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Safety assessment of protein A and derivation of a parenteral health-based exposure limit 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。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-09-06 DOI: 10.1016/j.yrtph.2024.105700

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.

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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引用次数: 0
Aspects of complexity in quality and safety assessment of peptide therapeutics and peptide-related impurities. A regulatory perspective 多肽疗法和多肽相关杂质质量与安全评估的复杂性。监管视角。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-09-06 DOI: 10.1016/j.yrtph.2024.105699

In recent years, a number of therapeutic peptides have been authorized in the EU market, and several others are in the clinical development phase or under assessment for full dossier or generic applications. Quality and safety guidelines specific to peptides are limited, and some aspects have to be considered. In particular, concerns relate to the analytical investigation for impurities and the toxicological assessment of these substances. The guidelines and the compendial pharmacopoeias provide certain references but that may be questionable if interpreted according to whether therapeutic peptides are considered chemical or biological entities, large or small. The characterization of peptide-related impurities cannot follow the small molecule approach but should consider aspects closely linked to the complex mechanisms of action that these large molecules can exert in the human body. Although direct genotoxic mechanisms cannot be excluded, hazardous interactions on biological systems cannot be ruled out, as in the case of natural peptide toxins and their specific interactions with cellular or membrane targets. From a regulatory perspective, only after specific risk identification and characterization should an equally specific safety threshold in relation to potential toxicity be defined.

近年来,一些治疗肽已获准进入欧盟市场,还有一些肽正处于临床开发阶段,或正在接受完整档案或非专利申请的评估。专门针对肽的质量和安全指南非常有限,有些方面必须加以考虑。特别是对这些物质的杂质分析调查和毒理学评估。指南和药典提供了一些参考,但如果按照治疗肽是化学实体还是生物实体、是大还是小来解释,则可能会有问题。肽相关杂质的特征描述不能沿用小分子方法,而应考虑与这些大分子在人体内的复杂作用机制密切相关的方面。虽然不能排除直接的基因毒性机制,但也不能排除对生物系统的有害相互作用,如天然肽毒素及其与细胞或膜靶点的特定相互作用。从监管的角度来看,只有在进行了具体的风险识别和特征描述之后,才能确定与潜在毒性相关的同样具体的安全阈值。
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引用次数: 0
Letter to the editors regarding “Inter-laboratory validation of bioaccessibility testing for metals” by Henderson et al. (2014) 就 "金属的生物可及性测试的实验室间验证 "致编辑的信,作者:.
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-08-22 DOI: 10.1016/j.yrtph.2024.105688
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引用次数: 0
Biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide: A global view 2,4-二氯苯氧乙酸(2,4-D)除草剂的生物监测:全球视野。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-08-19 DOI: 10.1016/j.yrtph.2024.105687

We conducted a literature review of urinary 2,4-D in populations not associated with a herbicide application. Of the 33 studies identified, the median/mean concentrations were similar for children, adults, and pregnant women regardless of geography. Individuals with highest concentrations may have had opportunities to directly contact 2,4-D outside of an application. Most studies were conducted in populations in North America and did not examine potential sources of 2,4-D, or what factors might influence higher or lower urinary 2,4-D concentrations. In the future, prioritizing the examination of 2,4-D biomonitoring in other regions and collecting information on sources and factors influencing exposures would better our understanding of 2,4-D exposures globally. In all the studies reviewed the concentrations of urinary 2,4-D observed were orders of magnitude below the US regulatory endpoints, suggesting that people are not being exposed to 2,4-D at levels high enough to result in adverse health effects.

我们对与施用除草剂无关的人群尿液中的 2,4-D 进行了文献综述。在已确定的 33 项研究中,儿童、成人和孕妇的中位数/平均浓度相似,与地域无关。浓度最高的人可能有机会在施用除草剂之外直接接触 2,4-D。大多数研究都是在北美地区的人群中进行的,没有研究 2,4-D 的潜在来源,也没有研究哪些因素可能会影响尿液中 2,4-D 浓度的高低。今后,优先审查其他地区的 2,4-D 生物监测情况,并收集有关影响暴露的来源和因素的信息,将有助于我们更好地了解全球的 2,4-D 暴露情况。在所审查的所有研究中,观察到的尿液中 2,4-D 的浓度都低于美国监管终点的数量级,这表明人们接触 2,4-D 的水平并没有高到足以对健康造成不良影响的程度。
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引用次数: 0
Prenatal developmental toxicity studies of allyl alcohol in rats and rabbits 工作标题:烯丙醇对大鼠和兔子的产前发育毒性研究。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-08-14 DOI: 10.1016/j.yrtph.2024.105684

Allyl alcohol (C3H6O; prop-2-en-1-ol; CAS RN 107-18-6; EINECS 203-470-7) is used as an intermediate/monomer in polymerization reactions producing chemicals/optical resins or as a coupling/cross-linking agent for unsaturated polyester and alkyd resins. Human exposure to allyl alcohol (AA) is restricted to workplace manufacturing facilities where it is used in enclosed systems, which limits release and impact on environmental receptors. To address regulatory questions about possible developmental toxicity, two OECD Guideline studies were conducted. A rat developmental toxicity study found fetal and maternal toxicity, in the form of resorptions and decreased body weight and food consumption, but no teratogenic effects. A rabbit developmental toxicity study was subsequently conducted upon request by the European Chemical Agency in 2011 under the REACH program and likewise reported maternal toxicity in the form of reductions in body weight gain and food consumption, but neither fetal toxicity or teratogenic effects. The results of both studies are presented and compared in this paper. Based on our review of the collective results of these studies, AA is considered non-teratogenic, yet does elicit increased post-implantation loss and reduced fetal body weight, possibly resulting from concomitant maternal toxicity. Based on the results of these studies, a maternal and developmental toxicity No Observed Adverse Effect Level of 10 mg/kg/day was apparent for both species.

烯丙醇(C3H6O;丙-2-烯-1-醇;化学文摘社编号:107-18-6;欧洲现存化学物质清单编号:203-470-7)在生产化学品/光学树脂的聚合反应中用作中间体/单体,或用作不饱和聚酯和醇酸树脂的偶联剂/交联剂。人类对烯丙基醇(AA)的接触仅限于在封闭系统中使用的工作场所生产设施,这限制了对环境受体的释放和影响。为了解决可能存在的发育毒性监管问题,我们进行了两项经合组织指南研究。一项大鼠发育毒性研究发现,该物质对胎儿和母体有毒性,表现为再孕、体重和食物消耗量下降,但没有致畸作用。随后,应欧洲化学品管理局的要求,我们于 2011 年根据 REACH 计划开展了一项兔子发育毒性研究,同样发现了母体毒性,表现为体重增加和食物消耗量减少,但未发现胎儿毒性或致畸效应。本文对这两项研究的结果进行了介绍和比较。根据我们对这些研究的综合结果的审查,AA 被认为不会致畸,但确实会引起着床后丢失率增加和胎儿体重下降,这可能是由于同时存在的母体毒性造成的。根据这些研究的结果,两个物种的母体和发育毒性 "未观察到的不良效应水平 "均为 10 毫克/千克/天。
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引用次数: 0
Toxicity reference values for force health protection: Provisional occupational exposure guidelines 部队健康保护毒性参考值:暂定职业接触准则》。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-08-14 DOI: 10.1016/j.yrtph.2024.105686

Force Health Protection programs in the U.S. Air Force endeavor to sustain the operational readiness of the warfighters. We have previously identified hundreds of chemical substances of interest and toxicity reference value (TRV) knowledge gaps that constrain risk based-decision-making for potential exposures. Multiple approaches to occupational TRV estimation were used to generate possible guideline values for 84 compounds (18% of the substances of interest). These candidate TRVs included values from international databases, chemical similarity (nearest neighbor) approaches, empirical adjustments to account for duration differences, quantitative activity relationships, and thresholds of toxicological concern. This present work describes derivation of provisional TRVs from these candidate values. Rodent bioassay-derived long-term worker Derived No-Effect Levels (DNELs) were deemed presumptively the most reliable, but only 19 such DNELs were available for the 84 substances with TRV gaps. In the absence of DNELs, the quality of the approaches and consistency among candidate values were key elements of the weight of evidence used to select the most suitable guideline values. The use of novel nearest-neighbor approaches, empirical adjustment of short term TRVs, and occupational exposure bands were found to be options that would allow occupational TRV estimation with reasonable confidence for nearly all substances evaluated.

美国空军的部队健康保护计划致力于维持作战人员的战备状态。我们之前已经确定了数百种相关化学物质和毒性参考值(TRV)知识缺口,这些知识缺口限制了对潜在暴露进行基于风险的决策。我们采用多种方法对职业 TRV 进行估算,为 84 种化合物(占相关物质的 18%)生成了可能的指导值。这些候选 TRV 值包括来自国际数据库的数值、化学相似性(近邻)方法、考虑持续时间差异的经验性调整、定量活动关系以及毒理学阈值。本研究介绍了从这些候选值推导出的临时 TRV 值。啮齿动物生物测定得出的长期工人衍生无效应水平(DNEL)被认为是最可靠的,但对于存在 TRV 缺口的 84 种物质来说,只有 19 个这样的 DNEL。在没有 DNEL 的情况下,方法的质量和候选值之间的一致性是用于选择最合适指导值的证据权重的关键因素。我们发现,使用新的近邻方法、对短期 TRV 进行经验调整以及职业接触带等方法,可以对几乎所有受评估物质的职业 TRV 进行有合理可信度的估算。
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引用次数: 0
Toxicity reference values (TRVs) for force health protection: Gap identification and TRV prediction 保护部队健康的毒性参考值 (TRV):差距识别和 TRV 预测。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-08-13 DOI: 10.1016/j.yrtph.2024.105685

The mission of the Force Health Protection (FHP) program of the U.S. Air Force (USAF), sustaining the readiness of warfighters, relies on determinations of acceptable levels of exposure to a wide array of substances that USAF personnel may encounter. In many cases, exposure details are limited or authoritative toxicity reference values (TRVs) are unavailable. To address some of the TRV gaps, we are integrating several approaches to generate health protective exposure guidelines. Descriptions are provided for identification of chemicals of interest for USAF FHP (467 to date), synthesis of multiple TRVs to derive Operational Exposure Limits (OpELs), and strategies for identifying and developing candidate values for provisional OpELs when authoritative TRVs are lacking. Rodent bioassay-derived long-term Derived No Effect Levels (DNELs) for workers were available only for a minority of the substances with occupational TRV gaps (19 of 84). Additional occupational TRV estimation approaches were found to be straightforward to implement: Tier 1 Occupational Exposure Bands, cheminformatics approaches (multiple linear regression and novel nearest-neighbor approaches), and empirical adjustment of short term TRVs. Risk assessors working in similar contexts may benefit from application of the resources referenced and developed in this work.

美国空军(USAF)部队健康保护(FHP)计划的任务是维持作战人员的战备状态,这依赖于对美国空军人员可能接触到的各种物质的可接受接触水平的确定。在许多情况下,暴露详情有限,或者没有权威的毒性参考值 (TRV)。为了填补 TRV 方面的一些空白,我们正在整合多种方法,以生成保护健康的暴露指南。本文介绍了如何确定美国空军 FHP 所关注的化学物质(迄今已有 467 种)、如何综合多个 TRV 值以得出操作接触限值 (OpEL),以及如何在缺乏权威 TRV 值的情况下确定和开发临时 OpEL 的候选值。只有少数存在职业 TRV 缺口的物质(84 种物质中的 19 种)可以通过啮齿动物生物测定得出工人的长期衍生无效应水平 (DNEL)。其他职业 TRV 估算方法被认为可以直接实施:第 1 级职业接触带、化学信息学方法(多元线性回归和新型近邻方法)以及短期 TRV 的经验调整。在类似情况下工作的风险评估人员可能会从应用这项工作中参考和开发的资源中受益。
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引用次数: 0
Endeavours made by trade associations, pharmaceutical companies and regulators in the replacement, reduction and refinement of animal experimentation in safety testing of pharmaceuticals 行业协会、制药公司和监管机构在替代、减少和改进药品安全测试中的动物实验方面所做的努力。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-08-06 DOI: 10.1016/j.yrtph.2024.105683

Following the European Commission decision to develop a roadmap to phase out animal testing and the signing of the US Modernisation Act, there is additional pressure on regulators and the pharmaceutical industry to abandon animal experimentation in safety testing. Often, endeavours already made by governments, regulators, trade associations, and industry to replace, reduce and refine animal experimentation (3Rs) are unnoticed. Herein, we review such endeavours to promote wider application and acceptance of 3Rs. ICH guidelines have stated 3Rs objectives and have enjoyed many successes driven by global consensus. Initiatives driven by US and European regulators such as the removal of the Abnormal Toxicity Test are neutralised by reticent regional regulators. Stream-lined testing requirements have been proposed for new modalities, oncology, impurity management and animal pharmacokinetics/metabolism. Use of virtual controls, value of the second toxicity species, information sharing and expectations for life-threatening diseases, human specific or well-characterised targets are currently being scrutinised. Despite much effort, progress falls short of the ambitious intent of decisionmakers. From a clinical safety and litigation perspective pharmaceutical companies and regulators are reluctant to step away from current paradigms unless replacement approaches are validated and globally accepted. Such consensus has historically been best achieved through ICH initiatives.

继欧盟委员会决定制定逐步淘汰动物实验的路线图以及美国签署《现代化法案》之后,监管机构和制药行业面临着更大的压力,要求在安全测试中放弃动物实验。通常情况下,政府、监管机构、行业协会和产业界为取代、减少和完善动物实验(3Rs)所做的努力并不为人所知。在此,我们将回顾这些努力,以促进 3Rs 的更广泛应用和接受。国际化学品管理委员会(ICH)指南已阐明了 3Rs 的目标,并在全球共识的推动下取得了许多成功。由美国和欧洲监管机构推动的倡议,如取消异常毒性试验,却被沉默寡言的地区监管机构所抵消。针对新模式、肿瘤学、杂质管理和动物药代动力学/代谢提出了简化测试要求。虚拟对照的使用、第二毒性物种的价值、信息共享以及对威胁生命的疾病、人类特异性或特征明确的靶点的期望等问题目前都在仔细研究之中。尽管做了很多努力,但进展仍未达到决策者的雄心壮志。从临床安全和诉讼的角度来看,制药公司和监管机构不愿意放弃当前的模式,除非替代方法得到验证并在全球范围内得到认可。这种共识历来是通过 ICH 计划达成的。
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引用次数: 0
The use of weight-of-evidence approaches to characterize developmental toxicity risk for therapeutic monoclonal antibodies in humans without in vivo studies 在没有进行体内研究的情况下,使用证据权重法确定治疗性单克隆抗体对人类发育的毒性风险。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-07-31 DOI: 10.1016/j.yrtph.2024.105682

Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label.

全球药物开发的监管指南依赖动物研究来评估对人类的安全风险,包括生殖毒性风险。证据权重法(WoE)越来越多地被用于评估风险。我们评估了单克隆抗体(mAbs)发育风险的证据权重法(WoE),以确定其是否能够追溯风险特征,并根据剩余的不确定性确定是否需要进一步进行体内试验。对 65 种 mAbs 的生殖毒性研究进行了审查,并与 WoE 进行了比较。52/65(80%)种 mAbs 不存在发育毒性。29/52(56%)例正确预测了无毒性。分别有 9/52 (17%) 和 14/52 (27%) 例预测为假阳性和模棱两可。3/65(5%)例 mAbs 的预测结果不明确。在有发育毒性发现的 mAbs 中(10/65,15%),WoE 在 9/10 例(90%)中正确预测了基于药理学的生殖毒性,没有任何假阴性预测,而在剩余的 1/10 例(1/10,10%)中,由于 WoE 结果不明确,建议进行体内研究。因此,这种 WoE 方法可以在不进行动物研究的情况下确定是否存在发育风险。目前的 WoE 可以将发育毒性研究的需求减少 42%,而不会损失标签中重要的患者信息。
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引用次数: 0
N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP 药品中的 N-亚硝胺杂质风险评估:利用体内突变相对效力比较法确定NTTP的可接受摄入量。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-07-26 DOI: 10.1016/j.yrtph.2024.105681

The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.

在市场上销售的药物中发现 N-亚硝基二乙胺 (NDEA) 和 N-亚硝基二甲胺 (NDMA) 后,实施了风险评估程序,旨在限制对整个亚硝胺类物质的接触。风险评估过程的一个重要组成部分是确定保护人类健康的暴露限值。确定新型 N-亚硝胺接触限值的一种方法是进行体内转基因啮齿动物 (TGR) 变异研究。现有的亚硝胺监管指南提供的决策标准是将体内转基因啮齿动物突变研究解释为总体阳性或阴性。不过,基准剂量 (BMD) 等出发点指标可用于定义效价,并为确定相关暴露限值提供机会。这可以通过将新型 N-亚硝胺与拥有可靠体内诱变性和致癌性数据的模型 N-亚硝胺进行相对效力比较来实现。目前的研究工作提供了 N-亚硝基哌啶 (NPIP) 的体内 TGR 突变数据,从而增加了模型 N-亚硝胺的数据集。此外,还为在含有西他列汀的产品中发现的一种新型 N-亚硝胺杂质 7-亚硝基-3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪(NTTP)生成了体内 TGR 突变数据。利用相对效力比较法,我们证明了每天接触 1500 纳克或以上水平的 NTTP 是安全的。
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引用次数: 0
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Regulatory Toxicology and Pharmacology
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