Dissolution Profile Similarity Assessment-Best Practices, Decision Trees and Global Harmonization.

During the write-up of the meeting summary reports from the 2019 dissolution similarity workshop held at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), several coauthors continued their discussions to develop a "best-practice" document defining the steps required to assess dissolution profiles in support of certain biowaivers and postapproval changes. In previous reports, current challenges related to dissolution profile studies were discussed such that the steps outlined in the two flow charts ("decision trees") presented here can be applied. These decision trees include both recommendations for the use of equivalence procedures between reference and test products as well as application of the dissolution safe space concept. Common approaches towards establishing dissolution safe spaces are described. This paper encourages the preparation of protocols clearly describing why and how testing is performed along with the expected pass/fail criteria prior to generating data on the materials to be evaluated. The target audience of this manuscript includes CMC regulatory scientists, laboratory analysts, as well as statisticians from industry and regulatory health agencies involved in the assessment of product quality via in vitro dissolution testing. Building upon previous publications, this manuscript provides a solution to the current ambiguity related to dissolution profile comparison. The principles outlined in this and previous manuscripts provide a basis for global regulatory alignment in the application of dissolution profile assessment to support manufacturing changes and biowaiver requests.

DISSOLUTION PROFILE SIMILARITY ANALYSES-STATISTICAL PRINCIPLES, METHODS AND CONSIDERATIONS.

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance with the emphasis given to the similarity factor f2 with little discussion of alternative methods. In an effort to highlight current practices to assess dissolution profile similarity and to strive toward global harmonization, a workshop entitled "In Vitro Dissolution Similarity Assessment in Support of Drug Product Quality: What, How, When" was held on May 21-22, 2019 at the University of Maryland, Baltimore. This manuscript provides in-depth discussion of the mathematical principles of the model-independent statistical methods for dissolution profile similarity analyses presented in the workshop. Deeper understanding of the testing objective and statistical properties of the available statistical methods is essential to identify methods which are appropriate for application in practice. A decision tree is provided to aid in the selection of an appropriate statistical method based on the underlying characteristics of the drug product. Finally, the design of dissolution profile studies is addressed regarding analytical and statistical recommendations to sufficiently power the study. This includes a detailed discussion on evaluation of dissolution profile data for which several batches per reference and/or test product are available.

Analysis of the Regulatory Divergence of Comparative Dissolution Requirements for Post-Approval Manufacturing Changes of Modified Release Solid Oral Dosage Forms.

This manuscript discusses global regulatory divergence of dissolution requirements for modified release solid oral dosage forms and the obstacles that must be addressed to be compliant with evolving guidance and legislation. The proliferation of local guidance documents, changing regulatory expectations, and increased legal enforcement has resulted in mismatched country-specific dissolution testing requirements and similarity criteria, and heightens industry's challenges with registration of modified release solid oral dosage forms. The lack of global harmonization and the complexity added by minor regional adaptations contributes to inefficiencies and hinders industry's goal of developing and delivering medicines. Awareness of country-specific similarity requirements and alignment between industry leaders and regulators is needed to facilitate global harmonization which will enable delivering new and improved medicines. The purpose of this manuscript is to compare and contrast in vitro conditions stated in local regulatory guidelines, raise awareness of the need to work toward harmonization of global requirements, and propose an initial study design toward that aspiration.

Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?

The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globally divergent regulatory requirements to meet local dissolution similarity requirements. In effect, experiments customized to meet the current international regulatory expectations for dissolution and drug release unnecessarily increase manufacturing costs, hinder science and risk-based approaches, increase collective regulatory burden, reduce continuous improvement and innovation, and potentially delay patient access to urgently needed medication. Comparative assessment of regulatory differences in applying dissolution to demonstrate product similarity is crucial to reduce non-scientifically justified experiments and foster collaborative harmonization among global regulatory health authorities and the pharmaceutical industry.

An Assessment of Escherichia coli O157:H7 Contamination Risks in Commercial Mayonnaise from Pasteurized Eggs and Environmental Sources, and Behavior in Low-pH Dressings.

An enterohemorrhaghic Escherichia coli O157:H7 (EHEC) outbreak in 1993 was epidemioiogically linked to commercial real mayonnaise. This study evaluated EHEC contamination risk during commercial mayonnaise and mayonnaise dressing production, and EHEC behavior in low-pH dressings. Two potential contamination sources, pasteurized liquid eggs and wet environmental areas, were surveyed for 4 months in three processing plants. One hundred eighty-eight egg lots and 114 environmental swabs were collected and analyzed for EHEC by enrichment and direct plating methods. All plant samples were EHEC negative. Commercial mayonnaise plants which use pasteurized eggs and employ effective good manufacturing practices (GMP) sanitation programs are unlikely EHEC harborage and contamination sources. Five commercial real-mayonnaise-based and reduced-calorie and/or fat mayonnaise dressings were inoculated with ≥6 log10 colony-forming units (CFU)/g EHEC contamination levels and stored at 25°C. The products contained a wide range of acetic acid, NaCl, and preservative levels, while pH varied from 3.21 to 3.94. Products below pH 3.6 rapidly inactivated EHEC, producing ≥7 log10 CFU/g decreases in ≤1 to ≤3 days. High EHEC lethality was also observed in the pH 3.94, egg white-mayonnaise dressing. Intact packages of commercial mayonnaise and mayonnaise dressings pose negligible EHEC contamination and health hazard risks. As with any food, consumers and food-service workers must use stringent hygienic practices to prevent microbial pathogen contamination during preparation, handling, and storage of mayonnaise-ingredient recipes such as chilled perishable salads and salad bar dressings.