Chapter 15 Clinically Relevant Dissolution for Low-Solubility Immediate-Release Products

Dickinson, Paul; Flanagan, Talia; Holt, David; Stott, PaulW.

doi:10.1201/9781315364537-16

Cited by 4 publications

(5 citation statements)

References 14 publications

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“…BCS Classes 2 and 4 span a much broader range of compound properties and, hence, a wide spectrum of biopharmaceutics risk. Therefore, the relationship between in vitro dissolution and in vivo performance for Class 2 and 4 compounds needs to be explored and understood on a compound-specific basis [11,12]. This will involve evaluation of product-specific clinical data to evaluate the relationship between in vivo performance and in vitro dissolution; in many cases, a clinical relative bioavailability study is performed with the specific aim of supporting development of CRDS.…”

Section: Clinically Relevant Specifications: Connecting Product Perfomentioning

confidence: 99%

Developing Clinically Relevant Dissolution Specifications for Oral Drug Products—Industrial and Regulatory Perspectives

McAllister

Flanagan

Boon³

et al. 2019

Pharmaceutics

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A meeting that was organized by the Academy of Pharmaceutical Sciences Biopharmaceutics and Regulatory Sciences focus groups focused on the challenges of Developing Clinically Relevant Dissolution Specifications (CRDS) for Oral Drug Products. Industrial Scientists that were involved in product development shared their experiences with in vitro dissolution and in silico modeling approaches to establish clinically relevant dissolution specifications. The regulators shared their perspectives on the acceptability of these different strategies for the development of acceptable specifications. The meeting also reviewed several collaborative initiatives that were relevant to regulatory biopharmaceutics. Following the scientific presentations, a roundtable session provided an opportunity for delegates to discuss the information that was shared during the presentations, debate key questions, and propose strategies to make progress in this critical area of regulatory biopharmaceutics. It was evident from the presentations and subsequent discussions that progress continues to be made with approaches to establish robust CRDS. Further dialogue between industry and regulatory agencies greatly assisted future developments and key areas for focused discussions on CRDS were identified.

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Section: Clinically Relevant Specifications: Connecting Product Perfomentioning

confidence: 99%

Developing Clinically Relevant Dissolution Specifications for Oral Drug Products—Industrial and Regulatory Perspectives

McAllister

Flanagan

Boon³

et al. 2019

Pharmaceutics

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“…Assessing the impact of changes to the extent and rate of dissolution (e.g., caused by formulation and process changes) on in vivo product performance is a key element of dissolution method development and establishment of the QC strategy. This topic has been the subject of numerous publications and conference presentations from industry and regulatory authorities (4,(6)(7)(8)(10)(11)(12). Establishing the link between in vitro dissolution and clinical product performance should be a key consideration for project teams, as this underpins selection of a relevant test with an appropriate degree of discriminatory power versus in vivo performance, and this is an important link to discuss with regulatory authorities when justifying the method and acceptance criteria.…”

Section: Characterize the In Vivo Performance Impact Of Your Highest mentioning

confidence: 99%

“…Hermans et al (6) and Dickinson et al (4) describe detailed approaches to establish the link between in vivo and in vitro performance as part of the development of clinically relevant dissolution tests and acceptance criteria. Often, this will involve the generation of clinical relative bioavailability data on relevant drug product process/formulation variants; several examples have been published and presented for specific drug products (4,6,8,10,13,14). Recently, in silico PBPK absorption modelling has emerged as a key tool in development of clinically relevant specifications to mechanistically explore and describe the link between the in vitro and in vivo data (9,15).…”

Section: Characterize the In Vivo Performance Impact Of Your Highest mentioning

confidence: 99%

“…The International Conference on Harmonisation (ICH) Q8R2 (3) describes the quality target product profile (QTPP) as: "A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product," thus explicitly connecting clinical performance with drug product quality attributes and tests. Establishing the clinical relevance of dissolution tests and acceptance criteria in the QbD paradigm has been the subject of numerous publications, presentations, and discussions between industry and regulators (4)(5)(6)(7). As a result, the expectations of a modern quality control (QC) dissolution test and the data needed to underpin its suitability have evolved significantly.…”

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Dissolution Universal Strategy Tool (DUST): A Tool to Guide Dissolution Method Development Strategy

Flanagan¹,

Mann²

2019

Dissolution Technol.

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Development of a dissolution method with suitable acceptance criteria is a key part of any oral drug products control strategy. As a key quality control test linked to safety and efficacy, dissolution strategy is often subject to extensive discussion during product development and with regulatory authorities during filing of the marketing application. A project review was recently performed at AstraZeneca to capture learning from dissolution method development and regulatory interactions from the last 10 years. The output of this review was distilled down to a few key messages that were critical to be considered when conducting dissolution method development. These key messages were then used as the building blocks for the Dissolution Universal Strategy Tool (DUST), that became part of the internal process at AstraZeneca for developing dissolution methods and acceptance criteria. The DUST can be used at all stages of product development and can be applied regardless of BCS Classification. The tool provides a common framework for cross-functional discussions, ensuring that project teams have a clear expectation of the role(s) of dissolution testing in drug product development, and that the understanding built during development will evolve into a suitable and clinically relevant QC test and acceptance criteria at time of submission which ensure the product will meet the patient's requirements.

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“…It began as a one-point quality control (QC) tool designed to profile and support bioequivalence testing and present where discriminatory and clinically relevant methods are expected (3)(4)(5)(6). Provided in the literature are recommendations and strategies on how to develop dissolution methods (7,8). If development is performed with a close eye on the in vivo performance and aligned with the biopharmaceutic risk assessment, the dissolution method could lead to clinically relevant drug products specifications (CRDPS).…”

Section: Introductionmentioning

confidence: 99%

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

Gray¹,

Mann²,

Barker³

et al. 2020

Dissolution Technol.

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The purpose of this article is to inform the dissolution scientist of a powerful emerging tool that provides in vivo linkage to dissolution methods. This tool is physiologically based biopharmaceutics modelling (PBBM). Dissolution scientists are mostly concerned with analytical sections of drug development, so exposure to modeling and other pharmacokinetics and biopharmaceutic concepts may be uncommon. PBBM is an in-silico model that focuses on the interactions between the in vivo physiology and the formulation and drug characteristics. The principles behind PBBM is that all mechanisms related to drug release, dissolution, and diffusion from the site of administration to the site of action can be described in a mechanistic way or semi-empirical way. The integration of in vitro dissolution data in PBBM is described, including examples of software and modeling applications. The expertise needed to use the software and appropriate training is discussed. The key inputs that are expected from the dissolution scientist include an understanding of the aqueous solubility across the physiological pH range, impact of in vivo relevant bile salts and phospholipids on solubilization, and the impact of surface pH on dissolution rate. An example of an advanced in vitro system, TNO intestinal model (TIM-1), will be discussed and its importance in establishing a biorelevant understanding of dissolution behavior. PBBM can evaluate the clinical relevance of a dissolution method and justify specifications and ultimately provide an approval advantage to the sponsor. A well-supported dissolution method that provides clinically relevant drug product specifications (CRDPS) will be viewed with favor by the regulators. Therefore, the partnering of a dissolution scientist and biopharmaceutics scientist to develop PBBM is clearly an important step forward in drug development.

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Chapter 15 Clinically Relevant Dissolution for Low-Solubility Immediate-Release Products

Cited by 4 publications

References 14 publications

Developing Clinically Relevant Dissolution Specifications for Oral Drug Products—Industrial and Regulatory Perspectives

Developing Clinically Relevant Dissolution Specifications for Oral Drug Products—Industrial and Regulatory Perspectives

Dissolution Universal Strategy Tool (DUST): A Tool to Guide Dissolution Method Development Strategy

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

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