Development of Conductivity Method as an Alternative to Titration for Hydrolytic Resistance Testing Used for Evaluation of Glass Vials Used in Pharmaceutical Industry.

The European Pharmacopeia surface test to analyze the hydrolytic resistance is a common industrial method to understand and ensure the quality of produced glass vials. Hydrolytic resistance is evaluated by calculating the alkalinity of water extract from autoclaved vials by titration. As an alternative to this titration technique, a conductivity technique was assessed, which directly measures the ions in the water extract. A conductivity meter with a 12 mm diameter electrode was calibrated with a 100 µS/cm conductivity standard and carryover minimized by rinsing the probe in a water beaker per analysis. The limit of quantification at 1 µS/cm was determined as having a signal-to-noise ratio of 3 compared with the water blank. The conductivity method was selective for glass-composing elements (boron, sodium, aluminum, silicon, potassium, and calcium) within the vial extract. Accuracies of spiked conductivity standard within the range of 1 to 100 µS/cm were ±7% and had linearity with coefficient of determination (R2) of ≥0.9999. Intraday precision had a relative standard deviation (RSD) (n = 5) of ≤6% for spiked conductivity standard within the range of 1 to 100 µS/cm. Interday precision had a RSD (n = 4) of ≤6% for 10 vials from three glass vial lots. Conductivity of water extracts from nine sets of seven lots of glass vials had a precise linear relationship [R2 = 0.9876, RSD = 1% (n = 9)] with titration volumes of the same lots. Conductivity results in µS/cm could be converted to titration volumes in milliliters by a conversion factor of 0.0275. The simplicity, sample stability, and individual vial analysis of the conductivity technique were more advantageous than the current titration technique. LAY ABSTRACT: The quality of glass vials used as primary containers in the pharmaceutical industry is of concern due to recent observations of glass flake-like delamination, or lamellae, under specific storage conditions. The current European Pharmacopoeia method to assess glass vial quality utilizes acid titration of vial extract pools to determine hydrolytic resistance or alkalinity. As an alternative to the European Pharmacopoeia method, the vial extracts were analyzed for conductivity, which directly determines the level of ions that were readily extracted from the vial surfaces. Lower quality glass would have greater surface defects that lead to higher ions extracted and higher conductivity value. The conductivity method was found to be suitable to measure the ions in water extracts and showed strong correlation with alkalinity. The advantage of the conductivity method over the alkalinity method was greater ease, lower volume requirements, stability, and flexibility in analysis.

Comparison of Acid Titration, Conductivity, Flame Photometry, ICP-MS, and Accelerated Lamellae Formation Techniques in Determining Glass Vial Quality.

Certain types of glass vials used as primary containers for liquid formulations of biopharmaceutical drug products have been observed with delamination that produced small glass like flakes termed lamellae under certain conditions during storage. The cause of this delamination is in part related to the glass surface defects, which renders the vials susceptible to flaking, and lamellae are formed during the high-temperature melting and annealing used for vial fabrication and shaping. The current European Pharmacopoeia method to assess glass vial quality utilizes acid titration of vial extract pools to determine hydrolytic resistance or alkalinity. Four alternative techniques with improved throughput, convenience, and/or comprehension were examined by subjecting seven lots of vials to analysis by all techniques. The first three new techniques of conductivity, flame photometry, and inductively coupled plasma mass spectrometry measured the same sample pools as acid titration. All three showed good correlation with alkalinity: conductivity (R(2) = 0.9951), flame photometry sodium (R(2) = 0.9895), and several elements by inductively coupled plasma mass spectrometry [(sodium (R(2) = 0.9869), boron (R(2) = 0.9796), silicon (R(2) = 0.9426), total (R(2) = 0.9639)]. The fourth technique processed the vials under conditions that promote delamination, termed accelerated lamellae formation, and then inspected those vials visually for lamellae. The visual inspection results without the lot with different processing condition correlated well with alkalinity (R(2) = 0.9474). Due to vial processing differences affecting alkalinity measurements and delamination propensity differently, the ratio of silicon and sodium measurements from inductively coupled plasma mass spectrometry was the most informative technique to assess overall vial quality and vial propensity for lamellae formation. The other techniques of conductivity, flame photometry, and accelerated lamellae formation condition may still be suitable for routine screening of vial lots produced under consistent processes. LAY ABSTRACT: Recently, delamination that produced small glass like flakes termed lamellae has been observed in glass vials that are commonly used as primary containers for pharmaceutical drug products under certain conditions during storage. The main cause of these lamellae was the quality of the glass itself related to the manufacturing process. Current European Pharmacopoeia method to assess glass vial quality utilizes acid titration of vial extract pools to determine hydrolytic resistance or alkalinity. As alternative to the European Pharmacopoeia method, four other techniques were assessed. Three new techniques of conductivity, flame photometry, and inductively coupled plasma mass spectrometry measured the vial extract pool as acid titration to quantify quality, and they demonstrated good correlation with original alkalinity. The fourth technique processed the vials under conditions that promote delamination, termed accelerated lamellae formation, and the vials were then inspected visually for lamellae. The accelerated lamellae formation technique also showed good correlation with alkalinity. Of the new four techniques, inductively coupled plasma mass spectrometry was the most informative technique to assess overall vial quality even with differences in processing between vial lots. Other three techniques were still suitable for routine screening of vial lots produced under consistent processes.

International guidelines for the in vivo assessment of skin properties in non-clinical settings: part 1. pH.

BACKGROUND: Skin surface pH is known to influence the dissolution and partitioning of chemicals and may influence exposures that lead to skin diseases. Non-clinical environments (e.g., workplaces) are highly variable, thereby presenting unique measurement challenges that are not typically encountered in clinical settings. Hence, guidelines are needed for consistent measurement of skin surface pH in environments that are difficult to control. METHODS: An expert workshop was convened at the 5th International Conference on Occupational and Environmental Exposure of Skin to Chemicals to review available data on factors that could influence the determination of skin surface pH in non-clinical settings with emphasis on the workplace as a worst case scenario. RESULTS: The key elements of the guidelines are: (i) minimize, to the extent feasible, the influences of relevant endogenous (anatomical position, skin health, time of day), exogenous (hand washing, barrier creams, soaps and detergents, occlusion), environmental (seasonality), and measurement (atmospheric conditions) factors; (ii) report pH measurements results as a difference or percent change (not absolute values) using a measure of central tendency and variability; and (iii) report notable deviations from these guidelines and other relevant factors that may influence measurements. CONCLUSION: Guidelines on the measurement and reporting of skin surface pH in non-clinical settings should promote consistency in data reporting, facilitate inter-comparison of study results, and aid in understanding and preventing occupational skin diseases.

Nanomaterial based self-referencing microbiosensors for cell and tissue physiology research.

Physiological studies require sensitive tools to directly quantify transport kinetics in the cell/tissue spatial domain under physiological conditions. Although biosensors are capable of measuring concentration, their applications in physiological studies are limited due to the relatively low sensitivity, excessive drift/noise, and inability to quantify analyte transport. Nanomaterials significantly improve the electrochemical transduction of microelectrodes, and make the construction of highly sensitive microbiosensors possible. Furthermore, a novel biosensor modality, self-referencing (SR), enables direct measurement of real-time flux and drift/noise subtraction. SR microbiosensors based on nanomaterials have been used to measure the real-time analyte transport in several cell/tissue studies coupled with various stimulators/inhibitors. These studies include: glucose uptake in pancreatic ß cells, cancer cells, muscle tissues, intestinal tissues and P. Aeruginosa biofilms; glutamate flux near neuronal cells; and endogenous indole-3-acetic acid flux near the surface of Zea mays roots. Results from the SR studies provide important insights into cancer, diabetes, nutrition, neurophysiology, environmental and plant physiology studies under dynamic physiological conditions, demonstrating that the SR microbiosensors are an extremely valuable tool for physiology research.

A 64-channel readout ASIC for nanowire biosensor array with electrical calibration scheme.

A 1.8-mW, 18.5-mm(2) 64-channel current readout ASIC was implemented in 0.18-µm CMOS together with a new calibration scheme for silicon nanowire biosensor arrays. The ASIC consists of 64 channels of dedicated readout and conditioning circuits which incorporate correlated double sampling scheme to reduce the effect of 1/f noise and offset from the analog front-end. The ASIC provides a 10-bit digital output with a sampling rate of 300 S/s whilst achieving a minimum resolution of 7 pA(rms). A new electrical calibration method was introduced to mitigate the issue of large variations in the nano-scale sensor device parameters and optimize the sensor sensitivity. The experimental results show that the proposed calibration technique improved the sensitivity by 2 to 10 times and reduced the variation between dataset by 9 times.

Precise blood lead analysis using a combined internal standard and standard addition approach with disposable screen-printed electrodes.

We report here a highly accurate and efficient method for blood lead analysis (BLA) through the use of a disposable electrode. A new type of mercury-plated preanodized screen-printed carbon electrode, together with a thallium(III) internal standard, simplifies calibration and gives easily quantifiable signals for accurate BLA. A preanodization procedure improves the preconcentration ability of the working electrode through the effect of lead (Pb) complexing with an electrogenerated surface functional group, mainly >C=O. Under optimized conditions, the ratio of the anodic stripping peak currents of Pb and Tl (i.e., i(Pb)/i(Tl)) is linear against [Pb] in the window of 1-300 ppb with a correlation coefficient and detection limit (signal-to-noise ratio=3) of 0.999 and 0.23 ppb, respectively. This approach was used to analyze blood samples (n=55) from workers at a local battery factory. The results are consistent with those obtained from graphite furnace atomic absorption spectroscopy and confirm the applicability of the proposed method.

A disposable voltammetric cell for determining the titratable acidity in vinegar.

A disposable voltammetric cell using three pencil leads as working, reference, and counter electrodes was developed for determining the titratable acidity, i.e. the acid content in vinegar. The materials of the pencil leads were graphite-reinforcement carbons (GRCs). A voltammetric determination of acid was made by measuring the reduction prepeak current of 3,5-di-t-butyl-1,2-benzoquinone (DBBQ) due to the presence of acids in unbuffered solution. The potential stability of the pseudo-reference electrode of GRC was examined. The prepeak current was found to be proportional to the acetic acid concentration from 0.05 to 2.7 mM with a correlation coefficient of 0.999. The cell-to-cell reproducibility for 1 mM acetic acid was evaluated with ten individual disposable cells. The RSD of the prepeak current and the SD of the prepeak potential were 2.56% and 0.008, respectively. The titratable acidity in five vinegar samples was determined by voltammetry using disposable cells and compared with that of the titratable acidity determined by the conventional potentiometric titration method. We then observed the results by both methods, and found a correlation coefficient of 0.972. As such, the voltammetry using disposable-cell required only one thousandth the volume of a vinegar sample for the titration method. The disposable cell was superior to the conventional electrochemical cell, in terms of facility, environment-friendly, and economy, and thus a sensor using the present cell would be useful for routine work in the quality control of vinegar.

Total body electrical conductivity measurements in the neonate.

TOBEC measurements are based on the premise that a conductive object will interact with an electromagnetic field and result in the dissipation of a small quantity of the field's energy. TOBEC instruments provide a measure of this energy loss, which for a given conductor varies according to its size. The conductive component of the body is that part that contains water with dissolved electrolytes, i.e., essentially the FFM. Fat, by definition, is anhydrous and does not contribute to a TOBEC measurement. To interpret TOBEC readings in terms of the quantity of FFM in the body requires the use of a calibration equation that is generated by measuring the FFM of a reference population using an alternative technique and relating this to each individual's TOBEC value. Because no alternative method exists to estimate the FFM of an infant, a calibration equation is used that was generated from measurements of young miniature piglets. The body composition of infants thus derived is consistent with our general understanding of the changes in fat and FFM in human infants in early life. Whether TOBEC can be used as described in premature or older children has yet to be determined. Variations in the composition of the FFM do not seem to compromise the accuracy of the technique. TOBEC measurements are precise, rapid, noninvasive, and safe and cause the subject no discomfort. These features not only make TOBEC a useful tool for the nutritional assessment of a pediatric patient but they also may be a useful diagnostic tool for the clinician.