Proposed Test Conditions Research Articles

Discussion of EMA Draft Guideline on Quality and Equivalence of Topical Products Based on Comparison of Approved Mometasone Furoate Drugs.

Today, the approval for a generic topical product includes the presentation of therapeutic equivalence to the originator based on clinical trials. To facilitate this procedure, in 2018 the European Medicines Agency (EMA) published a draft guideline on quality and equivalence of topical products, which includes request parameters regarding the quality of the newly developed generic product and test protocols for the implementation of equivalence tests regarding efficacy. To date, no data are available on the quality and evidence of the proposed test conditions. In this study, we performed an in vitro penetration test (IVPT) following the terms of the EMA draft guideline on two authorized topical products for which therapeutic equivalence was already proven during the approval process. The complex biometric data processing revealed that in vitro equivalence could not be observed for all skin sections for either originator or generic product. Moreover, the necessity of the negative control proposed in the draft guideline is more than questionable. From the results presented, there were indications that a reduced number of skin donors would be sufficient to achieve statistically significant equivalence in the comparison of all applied formulations. Here, n = 7 donors was proposed instead of n 12 as the EMA draft guideline demands, decreasing the degree of biodiversity simultaneously. Moreover, a higher number of independent replicates (n > 2) was proposed for proper statistics. This bioequivalence study shows insufficient parameters, which should be discussed together with the EMA draft guideline.

The Accuracy of Digital Implant Impressions when Using and Varying the Material and Diameter of the Dental Implant Scan Bodies.

The effects of using and varying the material and diameter of implant scan bodies (ISBs) on the level of accuracy of digital implant impressions is unclear. The purpose of this study was to investigate these effects on the level of accuracy of scans made by an extraoral scanner (EOS) and intraoral scanner (IOS). A stone cast with two sets of ISBs was used. ISBs were made of titanium (TI) or polyether ether ketone (PEEK). Each set consisted of two narrow diameter (ND) and two regular diameter (RD) ISBs. Sixtysix scans were performed and imported into an inspection and metrology software to conduct the three-dimensional (3D) comparisons (N=140) and obtain root mean square (RMS) values. RMS values were analyzed with descriptive and inferential non-parametric statistics (α=.05). The use of ISBs did not improve the overall EOS and IOS scans accuracies. Also, varying the ISBs' diameter and material influenced the EOS and IOS accuracies. For the EOS, the precision in descending order was as follows RD TI, ND TI, RD PEEK, ND PEEK. In contrast, for the IOS an inverse relationship was noted. Finally, precision assessment should always be performed for any reference scanner under the proposed test conditions.

Reliable Rate-of-Change-of-Frequency Measurements: Use Cases and Test Conditions

Based on user expectations and requirements, this article discusses three use cases (UCs) for measurements of power system frequency and rate-of-change-of-frequency (ROCOF) measurements, specifying accuracy and latency requirement for each UC. Furthermore, a set of realistic test conditions are proposed, extending those of the present IEC/IEEE 60255-118-1 standard, to ensure ROCOF measuring instruments are adequately tested on their suitability for reliable ROCOF measurements in power systems. Target worst case ROCOF errors (RFEs) are given for each test waveform and UC. Several published ROCOF algorithms are tested using the proposed test conditions. A selection of the test results is reported and compared against the target RFEs. The results show that the defined tests are indeed helpful in evaluating the ROCOF algorithms, and furthermore that the algorithms can be designed to meet all the requirements on RFEs for the tests proposed in this article.

Autoignition of diesel/oxygen/nitrogen mixture under elevated temperature in a heated shock tube

Ignition delay time (IDT) measurements of gas-phase diesel fuel were measured in a heated shock tube, covering the temperatures of T = 901–1371 K, equivalence ratios of ϕ = 0.37–1, and dilution molar ratios of N2/O2 = 3.76–8.52 under three pressures of 6, 10, 20 bar. Within the temperature range investigated, the increase in pressure showed a negative effect on the IDT, and same effect was observed with the increase in concentration of fuel and oxygen. On the contrary, the increase in dilution molar ratio N2/O2 directly lead to the reduction in the reactivity of the whole reaction system. Interestingly, convergence and divergence of IDT for different fuel and oxygen concentrations respectively was observed from the experimental results. The five kinetic models consisting of three kinetic mechanisms and three diesel surrogates were utilized to simulate the experiments of diesel fuel under the proposed test conditions. As compared to the other four models, Model 2 performed effectively in replicating the measured IDTs. The profile modeling of temperature and species with time was carried out at temperatures of 800 K and 1000 K on the basis of Model 2. The model indicated a two-stage ignition behavior at 800 K while only a single-stage ignition at 1000 K. The accuracy of mechanism and surrogate was found to be jointly influenced by the performance of the kinetic model. The experimental results in present study expand the test conditions of interest and provide benchmark ignition delay database of diesel fuel needed for development and validation of surrogate models.

Testing the Configurations of Redundant Integrated Equipment Complexes

We consider one of the tasks of managing the redundancy in a heterogeneous integrated complex of technical equipment defined by a system of linear discrete equations. The task consists in testing a predefined configuration of the complex for implementability. We formulate both sufficient and necessary and sufficient conditions for testing configurations formalized by interface matrices. We illustrate the application and efficiency of the proposed testing conditions with an example based on a redundant aircraft motion control system.

Improvement of Tests for the Control of Impurities in Antimicrobial Medicinal Products by Chromatographic Methods: Ciprofloxacin Case Study

The need to reduce analysis time when controlling impurities in medicinal products remains an urgent challenge. The aim of the study was to use the example of ciprofloxacin in order to select chromatographic conditions that will significantly accelerate and simplify determination of impurities in medicinal products. Methods: the study was performed using the Chromolith ® Performance RP-18e 100×4.6 mm and Acquity UPLC BEH C18 1.7 μ m, 100×2.1 mm columns and the Agilent 1290 Infinity chromatography system with a diode array detector. Results: the authors of the study worked out gradient elution modes for determination of ciprofloxacin impurities that involved 15 min run time for fast high-performance liquid chromatography and 12 min run time for ultra-performance liquid chromatography. The identification of impurities was performed based on relative retention times of impurity peaks and their comparison with the reference standard chromatogram. Conclusions: the study demonstrated the possibility of replacing the thin-layer chromatography method used for determination of fluoroquinolonic acid (ciprofloxacin impurity A) with high-performance liquid chromatography. The proposed test conditions allow for identification of ciprofloxacin impurities specified in well-established pharmacopoeias and manufacturers’ product specification files. The obtained data may be used for further development of rapid methods of ciprofloxacin impurities determination in medicinal products.

Strength and Wear Behavior of Mg Alloy AE42 Reinforced with Carbon Short Fibers

In addition to the advantage of the lightweight of magnesium alloys, magnesium composites have moderate strength and elastic modulus. The proposed application of magnesium composites as diesel truck pistons makes it necessary to assess their wear performance. Little research data have been discussed on wear behavior of Mg alloy AE42 matrix and its composites. Thus, this paper reports wear behavior of magnesium alloy AE42 (Mg–Al–Mn—RE; rare earth) and its composite AE42-C, which contains 23 vol% of randomly oriented carbon short fibers. Materials characterization, including density measurements, hardness testing, microstructures investigation, and compression testing at temperatures of 25, 150, and 300 °C, were conducted. Wear tests were performed under various loads and sliding distances. Wear mechanisms were also proposed based on the examination of worn surfaces using optical microscopy and scanning electron microscopy equipped with EDX (energy-dispersive X-ray spectrometry) analysis system. The hardness of AE42-23 vol% C composite is twice the hardness of the Mg matrix alloy AE42. Significant improvements to yield stress and compressive strength at temperatures of 25, 150, and 300 °C of the composite versus the AE42 alloy are achieved. Wear resistance of the composite is improved considerably versus that of the Mg alloy AE42 at the various sliding distances. Smearing of graphite on the worn surface produces a lubricating film that delays change from mild to severe wear of the composite, especially at high loads. EDX analysis of the worn surface shows oxidation of the matrix alloy at higher wear loads, and this mechanism decreases in the presence of carbon fibers under the same loads. Abrasive wear, oxidation, and plastic deformation are the dominant wear mechanisms for the alloy matrix AE42, whereas mainly abrasive wear is the wear mechanism of AE42-23 vol% C composite under the proposed testing conditions.

Assessing the risk of alcohol-induced dose dumping from sustained-release oral dosage forms: in vitro–in silico approach

Consumption of alcoholic beverages with sustained-release oral dosage forms may pose a risk to patients due to potential alcohol-induced dose dumping (ADD). Regulatory guidances recommend in vitro dissolution testing to identify the risk of ADD, but the question remains whether currently proposed test conditions can be considered biopredictive. The purpose of this study was to evaluate different dissolution setups to assess ADD, and the potential of combined in vitro–in silico approach to predict drug absorption after concomitant alcohol intake for hydrophilic and lipophilic sustained-release tablets containing ibuprofen or diclofenac sodium. According to the obtained results, the impact of ethanol was predominantly governed by the influence on matrix integrity, with the increase in drug solubility being less significant. Hydrophilic matrix tablets were less susceptible to ADD than lipophilic matrices, although the conclusion on formulation ethanol-vulnerability depended on the employed experimental conditions. In silico predictions indicated that the observed changes in drug dissolution would not result in plasma concentrations beyond therapeutic window, but sustained-release characteristics of the formulations might be lost. Overall, the study demonstrated that in vitro–in silico approach may provide insight into the effect of ADD on drug clinical performance, and serve as a tool for ADD risk assessment.

Estimation of the impact stress gradient in the range of size effect

This paper analyzes the size effect for bending loads. The reduction in fatigue properties in loads with a stress gradient is lower than in loads with homogenous distribution. The proposed test conditions for 1.4301 acid-resistant steel in respect of high-cycle fatigue allowed to verify this phenomenon. The tests were performed on a minispecimen and a standard specimen. Vulnerability of the tested material on changing cross-section size of the specimen depending on the type of load (axial, bending) was confirmed experimentally. Analytical calculations of estimating the characteristics other than for the tested cross-section were performed for KHC coefficient and a highly stressed volume model.

Evaluation of Measurement Uncertainty for Water Content Tests in Soil Samples

Measurement uncertainty in the water content test for soil samples is an index for evaluating the reliability of the experiment. It affects the accuracy of some parameters such as porosity and saturation, which are derived from water content. According to the requirements of the standard JJF 1059-1999 Uncertainty Evaluation and Denotation of the Measurement Results, the uncertainty for the measurement results of the water content in soil samples was evaluated. Concerning the characteristics of the water content determination in soil samples, a pail of soil sample was taken as specimen due to its relative homogeneity. The factors affecting the measurement accuracy were discussed. The result shows that the expanded uncertainty of measurement results of the water content in soil samples was 1.6% under the proposed testing conditions.

Juvenile food limitation in standardized tests: a warning to ecotoxicologists

Standard ecotoxicological tests are as simple as possible and food sources are mainly chosen for practical reasons. Since some organisms change their food preferences during the life-cycle, they might be food limited at some stage if we do not account for such a switch. As organisms tend to respond more sensitively to toxicant exposure under food limitation, the interpretation of test results may then be biased. Using a reformulation of the von Bertalanffy model to analyze growth data of the pond snail Lymnaea stagnalis, we detected food limitation in the early juvenile phase. The snails were held under conditions proposed for a standardized test protocol, which prescribes lettuce as food source. Additional experiments showed that juveniles grow considerably faster when fed with fish flakes. The model is based on Dynamic Energy Budget (DEB) theory, which allows for mechanistic interpretation of toxic effects in terms of changes in energy allocation. In a simulation study with the DEB model, we compared the effects of three hypothetical toxicants in different feeding situations. The initial food limitation when fed with lettuce always intensified the effect of the toxicants. When fed with fish flakes, the predicted effect of the toxicants was less pronounced. From this study, we conclude that (i) the proposed test conditions for L. stagnalis are not optimal, and require further investigation, (ii) fish flakes are a better food source for juvenile pond snails than lettuce, (iii) analyzing data with a mechanistic modeling approach such as DEB allows identifying deviations from constant conditions, (iv) being unaware of food limitation in the laboratory can lead to an overestimation of toxicity in ecotoxicological tests.Electronic supplementary materialThe online version of this article (doi:10.1007/s10646-012-0973-5) contains supplementary material, which is available to authorized users.

A quantitative method for evaluating inferior glenohumeral joint stiffness using ultrasonography

Subluxation of the affected shoulder in post-stroke patients is associated with nerve disorders and muscle fatigue. Clinicians must be able to accurately and reliably measure inferior glenohumeral subluxation in patients to provide appropriate treatment. However, quantitative methods for evaluating the laxity and stiffness of the glenohumeral joint (GHJ) are still being developed. The aim of this study was to develop a new protocol for evaluating the laxity and stiffness of the inferior GHJ using ultrasonography under optimal testing conditions and to investigate changes in the GHJ from a commercially available humerus brace and shoulder brace. Multistage inferior displacement forces were applied to create a glide between the most cephalad point on the visible anterosuperior surface of the humeral head and coracoid process in seven healthy volunteers. GHJ stiffness was defined as the slope of the linear regression line between the glides and different testing loads. The testing conditions were defined by different test loading mechanisms (n=2), shoulder constraining conditions (n=2), and loading modes (n=4). The optimal testing condition was defined as the condition with the least residual variance of measured laxity to the calculated stiffness under different testing loads. A paired t-test was used to compare the laxity and stiffness of the inferior GHJ using different braces. No significant difference was identified between the two test loading mechanisms (t=0.218, p=0.831) and two shoulder constraining conditions (t=−0.235, p=0.818). We concluded that ultrasonographic laxity measurements performed using a pulley set loading mechanism was as reliable as direct loading. Additionally, constraining the unloaded shoulder was proposed due to the lower mean residual variance value. Moreover, pulling the elbow downward with loading on the upper arm was suggested, as pulling the elbow downward with the elbow flexed and loading on the forearm may overestimate stiffness and pain in the inferior GHJ at the loading point due to friction between the wide belt and skin. Furthermore, subjects wearing a humerus brace with a belt, which creates the effect of lifting the humerus toward the acromion, had greater GHJ stiffness compared to subjects wearing a shoulder brace without a belt to lift the humerus under the proposed testing conditions. This study provides experimental evidence that shoulder braces may reduce GHJ laxity under an external load, implying that the use of a humeral brace can prevent subluxation in post-stroke patients. The resulting optimal testing conditions for measuring the laxity and stiffness of the GHJ is to constrain the unloaded shoulder and bend the loaded arm at the elbow with loading on the upper arm using a pulley system.

Schedulability analysis for non-preemptive fixed-priority multiprocessor scheduling

Non-preemptive scheduling is usually considered inferior to preemptive scheduling for time critical systems, because the non-preemptive block would lead to poor task responsiveness. Although this is true in single-processor scheduling, we found by empirical simulation experiments that it is not necessarily the case in multiprocessor scheduling. Additionally, non-preemptive scheduling enjoys other benefits like lower implementation complexity and run-time overhead. So non-preemptive scheduling may be a better alternative compared to preemptive scheduling for a considerable part of real-time applications on multiprocessor/multi-core platforms. As the technical contribution, we study the schedulability analysis problem of global non-preemptive fixed-priority scheduling ( NP-FP ) on multiprocessors. We propose schedulability test conditions for NP-FP , building upon the “problem window analysis” by Baruah [8] for preemptive scheduling. We firstly derive a linear-time general schedulability test condition that works on not only NP-FP , but also any other work-conserving non-preemptive scheduling algorithm. Then we improve the analysis and present a test condition of quadratic time-complexity for NP-FP , which has significant performance improvement comparing to the first one. A notable advantage of our proposed test conditions is, while the test in [8] needs to enumerate for a large number of possible problem window sizes, our proposed test conditions only need to be conducted with a single problem window size, and thereby are significantly more efficient. Experiments with randomly generated task sets are conducted to evaluate the performance of the proposed test conditions.

Tin Whisker Test Method Development

The International Electronics Manufacturing Initiative (iNEMI) proposed a set of tests that were subsequently standardized by the Joint Electron Device Engineering Council (JEDEC) Solid State Technology Association as JESD22A121. However, further optimization was needed to validate and verify proposed iNEMI tests to determine whether these test methods could differentiate between component surface finishes, to investigate the connection between short-term and long-term tests, and to determine optimal inspection intervals and test durations. In the current work, 15 surface finishes were evaluated using iNEMI's three proposed environmental test conditions. These finishes were evaluated for whisker presence and length using a scanning electron microscope (SEM) every 1000 h or 500 accelerated thermal cycles for a total of at least 9000 h of isothermal testing or 3000 accelerated thermal cycles. Test results showed that thermal cycling and high-temperature/humidity testing could grow whiskers for all Pb-free Sn-based finishes, while only a few finishes exhibited whiskers after 10 000 h in an air-conditioned office environment. The results described in this paper were used to change the JEDEC tin whisker test method from the original iNEMI proposal by decreasing the humidity of the high-temperature humidity test, controlling the ambient test condition to 30 degC and 60% relative humidity (RH), and increasing the number of leads per sample and number of samples (sample size) for inspection

Evaluation of the Newly Developed Test Method for the Lubricant Biodegradability

The conventional biodegradability test for lubricants relies on CEC L-33-A-93 worldwide, which, however, has several defects since the method determines biodegradability by C-H absorption intensity of infrared spectra. Nevertheless, the need for biodegradability tests for lubricants in various applications will continue to increase. In a previous paper the authors reported the development of a new test method by applying gas chromatography to overcome the defects of the CEC method. In this paper we examined the applicability of the new test method with various lubricant base materials and obtained good agreement with the results reported by Randles using the CEC method. Our new test method is applicable to a wider range of such lube base materials as mineral, natural, synthetic, and formulated products. Supplemental test proved that sterilization potential of biocide lasted longer than a test period of 4 weeks. Detailed gas chromatographic peak analyses on esters revealed that hydrolytic degradation did not take place under the proposed test conditions.

Migration testing of plastics and microwave‐active materials for high‐temperature food‐use applications

Temperatures have been measured using a fluoro-optic probe at the food/container or food/packaging interfaces as appropriate, for a range of foods heated in either a microwave or a conventional oven. Reheating ready-prepared foods packaged in plastics pouches, trays or dishes in the microwave oven, according to the manufacturers' instructions, resulted in temperatures in the range 61-121 degrees C. Microwave-active materials (susceptors) in contact with ready-prepared foods frequently reached local spot temperatures above 200 degrees C. For foods cooked in a microwave oven according to published recipes, temperatures from 91 degrees C to 200 degrees C were recorded, whilst similar temperatures (92-194 degrees C) were attained in a conventional oven, but over longer periods of time. These measurements form the basis for examining compliance with specific and overall migration limits for plastics materials. The testing conditions proposed depend on the intended use of the plastic - for microwave oven use for aqueous foods, for all lidding materials, and for reheating of foods, testing would only be required with aqueous simulants for 1 h at 100 degrees C; for unspecified microwave oven use, testing with olive oil would be required for 30 min at 150 degrees C; and for unspecified use in a conventional oven testing with olive oil would be required for 2 h at 175 degrees C. For microwave-active materials, it is proposed that testing is carried out in the microwave oven using a novel semi-solid simulant comprising olive oil and water absorbed onto an inert support of diatomaceous earth. The testing in this instance is carried out with the simulant instead of food in a package and heating in the microwave oven at 600 W for 4 min for every 100 g of simulant employed. There is an option in every case to test for migration using real foods rather than simulants if it can be demonstrated that results using simulants are unrepresentative of those for foods. The proposed testing conditions were validated as being realistic by measurement of the specific migration of various components from different plastics into foods under actual conditions of use and comparing with migration into simulants. Migration of plasticizers from PVC and VC/VDC copolymer films was monitored for both microwave reheating and cooking of foods. Total oligomer concentrations were measured from poly(ethylene terephthalate) (PET) trays, and volatile aromatics from thermoset polyester trays, using both types of container in microwave and conventional ovens.(ABSTRACT TRUNCATED AT 400 WORDS)

Stress Corrosion Cracking of the Stainless Steels in Hydrogen Sulfide Solution

The susceptibilities of the stainless steels to stress corrosion cracking in hydrogen sulfide-saturated water were studied. The U-bended pieces of the austenitic steels cracked under the following proposed test conditions; dipping in the water prepared to pH 3.0 with hydrochloric or sulfuric acid and saturated with hydrogen sulfide, at 80°C, and for 5-15 days. The cracks were transgranular in the solution-treated austenitic steels, and intergranular in the sensitized ones.Only shallow pittings were observed on the surfaces of the annealed ferritic steels, but intergranular stress corrosion crackings were observed in the sensitized ones under the same conditions mentioned above. In a new ferritic stainless steel, no crack was observed no but only shallow pittings were observed in both annealed and sensitized pieces.