Pharmaceutical Research

Fang, Lanyan; Tsakalozou, Eleftheria; Polli, James E.

doi: 10.1007/s11095-025-03868-6pmid: 40437346

Fang, Lanyan; Tsakalozou, Eleftheria; Wu, Fang; Ritterbeck, Daniel; Zhao, Liang; Zhang, Lei; Lionberger, Robert

doi: 10.1007/s11095-025-03861-zpmid: 40461748

This overview summarizes the history and advancements of the modeling and simulation programs utilized in drug development and regulatory assessment, including the FDA’s Model-Informed Drug Development (MIDD) Paired Meeting Program and the Model-Integrated Evidence (MIE) Meeting Pilot Between FDA and Generic Drug Applicants. The U.S. Food and Drug Administration’s (FDA) recent notice concerning the use of the Type V Drug Master File (DMF) for Model Master File (MMF) submissions to support abbreviated new drug applications (ANDAs) encourages and facilitates model-sharing and model-reusability in drug development, supporting MIE programs using a broad range of quantitative models, including, but not limited to physiologically based pharmacokinetic (PBPK), population pharmacokinetics (PPK) and computational fluid dynamics (CFD) modeling. This overview also introduces the considerations and representative mock examples of MMFs discussed in the workshop titled “Considerations and Potential Regulatory Applications for a Model Master File (MMF)” co-hosted by the U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) on May 2–3, 2024. MMFs promote modeling and simulation approaches by reducing the burden of resources in developing this type of approaches for the pharmaceutical industry while increasing consistency and efficiency in regulatory assessments.

Tsakalozou, Eleftheria; Fang, Lanyan; Skoda, Erin; Nicholas, Timothy; Kollipara, Sivacharan; Ren, Ke; Grosser, Stella; Rege, Bhagwant; Roy, Partha; Zhu, Hao; Zhao, Liang

doi: 10.1007/s11095-025-03839-xpmid: 40055245

Graphical Abstract[graphic not available: see fulltext]

Gong, Yuqing; Hopefl, Robert; Li, Tonglei; Hooker, Andrew C.; Silva, Daniela Amaral; Alam, Khondoker; Ducharme, Murray; Moody, Rebecca; Saha, Pratik; Babiskin, Andrew

doi: 10.1007/s11095-025-03824-4pmid: 39875758

The U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a public workshop on May 2–3, 2024, titled “Considerations and Potential Regulatory Applications for a Model Master File”. The workshop aimed to discuss the application of the Model Master File (MMF) concept in regulatory submissions that contain model integrated evidence (MIE), improving model sharing, model standardization, regulatory consistency, and regulatory efficiency. On Day 1, there was a session dedicated to MMF applications for long-acting injectables (LAIs). This perspective summarizes presentations, panel discussion, and small group discussion for the potential applications of MMFs in LAI product development, including case studies and potential situations in which MMFs can support regulatory submissions. The scientific presentations discussed the application of MMFs in mechanistic physiologically based pharmacokinetic (PBPK), multiphysics simulation, and population pharmacokinetics (popPK) models, as well as the potential utility of a model-integrated bioequivalence (MI-BE) framework. Additionally, challenges and considerations of implementing MMFs for LAIs were discussed in the panel and small groups. The anticipated benefits of MMFs are recognized among model developers, industries, and regulators.Graphical Abstract[graphic not available: see fulltext]

Cheng, Yi-Hsien; Pal, Arindom; Moody, Rebecca; Heimbach, Tycho; Lukacova, Viera; Patel, Nikunjkumar; Rullo, Gregory; Xu, Yunming; Ahmed, Tausif; Kerwash, Essam; Fang, Lanyan; Wu, Fang

doi: 10.1007/s11095-025-03865-9

Liu, Jiang; Yang, Yuching; Gobburu, Joga; Musante, Cynthia J.; Klein, Martin; Zhao, Liang; Madabushi, Rajanikanth; Zhu, Hao

doi: 10.1007/s11095-025-03831-5pmid: 40038161

Model-informed drug development (MIDD) approaches have become indispensable for new drug development and to address regulatory challenges. Dynamic tools, such as population pharmacokinetics (popPK), physiologically-based pharmacokinetics (PBPK), and quantitative systems pharmacology (QSP) models, are routinely employed to enhance the efficiency of drug development. Recently, the Fit-for-Purpose (FFP) initiative and the Model Master File (MMF) framework have emerged to support model reusability and sharing in regulatory settings. In this manuscript we share key insights from the Session "Pathways for Regulatory Acceptance of Dynamic Tools in the New Drug Space" of Workshop “Considerations and Potential Regulatory Applications for a Model Master File”, hosted by the U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) and discuss the considerations for regulatory acceptance of dynamic modeling tools. Presentations at the workshop explored current practices in PBPK model evaluation, the potential for popPK models in bioequivalence (BE) assessments, and the implications of reusing models. Challenges such as context-specific validation, version control, and the impact of scientific and technological advancements on model reuse were emphasized. The workshop underscored the importance of clear regulatory pathways and structured frameworks for the consistent application of reusable models. The MMF's potential to streamline reviews and reduce redundancies was noted, although operational details require further elaboration. Continued collaboration among stakeholders is essential to refine model-sharing practices, enhance model validation processes, and promote transparency, ensuring that MIDD approaches remain robust and adaptable to evolving regulatory needs.

Walenga, Ross L.; Alam, Khondoker; Clarke, James F.; De Backer, Jan; Fridén, Markus; Hamadeh, Abdullah; Mowli, Jay; Sonti, Sujatha; Spires, Jessica; Tan, Ming-Liang; Musuamba, Flora T.; Tsakalozou, Eleftheria

doi: 10.1007/s11095-025-03823-5pmid: 40011371

Graphical Abstract[graphic not available: see fulltext]

Kollipara, Sivacharan; Friden, Markus; Heimbach, Tycho; Saha, Pratik; De Backer, Jan; Ahmed, Tausif; Nicholas, Timothy

doi: 10.1007/s11095-025-03844-0pmid: 40075036

Modeling and simulation (M&S) based approaches have proven significant utility in both new drug and generic product development. Considering the plethora of applications of such novel approaches, the concept of model master file (MMF) has been introduced recently to streamline the regulatory submission process as well as to facilitate the use of M&S approaches. The MMF has potential to reduce the applicant’s efforts in preparing and submitting modeling-based applications and can result in reduced review timelines. Approved MMF’s are considered as reusable, sharable, portable and generalizable and thus can be used by the same applicant in multiple submissions or by multiple applicants. To further increase the understanding of the MMF framework and to understand potential applications, and limitations, the USFDA and the Center for Research on Complex Generics (CRCG, https://www.complexgenerics.org) co-hosted a hybrid public workshop titled “Considerations and Potential Regulatory Applications for a Model Master File”. This article summarizes the industry perspectives of MMF implementation from both new drug and generic product development perspectives. With the help of diverse case studies, an effort was made in the manuscript to discuss potential challenges, opportunities and benefits. The objective of this article is to portray industry thinking on the MMF concept and the use and implementation of the concept during drug discovery and development. The views presented in this manuscript are of industry participants present at the workshop and not the industry at large.Graphical Abstract[graphic not available: see fulltext]

De Backer, Jan; Clarke, James; Sadafi, Hosein; Ganley, William; Spires, Jessica

doi: 10.1007/s11095-025-03833-3pmid: 40011369

Model Master Files (MMFs) offer a much needed approach to integrating computational modelling into drug development and regulatory frameworks, supporting the growth of quantitative medicine. By acting as confidential repositories for validated models, MMFs enable streamlined submissions, model reuse, and context-specific reviews while safeguarding intellectual property. For technology companies (such as software providers), MMFs provide a structured pathway to engage with the FDA, align innovations with regulatory standards, and expand the use of models across diverse applications. A challenge with the current framework is the need to provide the same validation and verification information to multiple drug companies each time the submit an application. With an MMF in place, drug companies can refer to this same document which the technology provider can add to over time. However, challenges persist, including limited direct interaction with the FDA outside (A)NDA submissions and the need for consistent model validation and version management. Addressing these issues through enhanced collaboration and clear guidelines will maximize the potential of MMFs, fostering broader adoption of modelling and simulation in drug development and advancing personalized medicine.Graphical Abstract[graphic not available: see fulltext]

De Groot, Anne S.; Mattei, Aimee; Gabriel, Benjamin; Calderini, Jennifer; Roberts, Brian J.; Lelias, Sandra; McAllister, Mitchell; Boyle, Christine; Martin, William; Richard, Guilhem

doi: 10.1007/s11095-025-03843-1pmid: 40126816

Generic drugs have saved consumers billions of dollars in the United States. The demand for lower-cost and effective drugs, particularly for well-known peptide drugs like Ozempic and Wegovy (brand names for semaglutide), has resulted in a surge of generic drug development to address perceived shortages in the supply of the reference listed drugs (RLD). To address this demand for generics and expedite consumer access to lower-cost generic versions of approved drugs, the U.S. Food and Drug Administration (FDA) has developed an “Abbreviated New Drug Application” (ANDA) pathway that simplifies the generic drug review process and expands access to these much-needed medicines without compromising quality and safety standards. Guidelines for this pathway require sponsors to identify and characterize both process- and product-related impurities in drug formulations that differ in nature or concentration from the RLD. The ANDA pathway devotes specific attention to immunogenicity and recommends the use of orthogonal methods of assessment to demonstrate that a proposed generic drug is immunologically equivalent to its RLD and therefore suitable for submission via the ANDA pathway. In this perspective, we describe several orthogonal methods for immunogenicity risk assessment of generic peptide impurities and contrast these with other methods such as MHC-Associated Peptide Proteomics peptide elution (MAPPs) assays. Given their importance in the generic drug approval pathway, we have submitted the “PANDA®” immunogenicity risk assessment methods as a ‘model master file’.Graphical Abstract[graphic not available: see fulltext]