Comparison of Techniques to Control Ice Nucleation during Lyophilization

Controlling ice nucleation during lyophilization of parenteral drug products increases the homogeneity of critical quality attributes, such as residual moisture, across drug product batches and shortens lyophilization cycle time. In the present study, we compare three mechanistically different techniques to control ice nucleation during the freezing step of lyophilization, which are referred to as “depressurization”, “partial vacuum”, and “ice fog” techniques. The techniques are compared with respect to their operational limitations and challenges. Installation considerations are also discussed. Using the aforementioned nucleation techniques, we investigated a monoclonal antibody formulation and an enzyme formulation at different protein concentrations using feasible nucleation temperatures and different vial formats and fill volumes. Samples were compared for solid state properties and other critical quality attributes on stability. When nucleated at the same temperature, the three techniques produced products with the same quality attributes and stability behavior. Under conditions resulting in micro-collapse, stability behavior can be different. We found that each technology had considerations for achieving robust nucleation. The present comparison may serve as guidance in selecting a nucleation method

Switzerland

Nahinfrarotspektroskopie (NIR) wird seit den Siebzigerjahren als eine nicht zerstörende Technik verwendet. Zahlreiche Forschungsberichte haben die NIR-Effizienz auf dem pharmazeutischen Gebiet aufgezeigt. Die Vorteile, welche zur Popularität von NIR geführt haben, sind die Einfachheit in der Anwendung und die hohe Messgeschwindigkeit. Ausserdem erfordert NIR keine Probenvorbereitung und keine Zusatzchemikalien, was ihr den Spitznamen «grüne Chemie» einbrachte. Eine interessante Anwendung ist die Online-Restwasserbestimmung in gefriergetrockneten Produkten.Near-infrared (NIR) spectroscopy has been used since the seventies as a non-destructive technique. Numerous research papers have shown the NIR efficiency in the pharmaceutical field. The advantages that enabled the popularity of the NIR are its easiness of use, and its speediness. Furthermore, NIR requires no sample preparation, and no auxiliary chemicals, which earned it the nickname of “green chemistry”

Controlling Ice Nucleation during Lyophilization: Process Optimization of Vacuum-Induced Surface Freezing

Biopharmaceuticals are often lyophilized to improve their storage stability. Controlling ice nucleation during the freezing step of the lyophilization process is desired to increase homogeneity of product properties across a drug product batch and shorten the primary drying time. The present communication summarizes the process optimization of the freezing process when using vacuum-induced surface freezing to control ice nucleation, in particular for amorphous samples. We characterized freeze-dried samples for solid state properties, and compared these to uncontrolled nucleated samples using bovine serum albumin (BSA) as a model protein. Freezing parameters were optimized to obtain complete nucleation, adequate cake resistance during the subsequent lyophilization cycle, and elegant cakes. We highlight the challenges associated with vacuum-induced surface freezing and propose optimized freezing parameters to control ice nucleation, enabling manufacturing of amorphous samples

Near-infrared spectroscopy to determine residual moisture in freeze-dried products: Model generation by statistical design of experiments

peer reviewedMoisture content (MC) is a critical quality attribute of lyophilized biopharmaceuticals and can be determined by near-infrared (NIR) spectroscopy as nondestructive alternative to Karl-Fischer titration. In this study, we create NIR models to determine MC in monoclonal antibody lyophilisates by use of statistical design of experiments (DoE) and multivariate data analysis (MVDA). We varied the composition of the formulation as well as lyophilization parameters covering a large range of representative conditions, which is commonly referred to as ‘robustness testing’ according to quality-by-design concepts. We applied principles of chemometrics with partial least squares and principal component analyses (PCA). The NIR model excluded samples with complete collapse and MC > 6%. The two main components in the PCA were MC (91%) and protein:sugar ratio (6%). The third component amounted to only 3% and remained unspecified but may include variations in process parameters and cake structure. In contrast to traditional approaches for NIR model creation, the DoE-based model can be used to monitor MC during drug product development work including scale-up, and transfer without the need to update the NIR model if protein:sugar ratio and MC stays within the tested limits and cake structure remains macroscopically intact. The use of the DoE approach and MVDA ensures product consistency and improves understanding of the manufacturing process

Low-diffusion Xe-He gas mixtures for rare-event detection: electroluminescence yield

High pressure xenon Time Projection Chambers (TPC) based on secondary scintillation (electroluminescence) signal amplification are being proposed for rare event detection such as directional dark matter, double electron capture and double beta decay detection. The discrimination of the rare event through the topological signature of primary ionisation trails is a major asset for this type of TPC when compared to single liquid or double-phase TPCs, limited mainly by the high electron diffusion in pure xenon. Helium admixtures with xenon can be an attractive solution to reduce the electron diffu- sion significantly, improving the discrimination efficiency of these optical TPCs. We have measured the electroluminescence (EL) yield of Xe–He mixtures, in the range of 0 to 30% He and demonstrated the small impact on the EL yield of the addition of helium to pure xenon. For a typical reduced electric field of 2.5 kV/cm/bar in the EL region, the EL yield is lowered by ∼ 2%, 3%, 6% and 10% for 10%, 15%, 20% and 30% of helium concentration, respectively. This decrease is less than what has been obtained from the most recent simulation framework in the literature. The impact of the addition of helium on EL statistical fluctuations is negligible, within the experimental uncertainties. The present results are an important benchmark for the simulation tools to be applied to future optical TPCs based on Xe-He mixtures. [Figure not available: see fulltext.]

Electron drift and longitudinal diffusion in high pressure xenon-helium gas mixtures

We report new measurements of the drift velocity and longitudinal diffusion coefficients of electrons in pure xenon gas and in xenon-helium gas mixtures at 1-9 bar and electric field strengths of 50-300 V/cm. In pure xenon we find excellent agreement with world data at all E/P, for both drift velocity and diffusion coefficients. However, a larger value of the longitudinal diffusion coefficient than theoretical predictions is found at low E/P in pure xenon, below the range of reduced fields usually probed by TPC experiments. A similar effect is observed in xenon-helium gas mixtures at somewhat larger E/P. Drift velocities in xenon-helium mixtures are found to be theoretically well predicted. Although longitudinal diffusion in xenon-helium mixtures is found to be larger than anticipated, extrapolation based on the measured longitudinal diffusion coefficients suggest that the use of helium additives to reduce transverse diffusion in xenon gas remains a promising prospect

Radiogenic backgrounds in the NEXT double beta decay experiment

Natural radioactivity represents one of the main backgrounds in the search for neutrinoless double beta decay. Within the NEXT physics program, the radioactivity- induced backgrounds are measured with the NEXT-White detector. Data from 37.9 days of low-background operations at the Laboratorio Subterráneo de Canfranc with xenon depleted in Xe are analyzed to derive a total background rate of (0.84±0.02) mHz above 1000 keV. The comparison of data samples with and without the use of the radon abatement system demonstrates that the contribution of airborne-Rn is negligible. A radiogenic background model is built upon the extensive radiopurity screening campaign conducted by the NEXT collaboration. A spectral fit to this model yields the specific contributions of Co, K, Bi and Tl to the total background rate, as well as their location in the detector volumes. The results are used to evaluate the impact of the radiogenic backgrounds in the double beta decay analyses, after the application of topological cuts that reduce the total rate to (0.25±0.01) mHz. Based on the best-fit background model, the NEXT-White median sensitivity to the two-neutrino double beta decay is found to be 3.5σ after 1 year of data taking. The background measurement in a Q±100 keV energy window validates the best-fit background model also for the neutrinoless double beta decay search with NEXT-100. Only one event is found, while the model expectation is (0.75±0.12) events. [Figure not available: see fulltext.]

Energy calibration of the NEXT-White detector with 1% resolution near Q ββ of 136Xe

Excellent energy resolution is one of the primary advantages of electroluminescent high-pressure xenon TPCs. These detectors are promising tools in searching for rare physics events, such as neutrinoless double-beta decay (ββ0ν), which require precise energy measurements. Using the NEXT-White detector, developed by the NEXT (Neutrino Experiment with a Xenon TPC) collaboration, we show for the first time that an energy resolution of 1% FWHM can be achieved at 2.6 MeV, establishing the present technology as the one with the best energy resolution of all xenon detectors for ββ0ν searches. [Figure not available: see fulltext.