In vitro dissolution testing is a regulatory required critical quality measure for solid dose pharmaceutical drug products. Setting the acceptance criteria to meet compendial criteria is required for a product to be filed and approved for marketing. Statistical approaches for analyzing dissolution data, setting specifications and visualizing results could vary according to product requirements, company's practices, and scientific judgements. This paper provides a general description of the steps taken in the evaluation and setting of in vitro dissolution specifications at release and on stability.

Objectives: Ertugliflozin is a selective sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes in adults. In its natural form, ertugliflozin exists as an amorphous solid with physicochemical properties that prevent commercial manufacture. The commercial product was developed as an immediate-release tablet, consisting of an ertugliflozin-L-pyroglutamic acid cocrystal of 1 : 1 molar stoichiometry as the active pharmaceutical ingredient. The ertugliflozin cocrystal may partially dissociate when exposed to high humidity for extended periods, leading to the formation of free amorphous ertugliflozin. Therefore, a study was conducted to estimate the relative bioavailability of ertugliflozin when administered in non-commercial formulated tablets containing the amorphous form vs. the cocrystal form. Materials and methods: In this phase 1, open-label, randomized, two-period, two-sequence, single-dose crossover study, 16 healthy subjects received 15 mg immediate-release ertugliflozin in its amorphous and cocrystal forms under fasted conditions, separated by a washout period of >= 7 days. Blood samples were collected post-dose for 72 hours to determine plasma ertugliflozin concentrations. Results: Mean ertugliflozin plasma concentration-time profiles were nearly superimposable following administration of the amorphous and cocrystal forms. The 90% confidence intervals for the geometric mean ratios for AUC(inf) and C-ma(x). were wholly contained within the pre-specified criteria for similarity (70 - 143%), as well as the acceptance range for bioequivalence (80 - 125%). Most adverse events were mild in intensity. Conclusion: Any dissociation of ertugliflozin to the amorphous form that occurs in tablets containing the cocrystal will not have any clinically meaningful impact on the oral bioavailability of ertugliflozin.

Quality control dissolution testing represents a key product performance test for solid oral dosage forms and is the most likely QC test to result in laboratory investigations because of the relatively complex relationship between the dissolution performance, the drug product properties, and the systems necessary to measure the quality attribute. The Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has pooled our collective knowledge to outline some common ways that dissolution methods can fail. Examples and case studies are given to highlight errors related to equipment, method, materials, measurement, people, and the environment. Best practices for building method understanding and avoiding the exemplified issues are discussed. Case studies highlight the importance of buffer preparation, potential impact of contamination of the dissolution medium, additive-induced degradation, risks in the use of automation, differences between dissolution systems, and the effect of filter selection. Investing in analyst training programs, understanding the capabilities of your equipment portfolio, and using well-designed studies for robustness and ruggedness will reduce dissolution method investigations and improve compliance and productivity during the method lifecycle.

To date, few examples of dissolution models for real-time release testing (RTRT) have been approved for commercial drug products or published in literature. Thus, a structured approach has not been established by which a novice to the field could design, develop, validate, and implement an RTRT dissolution model. Moreover, with scant examples available, there has not been a body of work by which to learn of general regulatory expectations for such models. To address these gaps and to encourage conversation between regulatory and industrial experts on these topics, a virtual (web-based) workshop entitled "Predictive Dissolution Models for Real-Time Release Testing: Development and Implementation" was held November 11-12, 2021. This article summarizes key points from the podium presentations, panel discussions, and breakout sessions focusing on (1) the current best practices to establish predictive model specifications; (2) designing models to predict the "safe space" of a release test and creating models utilizing process analytical technology (PAT); and (3) exploring the strategy of compliant regulatory submissions, including model validation and post-approval lifecycle management. Industrial case studies were presented showcasing attempted approaches to and successful implementations of RTRT of dissolution for drug product manufacturing.

Apex vessels (previously known as PEAK vessels) are an important element of the dissolution scientist’s toolbox and are frequently used in pharmaceutical drug product development settings. However, their use in development has not translated widely into use in the final approved quality control (QC) method. This Stimuli article aims to demonstrate the significant benefit of the apex vessel relative to the standard vessel in overcoming coning for formulations that contain dense insoluble excipients. Industrial case studies outline the benefits obtained by the apex vessel such as improved clinical relevance, more robust and discriminatory methods, and streamlined in vitro bridging strategies. Furthermore, to understand the impact of apex vessels produced by different dissolution bath manufacturers, an interlaboratory study was performed across 11 partners, which demonstrated minimal differences in dissolution performance between partners when a controlled protocol was executed. This was supplemented by a comparison between the different manufacturer designs using a computational fluid dynamic model, which showed no significant differences between manufacturers. This led to a manufacturer proposed specification for an apex vessel alongside a qualification procedure for the use of the vessels. It is the authors’ intent by publishing this article that it will stimulate discussion leading to greater acceptance of the apex vessel such that it will be considered for a more prominent inclusion in future pharmacopeial chapters such as the US Pharmacopeia (USP) chapter The Dissolution Procedure: Development And Validation <1092> and ultimately inclusion into the USP chapter Dissolution <711> and other harmonized pharmacopoeia as an alternative vessel to the standard 1-L vessel to be used when scientifically justified. dx.doi.org/10.14227/DT280421P6 Reprinted with permission. © 2021 The United States Pharmacopeial Convention. All rights reserved. Correspondence should be addressed to: Margareth R. C. Marques, Senior Principal Scientist, ScienceGeneral Chapters, US Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790; email: mrm@usp.org.

Apex vessels (previously known as PEAK vessels) are an important element of the dissolution scientist's toolbox and are frequently used in pharmaceutical drug product development settings. However, their use in development has not translated widely into use in the final approved quality control (QC) method. This Stimuli article aims to demonstrate the significant benefit of the apex vessel relative to the standard vessel in overcoming coning for formulations that contain dense insoluble excipients. Industrial case studies outline the benefits obtained by the apex vessel such as improved clinical relevance, more robust and discriminatory methods, and streamlined in vitro bridging strategies. Furthermore, to understand the impact of apex vessels produced by different dissolution bath manufacturers, an interlaboratory study was performed across 11 partners, which demonstrated minimal differences in dissolution performance between partners when a controlled protocol was executed. This was supplemented by a comparison between the different manufacturer designs using a computational fluid dynamic model, which showed no significant differences between manufacturers. This led to a manufacturer proposed specification for an apex vessel alongside a qualification procedure for the use of the vessels. It is the authors' intent by publishing this article that it will stimulate discussion leading to greater acceptance of the apex vessel such that it will be considered for a more prominent inclusion in future pharmacopeial chapters such as the US Pharmacopeia (USP) chapter The Dissolution Procedure: Development And Validation <1092> and ultimately inclusion into the USP chapter Dissolution <711> and other harmonized pharmacopoeia as an alternative vessel to the standard 1-L vessel to be used when scientifically justified.

The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product.

L-pidolic acid is being used as a coformer for ertugliflozin, a sodium-glucose cotransport 2 inhibitor. A sensitive and rapid two-step achiral derivatization combined with gas chromatography with flame ionization detection or gas chromatography with mass spectroscopic detection was developed and validated for the enantiomeric purity determination of L-pidolic acid in the drug substance and drug product, respectively. The method was used to analyze ertugliflozin drug substance forced degradation samples and showed no racemization of pidolic acid in any of the solid or solution stress samples. Analysis of ertugliflozin drug product stability samples showed no significant levels of D-pidolic acid in the drug product indicating that no significant racemization of pidolic acid occurs in the drug product under normal storage conditions. Based on the data generated, a chiral control for pidolic acid is not necessary for drug substance or drug product, but rather can be controlled in the purchase of L-pidolic acid.

Drug product assay is one of several tests required for new drug products to ensure the quality of the product at release and throughout the life cycle of the product. Drug product assay testing is typically performed by preparing a composite sample of multiple dosage units to obtain an assay value representative of the batch. In some cases replicate composite samples may be prepared and the reportable assay value is the average value of all the replicates. In previously published work by Harrington et al. (2014) [5], a sample preparation composite and replicate strategy for assay was developed to provide a systematic approach which accounts for variability due to the analytical method and dosage form with a standard error of the potency assay criteria based on compendia and regulatory requirements. In this work, this sample preparation composite and replicate strategy for assay is applied to several case studies to demonstrate the utility of this approach and its application at various stages of pharmaceutical drug product development.

Media: 0.1M HCl Filter: nitrocellulose filter (Millipore, typeAA, 0.8 μm)Flow rate: 5 mL/min Temperature: 37± 0.5◦C UV: 380 nm→ The method used a flow-through dissolution cell anda dissolution medium thecomposition of which wasoptimized for both its capacity todissolve the gelatin capsule wallcompletely and to givehomogeneous filtrates of drugand oily excipient for convenientanalysis of the collectedfractions.

In pharmaceutical analysis, the results of drug product assay testing are used to make decisions regarding the quality, efficacy, and stability of the drug product. In order to make sound risk-based decisions concerning drug product potency, an understanding of the uncertainty of the reportable assay value is required. Utilizing the most restrictive criteria in current regulatory documentation, a maximum variability attributed to method repeatability is defined for a drug product potency assay. A sampling strategy that reduces the repeatability component of the assay variability below this predefined maximum is demonstrated. The sampling strategy consists of determining the number of dosage units (k) to be prepared in a composite sample of which there may be a number of equivalent replicate (r) sample preparations. The variability, as measured by the standard error (SE), of a potency assay consists of several sources such as sample preparation and dosage unit variability. A sampling scheme that increases the number of sample preparations (r) and/or number of dosage units (k) per sample preparation will reduce the assay variability and thus decrease the uncertainty around decisions made concerning the potency of the drug product. A maximum allowable repeatability component of the standard error (SE) for the potency assay is derived using material in current regulatory documents. A table of solutions for the number of dosage units per sample preparation (r) and number of replicate sample preparations (k) is presented for any ratio of sample preparation and dosage unit variability.

A multiplexed capillary electrophoresis (CE) system equipped with 96 channels was evaluated for high-throughput screening in drug discovery by microemulsion electrokinetic chromatography (MEEKC). Method transfer from a single channel to a multichannel CE system is described. Loss of efficiency and reduced migration times could be elucidated to the poor efficacy in Joule heat dissipation by forced air cooling in the multiarray system compared to liquid cooling in the single channel instrument. On the other hand, only 48 channels could actually be used because of the maximum total current of 3 mA. Precision data remained below 8% and 9% for migration times and peak areas, respectively. Some UV-detector cross-talk interference between neighboring capillary channels was noted. Impurities at 0.5% compared to the main peak (100%) could be detected with the multiplexed system which is 10 times lower compared to the single capillary system. Higher efficiency and improved figures of merit (absolute sensitivity and no cross-talk interferences) were obtained by using an array of only 24 capillaries.

Liquid-liquid extraction and solid-phase extraction are classical sample preparation techniques that have been used with various types of samples. The fundamentals of these two techniques, as well as several microextraction techniques based on the same principles, are described in this chapter. Application of these techniques to the sample preparation of pharmaceutical dosage forms for analysis is also discussed.

This chapter discusses techniques used to facilitate disintegration or dispersion of dosage forms. Shaking, stirring, vortexing, and sonication are common agitation techniques used to facilitate dispersion, mixing, and extraction of drug from various types of dosage forms. In many cases, particle size reduction techniques are used to increase the speed and efficiency of dosage form disintegration or dispersion. These techniques include grinding, milling or blending, homogenization, and sonication. Each of these techniques will be discussed.

Accurate potency and purity data are critical in the development of drug products. These results are used to make decisions regarding formulation development/selection, formulation stability, and process robustness, and are used to release clinical supplies and set clinical use periods. Sometimes aberrant potency values (e.g., assay values, content uniformity results, stratified core test results) are obtained and significant efforts are spent investigating these issues to identify the root cause, which may be manufacturing or method related. This chapter discusses a systematic approach for investigating aberrant potency values from the analytical method perspective. In addition, several case studies are described.

Sample preparation is the most time-consuming part of the analytical method for powder for oral suspension (POS) assay, purity, and preservative analysis, as this involves multiple dilution and filtration steps. The Tablet Processing Workstation (TPW) was used to automate the sample preparation of a POS formulation. Although the TPW is typically used to automate the preparation of solid oral dosage forms and powders, it contains all of the necessary components to perform POS sample preparation. The TPW exhibited acceptable repeatability in testing 3 lots using 10 replicate preparations per lot. Acceptable linearity of the drug and preservative in the presence of excipients was demonstrated over the range corresponding to 50-150% of intent. Accuracy showed suitable recoveries for all points evaluated. TPW results were shown to correlate to results obtained with the manual method. The TPW method was used to prepare samples in support of manufacturing scale-up efforts. With the efficiencies gained using the TPW, it was possible to analyze a large number of samples generated during process development activities for the POS formulation with minimal human intervention. The extensive data enabled trending of the manufacturing development runs and helped to identify optimization strategies for the process. (JALA 2011;16:229-34)

Sample preparation methods must be rugged and robust to ensure accurate results. Pharmaceutical development teams rely on these results to make critical decisions about formulations, manufacturing process conditions, and packaging. Once decisions are made, the manufacturing conditions and associated analytical methods are transferred to clinical and commercial manufacturing facilities where they will be used over the course of many years. At this stage, ensuring extraction robustness becomes increasingly important with the potential to impact patient safety, product efficacy, and business efficiency. This chapter describes a Quality by Design approach that can increase the probability that sample preparation conditions remain rugged, robust, and suitable for use throughout a product lifecycle.