Safety assessment of protein A and derivation of a parenteral health-based exposure limit

IF 3 4区医学 Q1 MEDICINE, LEGAL Regulatory Toxicology and Pharmacology Pub Date : 2024-09-06 DOI:10.1016/j.yrtph.2024.105700

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Abstract

Protein A (PA) is a bacterial cell wall component of Staphylococcus aureus whose function is to bind to Immunoglobulin G (IgG). Given its ability to bind IgG as well as its stability and resistance to harsh acidic and basic cleaning conditions, it is commonly used in the affinity chromotography purification of biotherapeutics. This use can result in levels of PA being present in a drug product and subsequent patient exposure. Interestingly, PA was previously evaluated in clinical trials as well as supporting nonclinical studies, resulting in a database that enables the derivation of a health-based exposure limit (HBEL). Given the widespread use of PA in the pharmaceutical industry, the IQ DruSafe Impurities Safety Working Group (WG) evaluated the available information with the purpose of establishing a harmonized parenteral HBEL for PA. Based on this thorough, collaborative evaluation of nonclinical and clinical data available for PA, a parenteral HBEL of 1.2 μg/kg/dose (60 μg/dose for a 50 kg individual) is expected to be health protective for patients when it is present as an impurity in a biotherapeutic.

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蛋白质 A 的安全性评估和基于健康的肠道外接触限值的推导。

蛋白 A (PA) 是金黄色葡萄球菌的一种细菌细胞壁成分，其功能是与免疫球蛋白 G (IgG) 结合。鉴于其结合 IgG 的能力及其稳定性和对苛刻的酸性和碱性清洗条件的耐受性，它常用于生物治疗药物的亲和层析纯化。这种使用会导致药物产品中的 PA 含量达到一定水平，从而使患者接触到 PA。有趣的是，PA 以前曾在临床试验和支持性非临床研究中进行过评估，从而形成了一个数据库，可用于推导基于健康的暴露限值 (HBEL)。鉴于 PA 在制药行业的广泛使用，IQ DruSafe 杂质工作组（WG）对现有信息进行了评估，目的是为 PA 建立一个统一的肠外 HBEL。根据对 PA 现有的非临床和临床数据进行的全面合作评估，当 PA 作为杂质存在于生物治疗药物中时，预计 1.2 μg/kg/dose 的肠外 HBEL（50 公斤体重的人为 60 μg/dose）可保护患者的健康。

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来源期刊

Regulatory Toxicology and Pharmacology 医学-毒理学

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)