Considerations and derivations of permitted daily exposure limits for impurities from intravitreal pharmaceutical products

IF 3 4区 医学 Q1 MEDICINE, LEGAL Regulatory Toxicology and Pharmacology Pub Date : 2024-11-22 DOI:10.1016/j.yrtph.2024.105745
Yi Yu Rice , David G. Dolan , Suren B. Bandara , Ryan E. Morgan , Michael Garry , Joyce Tsuji
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Abstract

Intravitreal (IVT) injection is an uncommon route of parenteral administration for therapeutic medications, but one of the most important for the treatment of ocular diseases, especially those related to macular degeneration. Nonetheless, there are currently no regulatory guidelines that specifically address how to establish a permitted daily exposure (PDE) for impurities and residual process reagents in IVT pharmaceutical drug products given the unique vulnerability of ocular tissues. The establishment of PDEs for IVT administration is complicated by the limited understanding of metabolism and clearance of small molecular weight chemicals from the human vitreous humor (VH), a problem compounded by the limited IVT-specific toxicological data. In this paper, we describe a feasible and comprehensive methodology for deriving PDE limits for impurities and residual process reagents from IVT drug products, as exemplified by five case studies, including inorganic elements, formic acid, polyethylene glycols, acetic acid, and caprolactam. The five case studies were selected to cover compounds with a wide range of impurity sources and toxicological data availability. The proposed framework considers both local ocular and systemic toxicity endpoints and advances the goal of a harmonized, science-based approach for deriving IVT PDE limits.
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考虑并推导出玻璃体内药物杂质的每日允许接触限值。
玻璃体内注射(IVT)是一种不常见的非肠道给药途径,但却是治疗眼部疾病(尤其是与黄斑变性有关的疾病)最重要的途径之一。然而,鉴于眼部组织的特殊脆弱性,目前还没有专门针对如何确定静脉注射药物产品中杂质和残留工艺试剂的允许日暴露量(PDE)的监管指南。由于对人类玻璃体液(VH)中小分子量化学物质的代谢和清除了解有限,制定静脉注射用药的 PDE 变得更加复杂,而静脉注射用药的特定毒理学数据有限又加剧了这一问题。在本文中,我们介绍了一种可行且全面的方法,用于推导静脉注射药物产品中杂质和残留工艺试剂的 PDE 限值,并通过无机元素、甲酸、聚乙二醇、乙酸和己内酰胺等五个案例研究加以说明。选择这五个案例研究是为了涵盖杂质来源和毒理学数据可用性范围广泛的化合物。建议的框架同时考虑了局部眼部和全身毒性终点,并推进了以科学为基础的统一方法推导 IVT PDE 限值的目标。
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来源期刊
CiteScore
6.70
自引率
8.80%
发文量
147
审稿时长
58 days
期刊介绍: Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health. Types of peer-reviewed articles published: -Original research articles of relevance for regulatory aspects covering aspects including, but not limited to: 1.Factors influencing human sensitivity 2.Exposure science related to risk assessment 3.Alternative toxicological test methods 4.Frameworks for evaluation and integration of data in regulatory evaluations 5.Harmonization across regulatory agencies 6.Read-across methods and evaluations -Contemporary Reviews on policy related Research issues -Letters to the Editor -Guest Editorials (by Invitation)
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