Stability analysis using mixed models: A critique of tolerance interval methods and a probabilistic solution.

Recently, tolerance interval approaches to the calculation of a shelf life of a drug product have been proposed in the literature. These address the belief that shelf life should be related to control of a certain proportion of batches being out of specification. We question the appropriateness of the tolerance interval approach.

Quantitation of soluble aggregates by sedimentation velocity analytical ultracentrifugation using an optical alignment system - Aspects of method validation.

Sedimentation velocity analytical ultracentrifugation (SV-AUC) is routinely used for quantitation of soluble aggregates as an orthogonal technique to size-exclusion chromatography (SEC). SV-AUC presents many advantages over the SEC, yet lower precision of aggregate quantitation by SV-AUC often complicates comparison between aggregate values generated by these techniques and subsequent decision making. In an earlier report, we described the development of an optical alignment (OA) system and evaluated the intermediate precision of aggregate quantitation offered by the OA.

A curve similarity approach to parallelism testing in bioassay.

Potency determination via bioassay is a relative measure that requires an evaluation of parallelism between the dose-response relationships of a reference standard and a sample material. Typical approaches for assessing parallelism include difference ([Formula: see text]-value) and equivalence tests. These traditional methods rely on a statistical assessment of model parameters as opposed to direct evaluation of the similarity of the dose-response curves.

An optical alignment system improves precision of soluble aggregate quantitation by sedimentation velocity analytical ultracentrifugation.

Appropriate characterization of soluble aggregates is an important aspect of biologics development and manufacturing, and sedimentation velocity analytical ultracentrifugation (SV-AUC) is often used an orthogonal technique to size-exclusion chromatography (SEC) for this purpose. Precise quantification of low levels of soluble aggregates by SV-AUC can be adversely impacted by improper cell alignment. This report describes the development of an optical system capable of quantifying cell alignment that affords a substantial improvement compared to historical approaches.

Use of Bayesian Methods to Analyze and Visualize Content Uniformity Capability Versus United States Pharmacopeia and ASTM Standards.

The purpose of this work was to develop a straightforward and robust approach to analyze and summarize the ability of content uniformity data to meet different criteria. A robust Bayesian statistical analysis methodology is presented which provides a concise and easily interpretable visual summary of the content uniformity analysis results. The visualization displays individual batch analysis results and shows whether there is high confidence that different content uniformity criteria could be met a high percentage of the time in the future.

Variability in Flow-Imaging Microscopy Measurements and Considerations for Biopharmaceutical Development.

Flow-imaging microscopy is widely used in the biopharmaceutical industry to characterize populations of subvisible (1-100 μm) particles due to high sensitivity and the ability to discriminate different particle morphologies. The present work provides a comprehensive assessment of the capabilities of flow-imaging microscopy by exploring the impacts of a variety of factors on the observed variability of these measurements. A novel graphical presentation is proposed to facilitate both determination of expected levels and detection of potential atypical results.

Arrhenius time-scaled least squares: a simple, robust approach to accelerated stability data analysis for bioproducts.

Defining a suitable product presentation with an acceptable stability profile over its intended shelf-life is one of the principal challenges in bioproduct development. Accelerated stability studies are routinely used as a tool to better understand long-term stability. Data analysis often employs an overall mass action kinetics description for the degradation and the Arrhenius relationship to capture the temperature dependence of the observed rate constant.