Pharmaceutical Production Facilities Research Articles

Mechanistic study on the synergy of cold plasma and sulfate radical in the degradation of azo and triarylmethane dyes using density functional theory

The activation of persulfate using cold plasma and the synergy of plasma-generated reactive species and SO4•− in mineralization of organic dyes were assessed. In this regard, solutions of crystal violet (CV) as a triarylmethane dye and methyl orange (MO) as an azo dye, were treated with cold plasma, UV-C-activated sulfate radicals, and their combination. The achieved results showed 95% TOC removal, a synergy factor of 1.3 and an energy yield of 1.68 (g kWh−1) for the combined system. The contribution of oxidant species in CV (SO4•− > O2•- > •OH) and MO (SO4•−> O2•- >1O2) degradation was explored. Moreover, analysis of degradation products and density functional theory (DFT) calculations were adopted to find the degradation mechanism based on the minimum energy pathway. Experimental and DFT results revealed that while radical and nucleophilic pathways were the drivers of CV degradation, the electrophilic attack of oxidants was a more plausible mechanism for MO degradation. Additionally, a comparison of the results of different DFT methods with experimental values showed that the Kohn–Sham DFT yielded more accurate results compared to recommended double hybrid methods. Analysis of a treated real wastewater revealed that the background constituents had negligible effects on MO and CV degradation. The high TOC removal efficiency of the combined system suggests its feasibility for treating wastewater from fertilizer and pharmaceutical production facilities.

АКТУАЛЬНЫЕ ВОПРОСЫ СИСТЕМЫ МЕНЕДЖМЕНТА КАЧЕСТВА В ФАРМАЦЕВТИЧЕСКОМ ПРОИЗВОДСТВЕ

The quality management system (QMS) is one of the prerequisites for successful production activities and serves as a basic mechanism to ensure strict compliance of medical and pharmaceutical organizations in the format of the requirements of applicable standards and regulations. The aim of the work was to analyze the quality management system of pharmaceutical production from the point of view of employees of the enterprise. As an information base the works of domestic and foreign scientists in the field of quality management system, as well as regulatory and organizational documentation on pharmaceutical activities were taken. The questionnaire method served as the main research method, as a result of which 96 employees of pharmaceutical production facilities in Orel, Kostroma, Moscow, Lipetsk and Leningrad regions were interviewed. It was found that from the documents of good manufacturing practices the respondents were most familiar with Good Manufacturing Practices, manufacturing (GMP). The provisions of other good manufacturing practices (GLP, GCP, GSP, GDP, GPP) are mostly unfamiliar to the employees. The majority of respondents believe that the quality of medicines has improved over the last five years, with 56.2% of respondents believing that not all manufacturers comply with good manufacturing practices, explaining that the rules are very complex and it is too expensive for a company to comply with them. The survey found that under the concept of "quality of medicines" employees of pharmaceutical companies mainly mean: safety when used (80.4%); efficacy (79.4%); compliance with the declared characteristics (78.4%). It was found that the specialists of pharmaceutical companies have a positive attitude to the processes of digitalization, but they note the high financial costs at the stages of its implementation and dependence on foreign-made equipment. Thus, we can conclude that the information base in the Russian pharmaceutical production is mainly focused on industry documentation and, to a lesser extent, on related areas; the current industry regulatory framework requires improvement in terms of formalizing processes and specifying requirements.

Agent-based simulation and optimization of hybrid flow shop considering multi-skilled workers and fatigue factors

In the past few decades, more and more studies have begun to consider the impact of human factors on manufacturing systems. This paper studies a hybrid flow shop scheduling problem considering multi-skilled workers and fatigue factors. An agent-based simulation system is established to cope with the uncertainties in the worker fatigue model. Furthermore, this paper proposes a novel simulation-based optimization (SBO) framework, which combines genetic algorithm (GA) and reinforcement learning (RL) to address the hybrid flow shop scheduling problem. Numerical experiments are conducted on several instances with different production configurations. In particular, a pharmaceutical production facility is modeled as a hybrid flow shop to demonstrate the feasibility and effectiveness of the proposed SBO method.

Interval-Valued Intuitionistic Fuzzy-Analytic Hierarchy Process for Evaluating the Wastes in a Pharmaceutical Company

Pharmaceutical manufacturing is a sector where good manufacturing practices (GMP) practices are applied and any process change will be completed with long processes. In this study, all production steps of a pharmaceutical production facility in Turkey, from raw material to finished product, were examined. Wastes determined using current state VSM were evaluated by IVIFAHP. The study's findings and the operational enhancements demonstrate that using VSM and IVIFAHP is a successful technique for these firms to enhance their processes and hence address their existing difficulties. By offering empirical proof of the application of VSM in Turkey, this paper contributes and can be used as a reference by managers and engineers to carry out particular process improvement initiatives in their organizations that are comparable to the ones described.

XANDAR PHARMACEUTICAL: A model plant for process engineering education

This study explores the implementation of a detailed model pharmaceutical production facility in an undergraduate engineering class. Xandar Pharmaceuticals (XP), a fictitious manufacturer, was created and presented to undergraduate engineering students during a current good manufacturing practices (cGMP11current Good Manufacturing Practices.) course in two forms: (1) 3D virtual model and (2) 3D printed model. Data was collected from three separate cohorts over three years with a total of 197 participants. Surveys would gauge student’s sentiments and collect feedback, while quizzes assessed technical understanding. Statistical analysis and effect size calculations would evaluate the differences among the three cohorts. Survey results indicate the 3D printed model has small positive effects on study vs control (groups) regarding understanding of general industry related functions and practices. The 3D printed model also improved students’ interest in critical thinking and investigation. Qualitative feedback and sentiment analysis indicate the model was well received by students and received positive feedback related to visualization, industrial relevance, and student engagement. Use of the 3D printed model (but not the 3D virtual model) has had positive quantitative effects on student quiz scores and feedback. Qualitative improvements to student attitudes and interest are encouraging and suggest further use of 3D printed models in other courses may be beneficial.

Impact of Early Fortification in Very Low Birth Weight Infants on the Incidence of Malnutrition During a Trophamine Shortage.

The devastation of pharmaceutical production facilities from Hurricane Maria caused a national shortage of parenteral amino acids in October 2017. Our institution decreased trophamine in very low birth weight (VLBW) infants and initiated human milk fortification at a lower feeding volume to increase enteral protein intake more quickly. The objective of this study was to assess how protein management during the shortage period affected the incidence of malnutrition. This was a retrospective cohort study of infants admitted to 2 neonatal intensive care units from June 1, 2017 to May 31, 2018. Infants between 23 and 32 weeks' gestation were included in this study. The primary outcome was the incidence of malnutrition at 14 days, defined as a z score decline of ≥0.8 SDs, in the pre-shortage period compared with the shortage period. Clinical data regarding adverse effects associated with early fortification and pharmacy costs were recorded. There were 68 infants prior to and 65 during the shortage who met inclusion criteria. There was no difference in malnutrition between the pre-shortage and shortage groups; however, a significant increase in malnutrition was observed in infants who did not receive early fortification during the shortage. No difference in time to full enteral feeds or necrotizing enterocolitis was observed with early fortification. Early fortification in VLBW infants receiving less trophamine during the shortage was not associated with an increase in malnutrition. Restricting trophamine in neonates during the shortage allowed for distribution to other critically ill patients.

Towards robotic laboratory automation Plug & Play: The "LAPP" framework.

Increasing the level of automation in pharmaceutical laboratories and production facilities plays a crucial role in delivering medicine to patients. However, the particular requirements of this field make it challenging to adapt cutting-edge technologies present in other industries. This article provides an overview of relevant approaches and how they can be utilized in the pharmaceutical industry, especially in development laboratories. Recent advancements include the application of flexible mobile manipulators capable of handling complex tasks. However, integrating devices from many different vendors into an end-to-end automation system is complicated due to the diversity of interfaces. Therefore, various approaches for standardization are considered in this article, and a concept is proposed for taking them a step further. This concept enables a mobile manipulator with a vision system to "learn" the pose of each device and - utilizing a barcode - fetch interface information from a universal cloud database. This information includes control and communication protocol definitions and a representation of robot actions needed to operate the device. In order to define the movements in relation to the device, devices have to feature - besides the barcode - a fiducial marker as standard. The concept will be elaborated following appropriate research activities in follow-up papers.

Pregnancy latency after preterm premature rupture of membranes: oral versus intravenous antibiotics

Following the destruction of pharmaceutical production facilities in Puerto Rico by Hurricane Maria in September 2017, a shortage of small-volume bags of sterile intravenous fluid for infusion led to a decreased ability to administer intravenous azithromycin and ampicillin efficiently for use in the treatment of patients with preterm premature rupture of membranes. This study aimed to assess pregnancy latency after preterm premature rupture of membranes following treatment with oral-only antibiotics compared with treatment with intravenous antibiotics followed by oral antibiotics. This is a retrospective historic control study comparing women with preterm premature rupture of membranes who were initiated on a 7-day oral-only regimen of azithromycin and amoxicillin (modified regimen) during a 12-month period beginning December 2017 (during which time there was a shortage of small-volume bags of intravenous fluid) to women with preterm premature rupture of membranes who were initiated on a 2-day regimen of intravenous ampicillin and azithromycin followed by 5 days of oral amoxicillin and azithromycin (standard regimen) from December 2016 to December 2018. Women were included in the study if they were diagnosed with preterm premature rupture of membranes at <34 weeks' gestation and were started on latency antibiotics, and women were excluded from the study if they had a contraindication to expectant management, a cerclage, or suspected fetal anomalies. The primary outcome was pregnancy latency, defined as time from the first dose of antibiotics to delivery. The 37 women who received the modified regimen and the 79 women who received the standard regimen had similar baseline characteristics. Mean (standard deviation) gestational age at time of preterm premature rupture of membranes was similar between the modified (30.5 weeks' gestation [±3.1]) and standard regimen groups (30.2 weeks' gestation [±3.2]), and the rate of group B streptococcus rectovaginal colonization was similar for both groups (27% vs 24%; P=.95). Pregnancy latency did not differ in the modified vs standard regimen (mean difference, -0.15 days; 95% confidence interval, -4.87 to 4.58) There was no statistically significant difference in the relative risk of composite maternal infection (relative risk, 0.43; 95% confidence interval, 0.05-3.53) or composite neonatal infection (relative risk, 0.43; 95% confidence interval, 0.05-3.52). Although limited by small sample size, our study suggested that adoption of an oral-only antibiotic regimen for pregnancy latency following preterm premature rupture of membranes is worthy of further study.

Concepts for the implementation of a technological platform for the production of specific antidotes for CBRN medical protection

"Abstract: All large armies (EU and/or NATO) have pharmaceutical production facilities to provide the necessary antidotes for the troops and the population: The French Army Medical Directorate produces many military-specific pharmaceutical products in its own laboratory, the Turkish Army owns its own medicines factory, including CBRN antidotes, the US Army, in addition to a sustained drug purchase program in the pharmaceutical industry has launched a new concept: Pharmacy on demand. Providing the armed forces with antidotes is a necessity, the concept for their endowement in this sense can be based on imports (sometimes impossible to achieve) or on the national development of a specialized production structure. The design or construction of a specific production capacity for antidotes can be accomplished on multiple variants, with a complexity proportional to the identified need. The total costs are high, but the objective and implementation of effective antidote supply mechanisms is a security guarantee for the armed forces and the civilian population (through commercialization to allied forces), given the risks of terrorist threats and hybrid warfare. Keywords: medical protection, antidote, production, technological platform, medical countermeasures, pharmaceutical technique, orphan drug production "

Comparative Advantages of National Pharmaceutical Industries through the Prism of New Indicators

Specific ways of the emergence of new actors in the global market of pharmaceutical goods is investigated, with substantiating the role of transnational corporations (TNC), their investment and technologies in establishing pharmaceutical industries in developing countries. The cases of Puerto Rico and Ireland are taken in order to demonstrate the background for expansion of manufacturing of medicines and medical products and analyze the tendencies in their export capacity building. The factors making pharmaceutical TNC transfer production facilities to India and China are substantiated and implications of this process are highlighted. It is revealed that due to the production internationalization, countries that had been net importers of pharmaceuticals just several decades ago have joined the group of key suppliers to external markets. Because American and European TNC are leading in the pharmaceutical industry by R&amp;D expenditure, they are the principal holders of advanced technologies in the industry. It follows that manufacturing of medicines and medical products in most part of countries either directly or indirectly depend on innovative products of TNC and their technology transfer via various channels (both licensing and imports of components, active pharmaceutical ingredients in particular). It is shown that with the emergence of new market actors coming from developing countries, traditional approaches to determining comparative advantages of counties in the global trade need to be improved. The cases of countries that are recipients of foreign technologies, on which territories powerful high tech pharmaceutical production facilities with high shares of intermediate consumption and heavy export supplies are located due to TNC investment or local public-private capital, give evidence that the classical RCA indicator allows to measure visible comparative advantages in the trade in goods rather than revealed ones. It is proposed that analyses of advantages at country level should include the indicator of high tech goods supplies, to provide for a more accurate description of the innovation component in advanced industries. A new approach to the assessment of comparative advantages of high tech pharmaceutical manufacturing is proposed and tested, which is based on the principle of specialization and use of the ratio of Comparative Advantage in Value Added Activity (CAVA) in particular. It is revealed that the pharmaceutical industry of Ireland, Jordan, Singapore, India or Columbia, with reliance on foreign investment and technologies, could gain advantages in value added creation and dominate the national economies. It is shown that Ukraine is enhancing the advantages in value added creation in the pharmaceutical industry; is it substantiated that due to low R&amp;D and innovation performance and heavy dependence on imported components, capacity building of this industry and its current advantages result from global tendencies and global market conjunctures rather than from the implementation of the national science &amp; technology priorities. According to the author’s recommendation, the proposed approach to determining comparative advantages in value added creation should be used for the assessment of other high tech industries, apart from the pharmaceutical industry, and that is should be supplemented by statistical tools for analysis of foreign trade in finished and intermediate high tech goods.

Efflux Pumps of Burkholderia thailandensis Control the Permeability Barrier of the Outer Membrane.

Burkholderia comprises species that are significant biothreat agents and common contaminants of pharmaceutical production facilities. Their extreme antibiotic resistance affects all classes of antibiotics, including polycationic polymyxins and aminoglycosides. The major underlying mechanism is the presence of two permeability barriers, the outer membrane with modified lipid A moieties and active drug efflux pumps. The two barriers are thought to be mechanistically independent and act synergistically to reduce the intracellular concentrations of antibiotics. In this study, we analyzed the interplay between active efflux pumps and the permeability barrier of the outer membrane in Burkholderia thailandensis We found that three efflux pumps, AmrAB-OprA, BpeEF-OprC, and BpeAB-OprB, of B. thailandensis are expressed under standard laboratory conditions and provide protection against multiple antibiotics, including polycationic polymyxins. Our results further suggest that the inactivation of AmrAB-OprA or BpeAB-OprB potentiates the antibacterial activities of antibiotics not only by reducing their efflux, but also by increasing their uptake into cells. Mass spectrometry analyses showed that in efflux-deficient B. thailandensis cells, lipid A species modified with 4-amino-4-deoxy-l-aminoarabinose are significantly less abundant than in the parent strain. Taken together, our results suggest that changes in the outer membrane permeability due to alterations in lipid A structure could be contributing factors in antibiotic hypersusceptibilities of B. thailandensis cells lacking AmrAB-OprA and BpeAB-OprB efflux pumps.

Recent Developments in the Scope, Practicality, and Mechanistic Understanding of Enantioselective Hydroformylation.

In the nearly 80 years since catalytic hydroformylation was first reported, hundreds of billions of pounds of aldehyde have been produced by this atom efficient one-carbon homologation of alkenes in the presence of H2 and CO. Despite the economy and demonstrated scalability of hydroformylation, the enantioselective process (asymmetric hydroformylation, AHF) currently does not contribute significantly to the production of chiral aldehydes and their derivatives. Current impediments to practical application of AHF include low diversity of chiral ligands that provide effective rates and selectivities, limited exploration of substrate scope, few demonstrations of efficient flow reactor processes, and incomplete mechanistic understanding of the factors that control reaction selectivity and rate. This Account summarizes developments in ligand design, substrate scope, reactor technology, and mechanistic understanding that advance AHF toward practical and atom-efficient production of chiral α-stereogenic aldehydes. Initial applications of AHF were limited to activated terminal alkenes such as styrene, but recent developments enable high selectivity for unactivated olefins and more complex substrates such as 1,1'- and 1,2-disubstituted alkenes. Expanded substrate scope primarily results from new chiral phosphine ligands, especially phospholanes and bisdiazaphospholanes (BDPs). These ligands are now more accessible due to improved synthesis and resolution procedures. One of the virtues of diazaphospholanes is the relative ease of derivatization, including attachment to heterogeneous supports. Hydroformylation involves toxic and flammable reactants, a serious concern in pharmaceutical production facilities. Flow reactors offer many process benefits for handling dangerous reagents and for systematically moving from research to production scales. New approaches to achieving good gas-liquid mixing in flow reactors have been demonstrated with BDP-derived catalyst systems and lend assurance that AHF can be practically implemented by the pharmaceutical and fine chemical industries. To date, progress in AHF has been empirically driven, because hydroformylation is a complex, multistep process for which the origins of chemo-, regio-, and enantioselectivity are difficult to elucidate. Mechanistic complexity arises from three concurrent catalytic cycles (linear and two diastereomeric branched paths), significant pooling of catalyst as off-cycle species, and multiple elementary steps that are kinetically competitive. Addressing such complexity requires new approaches to collecting kinetic and extra-kinetic information and analyzing these data. In this Account, we describe our group's progress toward understanding the complex kinetics and mechanism of AHF as catalyzed by rhodium bis(diazaphospholane) catalysts. Our strategy features both "outside-in" (i.e., monitoring catalytic rates and selectivities as a function of reactant concentration and temperature) and "inside-out" (i.e., building kinetic models based on the rates of component steps of the catalytic reaction) approaches. These studies include isotopic labeling, interception and characterization of catalytic intermediates using NMR techniques, multinuclear high-pressure NMR spectroscopy, and sophisticated kinetic modeling. Such broad-based approaches illuminate the kinetic and mechanistic origins of selectivity and activity of AHF and the elucidation of important principles that apply to all catalytic reactions.

The impact of a Wastewater Treatment Works in Southern Gauteng, South Africa on efavirenz and nevirapine discharges into the aquatic environment

Abstract There has been growing concern regarding the pollution of the aquatic environment with synthetic organic chemicals. Antiretroviral drugs, such as efavirenz and nevirapine, are pharmaceutical drugs and are referred to as emerging contaminants. Such drugs can be environmentally persistent and may be expected to pose potential risks to drinking water supplies. Sources of pharmaceutical drugs include effluents from Wastewater Treatment Works (WWTPs), hospital and pharmaceutical production facilities and the incorrect disposal of unused and expired medicines. Currently there are no monitoring programs and legislative guidelines for their regulations in South Africa. The aims of this study were firstly to develop a semi-quantitative method to extract and analyse efavirenz and nevirapine in the primary settling tank sludge. Secondly to use that method, and an existing method for liquid wastewater samples, to monitor the concentrations of efavirenz and nevirapine as the wastewater passes through the different stages of purification (anoxic; aerobic; pre and post chlorination) in the WWTP. This was repeated weekly over a period of 4 weeks. Thirdly, to determine if binding of efavirenz and nevirapine to the solids in the WWTP played a role in the removal of these compounds from the WWTP liquid phase. No references to the analysis of ARVDs in WWTP sludge were found in the literature. Grab samples of wastewater and sludge samples were collected from a WWTP (activated sludge treatment process) weekly for 4 weeks. Liquid samples were extracted solid phase extraction, solid samples were extracted using sonication followed by a QuEChERs clean-up. Sample extracts were then subjected to gas chromatography-time of flight mass spectrometry for analyte determination. Efavirenz concentrations entering the WWTP ranged between 5500 to almost 14 000 ng/L. The removal of efavirenz by the WWTP ranged between 27 and 71%. The largest removal occurred in the anoxic zone, smaller amounts were removed in the aerators. Slight increases in efavirenz concentrations were found after chlorination and the final effluent into the river post maturation ponds again were slightly lower. Solids were found to contain efavirenz at concentrations between 17 and 43 mg/kg dried primary settling tank sludge and it is proposed that this binding to the solids is the main mechanism of removal of efavirenz from the wastewater stream as it passes through the WWTP. Although an order of magnitude lower nevirapine concentrations displayed the opposite behaviour and gradually increased through the various stages of purification in the WWTP. Minor fluctuations occurred but the concentrations of nevirapine were higher at the effluent (between 92 and 473 ng/L) than those entering the WWTP. No nevirapine was detected in the PST sludge. The increase in nevirapine concentrations are likely to be the result of the de-conjugation of the hydroxylated metabolites of nevirapine in the WWTP, its resistance to degradation and the lack of binding of the nevirapine to the PST sludge.

District Heat-Driven Water Purification via Membrane Distillation: New Possibilities for Applications in Pharmaceutical Industries

Here, we presented a novel industrial application for membrane distillation (MD) in a pharmaceutical production facility’s wastewater treatment plant (WWTP). Two semicommercial air gap MD module designs (Xzero and Elixir500) were studied for comparison, with experimental results of product yield and heat demand up-scaled for inclusion in system simulations. District heating was considered to drive the 3 m3/h capacity MD process, with heat recovery employed in various process streams and for heating purposes in offices. The selected configurations show a high degree of thermal integration with an increase of yearly district heating purchases of 2–13%. Economic assessments of the full-scale MD system indicate that unit costs of purification would be $1.3/m3 and $7/m3 for Elixier500 and Xzero MD modules, respectively. Module heat losses should be considered in the future design of MD systems since the heat demand contributed to up to 77% of the specific costs.

Is the phototransformation of pharmaceuticals a natural purification process that decreases ecological and human health risks?

Sunlight photodegradation has long been considered a significant process in lowering the concentrations of pharmaceuticals in surface waters and thus decreasing the ecological risk. For the first time, this study identified the significance of investigating the environmental photodegradation of a pharmaceutical residue mixture (rather than a single compound) and the associated toxicity of transformation byproducts in environmental waters, including rivers, hospital wastewaters, and effluents from wastewater treatment plants and pharmaceutical production facilities. Pharmaceuticals undergo phototransformation rather than mineralization (11–23% in 34 h). Pharmaceutical mixtures could possibly act as dissolved organic matter for each individual compound and subsequently affect the photolysis rates. The increased toxicity of irradiated pharmaceutical mixtures challenges the validity of the current understanding of sunlight photolysis. The implications of this work suggest that current knowledge concerning the occurrence, natural attenuation, ecotoxicity, and human health risks of pharmaceuticals is far from complete; photolysis is not necessarily a purification process.

The Application of Uniplex, Duplex, and Multiplex PCR for the Absence of Specified Microorganism Testing of Pharmaceutical Excipients and Drug Products

Notable progress has been made in methods that encourage the use of polymerase chain reaction (PCR) as a rapid and accurate tool in microbiological testing of pharmaceuticals. In this study, the detection of the four main specified microorganisms according to the pharmacopeial recommendations, Salmonella spp, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, was optimized in different pharmaceutical dosage forms and raw materials. Uniplex PCR was performed for the detection of each microorganism individually targeting the conserved region in each bacterial genome. Further optimizations were done to perform duplex and multiplex PCR assays considering relative concentrations of competitor primers used in the reaction. The uniplex PCR amplicons were successfully sequenced, confirming the conservation of used primers. Other validation parameters such as specificity, sensitivity, and robustness were examined closely. The method provides a high-throughput screening method to test different pharmaceutical preparations for specified microorganisms for the detection of microbiological contamination. Strict regulations govern the production of pharmaceutical products whether they are sterile or nonsterile. Certain official tests are carried out in microbiology testing laboratory in any pharmaceutical production facility to ensure the pharmaceuticals microbiological quality according to the standard pharmacopeial recommendations. Nonsterile products must be free of specified microorganisms that are used as a check for their quality. Topical preparations must be free of Pseudomonas aeruginosa and Staphylococcus aureus, and oral preparations must be free of Salmonella spp and Escherichia coli. Conventional microbiological methods are time-consuming, labor-intensive, and require long incubation times, resulting in delaying the release of the products. In this study, we tested and validated a polymerase chain reaction identification approach to detect indicator bacteria in pharmaceutical preparations. The method depends on amplification of certain conserved genes located in the four specified bacteria. The method is optimized to be carried out individually or collectively to detect all indicator bacteria in a single reaction in different forms of pharmaceutical products.

Risk Assessment and Application of Engineering Controls to Reduce the Number of Occupational Related Musculoskeletal Disorders in a Large Pharmaceutical Production Facility

The high number of discomfort and lost work time cases in one department of a large pharmaceutical production facility, created a unique opportunity for ergonomics study and intervention. The first step in the project identified the three highest risk tasks using safety incident data. Each task was analyzed for ergonomics risk factors. Interventions were developed and implemented for these tasks. Biomechanical and subjective data were collected before and after all interventions to assess the effectiveness of the interventions. Three-dimensional dynamic flexion of the lower back data were collected using a Lumbar Motion Monitor (LMM). Electrogoniometers were used to measure wrist flexion. We used a force gauge, scale, and a tape measure to assess moments, forces, and weight. Subjective data were collected by questionnaire. A quantitative comparison of the subjective and electronic data showed reduced risk factors for Work-Related Musculoskeletal Disorders (WMSDs) of the wrist and back for all three tasks. All the interventions were shown by empirical methods to reduce the risk factors for WMSDs. The interventions were permanently implemented.

An Influenza A/H1N1/2009 Hemagglutinin Vaccine Produced in Escherichia coli

BackgroundThe A/H1N1/2009 influenza pandemic made evident the need for faster and higher-yield methods for the production of influenza vaccines. Platforms based on virus culture in mammalian or insect cells are currently under investigation. Alternatively, expression of fragments of the hemagglutinin (HA) protein in prokaryotic systems can potentially be the most efficacious strategy for the manufacture of large quantities of influenza vaccine in a short period of time. Despite experimental evidence on the immunogenic potential of HA protein constructs expressed in bacteria, it is still generally accepted that glycosylation should be a requirement for vaccine efficacy.Methodology/Principal FindingsWe expressed the globular HA receptor binding domain, referred to here as HA63–286-RBD, of the influenza A/H1N1/2009 virus in Escherichia coli using a simple, robust and scalable process. The recombinant protein was refolded and purified from the insoluble fraction of the cellular lysate as a single species. Recombinant HA63–286-RBD appears to be properly folded, as shown by analytical ultracentrifugation and bio-recognition assays. It binds specifically to serum antibodies from influenza A/H1N1/2009 patients and was found to be immunogenic, to be capable of triggering the production of neutralizing antibodies, and to have protective activity in the ferret model.Conclusions/SignificanceProjections based on our production/purification data indicate that this strategy could yield up to half a billion doses of vaccine per month in a medium-scale pharmaceutical production facility equipped for bacterial culture. Also, our findings demonstrate that glycosylation is not a mandatory requirement for influenza vaccine efficacy.

Comparative Analysis ofSambucus nigraandSambucus australisFlowers: Development and Validation of an HPLC Method for Raw Material Quantification and Preliminary Stability Study

This work was designed to develop a simple, effective, and reliable LC system to identify a chemical marker and compare Sambucus nigra L. and Sambucus australis Cham. et Schltdl. flower extracts (American and European elder). Rutin was the main constituent of both species. The developed method showed a linear response in the range of 10 to 45 microg x mL(-1) for rutin and 1.75 to 3.25 microg x mL(-1) for samples of the Sambucus species. Precision was determined and the relative standard deviations were 1.75 % for HSN and 1.28 % for HSA for intraday precision and 1.28 % and 1.51 % for inter-day precision, respectively, while accuracy was 97.9 % for HSN and 99.41 % for HSA. Quantification and detection limits as well as robustness were determined, presenting adequate results. The LC method showed an adequate performance for the separation of flavonoid glycosides in S. nigra and S. australis extracts, since the presence of interference had been previously evaluated. The analysis of thirty different samples of S. NIGRA and S. australis of different origins did not show significant variability among them. An accelerated stability study revealed a significant decrease in the first 30 days reaching 57 % in 90 days for S. australis samples and a total decrease of 25 % in 90 days for S. nigra samples, considering rutin as the chemical marker. These results will contribute to quality control analysis routines of these raw materials in pharmaceutical production facilities.

Occurrence of pharmaceuticals in Taiwan's surface waters: Impact of waste streams from hospitals and pharmaceutical production facilities

We investigated the occurrence and distribution of pharmaceuticals (including antibiotics, estrogens, non-steroidal anti-inflammatory drugs (NSAIDs), beta-blockers, and lipid regulators) in three rivers and in the waste streams of six hospitals and four pharmaceutical production facilities in Taiwan. The most frequently detected pharmaceuticals were acetaminophen, erythromycin-H 2O, sulfamethoxazole, and gemfibrozil. NSAIDs were the next most-often detected compounds, with a detection frequency > 60%. The other analytes were not detected or were seen in only a few samples at trace concentrations. The present study demonstrates a significant discharge of human medications from hospital and drug production facilities into surface waters in the Taipei district. The high concentrations of pharmaceuticals found in the Sindian and Dahan rivers demonstrate the alarming degree to which they have been impacted by urban drainage (waste effluents from hospitals, households, and pharmaceutical production facilities). The ubiquitous occurrence at extremely high concentrations of acetaminophen and erythromycin-H 2O in both rivers (up to 15.7 and 75.5 µg/L) and in wastewater from hospitals and pharmaceutical production facilities (up to 417.5 and 7.84 µg/L) was unique. This finding, in combination with acetaminophen's status as the drug most often prescribed by Taiwan's dominant clinical institute, suggests the potential use of acetaminophen as a molecular indicator of contamination of Taiwan's aqueous environments with untreated urban drainage.