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Changes in hyperthermic and MRI efficacies of magnetic nanoparticle suspensions following ligand exchange/phase transfer and in the gel phase reveals how the responses are determined by moment dynamics and particle and solvent diffusion.

The objective of this study is to develop an operation that can conduct separations based on diafiltration using semipermeable nanofiltration or ultrafiltration membranes in a fully continuous manner in a single stage configuration.

A highly scalable combined modular and 3D-printed falling film crystallization device is developed and demonstrated herein; the device uses a small, complex, printed overflow-based film distribution part that ensures formation of a well-distributed heated liquid film around a modular, tubular residence time/crystallizer section, enabling extended residence times to be achieved. A model API (ibuprofen) and impurity (ibuprofen ethyl ester) were used as a test system in the evaluation of the novel crystallizer design. The proposed crystallizer was run using three operational configurations: batch, cyclical batch, and continuous feed, all with intermittent removal of product. Results were suitable for intermediate purification requirements, and stable operation was demonstrated over multiple cycles, indicating that this approach should be compatible with parallel semicontinuous operation for intermediate purification and solvent swap applications in the manufacture of drugs.

Magnetic iron oxide nanoparticles have multiple biomedical applications in AC-field hyperthermia and magnetic resonance imaging (MRI) contrast enhancement. Here, two cubic particle suspensions are analyzed in detail, one suspension displayed strong magnetic heating and MRI contrast efficacies, while the other responded weakly. This is despite them having almost identical size, morphology, and colloidal dispersion. Aberration-corrected scanning transmission electron microscopy, electron energy loss spectroscopy, and high-resolution transmission electron microscopy analysis confirmed that the spinel phase Fe

In this work, a number of kinetic models describing adsorption processes that occur via a mixed mechanism of both simultaneous surface adsorption and internal ion exchange were developed. The propo...

Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal of transition metal from the process, (2)...

In a time of global vaccine shortages, especially for COVID-19 products, Serum Institute of India (SII) is straining to meet demand for vaccines in India. While this organization is not known worldwide, they entered into a recent alliance with AstraZeneca, who is partnered with Oxford University for Covid-19 vaccine, to manufacture their supply of vaccines for distribution in India. Several other such partnerships are also underway. And, SII is considering plans to become a much larger player, not only in India, but globally. This commentary is focused on if, when, where, why, and how global expansion could proceed. Our work was carried out as a class project to identify options and strategies appropriate for expansion and has been expanded subsequently as events continued to develop.

Identification of phenotypic characteristics in reproductively successful individuals provides important insights into the evolutionary processes that cause range shifts due to environmental change. Female beluga whales (Delphinapterus leucas) from the Baffin Bay region (BB) of the Canadian Arctic in the core area of the species’ geographic range have larger body size than their conspecifics at the southern range periphery in Hudson Bay (HB). We investigated the mechanism for this north and south divergence as it relates to ovarian reproductive activity (ORA = total corpora) that combines morphometric data with ovarian corpora counted from female reproductive tracts. Based on the previous finding of reproductive senescence in older HB females, but not for BB whales, we compared ORA patterns of the two populations with age and body length. Female beluga whale ORA increased more quickly with age (63% partial variation explained) in BB than in HB (41%). In contrast, body length in HB female beluga whales accounted for considerably more of the total variation (12 vs 1%) in ORA compared to BB whales. We speculate that female HB beluga whale ORA was more strongly linked with body length due to higher population density resulting in food competition that favors the energetic advantages of larger body size during seasonal food limitations. Understanding the evolutionary mechanism of how ORA varies across a species’ range will assist conservation efforts in anticipating and mitigating future challenges associated with a warming planet.

A low-cost, modular, robust, and easily customisable continuous liquid-liquid phase separator has been developed that uses a tubular membrane and annular channels to allow high fluidic throughputs while maintaining rapid, surface wetting dominated, phase separation. The system is constructed from standard fluidic tube fittings and allows leak tight connections to be made without the need for adhesives, or O-rings. The units tested in this work have been shown to operate at flow rates of 0.1 – 300 mL/min, with equivalent residence times from 80 to 4 seconds, demonstrating the simplicity of scale-up with these units. Further scale-up to litre per minute scales of operation for single units and tens of litres/minute through limited numbering up should allow these low cost concentric annular tubular membrane separators to be used at continuous production scales for pharmaceutical applications for many solvent systems. In principle this approach may be sufficiently scalable to be utilized in-line, in batch pharmaceutical manufacturing also, through further scale-up and numbering up of units. Several solvent systems with varying interfacial tensions have been investigated, and the critical process parameters affecting successful separation have been identified. An additively manufactured diaphragm based back pressure regulator was also developed and printed in PEEK, allowing highly accurate, adjustable, and chemically compatible pressure control to be accessed at low cost. Enterprise Ireland European Commission - European Regional Development Fund Science Foundation Ireland

In this work, the solubility of the γ - polymorphic form of 5-nitrofurazone (5-nitro-2-furaldehyde semi-carbazone) in mono-solvent systems and binary solvent mixtures was measured from 278.15 to 313.15 K, using a UV spectroscopic method. The results revealed that the solubility increased with increasing temperature in all investigated solvents within this temperature range. The experimental solubility data in the single solvent systems was well represented with the modified Apelblat equation and the NRTL model, while the λh equation and the NRTL model were used to correlate the experimental solubility data in the case of the binary solvent mixtures. In all cases, these models were shown to have an average relative deviation of lower than 5%. In addition, the thermodynamic mixing and dissolution properties of the γ - form of 5-nitrofurazone, in all investigated mono-solvent systems and binary solvent mixtures, were calculated based on NRTL model and experimental solubility data.

Identification of phenotypic characteristics in reproductively successful individuals provides important insights into the evolutionary processes that cause range shifts due to environmental change. Female beluga whales (Delphinapterus leucas) from the Baffin Bay region (BB) of the Canadian Arctic in the core area of the species’ geographic range have larger body size than their conspecifics at the southern range periphery in Hudson Bay (HB). We investigated the mechanism for this north and south divergence as it relates to reproductive activity (RA = total corpora) that combines morphometric data with ovarian corpora counted from female reproductive tracts. Based on the previous finding of reproductive senescence in older HB females, but not for BB whales, we compared RA patterns the of the two populations’ with age and body length. Female beluga whale RA increased more quickly with age (63% partial variation explained) in BB than in HB (41%). In contrast, body length in HB female beluga whale accounted for considerably more of the total variation (12 vs 1%) in RA compared to BB whales. We speculate that female HB beluga whale RA was more strongly linked with body length due to higher population density resulting in food competition that favors the energetic advantages of larger body size during seasonal food limitations. Understanding the evolutionary mechanism of how RA, and potentially fitness, varies across a species’ range will assist conservation efforts in anticipating and mitigating future challenges associated with a warming planet.

Ionic liquid (IL) forms of drugs are increasingly being explored to address problems presented by poorly water-soluble drugs and solid-state stability. However, before ILs of active pharmaceutical ingredients (APIs) can be routinely incorporated into oral solid dosage forms (OSDs), challenges surrounding their ease of handling and manufacture must be addressed. To this end a framework for transforming API-ILs into solid forms at high loadings based on spray encapsulation using an immiscible polymer has recently been demonstrated. The current work demonstrates that this framework can be applied to a broad range of newly synthesized low glass transition temperature (Tg) API-ILs. Furthermore, the work explores a second novel approach to solidification of API-ILs based on polymer-API-IL miscibility that, to the best of our knowledge, has not been previously demonstrated. Modulated differential scanning calorimetry (mDSC) and attenuated total reflectance Fourier transform infrared spectroscopy showed that it was possible to produce spray dried solid materials, at acceptable loadings and yields for OSD applications in the form of both two-phase phase encapsulated systems and single phase amorphous solid dispersions (ASDs). This was achieved by the appropriate selection of an API-IL insoluble polymer (ethyl cellulose) for phase separated systems, or a miscible polymer with an exceptionally high Tg (the polysaccharide, maltodextrin) for the ASDs. Both approaches successfully overcame the Tg suppression associated with room temperature ILs. This work represents the first step to understanding the fundamental critical physical attributes of these systems to facilitate a more mechanistic methodology for their design.

Active pharmaceutical ingredient (API)-based ionic liquids (API-ILs) present an exciting new paradigm for the formulation of poorly water-soluble drugs. In this study, a model room temperature API-IL (1-butyl-3-methyl imidazolium ibuprofenate) was demonstrated to be not just highly soluble but fully miscible and hence have effectively unlimited solubility in water, compared to 0.021 mg mL–1 solubility for the ibuprofen API. Solutions of the API-IL were found to be stable for up to 2 years, indicating that they have the potential to offer thermodynamic stability upon release, avoiding in vivo recrystallization issues that can limit the bioavailability of amorphous solid dispersions (ASDs) and some high-energy crystalline forms. The ibuprofen API-IL was successfully spray-dried into a polymer carrier in loadings of up to 75% w/w in order to transform it into a solid powder suitable for oral solid dosage (OSD) formulation. From modulated differential scanning calorimetry, hot-stage microscopy, powder X-ray diffraction, and attenuated total reflectance Fourier transform infrared spectroscopy measurements, the mechanism by which this high loading was achieved is based on the immiscibility between the polymer and API-IL, with the polymer encapsulating the phase-separated API-IL. Dissolution studies showed that solidification of the API-IL into microcapsules by spray drying in this manner had no detrimental effect on release characteristics. Failure to dissolve crystalline API forms into the polymer matrix eliminates the solubility enhancement of ASDs but not for highly soluble or fully miscible API-ILs. Furthermore, miscible API-IL/polymer dispersions at high loadings were found to possess less-favorable physical properties because of melting point depression, resulting, in some cases, in a failure to form a viable powder. As such, microencapsulated API-ILs at high loadings in immiscible or low-miscibility polymers that have solubility enhancement of the API-IL form, while providing solid powders for processing, represent a promising new platform for the formulation of poorly soluble compounds as OSDs. European Commission - European Regional Development Fund Irish Research Council Science Foundation Ireland

Chemically resistant parts for flow chemistry, with integrated mixing elements have been produced using the 3D printing process of fused filament fabrication, from poly(etheretherketone). Poly(etheretherketone) has greater chemical resistance than common fused filament fabrication materials such as acrylonitrile butadiene styrene, polypropylene, or even high-performance plastics like poly(etherimide), in addition to having superior thermal resistance and excellent mechanical strength. Printed reactors were demonstrated to be suitable for liquid–liquid extraction and flow chemistry and to be capable of withstanding pressures of at least 30 bar allowing superheated solvents to be used. Burst tests in simple geometries of 20 minute duration have indicated that increased operating pressures of up to 60 bar could be accommodated in future reactor designs. The ability to use fused filament fabrication for these reactors allows highly customisable, cost effective flow reactors and equipment to be fabricated on relatively inexpensive benchtop scale printers. X-ray microcomputed tomography was utilised to non-invasively image and verify the internal structure of the prints to ensure fidelity in reactor fabrication. This non-invasive method of equipment validation shows potential in helping to demonstrate regulatory compliance for bespoke additively manufactured components, for example in continuous pharmaceutical manufacturing where the methods and printer used in this work should be sufficient to produce, (continuous) manufacturing scale equipment. Enterprise Ireland Science Foundation Ireland Pfizer Inc.

Microfluidic technology provides a unique environment for the investigation of crystallization processes at the nano or meso scale. The convenient operation and precise control of process parameters, at these scales of operation enabled by microfluidic devices, are attracting significant and increasing attention in the field of crystallization. In this paper, developments and applications of microfluidics in crystallization research including: crystal nucleation and growth, polymorph and cocrystal screening, preparation of nanocrystals, solubility and metastable zone determination, are summarized and discussed. The materials used in the construction and the structure of these microfluidic devices are also summarized and methods for measuring and modelling crystal nucleation and growth process as well as the enabling analytical methods are also briefly introduced. The low material consumption, high efficiency and precision of microfluidic crystallizations are of particular significance for active pharmaceutical ingredients, proteins, fine chemicals, and nanocrystals. Therefore, it is increasingly adopted as a mainstream technology in crystallization research and development.

Interactions of active pharmaceutical ingredients (API) with surfactants remain an important research area due to the need to improve drug delivery systems. In this study, UV-Visible spectrophotometry was used to investigate the interactions between a model low molecular weight hydrophilic drug sodium valproate (SV) and cationic surfactant cetyltrimethylammonium bromide (CTAB). Changes in the spectra of SV were observed in pre- and post-micellar concentrations of CTAB. The binding constant (Kb) values and the number of drug molecules encapsulated per micelle were calculated, which posed the possibility of mixed micelle formation and strong complexation between SV and CTAB. These results were compared to those of a novel room temperature surface active ionic liquid, which was synthesized by the removal of inorganic counterions from a 1:1 mixture of CTAB and SV. In this new compound the drug now constitutes a building block of the carrier and, as such, has considerably different surfactant properties to its building blocks. In addition, enhanced solubility in a range of solvents, including simulated gastric fluid, was observed. The study provides valuable experimental evidence concerning the performance of drug based surfactant ionic liquids and how their chemical manipulation, without altering the architecture of the API, leads to control of surfactant behavior and physicochemical properties. In turn, this should feed through to improved and controlled drug release rates and delivery mechanisms, and the prevention of precipitation or formation of polymorphs typical of crystalline form APIs.

Owing to its strong reducing ability, high reaction activity, excellent adsorption properties, good mobility and relatively low cost, nano zerovalent iron (nZVI) is an extremely promising nanomaterial for use in water treatment. In this paper, the working mechanisms of nZVI in the degradation of various contaminants in water are outlined and discussed. Synthesis methods and their respective advantages and disadvantages are discussed in detail. Furthermore, a variety of modification methods which have been developed to improve the mobility and stability of nZVI as well as to facilitate the separation of nZVI from degraded systems are also summarized and discussed. Numerous studies indicate that nZVI has considerable potential to become an efficient, versatile and practical approach for large-scale water treatment.

Nucleation and growth kinetics of benzoic acid crystallized by cooling from 1.5:1 (w/w) water/ethanol solutions were determined using a 500 mL continuous mixed suspension, mixed product removal (MSMPR) crystallizer and a mathematical model of the MSMPR process. The developed model solves the population, moment, and mass balance relationships with the kinetic expressions for the system and is coupled with a nonlinear optimization routine for kinetic parameter estimation. Comprehensive experimental data for model fitting and parameter estimation was obtained by varying crystallizer operating conditions to induce changes in the rate-affecting variables for growth and nucleation (temperature, supersaturation, and suspension density). The size distribution was monitored in real-time using focused beam reflectance measurement (FBRM) to identify steady-state and hence to enable on-demand adjustment of the operating conditions to transition multiple steady-states for rapid acquisition of kinetic data. A Malvern M...

Fouling and clogging of lines in both continuous crystallization and flow chemistry still present a challenge in designing continuous processes. This paper presents a proof of concept for a novel unit operation designed for purification and to eliminate the need for slurry handling in API manufacturing by utilizing a dynamic (falling) film-based solution layer crystallization technique called “filtration-avoidance”. Fenofibrate (with fenofibric acid as an impurity) and acetaminophen (with metacetamol as an impurity) in different solvents were tested as crystallization systems, and the final purities and yields are reported. Sixteen different combinations of materials and process parameters were investigated. The results show significant improvement in the purity of the main compounds and a high yield for the process, which indicates a potential industrial application for a filtration-free continuous separation process, e.g., final purity of 99.4% was achieved from the experiment with a solution of 98% fen...

Control of polymorphism of the enantiotropic p-aminobenzoic acid at either the α or β polymorph while maintaining high yield was achieved by mixed suspension mixed product removal (MSMPR) cascade design. A systematic approach was developed to identify the operational window of the process variables, stage temperature and residence time, in which the stringent polymorph purity criterion (>95 wt %) and high yield were met. The comprehensive understanding of the polymorphism of the model compound, p-aminobenzoic acid, was the key for the identification of the operational window. On the basis of single-stage MSMPR experiments, three temperature regimes—thermodynamic control, energy barrier control, and kinetic competition—were identified, and the interplay between the crystallization kinetics and the thermodynamics in each regime was elucidated. Experimental studies also demonstrated the first polymorph specific MSMPR for enantiotropic systems. Single-stage MSMPRs at low temperature, e.g., 5 °C, were found to...

In this study, seed slurry from a single addition anti-solvent plug flow crystallization of benzoic acid was used to seed the equivalent batch cooling crystallization. The experimental conditions were carried out to simulate automated self-seeding. This involves withdrawal of solution from a batch crystallizer, which is then mixed with anti-solvent within a plug flow crystallizer, in order to generate a seed slurry which is fed directly back to the batch crystallizer. This seeding strategy allowed the final CSD of the batch crystallization to be controlled by variation of the crystal size from the plug flow seeding device at a constant seed loading. The ability to use unequal feed/anti-solvent inlet flowrates (in the Roughton vortex mixer) proved effective in controlling the batch CSD at 2% seed loading and constant feed composition. The morphology of batch product from plug flow seeding was found to have a much lower aspect ratio than the more needle like dry seed and primary nucleated product. Unlike dry seed, which was found to have rough irregular growth on the crystal surface, the plug flow product had flat regular growth as per primary nucleated batch crystallization.

A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at ≤106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so that the pores contain IBP solution. The imbibed particles of CPG are then rinsed with a minimal amount of solvent to remove excess solution at the surface of CPG, and a flow of air within the column is used to evaporate the solvent, resulting in crystallization of IBP within the pores of CPG. Crystallinity is determined using X-ray powder diffraction. IBP is confirmed as being in the nanosize range by observation of a negative shift in the melting point measured by differential scanning calorimetry, and loading of IBP nanocrystals within the pores (% w/w) is determined by thermogravimetric analysis. Parameters were investigated for the process and demonstrate that an increase in percentage loading is achieved with in...

Polymorph dynamics of l-glutamic acid were examined during continuous mixed suspension mixed product removal (MSMPR) crystallization as a function of residence time and temperature. Results indicate that it is possible to selectively produce metastable or stable polymorphs via a kinetically controlled crystallization in an MSMPR crystallizer by manipulating the crystallizer temperature and residence time. Additionally, on the basis of experimental and modeling studies, it was found that seeding is not necessarily sufficient to alter polymorphism at a given steady state, indicating that this traditional polymorph control strategy may not be applicable in MSMPR systems. The competition between nucleation and growth kinetics of the metastable α form and the stable β form is the major factor in determining the polymorphic outcome at particular steady state conditions. A metastable steady state with a population of the stable β polymorphic was experimentally obtained at 25 °C and 120 min residence time where a...

If continuous processing is to be employed in pharmaceutical production, it is essential that continuous crystallization techniques can meet the purity and yield achievable in current batch crystallization processes. Recycling of mother liquor in steady state MSMPR crystallizations allows the yield in the equivalent equilibrium batch process to be met or exceeded. However, the extent to which yield can be increased is limited by the buildup of impurities within the system. In this study, an organic solvent nanofiltration membrane was used to preferentially concentrate an API (deferasirox, M.W. = 373 Da) and purge the limiting impurity 4-hydrazinobenzoic acid (MW = 152 Da) from the mother liquor recycle stream in a mixed solvent (THF:ethanol) antisolvent (water) system. Incorporation of the membrane recycle allowed yields of 98.0% and 98.7% to be achieved. This compares to the following: a control MSMPR run without a membrane (70.3%), an equivalent batch process (89.2%), and the current commercial batch pr...

Continuous operation allows process conditions that are not attainable within batch crystallizers to be utilized. This in turn allows for product crystal attributes that are not possible in the equivalent batch crystallizations to be produced. In this study, the product crystal size distributions attainable from the anti-solvent crystallization of benzoic acid in plug flow, MSMPR and the equivalent fed batch and batch reverse addition crystallizations, were characterized. It was found that the continuous plug flow and MSMPR crystallizers were able to access crystal size distributions that are both smaller and larger than could be produced via the equivalent batch crystallizations, in addition to providing huge increases in productivity. In-situ process analytical techniques (FBRM, ATR-FTIR) were employed to characterize each of these processes, including a calibration-free ATR-FTIR technique. Furthermore, a novel intermittent pneumatic MSMPR withdrawal method, which negated clogging/fouling of transfer lines, is demonstrated. It is hoped that the use of such techniques may facilitate the uptake of continuous processes in pharmaceutical crystallization where limitations on development time and concerns about slurry transport are perceived to be barriers to the implementation of this technology.

This work presents a study of a Roughton-type vortex mixer combined with a tubular reactor for the drowning out crystallization of benzoic acid from aqueous ethanol solutions using water as the anti-solvent. Mixing times in vortex mixers have been shown to be as low as 1 ms and have also been found to be largely independent of the relative flow rates of inlet streams. This enables operation with larger anti-solvent ratios, without sacrificing mixing efficiency. Permitting the generation of higher supersaturations, and smaller particles, while also increasing flexibility of the system by broadening the range of compounds that can be used. Process analytical technologies (FBRM, PVM, ATR FT-IR) were applied in-situ in order to characterize crystallization via the use of a novel flow cell. A calibration-free method for concentration monitoring was successfully utilized to monitor the progress of the process. It was seen that the achievable particle size could be significantly reduced in size compared to batch operation, with a reduction in the square-weighted chord length from 152 to 52 μm. For a given feed concentration, significant control over the product size within the plug flow crystallizer could be achieved, with an average square weighted chord length range of 52–87 μm observed for the conditions investigated in this work.

The use of in situ tools to monitor the transformation of a polymorphic material has the potential to provide unique information about the mechanism and rate of transformation of the polymorphs. In this paper, the solution mediated transformation between α and β form p-aminobenzoic acid (PABA) was investigated in detail. Solubility of α and β form PABA in pure ethanol was also reported for the first time, allowing the accurate determination of the transition temperature of 13.8 °C. For the transformation experiments, Raman spectroscopy and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy were used to in situ monitor the solid phase concentration and liquid concentration, respectively; Focused Beam Reflectance Measurement (FBRM) was used to in situ track the changes in the size and morphology of the particles. The observed changes were confirmed using PVM in-process imaging. It was proved by solubility data and transformation experiments that the relationship between α and β ...

The Harvard Ambient Particle Concentrator (HAPC) has been used routinely for exposure testing for a period of approximately three years. The stability of concentrator performance has been investigated as a function of local meteorological conditions, ambient particle concentrations, composition, and size distribution. Concentrator performance is characterized by the concentration enrichment factor (CEF), a ratio of concentrated particle mass (or sulfate) concentration to the ambient concentration. Over three years of normal operation, the mass and sulfate CEFs averaged 27.9 and 28.6, respectively. The majority of variability in the CEF was found to be related to the mass median aerodynamic diameter (MMAD) of ambient particles and to the HAPC's total operating pressure drop. The 50% cutpoint of the HAPC is 0.15 μ m. Between 0.15 and 2.5 μ m, the HAPC concentrates ambient particle mass by approximately a factor of 28. It is logical that changes in particle CEF should be influenced by the amount of ambient p...

Biopharmaceuticals are therapeutic products based on biotechnology. They are manufactured by or from living organisms and are the most complex of all commercial medicines to develop, manufacture and qualify for regulatory approval. In recent years biopharmaceuticals have rapidly increased in number and importance with over 400() already marketed in the U.S. and European markets alone. Many companies throughout the world are now ramping up investments in biopharmaceutical RD and expanding their portfolios through licensing of early-stage biotechnologies from universities and other non-profit research institutions, and there is an increasing number of license agreements for biopharmaceutical product development relative to traditional small molecule drug compounds. This trend will only continue as large numbers of biosimilars and biogenerics enter the market.A primary goal of technology transfer offices associated with publicly-funded, non-profit research institutions is to establish patent protection for inventions deemed to have commercial potential and license them for product development. Such licenses help stimulate economic development and job creation, bring a stream of royalty revenue to the institution and, hopefully, advance the public good or public health by bringing new and useful products to market. In the course of applying for such licenses, a commercial development plan is usually put forth by the license applicant. This plan indicates the path the applicant expects to follow to bring the licensed invention to market. In the case of small molecule drug compounds, there exists a widely-recognized series of clinical development steps, dictated by regulatory requirements, that must be met to bring a new drug to market, such as completion of preclinical toxicology, Phase 1, 2 and 3 testing and product approvals. These steps often become the milestone/benchmark schedule incorporated into license agreements which technology transfer offices use to monitor the licensee's diligence and progress; most exclusive licenses include a commercial development plan, with penalties, financial or even revocation of the license, if the plan is not followed, e.g., the license falls too far behind.This study examines whether developmental milestone schedules based on a small molecule drug development model are useful and realistic in setting expectations for biopharmaceutical product development. We reviewed the monitoring records of all exclusive Public Health Service (PHS) commercial development license agreements for small molecule drugs or therapeutics based on biotechnology (biopharmaceuticals) executed by the National Institutes of Health (NIH) Office of Technology Transfer (OTT) between 2003 and 2009. We found that most biopharmaceutical development license agreements required amending because developmental milestones in the negotiated schedule could not be met by the licensee. This was in stark contrast with license agreements for small molecule chemical compounds which rarely needed changes to their developmental milestone schedules. As commercial development licenses for biopharmaceuticals make up the vast majority of NIH's exclusive license agreements, there is clearly a need to: 1) more closely examine how these benchmark schedules are formed, 2) try to understand the particular risk factors contributing to benchmark schedule non-compliance, and 3) devise alternatives to the current license benchmark schedule structural model. Schedules that properly weigh the most relevant risk factors such as technology classification (e.g., vaccine vs recombinant antibody vs gene therapy), likelihood of unforeseen regulatory issues, and company size/structure may help assure compliance with original license benchmark schedules. This understanding, coupled with a modified approach to the license negotiation process that makes use of a clear and comprehensive term sheet to minimize ambiguities should result in a more realistic benchmark schedule.

To the Editor. —The intuitive reasoning appears logical in the article by Reding et al. 1 It certainly seems plausible that increased motivation and participation may yield increased scores on the Barthel scale. However, conclusions reached in this article are not warranted by the available data. Both methodologic and interpretive problems exist. Furthermore, the absence of actual numbers of patients per category makes interpretation of the data difficult (for example, exactly how many patients had abnormal Zung depression scores and received placebo treatment, and how many of these reached target doses of medication or placebo?). Merely adding averages given in Table 1 shows placebo groups had higher initial Barthel scale scores than treatment groups (45 vs 33), and especially in the abnormal dexamethasone suppression test (DST) results group (51 vs 22). Randomization of matched groups according to preliminary scores should have been used. While the authors note that there was