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Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls

This workshop is a collaboration between FDA's Division of Biopharmaceutics, Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER), CDER Small Business and Industry Assistance (SBIA), the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI).

AgendaSpeaker Bios
FDA's White Oak Campus

Physiologically based biopharmaceutics modeling (PBBM) can facilitate the incorporation of clinical relevance in product quality from initial development through marketing approval to lifecycle management, thereby minimizing the need of additional in vivo BE studies, leading to reducing cost in product development and supporting regulatory decisions. The purpose of this workshop is to identify and begin to fill the gaps in knowledge on the use of PBBM for drug product quality (e.g., to study in vivo impact of formulation and manufacturing changes).

The workshop served as a forum for regulators, drug developers, and academicians to:

1) identify biopharmaceutics and modeling strategies (including model development, verification, and validation) to facilitate formulation development and to enhance risk management of bioperformance over the product's life cycle;
2) demonstrate the rewards and challenges of coupling biopredictive dissolution testing with translational PBBM; and
3) identify knowledge gaps, and a path forward to advance the application of PBBM.

 

For speakers who have given permission, the workshop slides and video links are posted below on this webpage (see hyperlinks).

Monday, September 23

In vitro Biopredictive Methods

Moderators: Jennifer Dressman (Goethe University), Xavier Pepin (AstraZeneca) and Poonam Delvadia (FDA)

7:30 - 8:30 a.m.

Welcome & Workshop Objectives
Sandra Suarez
Center for Drug Evaluation and Research (CDER)

8:40 a.m.

The impact and future of physiological based biopharmaceutics modeling (PBBM) in support of drug product quality

Paul Seo (CDER)

9:10 a.m.

Approaches to measure equilibrium (intrinsic) and kinetic solubility, surface pH and the impact on dissolution and membrane transport kenetics
Lynne Taylor
Purdue University

9:40 a.m.

The value of biorelevant media for measuring solubility and in the development of biopredictive dissolution methods
Jennifer Dressman
Goethe University


 
Break

 


 

10:25 a.m.

Measurement and prediction of human permeability: current best practices, regional differences and future developments
Erik Sjögren
Pharmatheus

10:55 a.m.

Biopredictive dissolution methods with a view to integration in PBPK; Challenges for low solubility IR drug products
James Butler
GlaxoSmithKlein

11:25 a.m.

 In vitro approaches to understanding supersaturation and precipitation of weak bases and enabling formulations
Ed Kostewicz
Goethe University

 

Lunch

 

12:45 p.m.

The importance of fluid volume kinetics in the development of biopredictive dissolution methods
Mirko Koziolek
University of Greifswald

1:15 p.m.

Introduction and expectations for breakout sessions
Xavier Pepin
AstraZeneca

1:30 p.m.

Break
Transition to breakout sessions
 

 

1:45 p.m.
Breakout Session A

Best strategies for determining solubility, supersaturation and critical supersaturation

Moderators: Vidula Kolhatkar (CDER), James Butler (GSK)
Scribes:
Jennifer Dressman, Goethe University
Lynne Taylor, Purdue University

1:45 p.m.
Breakout Session B

Best strategies for the development of biopredictive (clinically relevant) dissolution methods, a key element for successful modeling and simulation

Moderators: Bertil Abrahamsson (AstraZeneca), Poonam Delvadia (CDER)

Scribes:
Ed Kostewicz, Goethe University 
Filippos Kesisoglou, Merck & Co., Inc.

1:45 p.m.
Breakout Session C

Gastrointestinal systems parameters (mucus, volume, motility): Where are the pitfalls and how can we overcome them?

Moderators: Mirko Koziolek (University of Greifswald), Xavier Pepin (AstraZeneca)
Scribes:
Andre Dallmann, Bayer AG
Yang Zhao, CDER

1:45 p.m.
Breakout Session D

Permeability along the gastrointestinal tract. Translation from biopharmaceutical measurement to a model parameter?

Moderators: Xinyuan Zhang (CDER), Neil Parrott (Roche)

Scribes:

Andrew Babiskin, CDER
Erik Sjögren, Pharmatheus
3:45 p.m.

 
Break
Moderators and scribes to convene


 

4:30 p.m.

Summary of breakout discussions

Lead Moderators

5:15 p.m.

 Discussion

 

6:00 p.m.

Adjourn

 

Tuesday, September 24

Best Practices for Model Development, Verification, and Validation

Moderators: Neil Parrott (Roche) and Sandra Suarez (CDER)

8:30 a.m.

Welcome & Logistics
Sandra Suarez
Center for Drug Evaluation and Research (CDER)

8:35 a.m.

Opportunities and challenges for modeling the clinical impact (i.e. systemic exposure) of formulation and manufacturing changes
David Good
Bristol-Myers Squibb

9:05 a.m.

Best practices in model development: input of solubility, supersaturation, precipitation and permeability

 Christian Wagner
Merck Healthcare KGaA

9:35 a.m.

Best practices for model building: parameter optimization, sensitivity analysis and how to assess the match to clinical data
André Dallmann
Bayer AG


 
Break

 


 

10:20 a.m.

Translating the effect of product manufacturing variants from in vitro to the clinic; Current possibilities and gaps for immediate release formulations
James Mullin
Simulations Plus

10:50 a.m.

Translating the effect of product manufacturing variants from in vitro to the clinic. Current possibilities and gaps for extended release formulations

 Nikunjkumar Patel
Certara

11:20 a.m.

 Approaches for entering dissolution into the absorption model, reasons for selection, model assumptions, and parameter estimation strategies
Filippos Kesisoglou
Merck & Co., Inc.

 

Lunch

 

12:35 p.m.

Considerations for the verification and validation of models
Arian Emami Riedmaier
AbbVie

1:05 p.m.

Impact of population variability (intra and inter) and sample size for model validation and data needed to justify application of virtual bioequivalence

 Amitava Mitra
Sandoz

1:35 p.m.

Introduction & Expectations for Breakout Sessions
Neil Parrott
Roche

1:50 p.m.
Break
Transition to breakout sessions
  

2:05 p.m.
Breakout Session A

Challenges to predict effects of formulation changes (e.g. particle size distribution changes) on dissolution and in vivo performance using in silico models. Are the tools ready?

Moderators: Sandra Suarez (CDER), Filippos Kesisoglou (Merck & Co., Inc.)

Scribes:
Kimberly Raines, CDER
James Butler, GSK

2:05 p.m.
Breakout Session B

Strategies to handle parameter uncertainty and variability within and between subjects

Moderators: Maziar Kakhi (CDER), Neil Parrott (Roche)
Scribes:
David Good, BMS
Nikunjkumar Patel, Certara

2:05 p.m.
Breakout Session C

Best practices for model development, verification and validation, and criteria for defining prediction success.

Moderators: Min Li (CDER), Xavier Pepin (AstraZeneca)

Scribes:
Arian Emami Riedmaier, AbbVie
James Mullin, Simulations Plus

2:05 p.m.
 
Approaches to establish sameness following manufacturing/formulation changes: Advantages and disadvantages of virtual bioequivalence
 
Moderators: Eleftheria Tsakalozou (CDER), Amitava Mitra (Sandoz)

Scribes:
Yang Zhao, CDER
Christian Wagner, Merck Healthcare KGaA

 

4:05 p.m.

Break
Moderators and scribes to convene

 

4:45 p.m.

 Summary of breakout sessions

Lead Moderators

5:30 p.m.

Discussion

6:15 p.m.

Adjourn

  

 

Wednesday, September 25

Applications to PBBM to support Drug Product Quality

Moderators: Amitava Mitra (Sandoz) and Andrew Babiskin (CDER)

8:30 a.m.

Welcome & Logistics
Andrew Babiskin
Center for Drug Evaluation and Research (CDER)

8:35 a.m.

FDA expectations in building a safe space to gain regulatory flexibility based on PBBM
Yang Zhao
CDER
Sandra Suarez
CDER

9:05 a.m.

European Medicines Agency expectations in building a safe space to gain regulatory flexibility based on PBBM

 Evangelos Kotzagiorgis
European Medicines Agency (EMA)

9:35 a.m.

Case Study: Application of PBBM in risk assessment of effect of acid reducing agents (ARA) on pharmacokinetics and formulation development
Neil Parrott
Roche


 
Break

 


 

10:20 a.m.

Prediction of human pharmacokinetics utilizing in vitro chewing method and physiologically based pharmacokinetic (PBPK)
Satish Sharan
CDER

10:50 a.m.

Case Study: Bridging physiology-based dissolution testing to quality control testing using PBBM

 Christophe Tistaert
Janssen

11:20 a.m.

 The use of PBBM and biomarkers to provide detailed understanding of in vivo dissolution and absorption for Acalabrutinib Xavier Pepin
AstraZeneca

 

Lunch

 

12:40 p.m.

Case Studies: Physiologically Based Biopharmaceutics Modeling For Food Effects – Possibilities and Opportunities
Tyco Heimbach
Novartis

1:10 p.m.

Introduction and expectation for breakout sessions

 Amitava Mitra
Sandoz

1:25 p.m.
Break
Transition to breakout sessions
  

1:40 p.m.

Breakout Session A

Discussion of several terminologies related to physiologically based pharmacokinetics modeling in support of drug product quality (e.g., physiologically based biopharmaceutics modeling)

Moderators: Banu Zolnik (CDER), Erik Sjögren (Pharmatheus)

 Scribes:
Fang Wu, CDER
Tycho Heimbach, Novartis

1:40 p.m.
 
Risk-based approach in the development and implementation of PBBM modeling to support drug and product quality and clinically relevant specifications setting
 
Moderators: Om Anand (CDER), Shefali Kakar (Novartis)

Scribes:
Min Li, CDER
Xavier Pepin, AstraZeneca

1:40 p.m.
Breakout Session C

The road towards harmonization among regulatory agencies on evidentiary standards for PBBM

Moderators: Shereeni Veerasingham (Health Canada), Shinichi Kijima (Pharmaceuticals and Medical Devices Agency (PMDA)),  Baoming Ning (National Institutes for Food and Drug Control (NIFDC)), Gustavo Mendes Lima Santos (Anvisa), Kimberly Raines (CDER)
Scribes:
Greg Rullo, AstraZeneca
Haritha Mandula, CDER

1:40 p.m.
Breakout Session D

Strategies for bridging biorelevant and quality control dissolution via PBBM

Moderators: Sandra Suarez (CDER), Christophe Tistaert (Janssen)

Scribes:
Poonam Delvadia, CDER
Jennifer Dressman, Goethe University
Paul Dickinson, SEDA

4:30 p.m.
 

 Summary of breakout sessions
 

Lead Moderators

5:15 p.m.

Conclusions & Next Steps

 

5:30 p.m.

 Discussion

 

6:00 p.m.

Adjourn

  

 

Continuing Education

  • This event is RAPS (Regulatory Affairs Professional Society) eligible for credit towards a participant's RAC (Regulatory Affairs Certification) recertification.
  • SOCRA (The Society of Clinical Research Associates) accepts documentation of candidate participation in continuing education programs for re-certification if the program is applicable to clinical research regulations, operations or management, or to the candidate's clinical research therapeutic area.
  • This event is SQA (Society of Quality Assurance) approved for 0.25 non-GCP or non-GLP units per 1 hour towards RQAP re-registration
  • ACRP (Association of Clinical Research Professionals) provides continuing medical education for the completion of this educational activity. Contact hours are provided at 1 unit for at least 45 minutes of qualified material.
  • Attendance certificates are only available during the two weeks after the event. Attendance is required.

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