Event

In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality

Tuesday, May 21, 2019
8:30 a.m.-5:30 p.m.
University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore MD 21201
Ann Anonsen
301 405 0285
aanonsen@umd.edu
https://www.pharmacy.umaryland.edu/centers/cersievents/dissolution-similarity/

About the Two-Day Event: May 21-22, 2019

Evaluating rate and extent of in vitro drug release is an integral element of drug product development and often critical in the assessment of consistent in vivo drug product performance. The development of safe space and establishment of clinically relevant dissolution specifications to support drug product life-cycle management ensures consistent in vivo drug product performance compared to the biobatch/pivotal clinical trial formulation.¹ However, dissolution profile comparisons -- often performed under various experimental conditions but without demonstrated clinical relevance -- are still acceptable from a global regulatory perspective to confirm consistent product in vitro performance when certain formulation and manufacturing changes are made, which could negatively impact in vivo performance. For example, the SUPAC-IR² and SUPAC-MR³ FDA guidances for immediate release and modified release oral formulations, provide recommendations to the pharmaceutical industry in terms of the data needed to support formulation and manufacturing changes for scale-up and post product approval. The data needed to support these variations depend on the complexity of the changes, the level of risk and risk mitigation strategies. To support certain changes (e.g., formulation, process scale-up and manufacturing site changes), data such as in vitro dissolution/drug release profile comparisons obtained by performing the testing under the proposed/ approved regulatory [Quality Control (QC)] method or in some cases in multi pH-media and water may be required. Dissolution profiles may be considered similar provided the similarity criterion is met and if the overall dissolution profile is satisfactorily characterized using adequate sample time points. The FDA guidance on Dissolution Testing⁴ describes three statistical methods for the evaluation of similarity, (1) Model Independent Approach Using a Similarity Factor; (2) Model Independent Multivariate Confidence Region Procedure; and (3) Model Dependent Approaches.

Similarity factor (f2) has been widely used to assure product sameness under FDA³, WHO⁵, Japanese⁶, European guidance⁷, and other regulatory agencies. The FDA dissolution guidance specifies that if the within-batch variability of drug release is high (more than 15% CV), the f2 test is not applicable. In this case, multivariate statistical distance (MSD) could be used to compare the dissolution similarity with the assumption that the dissolution data are multivariate normally distributed. The most common methods included in regulatory submissions to test for similarity in dissolution profiles when high variability in the data is observed are f2 bootstrapping and the Mahalanobis Distance Test (MDT). However, it is uncertain whether the same conclusions for regulatory decision-making can be drawn when using either method. In addition, in the published scientific literature, several statistical methods have been explored and compared for their design and performance^{8, 9, 10}. Furthermore, scientists have developed local decision trees, employing a range of statistical methods¹¹. Hence, this workshop will be critical in identifying the most suitable statistical approaches and filling in the knowledge gaps in dissolution similarity evaluation of pharmaceutical products.

Scope of the Workshop:

This workshop is designed to:

1. Clarify the regulatory application of dissolution similarity testing (e.g., when and how it can be used);
2. Review how the standards for dissolution similarity were established and discuss the definition of similarity;
3. Delineate and contrast commonly used approaches to address dissolution similarity and to discuss novel methods;
4. Create a robust statistical path (e.g., decision tree) for dissolution similarity assessment
5. Delineate the value of similarity testing in light of clinically relevant specifications and safe space;
6. Provide an opportunity for direct dialogue between Regulatory, Industry and Academic stakeholders to identify gaps in knowledge and potential paths forward (e.g. research opportunities in dissolution similarity assessment).

Expected Outcome and Deliverables:

• Achieve thorough understanding of:
  • Reliability/predictive ability of most commonly used mathematical approaches to assess similarity of dissolution profiles;
  • Identify best practices for the assessment of similarity in dissolution profiles;
  • The role of similarity testing considering safe space/clinically relevant dissolution specifications;
• Propose a decision tree (s) on how/when to apply certain method(s) to assess for similarity testing.
• Manuscripts that summarize the workshop presentations and breakout session discussions.

For More Information:

More information about this workshop, including registration, an agenda, and information about parking and directions, is available on this website.

If special accommodations at the workshop are needed due to a disability, please email Ann Anonsen ( aanonsen@umd.edu ) at least 7 days in advance of the workshop. Requests for sign language interpretation or Computer Aided Realtime Translation (CART)/captioning should be made 2 weeks in advance of the workshop and should be sent directly to the FDA Interpreting Services Staff email account: interpreting.services@oc.fda.gov.

References:

¹ Sandra Suarez-Sharp, M. Cohen, F. Kesisoglou, et. al. Applications of Clinically Relevant Dissolution Testing. AAPS J. 2018 Apr 9;20(3):60.

² U.S. Department of Health and Human Services - Food and Drug Administration; CDER, Guidance for Industry - Immediate Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation. 1995.

³ U.S. Department of Health and Human Services - Food and Drug Administration; CDER, Guidance for Industry - Extended Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation. 1995.

⁴ U.S. Department of Health and Human Services - Food and Drug Administration, CDER., Guidance for Industry - Dissolution Testing of Immediate Release Solid Oral Dosage Forms. 1997.

⁵ Dekker T. Training workshop on assessment of quality part of Dossier. In World Health Organization Prequalification Programme; 2011; Copenhagen, Denmark.

⁶ Pharmaceuticals and Medical Devices Agency, Japan. Guideline for bioequivalence studies for formulation changes of oral solid dosage forms. English translation of Attachment 3 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau. 2012 February.

⁷ European Medicines Agency. Committee for medicinal products for human use. Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev.1/Corr. 2010.

⁸ Costa P. Modeling and Comparison of Dissolution Profiles. Eur.J. Pharm. Sci. (2001), 13:2, 123-133.

⁹ Diaz, DA et al. Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations? AAPS J. 2016 Jan; 18(1): 15–22.

¹⁰ Moore J, Flanner H. Mathematical comparison of dissolution profiles. Pharm Technol. 1996;20(6):64–74.

¹¹ Yanbing Zheng et al. Rational Statistical Analysis Practice in Dissolution Profile Comparison for Product Quality Assessment of Similarity through Real Case Studies. 2017 AAPS poster session. San Diego, CA.