Abstract
This publication summarizes the proceedings of day 3 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.
Notes
The agenda and power point presentations can be found at the following link: http://pharmacy.umaryland.edu/centers/cersievents/dissolution-and-translational-modeling-strategies/
The terms physiologically based absorption M&S (PBAM) and physiologically based biopharmaceutics (PBBP) M&S are used interchangeable for the purpose of this publication.
Note that for the purpose of this summary and to distinguish from Dr. Abend’s summary, the approaches referred in the past by this author as 1, 2, and 3 have been renamed as A, B, and C1/C2.
References
Abend A, Heimbach T, Cohen M, Kesisoglou F, Pepin X, Suarez-Sharp S. Dissolution ad translational modeling strategies enabling patient-centric drug product development: M-CERSI workshop summary report. AAPS J. 2018;20:60.
Dissolution testing in drug product development: summary of day 1 from the 2017 dissolution and translational modeling workshop at the M-CERSI. In preparation.
Dissolution and translational modeling strategies enabling patient-centric drug product development, M-CERSI Workshop Summary—establishing in vitro in vivo link using PBPK absorption modeling. In preparation.
Kotzagiorgis E, Framework of setting clinically relevant specifications: approach, information needed, and criteria, in dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore.
European Medicines Agency, Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action. (EMA/CHMP/CVMP/QWP/336031/2017). 2017.
European Medicines Agency, Guideline on the Qualification and Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation. (EMA/CHMP/458101/2016). 2016.
Nordmark A, EMA draft Guideline on the Qualification and Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation, in Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development. 2017: Baltimore.
Abend A, Framework for setting clinically relevant dissolution specifications, in Dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore.
Hermans A, Abend AM, Kesisoglou F, Flanagan T, Cohen MJ, Diaz DA, et al. Approaches for establishing clinically relevant dissolution specifications for immediate release solid oral dosage forms. AAPS J. 2017;19(6):1537–49.
Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83.
U.S. Department of Health and Human Services - Food and Drug Administration, CDER, Guidance for industry—waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification, 2017.
European Medicine Agency (EMA), Guideline on the investigation of bioequivalence, 2010.
Suarez-Sharp S. In Case studies: models for establishing clinically relevant drug specifications. Washington, DC: AAPS Annual Meeting and Exposition; 2011.
Suarez-Sharp S. In Establishing clinically relevant drug specifications: FDA perspective. Chicago: AAPS Annual Meeting and Exposition; 2012.
Dickinson PA, Lee WW, Stott PW, Townsend AI, Smart JP, Ghahramani P, et al. Clinical relevance of dissolution testing in quality by design. AAPS J. 2008;10(2):380–90.
Suarez-Sharp S, Li M, Duan J, Shah H, Seo P. Regulatory experience with In vivo-in vitro correlations (IVIVC) in new drug applications. AAPS J. 2016;18(6):1379–90.
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.
Suarez-Sharp S. Paving the road towards setting clinically relevant specifications: biopharmaceutics perspectives on information needed, approach, and criteria, in Dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore.
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.
Suarez-Sharp S. In FDA experience on the application of modeling and simulation in setting clinically relevant drug specifications. Rockville: 3rd PQRI/FDA Conference on Advancing Product Quality; 2017.
Cohen M. The Role of Bio-predictive dissolution methods in the selection of CMAs, CPPS, and verification of design space (s): case studies, in dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore.
U.S. Department of Health and Human Services - Food and Drug Administration, CDER., Guidance for industry—extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. 1997.
U.S. Department of Health and Human Services - Food and Drug Administration, CDER, Guidance for industry—dissolution testing and specification criteria for immediate-release solid oral dosage forms containing biopharmaceutics classification system class 1 and 3 drugs. 2015. Draft Guidance.
Luzon E, Blake K, Cole S, Nordmark A, Versantvoort C, Berglund EG. Physiologically based pharmacokinetic modeling in regulatory decision-making at the European medicines agency. Pharmacol Ther. 2017;102(1):98–105.
Li M, Zhao P, Pan Y, Wagner C. Predictive performance of physiologically based pharmacokinetic models for the effect of food on oral drug absorption: current status. CPT: Pharmacometrics & Systems Pharmacology. 2017;7(2):82–9.
Kesisoglou F. The Utility of on level C IVIVC for setting clinically relevant specifications: case studies and implications, in Dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore.
Kesisoglou F, Rossenu S, Farrell C, van den Heuvel M, Prohn M, Fitzpatrick S, et al. Development of in vitro–in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers. J Pharm Sci. 2014;103(11):3713–23.
Kesisoglou F, Hermans A, Neu C, Yee KL, Palcza J, Miller J. Development of in vitro–in vivo correlation for amorphous solid dispersion immediate-release suvorexant tablets and application to clinically relevant dissolution specifications and in-process controls. J Pharm Sci. 2015;104(9):2913–22.
Davit B. Case study: use of in vivo pharmacokinetic data to develop a CRS for in vitro dissolution testing, in dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore.
Marroum P. Establishing clinically relevant specifications during product life cycle: case studies in dissolution and translational modeling strategies enabling patient-centric product development. 2017: Baltimore, MD.
Marroum P. Clinically relevant dissolution methods and specifications. American Pharmaceutical Reviews. 2012;15(1):36–41.
Acknowledgements
The meeting organizers are indefinitely grateful to Drs. James Polli (University of Maryland, School of Pharmacy, Baltimore, MD) and Tzuchi (Rob) Ju (AbbVie, Inc.) and Ms. Ann Anonsen (UM) for their tremendous efforts in helping in the organization of this workshop.
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Guest Editors: Marilyn N. Martinez, Sandra Suarez, and Andreas Abend
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Suarez-Sharp, S., Cohen, M., Kesisoglou, F. et al. Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report. AAPS J 20, 93 (2018). https://doi.org/10.1208/s12248-018-0252-3
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DOI: https://doi.org/10.1208/s12248-018-0252-3