1.1 本指南描述了综合解释与活性药物成分（API）有关的所有数据的科学程序，其中考虑了研究的充分性、相关性、可靠性、有效性和化合物的特定特征（例如，效价、毒理学特征和药代动力学），从而得出API的数值，它进一步用于同一制造设施中不同产品制造过程中交叉污染的质量风险管理（ICH Q9）。 1.2 本指南描述了计算和记录健康状况的一般指南- 基于暴露极限（HBEL）。它应为相关合格专家提供HBEL推导的参考，并应尽可能协调不同的方法和术语。 1.3 当需要或必要时，本指南应用于计算和记录用于清洁验证和验证的原料药（包括生物制剂）、中间体、清洁剂、赋形剂和其他化学品（即试剂、制造残留物等）的HBEL（指南 F3127 和 E3106 ). 范围包括制造设备和医疗器械表面的清洁和交叉污染，但不包括浸出物/可萃取物（21 CFR 211）。 67、21 CFR 610.11、21 CFR 820.70和21 CFR 111.27）。 1.4 本指南中的原则也可作为设定职业接触限值的基础。 1.5 本指南中的原则可应用于小分子量或大分子量药物以及分离药物中间体的开发和商业制造过程中。 1.6 必要时（例如，由于生物利用度的差异），可以为特定暴露途径（例如，口服、吸入和肠外）和特定患者群体（例如，儿童）设置后续产品HBEL值，如果生产的制剂中一日剂量不适用于50 kg标准成人，但将剂型调整为目标剂量体重较低的人群。 1.7 本指南的主要范围是确保通过药品接触残留活性物质和中间体的患者的安全。本指南的一般原则也适用于兽药产品的制造。然而，可能存在某些独特的毒理学和药理学物种特异性差异，如代谢和敏感性，以及本指南中未提及的假设，如兽药的体重。 1.8 本指南可单独使用，也可与ASTM国际发布的其他拟议E55标准结合使用。 1.9 单位- 以国际单位制表示的数值应视为标准值。本标准不包括其他计量单位。 1.10 本标准并非旨在解决与其使用相关的所有安全问题（如有）。本标准的用户有责任在使用前制定适当的安全、健康和环境实践，并确定监管限制的适用性。 1.11 本国际标准是根据世界贸易组织技术性贸易壁垒（TBT）委员会发布的《关于制定国际标准、指南和建议的原则的决定》中确立的国际公认标准化原则制定的。 ====意义和用途====== 4.1 作为国际质量要求的一部分，各种全球法规要求制定关于人类意外接触活性药物成分（API）的指南，作为良好的产品管理，这些指南被视为行业标准。 4.2 本指南中所述方法的应用采用了一种科学合理、数据驱动的方法来推导意外接触个别物质的安全限值。然后，这些限值可以进一步用于计算药品制造质量风险评估中使用的清洁限值。 HBEL方法考虑了物质的特定特性（作用类型、效力、药理学、安全性等）。具体方法适用于不同类别的物质和药物开发的特定阶段。 4.3 HBEL推导的基础是所有可用的物质特定数据。对这些数据的解释考虑了数据库的数量和稳健性以及数据的可靠性和相关性。通常，调整因子（AFs）用于解决不同参数中的可变性和不确定性，以确定人体安全接触限值，尽管是替代的、故意保守的方法[例如毒理学关注阈值（TTC），阅读- 可酌情使用。 4.4 本指南支持并符合欧盟委员会（EU）关于人用和兽医用医药产品良好生产规范的指导原则 ( 27 , 28 ) 以及国际制药工程师学会（ISPE）的指导 ( 29 ) 其中提到，相关残留限量应基于毒理学评估。 4.5 关键概念- 本指南适用于以下步骤:( 1. )危险特性( 2. )识别关键效应，包括剂量反应评估( 3. )确定一个或多个出发点（PoD）( 4. )PoD特定AFs的应用，以及( 5. )计算HBEL，包括所选HBEL的理由 ( 18 ) （参见 图1 ). 图1 HBEL的计算和最终选择过程 注1: 该图显示了一个示例，其中基于三个不同的临界效应选择了三个可能的PoD，然后是AFs的PoD特定应用和三个HBEL的计算。

1.1 This guide describes the scientific procedures underlying the integrative interpretation of all data concerning an active pharmaceutical ingredient (API) taking into account study adequacy, relevance, reliability, validity, and compound-specific characteristics (for example, potency, toxicological profile, and pharmacokinetics) leading to a numerical value for the API, which is used further in the quality risk management (ICH Q9) of cross contamination during the manufacture of different products in the same manufacturing facilities. 1.2 This guide describes general guidance for calculating and documenting a health-based exposure limit (HBEL). It should serve the involved qualified experts as a reference for HBEL derivations and should harmonize the different approaches and nomenclature to the greatest extent possible. 1.3 This guide should be used for calculating and documenting an HBEL, when required or necessary, for APIs (including biologics), intermediates, cleaning agents, excipients, and other chemicals (that is, reagents, manufacturing residues, and so forth) used for cleaning validation and verification (Guides F3127 and E3106 ). In scope is the cleaning and cross contamination of surfaces of manufacturing equipment and medical devices but does not include leachables/extractables (21 CFR 211.67, 21 CFR 610.11, 21 CFR 820.70, and 21 CFR 111.27). 1.4 The principles in this guide may also be used as a basis for setting occupational exposure limits. 1.5 The principles in this guide may be applied during the development and commercial manufacturing of small or large molecular weight medicines as well as isolated pharmaceutical intermediates. 1.6 Subsequent-product HBEL values may be set for specific routes of exposure (for example, oral, inhalation, and parenteral) when necessary (for example, because of differences in bioavailability) and for specific patient populations (for example, children) if formulations are manufactured in which one daily dose is not for the 50 kg standard adult but the dosage form is adjusted to a target population with a lower body weight. 1.7 The primary scope of this guide is to ensure the safety of human patients exposed to residual active substances and intermediates via medicinal products. The general principles of this guide can also be applied to the manufacture of veterinary medicinal products. However, there may be certain unique toxicological and pharmacological species-specific differences, such as metabolism and sensitivity, as well as assumptions such as body weight for veterinary medicines that are not addressed in this guide. 1.8 This guide may be used independently or in conjunction with other proposed E55 standards published by ASTM International. 1.9 Units— The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard. 1.10 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use. 1.11 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee. ====== Significance And Use ====== 4.1 Guidelines for unintended human exposure to active pharmaceutical ingredients (APIs) are required by various global regulations as part of international quality requirements, needed as good product stewardship, and are considered the industry standard. 4.2 Application of the approach described within this guide applies a scientifically justified, data-driven, approach to deriving safe limits for unintended exposures to individual substances. These limits can then be further used to calculate cleaning limits used in quality risk assessment for the manufacture of pharmaceuticals. The HBEL approach considers substance-specific properties (type of effect, potency, pharmacology, safety profile, and so forth). Specific approaches are applicable to different categories of substances and in specific stages in drug development. 4.3 The basis for the HBEL derivation is all available substance-specific data. Interpretation of these data considers the quantity and robustness of the database and the reliability and relevance of the data. Typically, adjustment factors (AFs) are used to address variability and uncertainty in different parameters to determine a safe human exposure limit, although alternative, purposefully conservative, approaches [for example, threshold of toxicological concern (TTC), read-across] may be used as appropriate. 4.4 This guide supports, and is consistent with, elements of the European Commission (EU) Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use ( 27 , 28 ) and guidance from the International Society of Pharmaceutical Engineers (ISPE) ( 29 ) in which it is mentioned that relevant residue limits should be based on a toxicological evaluation. 4.5 Key Concepts— This guide applies the following steps: ( 1 ) hazard characterization, ( 2 ) identification of the critical effect(s) including dose-response assessment, ( 3 ) determination of one or several points of departure (PoD)s, ( 4 ) application of PoD-specific AFs, and ( 5 ) calculation of HBELs including justification of selected HBEL ( 18 ) (see Fig. 1 ). FIG. 1 Process Underlying the Calculation and Final Selection of an HBEL Note 1: This figure represents an example where three possible PoDs have been selected based on three distinctive critical effects, followed by PoD-specific application of AFs and calculation of three HBELs.