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.

FIP Guidelines for Dissolution Testing of Solid Oral Products.

Dissolution testing is an important physiochemical test for the development of solid oral dosage forms, tablets, and capsules. As a quality control test, the dissolution test is used for assessment of drug product quality and is specified for batch release and regulatory stability studies. In vitro dissolution test results can often be correlated with the biopharmaceutical behavior of a product.This article provides a summary of views from major global agencies (Europe, Japan, United States), pharmacopoeias, academia, and industry. Based on available guidance and literature, this article summarizes highlights for development and validation of a suitable dissolution method, setting appropriate specifications, in vitro-in vivo comparison, and how to obtain a biowaiver.

Biorelevant in vitro performance testing of orally administered dosage forms-workshop report.

Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.

In vivo predictive release methods for medicated chewing gums.

Understanding the performance of a drug product in vivo plays a key role in the development of meaningful in vitro drug release methodology. In case of functional chewing gums, the mode and the mechanism of release and the site of application differ significantly from other conventional solid oral dosage forms and require a special consideration to extract meaningful information from clinical studies. In the current study, suitable drug release methodology was developed to predict the in vivo performance of an investigated chewing gum product. Different parameters of the drug release testing apparatus described in the Ph. Eur. and Pharmeuropa were evaluated. Drug release data indicate that the parameters, chewing distance, chewing frequency and twisting motion, affect the drug release. Higher drug release was observed when the frequency was changed from 40 chews/min to 60 chews/min for apparatus A and B, as was the case for the twisting motion when changed from 20º to 40º for apparatus B. As far as the chewing distance is concerned, the release rate was in the following order; apparatus A: 0.3 mm > 0.5 mm > 0.7 mm; apparatus B: 1.4 mm > 1.6 mm > 1.8 mm. A suitable apparatus set-up for in vitro release testing was identified. The method will be useful for the establishment of in vitro in vivo correlations (IVIVC) for medicated chewing gums. Interchangeability of the apparatus for a product is not generally recommended without prior knowledge of the performance of the product, as the construction and principle of operation for the apparatus differ considerably.

Dissolution testing of orally disintegrating tablets.

For industrially manufactured pharmaceutical dosage forms, product quality tests and performance tests are required to ascertain the quality of the final product. Current compendial requirements specify a disintegration and/or a dissolution test to check the quality of oral solid dosage forms. These requirements led to a number of compendial monographs for individual products and, at times, the results obtained may not be reflective of the dosage form performance. Although a general product performance test is desirable for orally disintegrating tablets (ODTs), the complexity of the release controlling mechanisms and short time-frame of release make such tests difficult to establish. For conventional oral solid dosage forms (COSDFs), disintegration is often considered to be the prerequisite for subsequent dissolution. Hence, disintegration testing is usually insufficient to judge product performance of COSDFs. Given the very fast disintegration of ODTs, the relationship between disintegration and dissolution is worthy of closer scrutiny. This article reviews the current status of dissolution testing of ODTs to establish the product quality standards. Based on experimental results, it appears that it may be feasible to rely on the dissolution test without a need for disintegration studies for selected ODTs on the market.

FIP position paper on qualification of paddle and basket dissolution apparatus.

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federation's (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General. In addition, the SIG reviewed the Food and Drug Administration (FDA) Draft Guidance for Industry, "The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2-Current Good Manufacturing Practice (CGMP)" and the related ASTM Standard E2503-07. Based on this review and several in-depth discussions, the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If additional system performance information is desired, a performance verification test using US Pharmacopeia Reference Standard tablet or an established in-house reference product can be conducted. Any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.