The Center for Research on Complex Generics (CRCG) hosted the online event, "In Vitro Release Test (IVRT) and In Vitro Permeation Test (IVPT) Methods: Best Practices and Scientific Considerations for ANDA Submissions," on Aug. 18-20, 2021.
About the Event:
The U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a free virtual public workshop on August 18-20, 2021, titled "In Vitro Release Test (IVRT) and In Vitro Permeation Test (IVPT) Methods: Best Practices and Scientific Considerations for ANDA Submissions.".
IVRT and IVPT are important methods used by the generic drug industry and in other contexts to support demonstrations of bioequivalence for generic topical drug products, evaluations of the heat effects and product quality for generic transdermal delivery systems (also known as patches), assessments of the bioavailability of ingredients in sunscreen products, and characterization of other biopharmaceutical aspects of topical and transdermal generic drug products.
The purpose of this workshop was to discuss the scientific principles and practical considerations that inform current FDA thinking and USP recommendations for IVRT and IVPT studies, explore challenging issues that would benefit from broader discussion, identify areas that would benefit from further research, and discuss opportunities for coordination and collaboration between the FDA, USP, academic institutions, product manufacturers, diffusion cell equipment manufacturers, contract research organizations, consultants, and other stakeholders.
FDA and the CRCG — which is a collaboration between the University of Maryland School of Pharmacy and the University of Michigan College of Pharmacy — are dedicated to advancing programs that stimulate scientific dialogue, disseminate current insights about complex generics, and generate new knowledge in support of FDA’s mission to promote and protect the public health by increasing access to safe and effective generic medicines.
Workshop Topics and Agenda:
Topics that were covered during the workshop are outlined below. Attendees are also welcome to download the complete workshop agenda here.
- IVRT study designs in different contexts including supporting a demonstration of bioequivalence for topical generics, scale-up and post-approval changes, and different dosage forms
- IVPT study designs in different contexts including supporting a demonstration of bioequivalence for topical generics, heat effects for topical or transdermal delivery systems, and bioavailability for sunscreen products
- Challenges with aberrant data, outliers, inclusion/exclusion criteria, and statistical analysis of IVPT data
- Theoretical principles and practical challenges with IVRT and IVPT method development, validation, and transfer
- Operational principles and practical challenges for IVRT and IVPT diffusion cell apparatus
- Submission of IVRT and IVPT information in ANDAs, including reportable information, format of data/results, organization of information, and common deficiencies
- Quality management systems, retention samples, laboratory qualification, documentation, and inspections for IVRT and IVPT studies submitted in ANDAs
Download speaker biographies to learn more about the experts who delivered presentations during the workshop.
Workshop Recordings:
August 18, 2021
IVRT/IVPT Conference: Day 1 Introduction
IVRT/IVPT Conference: Day 1, Dr. Howard Maibach Presentation
IVRT/IVPT Conference: Day 1, Dr. Sam Raney Presentation
IVRT/IVPT Conference: Day 1, Dr. Yang Yang Presentation
IVRT/IVPT Conference: Day 1, Dr. E. Dennis Bashaw Presentation
IVRT/IVPT Conference: Day 1, Dr. Audra Stinchcomb Presentation
IVRT/IVPT Conference: Day 1, Leandro Santos Presentation
IVRT/IVPT Conference: Day 1, Paul Lehman Presentation
IVRT/IVPT Conference: Day 1, Elena Rantou Presentation
Day 1, Panel Session 1
IVRT/IVPT Conference: Day 1, Panel 1: IVPT Role in BE
IVRT/IVPT Conference: Day 1, Panel 1: Why Measure Receptor Solution, Not Skin
IVRT/IVPT Conference: Day 1, Panel 1: Barrier Integrity Test Selection
IVRT/IVPT Conference: Day 1, Panel 1: Handle Skin Storage
IVRT/IVPT Conference: Day 1, Panel 1: Enhance Receptor Solution Solubility
IVRT/IVPT Conference: Day 1, Panel 1: Skin Handling Prior to Study
IVRT/IVPT Conference: Day 1, Panel 1: Potential Alcohol Use in Receptor Solution
Day 1, Panel Session 2
IVRT/IVPT Conference: Day 1, Panel 2: IVPT Apparatus Considerations
IVRT/IVPT Conference: Day 1, Panel 2: Skin Selection, Preparation and Storage
IVRT/IVPT Conference: Day 1, Panel 2: Skin Barrier Integrity Testing
IVRT/IVPT Conference: Day 1, Panel 2: Receptor Solution Selection
IVRT/IVPT Conference: Day 1, Panel 2: Receptor Solution Sampling Qualification
IVRT/IVPT Conference: Day 1, Panel 2: IVPT Parameter Optimization
IVRT/IVPT Conference: Day 1, Panel 2: Jmax
IVRT/IVPT Conference: Day 1, Panel 2: IVPT Sensitivity
IVRT/IVPT Conference: Day 1, Panel 2: IVPT Selectivity-Pilot Studies
Day 1, Panel Session 3
IVRT/IVPT Conference: Day 1, Panel 3: IVPT Data Analysis Challenges (IVPT Study Results)
IVRT/IVPT Conference: Day 1, Panel 3: IVPT Data Challenges (IVPT Sensitivity and Selectivity Studies)
IVRT/IVPT Conference: Day 1, Panel 3: IVPT Data Challenges (IVPT Pivotal Study)
IVRT/IVPT Conference: Day 1, Panel 3: IVPT Data Analysis Challenges
IVRT/IVPT Conference: Day 1, Panel 3: Statistical Analysis Challenges
IVRT/IVPT Conference: Day 1, Panel 3: Acknowledgements
August 19, 2021
IVRT/IVPT Conference: Day 2 Introduction
IVRT/IVPT Conference: Day 2, Dr. Vinod Shah Presentation
IVRT/IVPT Conference: Day 2, Dr. Sam Raney Presentation
IVRT/IVPT Conference: Day 2, Dr. Margareth Marques Presentation
IVRT/IVPT Conference: Day 2, Dr. Leandro Santos Presentation
IVRT/IVPT Conference: Day 2, Dr. Theo Kapanadze Presentation
IVRT/IVPT Conference: Day 2, Dr. Cristina Yen Presentation
IVRT/IVPT Conference: Day 2, Dr. Kailas Thakker Presentation
Day 2, Panel Session 1
IVRT/IVPT Conference: Day 2, Panel 1: IVRT Validation (Sensitivity and Alternate Strength)
IVRT/IVPT Conference: Day 2, Panel 1: Apparatus Qualification
IVRT/IVPT Conference: Day 2, Panel 1: Membrane Selection
IVRT/IVPT Conference: Day 2, Panel 1: IVRT Infinite Dose
IVRT/IVPT Conference: Day 2, Panel 1: IVRT Duration and Sampling Time Points
IVRT/IVPT Conference: Day 2, Panel 1: Organic Solvent-Surfactant Use in Receptor Solution
IVRT/IVPT Conference: Day 2, Panel 1: Dose Loading in Different Apparatus for IVRT
IVRT/IVPT Conference: Day 2, Panel 1: Receptor Solution Drug Concentration
IVRT/IVPT Conference: Day 2, Panel 1: IVRT Quality Control Tool
IVRT/IVPT Conference: Day 2, Panel 1: IVRT Utility for New Topical Products
IVRT/IVPT Conference: Day 2, Panel 1: IVRT Blinding
Day 2, Panel Session 2
IVRT/IVPT Conference: Day 2, Panel 2: Apparatus Selection
IVRT/IVPT Conference: Day 2, Panel 2: Apparatus Qualification
IVRT/IVPT Conference: Day 2, Panel 2: Receptor Solution
IVRT/IVPT Conference: Day 2, Panel 2: Membrane
IVRT/IVPT Conference: Day 2, Panel 2: IVRT Design Duration and Linearity
IVRT/IVPT Conference: Day 2, Panel 2: IVRT Design Dosing
IVRT/IVPT Conference: Day 2, Panel 2: IVRT Design Sampling
IVRT/IVPT Conference: Day 2, Panel 2: IVRT Methodology
IVRT/IVPT Conference: Day 2, Panel 2: IVRT Validation
IVRT/IVPT Conference: Day 2, Panel 2: IVRT Sample Analysis
IVRT/IVPT Conference: Day 2, Panel 2: Acknowledgements
August 20, 2021
IVRT/IVPT Conference: Day 3 Welcome and Opening Remarks
IVRT/IVPT Conference: Day 3, Ahmed Zidan Presentation
IVRT/IVPT Conference: Day 3, Ashvin Patel Presentation
IVRT/IVPT Conference: Day 3, Jon Lenn Presentation
IVRT/IVPT Conference: Day 3, Luke Lee Presentation
IVRT/IVPT Conference: Day 3, Tian Ma Presentation
IVRT/IVPT Conference: Day 3, Archana Manerikar Presentation
IVRT/IVPT Conference: Day 3, Sam Haidar Presentation
IVRT/IVPT Conference: Day 3, Kendall Powell Presentation
Day 3, Panel Session 1
IVRT/IVPT Conference: Day 3, Panel 1: Immersion vs. Vertical Diffusion Cells (Advantages-Limitations)
IVRT/IVPT Conference: Day 3, Panel 1: Common Mistakes with Vertical and Flow-Through Cells
IVRT/IVPT Conference: Day 3, Panel 1: Membrane or Skin Equilibration
IVRT/IVPT Conference: Day 3, Panel 1: Monitoring Measuring Temperature
IVRT/IVPT Conference: Day 3, Panel 1: Robustness Parameter Failure
IVRT/IVPT Conference: Day 3, Panel 1: Release or Permeation Profile Differences Using Apparatuses
IVRT/IVPT Conference: Day 3, Panel 1: USP-1724 Updates, Design, and Apparatus Features
IVRT/IVPT Conference: Day 3, Panel 1: IVPT Considerations for Topical Foam
IVRT/IVPT Conference: Day 3, Panel 1: Final Remarks
Day 3, Panel Session 2
IVRT/IVPT Conference: Day 3, Panel 2: Panel Introduction
IVRT/IVPT Conference: Day 3, Panel 2: IVRT Dosing Amount, Stirring Rate, USP Apparatus, Dose Application
IVRT/IVPT Conference: Day 3, Panel 2: Membrane and Receptor Temperature
IVRT/IVPT Conference: Day 3, Panel 2: BE Summary Table
IVRT/IVPT Conference: Day 3, Panel 2: Supporting Data
IVRT/IVPT Conference: Day 3, Panel 2: IVPT Study
IVRT/IVPT Conference: Day 3, Panel 2: IVPT API Stability
IVRT/IVPT Conference: Day 3, Panel 2: Skin Preparation
IVRT/IVPT Conference: Day 3, Panel 2: Raw Data Submission
IVRT/IVPT Conference: Day 3, Panel 2: IVPT Robustness Data
IVRT/IVPT Conference: Day 3, Panel 2: IVPT Summary Table
IVRT/IVPT Conference: Day 3, Panel 2: IVPT Dose Depletion
IVRT/IVPT Conference: Day 3, Panel 2: IVPT Method Validation and Justification
IVRT/IVPT Conference: Day 3, Panel 2: Heat-Separated Epidermis
IVRT/IVPT Conference: Day 3, Panel 2: Final Remarks
Day 3, Panel Session 3
IVRT/IVPT Conference: Day 3, Panel 3: GLP Regulations Applicability to BE Studies
IVRT/IVPT Conference: Day 3, Panel 3: Method Revalidation Due to Minor Changes
IVRT/IVPT Conference: Day 3, Panel 3: Reserving Samples for Validation and Pivotal Studies
IVRT/IVPT Conference: Day 3, Panel 3: GLP Regulations Applicability for BE Studies
IVRT/IVPT Conference: Day 3, Panel 3: Reserving Product Samples with Multi-Dose Containers
IVRT/IVPT Conference: Day 3, Panel 3: Lab Accreditation
IVRT/IVPT Conference: Day 3, Panel 3: Batches for IVRT and IVPT Studies
IVRT/IVPT Conference: Day 3, Panel 3: DRL Response Timeline
IVRT/IVPT Conference: Day 3, Panel 3: GLP Regulations Applicability for BE Studies 2
IVRT/IVPT Conference: Day 3, Panel 3: Informing Industry of QMS Expectations
IVRT/IVPT Conference: Day 3, Panel 3: Guidance Availability and Industry Collaboration
IVRT/IVPT Conference: Day 3, Panel 3: Current Status and Future Outlook of QMS Establishment
IVRT/IVPT Conference: Day 3, Panel 3: IVRT-IVPT Studies' Parameter Focus
IVRT/IVPT Conference: Day 3, Panel 3: Possibility for CRO to Rely on Previous Work for Products/Clients
IVRT/IVPT Conference: Day 3, Panel 3: Master Schedule Need for Analytical and BE Testing
IVRT/IVPT Conference: Day 3, Panel 3: FDA's Activities at Virtual Inspections
IVRT/IVPT Conference: Day 3, Panel 3: Specifying IVRT-IVPT Site Details in Form 365h
IVRT/IVPT Conference: Day 3, Panel 3: Possibility for CRO to Rely on Previous Work for Products/Clients 2
IVRT/IVPT Conference: Day 3, Panel 3: Informing FDA of CRO Location Change Closing
IVRT/IVPT Conference: Day 3, Panel 3: Specifying IVRT/IVPT Site Details in Form 365h
IVRT/IVPT Conference: Day 3, Panel 3: Statistical Criteria for IVPT Sensitivity and Selectivity Studies
IVRT/IVPT Conference: Day 3, Panel 3: Tightening of IVRT Statistical Criteria
IVRT/IVPT Conference: Day 3: Workshop Summation
IVRT/IVPT Conference: Day 3: Closing Remarks
Workshop Slides:
August 18, 2021
Keynote Address
The In Vitro Permeation Test (IVPT): Historical Perspective, Current Context, and Future Directions
Howard Maibach, MD Professor of Dermatology, University of California, San Francisco
Foundation Lecture
IVPT Fundamentals: Scientific and Practical Considerations
Sam Raney, PhD, Associate Director for Science, ORS, OGD, FDA
Scientific and Regulatory Uses of IVPT Studies
IVPT Studies with Sunscreen Products: Experimental Parameters
Yang Yang, PhD, Staff Fellow, DPQR, OTR, OPQ, FDA
IVPT Studies with Sunscreen Products: Potential Regulatory Utility
Dennis Bashaw, PharmD Senior Science Advisor, OCP, OTS, FDA (retired)
IVPT Studies with Topical and Transdermal Products
Audra Stinchcomb, PhD, Professor of Pharmaceutical Sciences, University of Maryland, Baltimore
IVPT Method Development, Validation, and Transfer
IVPT Studies During Topical Product Development
Leandro Santos, PhD, Associate Director for Clinical Research, Incyte
Panel Discussion
In-vitro Permeation Test (IVPT) Method Development, Validation, and Transfer
Hiren H. Patel, Ph.D. Staff Fellow, Division of Bioequivalence II Office of Bioequivalence, Office of Generic Drugs
IVPT Data Challenges and Statistical Analysis
IVPT Data Challenges in the Real World
Paul Lehman, MS, Vice President and Head of Dermal and Transdermal Research, QPS, LLC
IVPT Data Analysis and Statistics
Elena Rantou, PhD, Lead Mathematical Statistician, DB-VII, OB, OTS, FDA
Panel Discussion
IVPT Data Challenges and Statistical Analysis
Priyanka Ghosh, Ph.D. Acting Team Lead/ Co-chair of the Bioequivalence Standards for Topicals Committee Office of Research and Standards (ORS), Office of Generic Drugs (OGD)
August 19, 2021
Keynote Address
The In Vitro Release Test (IVRT): Historical Perspective, Current Context, and Future Directions
Vinod Shah, PhD, Consultant, VPS Consulting, LLC
Foundation Lecture
IVRT Fundamentals: Scientific and Practical Considerations
Sam Raney, PhD, Associate Director for Science, ORS, OGD, FDA
U.S. Pharmacopeia (USP) General Chapters <1724> and <1002>
USP General Chapter Revision Process
Margareth Marques, PhD, Principal Scientific Liaison, USP
USP and Prospective Scope and ContentLeandro Santos, PhD, Associate Director for Clinical Research, Incyte
IVRT Method Development, Validation, and Transfer
Key Aspects in Developing Appropriate IVRT Methods for Topical Generic Products: Advances and Challenges
Theo Kapanadze, PhD, Chief Science Officer, Diteba
IVRT Studies During Topical Product Development: Lifecycle Management for SUPAC-SS and Generics
Cristina Yen, BS, Senior Manager, IVRT, Tergus Pharma
IVRT Studies During Topical Product Development: Challenges in Method Development and Transfer
Kailas Thakker, PhD, President, TopiKail Consulting
Panel Discussion
IVRT Method Development, Validation, and Transfer Theoretical Principles and Practical Challenges
Tannaz Ramezanli, Pharm.D., Ph.D. Pharmacologist, Division of Therapeutic Performance I/Office of Research and Standards
August 20, 2021
Diffusion Cell Apparatus
Diffusion Cell Apparatus: Scientific Principles and Practical Challenges I
Ahmed Zidan, PhD, Senior Staff Fellow, DPQR, OTR, OPQ, FDA
Diffusion Cell Apparatus: Scientific Principles and Practical Challenges II (Slides not available)
Jon Lenn, PhD, Chief Scientific Officer, MedPharm Ltd.
Diffusion Cell Apparatus: Considerations for Design and Use I
Ashvin Patel, PhD, Director, Analytical Research and Business Development, Teledyne
Diffusion Cell Apparatus: Considerations for Design and Use II
Luke Lee, PhD, President, Logan Instruments Corp.
Submission of Information in Abbreviated New Drug Applications (ANDAs)
Expectations for IVRT Data and Information Submitted in ANDAs
Tian Ma, PhD, Staff Fellow, DB-I, OB, OGD, FDA
Expectations for IVPT Data and Information Submitted in ANDAs
Archana Manerikar, MS, PharmD, Pharmacologist, DB-I, OB, OGD, FDA
Quality Management Systems (QMS)
QMS: Study Integrity Considerations
Sam Haidar, PhD, Senior Science Advisor, OSIS, OTS, FDA
QMS: Industry Perspectives
Kendall Powell, PhD, Senior Director of Bioanalytical, MedPharm Ltd.
Audience:
Generic drug industry stakeholders, including scientists/researchers, clinicians, and regulatory affairs professionals who work on or are interested in the development of IVRT and IVPT studies.
For More Information:
If you have any questions about this workshop, please contact complexgenerics@rx.umaryland.edu.