Leachable and extractable studies on single-use system technologies in commercial scale drug filling lines

Stir-bar sorptive extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC-MS) is widely accepted as the gold–standard analysis method for trace amounts of organic substances, including leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method’s recovery. The scope of the present work was to fill in the unexplored territory in a fourfold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG)-PDMS), 3) by determining the concentration behavior of SBSE in alcoholic solutions compared to the direct injection and 4) by proposing among possible optimizations a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of leachables with a log K O/W ≥ 3.6 is negligible (-3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of -42.9%. For leachables with a log K O/W 0.992). On average, the conventional PDMS coating resulted in a 28-fold higher signal-to-noise ratio compared to EG-PDMS. Moreover, the PDMS coated stir-bar reached better reconcentrate in inhibitory alcoholic solutions. Furthermore, a broader range of leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection. The increasing application of Single-Use Systems (SUSs) in pharmaceutical manufacturing lines poses a potential risk of polymer-related impurities leaching into the process stream and persisting through the manufacturing process. To minimize any potential toxicity and impairment to the product’s quality, safety thresholds are strictly regulated and enforced in particular for parenteral solutions. At present, impurities are estimated from extractable profiles, which are generated for each SUS with thermal or static extraction. In this study we employed target leachable-testing by taking samples directly from an industrial filling line probed during real-life processing of three parenteral drugs (n=2) under actual process-conditions, to estimate the concentration of leachables throughout drug-manufacturing. At five different points, samples were drawn to study the individual impact of SUSs on the leachable accumulation within the drug-filling process. The drug products were examined for leachables using stir-bar-sorptive-extraction (SBSE) with poly-dimethylsiloxane (PDMS) and ethylene glycol (EG)-PDMS coated stir-bars. Subsequent extraction from the stir-bars and analysis of the substances was performed with TD-GC-MS and solvent-back-extraction (SBE)-UPLC/QTOF-MS/MS analytics. Our study revealed the following main results: 1) Leachables were found in extremely low concentrations, all below toxicological thresholds (highest leachable concentration in the final drug product 1 (DP1): 0.274 ppm < drug specific threshold: 6.0 ppm; DP2: 0.010 ppm < 0.2 ppm; DP3: 0.011 ppm < 0.5 ppm). All compounds identified in the leachables study were found to be non-genotoxic. 2) Most of the leachables (68%) that were found were already observed at the beginning of the filling process, delivered by the API either a common source of leaching could be identified within the filling-line nor a specific product influence on quality or quantity of leachables. 3) No leachable increase could be observed over the filling process. On the contrary leachable concentrations declined with 83%, which was partly due to dilution by buffer-feed and to a proven absorption of leachables by filters and silicon tubing. 4) No active ingredient influence on the leachable-outcome was observed by placebo to drug product comparison. In contrast, the pH-setting of the drug product influenced the leaching-behavior to the greatest possible extent

Leachable and extractable studies on single-use system technologies in commercial scale drug filling lines

Stir-bar sorptive extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC-MS) is widely accepted as the gold–standard analysis method for trace amounts of organic substances, including leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method’s recovery. The scope of the present work was to fill in the unexplored territory in a fourfold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG)-PDMS), 3) by determining the concentration behavior of SBSE in alcoholic solutions compared to the direct injection and 4) by proposing among possible optimizations a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of leachables with a log K O/W ≥ 3.6 is negligible (-3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of -42.9%. For leachables with a log K O/W 0.992). On average, the conventional PDMS coating resulted in a 28-fold higher signal-to-noise ratio compared to EG-PDMS. Moreover, the PDMS coated stir-bar reached better reconcentrate in inhibitory alcoholic solutions. Furthermore, a broader range of leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection. The increasing application of Single-Use Systems (SUSs) in pharmaceutical manufacturing lines poses a potential risk of polymer-related impurities leaching into the process stream and persisting through the manufacturing process. To minimize any potential toxicity and impairment to the product’s quality, safety thresholds are strictly regulated and enforced in particular for parenteral solutions. At present, impurities are estimated from extractable profiles, which are generated for each SUS with thermal or static extraction. In this study we employed target leachable-testing by taking samples directly from an industrial filling line probed during real-life processing of three parenteral drugs (n=2) under actual process-conditions, to estimate the concentration of leachables throughout drug-manufacturing. At five different points, samples were drawn to study the individual impact of SUSs on the leachable accumulation within the drug-filling process. The drug products were examined for leachables using stir-bar-sorptive-extraction (SBSE) with poly-dimethylsiloxane (PDMS) and ethylene glycol (EG)-PDMS coated stir-bars. Subsequent extraction from the stir-bars and analysis of the substances was performed with TD-GC-MS and solvent-back-extraction (SBE)-UPLC/QTOF-MS/MS analytics. Our study revealed the following main results: 1) Leachables were found in extremely low concentrations, all below toxicological thresholds (highest leachable concentration in the final drug product 1 (DP1): 0.274 ppm < drug specific threshold: 6.0 ppm; DP2: 0.010 ppm < 0.2 ppm; DP3: 0.011 ppm < 0.5 ppm). All compounds identified in the leachables study were found to be non-genotoxic. 2) Most of the leachables (68%) that were found were already observed at the beginning of the filling process, delivered by the API either a common source of leaching could be identified within the filling-line nor a specific product influence on quality or quantity of leachables. 3) No leachable increase could be observed over the filling process. On the contrary leachable concentrations declined with 83%, which was partly due to dilution by buffer-feed and to a proven absorption of leachables by filters and silicon tubing. 4) No active ingredient influence on the leachable-outcome was observed by placebo to drug product comparison. In contrast, the pH-setting of the drug product influenced the leaching-behavior to the greatest possible extent

Corrélation entre la forme d'inclusions intergranulaires et l'énergie de joints de grains dans un alliage Cu-1Pb

Le plomb ajouté dans le cuivre et ses alliages est présent aux joints de grains à l'équilibre capillaire sous la forme de lentilles dont la géométrie est gouvernée par leur angle dièdre. Une méthode de mesure de l'angle dièdre permettant d'accéder à une valeur précise pour chaque inclusion a été développée et appliquée aux inclusions individuelles dans un alliage Cu-1Pb. Les résultats obtenus sur une série d'inclusions montrent une grande dispersion à l'échelle d'un échantillon. Cette observation est interprétée comme une conséquence du fait que, pour une température d'équilibration spécifique, l'angle dièdre sur un joint de grains défini dépend de l'énergie de celui-ci. La dispersion constatée sur les valeurs d'angle dièdre obtenues sur un même échantillon peut dès lors être reliée à la dispersion de l'énergie des joints de grains au sein d'un polycristal, laquelle peut à son tour être reliée à la désorientation relative entre les grains, puisque cette dernière est mesurable par analyse EBSD. Le présent article présente des premiers résultats de cette approche

Toward Clinically Compatible Phase-Contrast Mammography

Phase-contrast mammography using laboratory X-ray sources is a promising approach to overcome the relatively low sensitivity and specificity of clinical, absorption-based screening. Current research is mostly centered on identifying potential diagnostic benefits arising from phase-contrast and dark-field mammography and benchmarking the latter with conventional state-of-the-art imaging methods. So far, little effort has been made to adjust this novel imaging technique to clinical needs. In this article, we address the key points for a successful implementation to a clinical routine in the near future and present the very first dose-compatible and rapid scan-time phase-contrast mammograms of both a freshly dissected, cancer-bearing mastectomy specimen and a mammographic accreditation phantom

Toward Clinically Compatible Phase-Contrast Mammography

Phase-contrast mammography using laboratory X-ray sources is a promising approach to overcome the relatively low sensitivity and specificity of clinical, absorption-based screening. Current research is mostly centered on identifying potential diagnostic benefits arising from phase-contrast and dark-field mammography and benchmarking the latter with conventional state-of-the-art imaging methods. So far, little effort has been made to adjust this novel imaging technique to clinical needs. In this article, we address the key points for a successful implementation to a clinical routine in the near future and present the very first dose-compatible and rapid scan-time phase-contrast mammograms of both a freshly dissected, cancer-bearing mastectomy specimen and a mammographic accreditation phantom

Improved Diagnostics by Assessing the Micromorphology of Breast Calcifications via X-Ray Dark-Field Radiography

Breast microcalcifications play an essential role in the detection and evaluation of early breast cancer in clinical diagnostics. However, in digital mammography, microcalcifications are merely graded with respect to their global appearance within the mammogram, while their interior microstructure remains spatially unresolved and therefore not considered in cancer risk stratification. In this article, we exploit the sub-pixel resolution sensitivity of X-ray dark-field contrast for clinical microcalcification assessment. We demonstrate that the micromorphology, rather than chemical composition of microcalcification clusters (as hypothesised by recent literature), determines their absorption and small-angle scattering characteristics. We show that a quantitative classification of the inherent microstructure as ultra-fine, fine, pleomorphic and coarse textured is possible. Insights underlying the micromorphological nature of breast calcifications are verified by comprehensive high-resolution micro-CT measurements. We test the determined microtexture of microcalcifications as an indicator for malignancy and demonstrate its potential to improve breast cancer diagnosis, by providing a non-invasive tool for sub-resolution microcalcification assessment. Our results indicate that dark-field imaging of microcalcifications may enhance the diagnostic validity of current microcalcification analysis and reduce the number of invasive procedures

Improved Diagnostics by Assessing the Micromorphology of Breast Calcifications via X-Ray Dark-Field Radiography

Breast microcalcifications play an essential role in the detection and evaluation of early breast cancer in clinical diagnostics. However, in digital mammography, microcalcifications are merely graded with respect to their global appearance within the mammogram, while their interior microstructure remains spatially unresolved and therefore not considered in cancer risk stratification. In this article, we exploit the sub-pixel resolution sensitivity of X-ray dark-field contrast for clinical microcalcification assessment. We demonstrate that the micromorphology, rather than chemical composition of microcalcification clusters (as hypothesised by recent literature), determines their absorption and small-angle scattering characteristics. We show that a quantitative classification of the inherent microstructure as ultra-fine, fine, pleomorphic and coarse textured is possible. Insights underlying the micromorphological nature of breast calcifications are verified by comprehensive high-resolution micro-CT measurements. We test the determined microtexture of microcalcifications as an indicator for malignancy and demonstrate its potential to improve breast cancer diagnosis, by providing a non-invasive tool for sub-resolution microcalcification assessment. Our results indicate that dark-field imaging of microcalcifications may enhance the diagnostic validity of current microcalcification analysis and reduce the number of invasive procedures

Formation of nanoscale structures by inductively coupled plasma etching

This paper will review the top down technique of ICP etching for the formation of nanometer scale structures. The increased difficulties of nanoscale etching will be described. However it will be shown and discussed that inductively coupled plasma (ICP) technology is well able to cope with the higher end of the nanoscale: features from 100nm down to about 40nm are relatively easy with current ICP technology. It is the ability of ICP to operate at low pressure yet with high plasma density and low (controllable) DC bias that helps greatly compared to simple reactive ion etching (RIE) and, though continual feature size reduction is increasingly challenging, improvements to ICP technology as well as improvements in masking are enabling sub-10nm features to be reached. Nanoscale ICP etching results will be illustrated in a range of materials and technologies. Techniques to facilitate etching (such as the use of cryogenic temperatures) and techniques to improve the mask performance will be described and illustrated

Nurses Alumni Association Bulletin, Fall 1982

Alumni Calendar Officers and Chairmen of Committees Letter from the President School of Nursing Annual Report to the Alumni Association 1980-1981 Thomas Jefferson University, College of Allied Health Sciences- School of Nursing Awards 1982 Historical Highlights, Jefferson School of Nursing The History of the Jefferson Cap Two Firsts for Doris Bowman Congratulations, Jeraldine Kohut Tribute to Elizabeth Sweeney 1982 Commencement Address Nero Fiddles While Rome Burns A Fiftieth Reunion Fiftieth Anniversary- Class of 1932 White Haven Alumnae Celebrate 35th Anniversary Treasurers\u27 Financial Report Social Report Scholarship Report Report of Sick and Welfare Committee Martha Riland Reports Nurses\u27 Relief Fund Nurses\u27 Scholarship Fund Resume\u27 of Minutes of Alumni Association Meetings Happy Birthday Finance Committee Report Pictures, Luncheon School of Nursing, Graduates 1982 Class Notes In Memoriam, Names of Deceased Members Notices Change of Address For

Life Under Hypoxia Lowers Blood Glucose Independently of Effects on Appetite and Body Weight in Mice

Blood glucose and the prevalence of diabetes are lower in mountain than lowland dwellers, which could among other factors be due to reduced oxygen availability. To investigate metabolic adaptations to life under hypoxia, male mice on high fat diet (HFD) were continuously maintained at 10% O2. At variance to preceding studies, the protocol was designed to dissect direct metabolic effects from such mediated indirectly via hypoxia-induced reductions in appetite and weight gain. This was achieved by two separate control groups on normal air, one with free access to HFD, and one fed restrictedly in order to obtain a weight curve matching that of hypoxia-exposed mice. Comparable body weight in restrictedly fed and hypoxic mice was achieved by similar reductions in calorie intake (−22%) and was associated with parallel effects on body composition as well as on circulating insulin, leptin, FGF-21, and adiponectin. Whereas the effects of hypoxia on the above parameters could thus be attributed entirely to blunted weight gain, hypoxia improved glucose homeostasis in part independently of body weight (fasted blood glucose, mmol/l: freely fed control, 10.2 ± 0.7; weight-matched control, 8.0 ± 0.3; hypoxia, 6.8 ± 0.2; p &lt; 0.007 each; AUC in the glucose tolerance test, mol/l*min: freely fed control, 2.54 ± 0.15; weight-matched control, 1.86 ± 0.08; hypoxia, 1.67 ± 0.05; p &lt; 0.05 each). Although counterintuitive to lowering of glycemia, insulin sensitivity appeared to be impaired in animals adapted to hypoxia: In the insulin tolerance test, hypoxia-treated mice started off with lower glycaemia than their weight-matched controls (initial blood glucose, mmol/l: freely fed control, 11.5 ± 0.7; weight-matched control, 9.4 ± 0.3; hypoxia, 8.1 ± 0.2; p &lt; 0.02 each), but showed a weaker response to insulin (final blood glucose, mmol/l: freely fed control, 7.0 ± 0.3; weight-matched control, 4.5 ± 0.2; hypoxia, 5.5 ± 0.3; p &lt; 0.01 each). Furthermore, hypoxia weight-independently reduced hepatic steatosis as normalized to total body fat, suggesting a shift in the relative distribution of triglycerides from liver to fat (mg/g liver triglycerides per g total fat mass: freely fed control, 10.3 ± 0.6; weight-matched control, 5.6 ± 0.3; hypoxia, 4.0 ± 0.2; p &lt; 0.0004 each). The results show that exposure of HFD-fed mice to continuous hypoxia leads to a unique metabolic phenotype characterized by improved glucose homeostasis along with evidence for impaired rather than enhanced insulin sensitivity