Dean C. Ripple

Platinum versus palladium thermocouples: an emf-temperature reference function for the range 0 °C to 1500 °C

We present an emf-temperature reference function for platinum versus palladium (Pt/Pd) thermocouples in air for the range 0 °C to 1500 °C. The reference function is based on the International Temperature Scale of 1990 (ITS-90) and has an expanded uncertainty (coverage factor of two) of less than the equivalent of 11 mK for temperatures up to 1050 °C and rising smoothly to approximately 0.3 K at 1500 °C. The reference function is based on a set of Pt/Pd thermocouples of exceptional stability and homogeneity constructed from Pt and Pd wire of very high purity (99.999% mass fraction and 99.997% mass fraction, respectively). Experimental results are presented on the thermoelectric stability of Pt/Pd thermocouples at high temperatures and on the calibration of Pt/Pd thermocouples based on this reference function.

Protein particles: What we know and what we do not know

All therapeutic protein products contain intrinsic particles formed by the aggregation of protein monomers. There is growing interest in understanding particles in biopharmaceutical products, fostered on one hand by significant advancements in particle analysis and on the other hand by concerns about potential impact of particles on product quality and safety. With currently available methods, particles in therapeutic proteins can be counted, sized, and characterized in a rudimentary way over a broad size range (from 10s of nanometers to 100 s of micrometers). Here, we review the known attributes of common protein particles, and then discuss the gaps in our current knowledge. The capabilities, limitations, and opportunities for improvement of common particle counting and characterization methods are listed. We conclude that further analytical progress is needed to better classify and characterize the diversity of particles encountered in therapeutic proteins, which may vary in the degree of protein unfolding, the inclusion of nonprotein nucleation centers, and aggregate morphology. Very little is known about the potential correlation between specific particle attributes and increased immunogenicity. In this environment of uncertainty, a deeper understanding about specific particle attributes and potentially increased immunogenicity is greatly needed and will likely be an area of future intensive research.

Subvisible (2–100 μm) Particle Analysis During Biotherapeutic Drug Product Development: Part 1, Considerations and Strategy

Measurement and characterization of subvisible particles (defined here as those ranging in size from 2 to 100 μm), including proteinaceous and nonproteinaceous particles, is an important part of every stage of protein therapeutic development. The tools used and the ways in which the information generated is applied depends on the particular product development stage, the amount of material, and the time available for the analysis. In order to compare results across laboratories and products, it is important to harmonize nomenclature, experimental protocols, data analysis, and interpretation. In this manuscript on perspectives on subvisible particles in protein therapeutic drug products, we focus on the tools available for detection, characterization, and quantification of these species and the strategy around their application.

Thin-Film Resistance Thermometers on Silicon Wafers

We have fabricated Pt thin-film resistors directly sputtered on silicon substrates to evaluate their use as resistance thermal detectors (RTDs). This technique was chosen to achieve more accurate temperature measurements of large silicon wafers during semiconductor processing. High-purity (0.999 968 mass fraction) platinum was sputter deposited on silicon test coupons using titanium and zirconium bond coats. These test coupons were annealed, and four-point resistance specimens were prepared for thermal evaluation. Their response was compared with calibrated platinum–palladium thermocouples in a tube furnace. We evaluated the effects of furnace atmosphere, thin-film thickness, bond coats, annealing temperature and peak thermal excursion of the Pt thin films. Secondary ion mass spectrometry (SIMS) was performed to evaluate the effect of impurities on the thermal resistance coefficient, α. We present typical resistance versus temperature curves, hysteresis plots versus temperature and an analysis of the causes of uncertainties in the measurement of seven test coupons. We conclude that sputtered thin-film platinum resistors on silicon wafers can yield temperature measurements with uncertainties of less than 1 °C, k = 1 up to 600 °C. This is comparable to or better than commercially available techniques.

Progress in Primary Acoustic Thermometry at NIST: 273 K to 505 K

The NIST Acoustic Thermometer determines the thermodynamic temperature by measuring the speed of sound of argon in a spherical cavity. We obtained the thermodynamic temperature of three fixed points on the International Temperature Scale of 1990: the melting point of gallium [T(Ga) = 302.9146 K] and the freezing points of indium [T(In) = 429.7485 K] and tin [T(Sn) = 505.078 K]. The deviations of thermodynamic temperature from the ITS‐90 defined temperatures are T − T90 = (4.7 ± 0.6) mK at T(Ga) , T − T90 = (8.8 ± 1.5) mK at T(In) , and T − T90 = (10.7 ± 3.0) mK at T(Sn) , where the uncertainties are for a coverage factor of k = 1. Our results at T(In) and T(Sn) reduce the uncertainty of T − T90 by a factor of two in this range. Both T − T90 at T(Ga) and the measured thermal expansion of the resonator between the triple point of water and T(Ga) are in excellent agreement with the 1992 determination at NIST. The dominant uncertainties in the present data come from frequency‐dependent and time‐dependent cros...

An Interlaboratory Comparison of Sizing and Counting of Subvisible Particles Mimicking Protein Aggregates

Accurate counting and sizing of protein particles has been limited by discrepancies of counts obtained by different methods. To understand the bias and repeatability of techniques in common use in the biopharmaceutical community, the National Institute of Standards and Technology has conducted an interlaboratory comparison for sizing and counting subvisible particles from 1 to 25 μm. Twenty-three laboratories from industry, government, and academic institutions participated. The circulated samples consisted of a polydisperse suspension of abraded ethylene tetrafluoroethylene particles, which closely mimic the optical contrast and morphology of protein particles. For restricted data sets, agreement between data sets was reasonably good: relative standard deviations (RSDs) of approximately 25% for light obscuration counts with lower diameter limits from 1 to 5 μm, and approximately 30% for flow imaging with specified manufacturer and instrument setting. RSDs of the reported counts for unrestricted data sets were approximately 50% for both light obscuration and flow imaging. Differences between instrument manufacturers were not statistically significant for light obscuration but were significant for flow imaging. We also report a method for accounting for differences in the reported diameter for flow imaging and electrical sensing zone techniques; the method worked well for diameters greater than 15 μm.

Determination of the uncertainties for ITS-90 realization by SPRTs between fixed points

Calibrated standard platinum resistance thermometers (SPRTs) are used to realize the International Temperature Scale of 1990 (ITS-90) from 13.8033 K to 1234.93 K. The SPRTs are calibrated at a series of fixed points, each assigned a temperature on the ITS90, by measuring the ratios of the SPRT resistances at those temperatures to that at the triple point of water (TPW). For realizing the scale with a calibrated SPRT, a user measures the resistance ratio at the unknown temperature and uses ITS-90-defined equations to interpolate between fixed points. The uncertainty of the SPRT temperature is therefore largely influenced by the propagation of fixed-point resistance-ratio uncertainties. In this paper, we rigorously derive the equations for calculating these uncertainties for a variety of circumstances and we use software tools written by us to perform these calculations using realistic uncertainties for fixed points and other input parameters. For properly calculating the standard uncertainty for SPRT realization of the ITS-90, correlations between the input quantities must be considered, in particular those involving measurement of the TPW resistance. The proper calculation depends on three factors involving SPRT use and calibration. The different combinations of these factors result in six different equations for calculating the realization uncertainty. We derive these six equations, specify the conditions of their use and discuss the relevant uncertainty components for each of them. We also compare the results of these equations with those of two approximations that may be used for calculating the standard uncertainty and explain the conditions under which the simpler approximations agree with the more detailed calculations. Because these calculations are complicated, we are making our software tools available upon request to the user community.

The Use of Index-Matched Beads in Optical Particle Counters.

In this paper, we demonstrate the use of 2-pyridinemethanol (2P) aqueous solutions as a refractive index matching liquid. The high refractive index and low viscosity of 2P-water mixtures enables refractive index matching of beads that cannot be index matched with glycerol-water or sucrose-water solutions, such as silica beads that have the refractive index of bulk fused silica or of polymethylmethacrylate beads. Suspensions of beads in a nearly index-matching liquid are a useful tool to understand the response of particle counting instruments to particles of low optical contrast, such as aggregated protein particles. Data from flow imaging and light obscuration instruments are presented for bead diameters ranging from 6 µm to 69 µm, in a matrix liquid spanning the point of matched refractive index.

Techniques for Primary Acoustic Thermometry to 800 K

The NIST Primary Acoustic Thermometer will measure the difference between the International Temperature Scale of 1990 and the Kelvin Thermodynamic Scale throughout the range 273 K to 800 K with uncertainties of only a few millikelvins. The acoustic thermometer determines the frequencies of the acoustic resonances of pure argon gas contained within a spherical cavity with uncertainties approaching one part in 106. To achieve this small uncertainty at these elevated temperatures we developed new acoustic transducers and new techniques for the maintenance of gas purity and for temperature control. The new electro‐acoustic transducers are based on the capacitance between a flexible silicon wafer and a rigid backing plate. Without the damping usually provided by polymers, mechanical vibrations caused unstable, spurious acoustic signals. We describe our techniques for suppression of these vibrations. Our acoustic thermometer allows the argon to be continuously flushed through the resonator, thereby preventing t...

A compact, high‐pressure capillary viscometer

A high‐pressure capillary viscometer is described. Similar to an Ubbelhode viscometer, the instrument is compact, requires a sample of only 1 ml of saturated liquid, and is simple to make and use. The viscometer can readily measure kinematic viscosities as small as 2×10−7 m2/s and can sustain vapor pressures over 1 MPa. The sample contacts only sapphire, stainless steel, and gold, allowing measurement of corrosive liquids. The overall accuracy is approximately 3%.