Yi Yu Rice , David G. Dolan , Suren B. Bandara , Ryan E. Morgan , Michael Garry , Joyce Tsuji
{"title":"Considerations and derivations of permitted daily exposure limits for impurities from intravitreal pharmaceutical products","authors":"Yi Yu Rice , David G. Dolan , Suren B. Bandara , Ryan E. Morgan , Michael Garry , Joyce Tsuji","doi":"10.1016/j.yrtph.2024.105745","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"155 ","pages":"Article 105745"},"PeriodicalIF":3.0000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Regulatory Toxicology and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0273230024001867","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, LEGAL","Score":null,"Total":0}
引用次数: 0
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.
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)