TY - JOUR
AU - Ling,, Geoffrey
AB - Abstract Purpose Developmental pharmaceutical manufacturing systems and techniques designed to overcome the shortcomings of traditional batch processing methods are described. Summary Conventional pharmaceutical manufacturing processes do not adequately address the needs of military and civilian patient populations and healthcare providers. Recent advances within the Defense Advanced Research Projects Agency (DARPA) Battlefield Medicine program suggest that miniaturized, flexible platforms for end-to-end manufacturing of pharmaceuticals are possible. Advances in continuous-flow synthesis, chemistry, biological engineering, and downstream processing, coupled with online analytics, automation, and enhanced process control measures, pave the way for disruptive innovation to improve the pharmaceutical supply chain and drug manufacturing base. These new technologies, along with current and ongoing advances in regulatory science, have the future potential to (1) permit “on demand” drug manufacturing on the battlefield and in other austere environments, (2) enhance the level of preparedness for chemical, biological, radiological, and nuclear threats, (3) enhance health authorities’ ability to respond to natural disasters and other catastrophic events, (4) minimize shortages of drugs, (5) address gaps in the orphan drug market, (6) support and enable the continued drive toward precision medicine, and (7) enhance access to needed medications in underserved areas across the globe. Conclusion Modular platforms under development by DARPA’s Battlefield Medicine program may one day improve the safety, efficiency, and timeliness of drug manufacturing. There have been major technological advancements in the manufacturing sector in recent decades, including three-dimensional printing, microfabrication of materials, and innovation with continuous-flow chemistry processes in the petrochemical and bulk chemical industries. In contrast, the methods of manufacturing pharmaceuticals, while typically more complex than those for producing commodity chemicals, have remained largely stagnant and unchanged for over 50 years. Drug manufacturing continues to be characterized as an inefficient, capital-intensive, and inflexible process. The ongoing crisis of drug shortages in the United States has resulted in notable quality issues, delays, and discontinuations of needed pharmaceuticals. More importantly, it has resulted in patient harm. 1,2 Pharmacists and other healthcare providers continue to try to function with a drug manufacturing base that is unresponsive to fluctuations and changes in demand. While we have witnessed some incremental benefit as a result of efforts on the part of the Food and Drug Administration (FDA) and some drug manufacturers, the number of shortages (peaking at 320 at the end of the third quarter of calendar year 2014) remains unacceptably high (Figure 1). A lack of incentives for and focus on quality, combined with aging facilities and a lack of innovation and incorporation of new technologies into generic drug manufacturing, has been identified as a major source of the drug-shortage crisis and drug-quality issues that we continue to experience in the United States. 3,–5 In the military drug supply chain, it can take weeks or months to prepare small-molecule organic pharmaceutical drugs and large-molecule therapeutic proteins needed on the battlefield and airlift them to the front lines. As a result, needed medications may in many instances not reach the patients who most urgently need them. These delays also affect civilians living in remote and underserved areas of the world and victims of natural disasters, who may temporarily lack access to life-saving drugs. Such inefficiencies also extend to medication preparedness efforts focused on chemical, biological, radiological, and nuclear threats, as well as efforts to prepare for potential pandemic outbreaks and new emerging infectious diseases. The Centers for Disease Control and Prevention’s Strategic National Stockpile of medications is a cache of antibiotics, antitoxins, antidotes, and other life-sustaining medications. This is a valuable and important resource; however, the inefficiency of procuring and stockpiling massive amounts of medications with relatively short expirations is obvious. In addition, such an approach logically requires that we know what threat to anticipate and prepare for in order to stockpile the right medication so that we are prepared to nimbly respond to that potential threat. A more flexible, portable, and nimble drug manufacturing and supply chain platform is desirable in order to more efficiently and effectively meet both known and unknown medication needs in the setting of catastrophic events. There is a need to fundamentally change how organic and biological drugs are manufactured and delivered. This begins with the development of underlying science and technologies that can enable rapid, distributed, and flexible manufacturing of drugs. The Battlefield Medicine program of the Defense Advanced Research Projects Agency (DARPA) is developing innovative miniaturized pharmaceutical and biological manufacturing platforms capable of producing multiple drugs. The program is composed of two integrated research thrusts to enhance the capabilities of far-forward medical providers: the Pharmacy on Demand program and the Biologically-derived Medicines on Demand program. The aggressive timeline and metrics for the DARPA programs include the production of multiple FDA-approvable pharmaceuticals, at appropriate purity and potency levels, within the same miniaturized manufacturing platform and with very short end-to-end manufacturing times (less than 24 hours). During the course of development of the Pharmacy on Demand and Biologically-derived Medicines on Demand manufacturing platforms, novel chemistries, technologies, and concepts have been created and utilized. These advancements include leveraging the use of continuous-flow chemistries to enable new reaction schemes and conditions for multiple active pharmaceutical ingredients. 6,7 Key Points Conventional batch processing of pharmaceuticals has remained largely unchanged in the past 50 years. Waste, inefficiencies, and quality concerns associated with conventional manufacturing have contributed to increasing drug costs and frequent drug shortages. Continuous-flow synthesis and new manufacturing technologies and techniques will enable new types of chemistries, minimize waste, and allow for platform miniaturization. The DARPA Battlefield Medicine program aims to disrupt how pharmaceuticals and biologics are currently produced by developing innovative technologies and flexible, distributed manufacturing platforms to produce multiple drugs “on demand.” The profession of pharmacy should take note of technological innovations that may enable on-demand drug manufacturing at the point of care and consider ways the profession can prepare for the utilization of this technology to improve patients’ access to needed medications and the quality of patient care. Manufacturing of small-molecule organic medications Batch versus continuous-flow manufacturing Traditional batch processing, which is currently used in the vast majority of pharmaceutical manufacturing processes, is materials, labor, time, and cost intensive. As large batches go through different reactions and processing in succession, extensive infrastructure, heterogeneous reaction conditions, extended processing times, and, oftentimes, a complex logistics train are required (Figure 2). As drug development progresses through each stage, manufacturing requirements scale up by several orders of magnitude. These requirements proceed from milligram quantities for initial testing to kilogram quantities for clinical trials to as much as hundreds of tons per year for mass production and broad clinical use. 8 The batch process requires reiterative optimizations during “scale-up” that can lead to inefficiencies in chemical reaction pathways and heat-exchange processes and suboptimal yields. Moreover, when large-scale batch operations fail quality testing, this can result in the waste of large quantities of intermediate products or raw materials. A list of limitations and advantages of batch processing is provided in the appendix. Figure 1 Open in new tabDownload slide Trend of U.S. drug shortages, January 2010–September 2015. Reprinted with permission from Erin Fox, University of Utah Drug Information Service. Figure 1 Open in new tabDownload slide Trend of U.S. drug shortages, January 2010–September 2015. Reprinted with permission from Erin Fox, University of Utah Drug Information Service. Figure 2 Open in new tabDownload slide Example of traditional tablet manufacturing process. The product is collected after each unit operation, and the finished product is tested at outside laboratories, resulting in overall processing times of days to weeks. Reprinted from reference 10. Figure 2 Open in new tabDownload slide Example of traditional tablet manufacturing process. The product is collected after each unit operation, and the finished product is tested at outside laboratories, resulting in overall processing times of days to weeks. Reprinted from reference 10. Typically, chemical synthesis and drug product formulation are conducted in separate facilities. This has the potential to negatively affect quality control, as compliance with current good manufacturing practices becomes more burdensome with the use of multiple facilities. It is worth noting that in recent years, FDA has encouraged “quality by design”: a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control. It is based on sound science and quality-risk management. Essentially, it is building quality into a drug product by leveraging a comprehensive knowledge of the product and its key characteristics, a robust understanding of the manufacturing process, and enhanced analytics to allow control and detection of process and product variations. Instituting quality by design requires meaningful improvement over current manufacturing practices (as described above) by ensuring consistent product quality throughout the manufacturing process and identifying when contamination and other production failures may occur. 10,11 By reducing the likelihood of production failures, principles of quality by design also have the potential to reduce product development and manufacturing costs. In contrast to batch processing, the Pharmacy on Demand platform uses continuous-flow synthesis that allows for multiple-step reactions to be conducted by adding new reactants to the work flow at specific points and for reactions that produce large amounts of heat to be run safely. In a continuous-flow process, intermediate chemical entities exist for only short periods and in small quantities before moving through the next reaction; this allows for the potential utilization of chemical reactions for enhanced product yield and efficiency of manufacturing that were previously “forbidden” due to unstable or hazardous intermediates or products. Additionally, development of chemical reactions that can take place as reactants flow through chemically compatible materials and device components enables miniaturization and minimizes waste, making a continuous-flow process “greener.” 12 Furthermore, a continuous-flow process enables integration of reaction, crystallization, purification, and formulation with advanced control and real-time monitoring capabilities, thus enabling the application of quality-by-design principles and miniaturization of the entire end-to-end manufacturing platform (Figure 3). The advantages and disadvantages of continuous-flow manufacturing are provided in the appendix. Figure 3 Open in new tabDownload slide Schematic of Pharmacy on Demand pharmaceutical manufacturing platform showing both upstream and downstream processes. API = active pharmaceutical ingredient. Figure 3 Open in new tabDownload slide Schematic of Pharmacy on Demand pharmaceutical manufacturing platform showing both upstream and downstream processes. API = active pharmaceutical ingredient. Pharmacy on Demand program Leveraging recent advances in continuous-flow synthesis and manufacturing techniques, 13,–26 DARPA’s technical approach to the Pharmacy on Demand system has focused on developing continuous-manufacturing capabilities to enable a modular platform containing a “reaction toolbox.” This platform enables a manufacturing approach whereby each reaction step is decoupled from others and specific steps are selected based on the chemical synthesis pathway for a given active pharmaceutical ingredient; through the assembly of individual reaction steps on the platform, a fully integrated multistep synthesis, purification, and formulation process for each drug can be achieved. Initiated just over three years ago, the Pharmacy on Demand program has already developed a fully operational miniaturized synthesis platform. The Pharmacy on Demand platform is composed of two merged modular components, each measuring 6 × 2 × 1.5 feet, for upstream (active pharmaceutical ingredient synthesis) and downstream (active pharmaceutical ingredient crystallization, filtration, and formulation) processes to achieve production of more than 1000 doses of each active pharmaceutical ingredient per day. The Pharmacy on Demand platform has been demonstrated to be capable of accomplishing, for the first time ever, end-to-end manufacturing of four agents (diphenhydramine, lidocaine, diazepam, and fluoxetine) on the same platform at purities that meet United States Pharmacopeia standards. The fully automated and integrated processes produced the following outputs: 439 g of diphenhydramine (17,560 25-mg doses) per day, 225 g of lidocaine (2,250 100-mg doses) per day, 195 g of diazepam (19,500 10-mg doses) per day, and 22 g of fluoxetine (1,100 20-mg doses) per day. Table 1 Comparative Operational Variables With Traditional Batch Manufacturing Process and Pharmacy on Demand System Variable Batch Process Pharmacy on Demand Residence times Hours to days A few minutes Inventory volumes 1000 L A few liters End-to-end manufacturing times >300 hr per batch 10–15 hr Variable Batch Process Pharmacy on Demand Residence times Hours to days A few minutes Inventory volumes 1000 L A few liters End-to-end manufacturing times >300 hr per batch 10–15 hr Open in new tab Table 1 Comparative Operational Variables With Traditional Batch Manufacturing Process and Pharmacy on Demand System Variable Batch Process Pharmacy on Demand Residence times Hours to days A few minutes Inventory volumes 1000 L A few liters End-to-end manufacturing times >300 hr per batch 10–15 hr Variable Batch Process Pharmacy on Demand Residence times Hours to days A few minutes Inventory volumes 1000 L A few liters End-to-end manufacturing times >300 hr per batch 10–15 hr Open in new tab The Pharmacy on Demand platform offers notably improved performance by helping to overcome multiple operational limitations of traditional batch processing. These benefits are achieved primarily through reduced residence times, inventory volumes, and end-to-end manufacturing times (Table 1). Notably, end-to-end manufacturing of the four active pharmaceutical ingredients listed above using continuous-flow synthesis took considerably less time than traditional processes. During the synthesis of the active pharmaceutical ingredients, the average total residence volumes of reagents and solvents were no more than 50 mL, and the volume required for the active pharmaceutical ingredient purification was no more than 2 L; by comparison, volumes of (at minimum) thousands of liters are required for batch operations. The Pharmacy on Demand team devised various materials and engineering solutions to counter chemical compatibility problems in the spiral reactors, pumps, and tubing to enable the use of high pressures (average, 250 psi; maximum, 300 psi), high temperatures (maximum, 200 C), and aggressive or corrosive chemicals. The modular components of the Pharmacy on Demand system (including the reactors, pumps, and separators) enable the manufacture of multiple pharmaceuticals and the performance of multiple reaction and extraction steps for a given active pharmaceutical ingredient within the same system. Noteworthy challenges emerged in the course of developing the Pharmacy on Demand platform. In many instances, commercially available components were not able to perform under the wide range of chemical compatibility, temperature, and pressure conditions necessary to complete manufacturing processes. For example, pumping aggressive chemicals at elevated pressures (250 psi) and flow rates (up to 5 mL/min) required the Pharmacy on Demand team to develop specialized components, including microreactors, pumps, tubing, and inline separators. It was discovered in the early development of the Pharmacy on Demand program that reactions and chemical synthesis routes that work well in batch conditions and operations do not necessarily scale well to continuous-flow conditions. Therefore, the Pharmacy on Demand team created new synthesis methods, reaction schemes, and conditions that were successful under continuous-flow conditions. Due to the ability of microreactors operating under continuous-flow conditions to more efficiently transfer heat, more precisely control temperatures, and handle volatile organic compounds, increased flexibility in terms of the types of chemistries to be developed and implemented effectively expands the reaction toolbox and invites innovative synthetic approaches not imagined previously. Manufacturing of biologicals Manufacturing of protein-based therapeutics typically occurs in large manufacturing plants and involves the use of specialized cell cultures. These cultures are grown over multiple days or weeks in large (10- to 10,000-L) bioreactors under batch conditions. 27 The bioreactors are then harvested, and the expressed proteins are recovered, purified, stabilized, and stored as an intermediate bulk drug substance. This intermediate bulk drug substance is then further formulated and filled (sometimes in a separate plant or facility) into vials or other delivery devices before shipment to the end user at the point of care. This entire manufacturing process can take anywhere from weeks to many months for a typical FDA-approved biological agent. Similar to the manufacturing of small-molecule organic drugs, the biological manufacturing process is materials, labor, time, and cost intensive. Relative to the synthesis of organic small molecules, the manufacturing of large-molecule therapeutic proteins is much more complex (oftentimes unique). In addition to polypeptide synthesis, additional purification and post-translational modification steps are often necessary; all of those steps can affect biological activity and potency. With regard to appropriately characterizing a therapeutic protein and its target protein profile and measuring the therapeutic protein’s critical attributes and biological activity, potency, and immunogenicity in order to meet quality-by-design standards, the number and complexity of analytical measurements are orders of magnitude higher than those required to test and measure a small organic molecule. Add to those challenges the ever-increasing pace of scientific breakthroughs in this domain and the evolving regulatory framework around biosimilars in the United States, 28 and the biological manufacturing landscape becomes even more complex. Biologically-derived Medicines on Demand program To produce multiple biologicals on a mobile platform in response to specific demands, the Biologically-derived Medicines on Demand program requires the generation and assessment of new and flexible approaches to manipulating and engineering protein-synthesis systems, including microbial, mammalian, and cell-free translation systems. The goal of the program is to demonstrate the capability to produce multiple FDA-approvable protein-based therapeutics (i.e., biosimilars) of high purity, efficacy, and potency at the point of care in time frames of less than 24 hours. The Biologically-derived Medicines on Demand program started just over two years ago and is developing and testing two different approaches to protein synthesis. One is a cell-free protein synthesis approach using hamster ovary cell lysates. This “in vitro translation” approach focuses on developing cell lysate mixtures containing only the components required for protein production, such as ribosomes and other cellular organelles, and includes the addition of DNA that codes for expression of a specific therapeutic protein. 29,–35 An in vitro translation approach to protein synthesis is advantageous for a number of reasons. 29,–35 First, in comparison to cell-based approaches, it requires a shorter time for protein synthesis. Typical production times are on the order of one or two days (including cell extract preparation), as compared with one or two weeks for typical in vivo approaches. This time advantage results from the reduced number of steps involved (e.g., no genetic engineering, no cell culture growth, less extensive purification schemes). In addition, monitoring and direct manipulation of the chemical environment for optimization purposes is possible due to the lack of a cell wall. In contrast to cell-based systems, with the in vitro translation approach there is no concern that the proteins produced will themselves have toxic effects on living cells. Lastly, the in vitro translation platform possesses more flexibility to introduce non-natural amino acid sequences and to produce viruslike particles that are important components of vaccines. The other Biologically-derived Medicines on Demand approach for protein synthesis focuses on using a cell-based eukaryotic yeast organism (Pichia pastoris) to synthesize biologicals. The use of a yeast cell–based vehicle like P. pastoris instead of a cell-based system offers other advantages. 36,–40 First, there is a reduced risk of DNA degradation by endogenous nucleases. Second, P. pastoris is amenable to lyophilization, which in theory can reduce or eliminate the need for a cold supply chain. Third, purification complexity is reduced because P. pastoris possesses an endogenous mechanism for protein secretion and does not harbor viruses found in mammalian cultures. Lastly, P. pastoris strains are capable of humanized protein folding, glycosylation, and other posttranslational modifications. The Biologically-derived Medicines on Demand efforts thus far have shown that miniaturized bioreactors that can control temperature and agitation while monitoring dissolved oxygen, oxidation-reduction potential, and the pH of cell lysates can be developed. These bioreactor prototypes for in vitro translation have also been demonstrated to be capable of producing therapeutic doses of erythropoietin and streptokinase within four hours of the addition of complementary DNA to the bioreactor prototype containing the lysate mixture. The future vision is to combine these bioreactors with novel protein purification systems and inline analytics in a mobile device that contains all of the elements necessary to express, purify, and analyze any target protein. Microfluidics-based bioreactors have the demonstrated capability to perform stable two-week fermentations (in P. pastoris) of interferon alfa-2b and human growth hormone, with crude protein being produced within a few hours. 41 These microfluidic bioreactors have unique channels and chambers enabling the user to collect cells from the growth chambers, perfused material, and waste independently and allowing for diffusion of molecules between gas and liquid phases. It is conceivable, given the genomic stability of P. pastoris, that genetic circuitry can be developed to enable tunable production of two or more biologicals from the same P. pastoris organism (as opposed to using separate strains for different biologicals) in a sequential manner. Preliminary research results have demonstrated these systems’ ability to sequentially induce the production of interferon alfa-2b and human growth hormone by changing the medium and, thus, the chemical environment. These components will be integrated into a milliliter-scale tabletop system for semicontinuous operation consisting of a parallel set of microbioreactors for filtration of cell debris from the secreted protein product and novel affinity-based purification, polishing, and finishing processes, as well as integrated online analytics and process control for quality-by-design production and product quality testing. Beyond the complexity of protein synthesis itself, the Biologically-derived Medicines on Demand platform will require complex downstream processing steps. There are various technical challenges that need to be addressed. Impurities, including host cell proteins, DNA, aggregates, and viruses, will need to be separated and removed at acceptable levels to attain therapeutic-grade purity whether the protein is produced from a cell lysate or secreted from a cell. In traditional batch manufacturing of biologicals, the downstream process must be validated for its ability to remove or inactivate these impurities and contaminants. However, it is not practical to perform these validation studies throughout the entire manufacturing process due to the large scale involved. Therefore, a downscaled purification process (e.g., a laboratory-scale mimic of the process) is often used for these validation purposes. An obvious limitation to this is ensuring that the scaled-down process provides an accurate indication of what is occurring in the full-scale process. In this regard, the current Biologically-derived Medicines on Demand platforms have potential advantages over the current methodology. As the Biologically-derived Medicines on Demand teams develop reliable methods of purifying the target proteins “in line” as they are synthesized, this may enable inline analytical assessments during production such that the purity of the entire small volume of target product is known at any given time during the downstream process. The ability of a protein to exert its biological function is dependent on not only the correct amino acid sequence in the polypeptide chain but also the protein’s overall shape, specifically its tertiary or quaternary structure, which is determined by the amino acid sequence and post-translational modifications (PTMs). There are many types of PTMs that can introduce functional groups to the polypeptide chain, including but not limited to phosphates, amide groups, and carbohydrates (through glycosylation). 41 These PTMs can affect a protein’s folding and stability and, thus, its tertiary and quaternary structures, thereby affecting the protein’s fundamental ability to exert its biological activity. Specifically, achieving humanlike N-glycosylation so that structural and functional activity is preserved will be a unique challenge for both mammalian in vitro translation–produced and yeast-secreted proteins. 39,42,–44 To address this issue, part of the solution will involve engineering cell extracts or cells, as well as developing additional glycosylation enzymes and sugar substrates, in order to successfully produce the final glycosylation pattern. The Biologically-derived Medicines on Demand teams are working to develop platforms that include a suite of online analytical tools. These will include novel optical, microfluidic, and nanosensor technologies. In addition to analyzing PTMs, these tools will be capable of analyzing target product identity, purity, quality, biological activity, and aggregation. Integration of the biosynthetic pathways with the purification modules into a miniaturized manufacturing system, along with the development of a semiuniversal purification scheme to address multiple target proteins and online orthogonal analytics, is another unique challenge being addressed. Discussion The future potential of the Pharmacy on Demand and Biologically-derived Medicines on Demand systems to produce multiple drugs on a modular and/or mobile platform, at a reduced expense, while leveraging automation and continuous monitoring of quality and reliability is enormous. These systems have the potential to enhance our ability to care for military personnel and patients around the globe in many ways. The number of medications currently produced on these platforms is limited; the technology itself is very early in development, and there remains much work to be done. The initial thrust of the two DARPA Battlefield Medicine programs was to conduct proof-of-concept research focused on therapeutic agents with diverse chemical structures and synthetic pathways by methods that can be “retrofitted” in the synthesis of other agents. In addition to the four agents produced in the Pharmacy on Demand program, efforts to demonstrate production of additional agents in order to further demonstrate proof of concept are ongoing; examples of such agents include atropine, ibuprofen, doxycycline, ciprofloxacin, azithromycin, etomidate, nicardipine, neostigmine, albuterol, and rufinamide. Over time, we expect that the library of modular chemical reactions will expand with further development of microreactors and downstream processes involving continuous-flow techniques. We can envision a future wherein modular Pharmacy on Demand platforms are transported to forward operating bases along with a limited number of raw precursor ingredients and other reagents to enable on-demand synthesis of a host of ready-to-use pharmaceuticals. Similar applications can be envisioned with the Biologically-derived Medicine on Demand platform. These technologies are new, and the pace of development of biotechnology is rapid. With a mobile platform capable of reliably producing protein-based therapeutics, in conjunction with new developments in rapid diagnostics, disease detection, and protein sequencing, one can envision a deployable manufacturing force equipped to produce antibodies, vaccines, and antidotes in rapid response to an identified threat or outbreak. Combined, the two Battlefield Medicine platforms could support military personnel in the direct care of soldiers (including those wounded on the battlefield), provide a platform to allow for more flexible medical countermeasure–oriented threat response with reduced stockpiles, and enhance efforts to respond to disasters around the world via medical diplomacy missions. With regard to the commercial drug supply chain, initiatives to move drug manufacturing closer to the patient in a safe, regulated, efficient, and flexible manner through the use of state-of-the-art manufacturing technologies and quality control would be expected to have a favorable impact on the drug shortage crisis. Moreover, technologies and platforms under development have the future potential to address gaps in the orphan drug market and, more generally, expand access to needed medications for patients in underserved areas across the globe. A critical aspect of the safe adoption and utilization of these new technologies is developments on the regulatory front, where FDA has been encouraging the pharmaceutical industry to adopt novel approaches to manufacturing. With recent advances in technologies for producing biosimilars, there is growing optimism that current drug manufacturing operations can be beneficially disrupted in order to meet medical needs today and into the future. As with any new technology or science, the development of drug manufacturing technologies such as those described here poses questions for healthcare professionals and for society. These technologies are envisioned as “plug-and-play” modules, with enhanced automation and quality-control technologies built in; that begs questions for pharmacists: Can you envision putting a Pharmacy on Demand platform (or similar technology) in a cleanroom in order to manufacture drugs in the event of a shortage? Who would be considered qualified to run such a platform safely? In multihospital systems that compound medications at a central site, could a Pharmacy on Demand platform provide a cost-effective mechanism to manufacture, prepare, and dispense generic medications across the institution? Should large health systems consider becoming de facto generic drug manufacturers in order to supply their patients? In the era of precision biomarkers and enhanced diagnostic techniques, can you envision a time in the near future when patients with very rare diseases would have the option to ask that precision medicines tailored to their specific conditions be manufactured and made available to them? While DARPA’s Battlefield Medicine program is already demonstrating the capability to achieve end-to end manufacturing of some pharmaceuticals in a “small-footprint” system, continued development and refinement are required before these technologies could be incorporated into the drug supply chain. However, one of the main points of this article is to make pharmacists and leaders in the profession aware of these technological advancements and ask the question: How can the profession prepare to make the most of these potential technological realities in order to enhance the quality of patient care? The DARPA Battlefield Medicine program is research in progress. While early efforts have been very successful, the research is ongoing. It is challenging to predict the future of this technology and the changes to the drug supply chain that might ensue as the technology continues to mature and develop. The early scientific and engineering breakthroughs accomplished in the program make envisioning a future state wherein small-molecule organic and therapeutic proteins can be manufactured safely and reliably at the point of care—in short time frames, with real-time analytics for verification of purity, potency, and quality—a potential reality. Pharmacists and pharmacy leaders should take note of these new technological developments and begin to consider the potential beneficial impacts on the drug supply chain and the readiness of the profession to adopt such technologies for the betterment of patient care. Conclusion Modular platforms under development by DARPA’s Battlefield Medicine program may one day improve the safety, efficiency, and timeliness of drug manufacturing. Disclosures Presented in part at the ASHP Midyear Clinical Meeting in New Orleans, LA as the Spotlight on Science presentation on December 9, 2015. Dr. Lewin serves as a consultant to the Defense Advanced Research Projects Agency. The other authors have declared no potential conflicts of interest. Additional information The opinions and views expressed in this article belong only to the authors. These view and opinions are not, nor should they be implied to be, those of or endorsed by the Department of Defense or any other agency of the U.S. government. Appendix–Advantages and disadvantages of batch versus continuous-flow pharmaceutical manufacturing 8,9 Batch pharmaceutical manufacturing Advantages Inexpensive reactors Established processes Equipment may potentially support multiple products Disadvantages Capital and infrastructure intensive Time intensive Defects not often immediately recognized High risk of large amounts of waste Difficulty in cooling or heating large vats Heterogeneous reaction conditions Inability to produce reactive or dangerous chemical intermediates Often requires numerous, diverse chemical reaction steps Chemical synthesis and formulation processes often carried out in separate plants and locations Continuous-flow pharmaceutical manufacturing Advantages Potential for improved control over quality and process safety Quality assurance testing in real time Reduced hazard (smaller reactor volume and greater ease of containment) Lower capital and operating costs Enhanced mass and heat transfer rates Improved product yield vii. Utilization of previously “forbidden” reactions Controlled use of higher pressures and temperatures to optimize yield and reduce impurities Easier “scale-up” from laboratory to production More flexible manufacturing process to fine-tune production to meet demand Shorter throughput times, with a reduced equipment footprint “Greener” processes resulting from less solvent use Reduced raw material inventories Disadvantages Relatively new technology for fine chemicals and pharmaceuticals References 1 Paparella SF . Drug shortages in the emergency department: managing a threat to patient safety . J Emerg Nurs . 2012 ; 38 : 466 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Institute for Safe Medication Practices . Drug shortages: national survey reveals high level of frustration, low level of safety ( September 23 , 2010 ). www.ismp.org/newsletters/acutecare/articles/20100923.asp (accessed 2015 Oct 13). 3 Fox ER , Sweet BV , Jensen V . 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TI - Pharmacy on demand: New technologies to enable miniaturized and mobile drug manufacturing
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp150639
DA - 2016-01-15
UR - https://www.deepdyve.com/lp/oxford-university-press/pharmacy-on-demand-new-technologies-to-enable-miniaturized-and-mobile-7IXrzyElyp
SP - 45
VL - 73
IS - 2
DP - DeepDyve
ER -