Current Approaches for Dissolution Similarity Assessment, Requirements, and Global Expectations.

This report summarizes podium presentations and breakout sessions from the second day of the 2019 M-CERSI workshop on In Vitro Dissolution Similarity Assessment in Support of Drug Product Quality: What, How, and When? Presenters from the U.S. Food and Drug Administration (FDA), Health Canada (HC), European Medicines Agency (EMA), Brazilian Health Surveillance Agency (ANVISA), and the pharmaceutical industry shared experiences/concerns with dissolution profile similarity assessment supporting minor/moderate Chemistry, Manufacturing and Control (CMC) changes. Members from regulatory agencies explained that dissolution profile similarity testing is only part of the overall assessment of the acceptability of the proposed changes; decisions are usually made based on aggregate weight of evidence. Scientific shortcomings of f2 were highlighted but no proposal on how to replace it was made. Controlling dissolution timepoint variability and application of pairwise batch-to-batch comparisons (PBC) of dissolution profiles caused considerable debate. Several industry participants suggested increased sample sizes to raise confidence in decision-making and to avoid PBC. They proposed identification of a single mathematical method with predefined acceptance criteria and suggested that dissolution timepoint selection should follow EMA and HC guidance. A majority of meeting attendees favored applying clinically relevant dissolution specifications (CRDS) and dissolution safe space to determine the impact of minor/moderate CMC changes as opposed to dissolution profile similarity assessment via statistical methods. Day 2 of the workshop highlighted the need and opportunities for global harmonization including variability, timepoint selection, role of CRDS, and statistical methods to address the ambiguity globally operating pharmaceutical companies are currently facing.

Disintegration testing augmented by computer Vision technology.

Oral solid dosage forms, specifically immediate release tablets, are prevalent in the pharmaceutical industry. Disintegration testing is often the first step of commercialization and large-scale production of these dosage forms. Current disintegration testing in the pharmaceutical industry, according to United States Pharmacopeia (USP) chapter 〈701〉, only gives information about the duration of the tablet disintegration process. This information is subjective, variable, and prone to human error due to manual or physical data collection methods via the human eye or contact disks. To lessen the data integrity risk associated with this process, efforts have been made to automate the analysis of the disintegration process using digital lens and other imaging technologies. This would provide a non-invasive method to quantitatively determine disintegration time through computer algorithms. The main challenges associated with developing such a system involve visualization of tablet pieces through cloudy and turbid liquid. The Computer Vision for Disintegration (CVD) system has been developed to be used along with traditional pharmaceutical disintegration testing devices to monitor tablet pieces and distinguish them from the surrounding liquid. The software written for CVD utilizes data captured by cameras or other lenses then uses mobile SSD and CNN, with an OpenCV and FRCNN machine learning model, to analyze and interpret the data. This technology is capable of consistently identifying tablets with ≥ 99.6% accuracy. Not only is the data produced by CVD more reliable, but it opens the possibility of a deeper understanding of disintegration rates and mechanisms in addition to duration.

Determining the Sources of Variance in the Preparation of Analytical Standards for Chromatographic Analysis of a Lyophilized Peptide Drug Substance by Nested ANOVA Statistical Analysis.

Synthetic peptides used as therapeutic medicines is continuing to grow as an area of focus within the pharmaceutical industry due to specificity and potency. As such, quality control areas need to continue to advance their capabilities to ensure that appropriate analyses are being performed, and that the data generated are both accurate and precise. One area which poses a significant challenge compared with traditional small molecule drug products is having a highly robust, low variability method of quantifying the assay of the active substance. As many peptide therapeutics are formulated as liquid drug products for injection and preparation procedures to make these samples amenable to traditional chromatographic analysis are inherently low variability (i.e., a simple dilution), potential sources of variance derived from the preparation of the analytical standards used to quantify the assay of the product must be investigated. Here, a fully nested ANOVA experimental design was utilized to examine this process. Such a design allowed for multiple variables to be interrogated as well as the potential interplay of such differences. It was determined that sonication of the standards contributed the most variance, while the balance used and scale on which the standard preparation procedure was performed also contributed significantly. Finally, different procedures for introducing the material into a coulometric Karl Fischer (KF) titration device to quantify the water content of the drug substance were compared and showed that indirect quantification by anhydrous methanol extraction is a significantly more variable method than using an Oven KF autosampler.

Strategies of bringing drug product marketing applications to meet current regulatory standards.

In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts.

Development and validation of a high-throughput GC measurement for water activity.

The development and validation of a headspace GC method to measure the water activity of pharmaceutical samples is presented. Thermal and moisture transfer equilibration rates are shown to be critical variables in the measurement. Several different calibration schemes are discussed with their advantages and disadvantages. The high-throughput applications and experimental considerations of this approach are discussed. The method is shown to be a useful tool to measure a high throughput of water activity samples.