North Carolina State University and Duke University. The Novartis contract is valued at approximately $60 million over the first four years. The Texas A&M University System will lead a third center collaborating with GlaxoSmithKline Vaccines of Marietta, Pennsylvania.; Lonza of Houston, Texas, and Kalon Biotherapeutics of College Station, Texas. This contract is valued at approximately $176 million during the first five years.

Novartis, GlaxoSmithKline, and Lonza are among those participating in newly formed consortiums for developing and producing medical countermeasures.