ASTM E3219-25 基于健康的暴露限值（HBEL）推导指南-质量人文档

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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.

Designation:E3219-25

INTERNATIONAL

Standard Guide for

Derivation of Health-Based Exposure Limits(HBELs)

This standard is issued under the fixed designation E3219;the number immediately following the designation indicates the year of

original adoption or,in the case of revision,the year of last revision.A number in parentheses indicates the year of last reapproval.A

superscript epsilon(e)indicates an editorial change since the last revision or reapproval.

1.Scope

1.1 This guide describes the scientific procedures underly-

ing 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 ap-

proaches and nomenclature to the greatest extent possible.

1.3 This guide should be used for calculating and document-

ing 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 contami-

nation 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).

The forthcoming ICH Q3E guideline will address leachables/

extractables from manufacturing equipment.

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 spe-

cific routes of exposure(for example,oral,inhalation,and

parenteral)when necessary(for example,because of differ-

!This guide is under the jurisdiction of ASTM Committee E55 on Manufacture

of Pharmaceuical and Biopharmaceutical Products and is the direct responsibility of

Subcommittee E55.14 on Measurement Systems and Analysis.

Current edition approved March 15,2025.Published June 2025.Originally

approved in 2020.Last previous edition approved in 2020 as E3219-20.DOI:

10.1520/E3219-25.

ences 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 Inter-

national.

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 appro-

priate safety,health,and environmental practices and deter-

mine the applicability of regulatory limitations prior to use.

1.11 This international standard was developed in accor-

dance with internationally recognized principles on standard-

ization established in the Decision on Principles for the

Development of International Standards,Guides and Recom-

mendations issued by the World Trade Organization Technical

Barriers to Trade (TBT)Committee.

2.Referenced Documents

2.1 ASTM Standards:²

E29 Practice for Using Significant Digits in Test Data to

Determine Conformance with Specifications

E1262 Guide for Performance of Chinese Hamster Ovary

Cell/Hypoxanthine Guanine Phosphoribosyl Transferase

²For referenced ASTM standards,visit the ASTM website,www.astm.org,or

contact ASTM Customer Service at www.astm.org/contact.For Annual Book of

ASTM Standards volume information,refer to the standard's Document Summary

page on the ASTM website.

Copyright ◎ASTM Intermational,100 Barr Harbor Drive,PO Box C700,West Conshohocken,PA 19428-2959.United States

2

E3219-25

Gene Mutation Assay

E3106 Guide for Science-Based and Risk-Based Cleaning

Process Development and Validation

E3263 Practice for Qualification of Visual Inspection of

Pharmaceutical Manufacturing Equipment and Medical

Devices for Residues

F619 Practice for Extraction of Materials Used in Medical

Devices

F719 Practice for Testing Materials in Rabbits for Primary

Skin Irritation

F748 Practice for Selecting Biological Test Methods for

Materials and Devices

F750 Practice for Evaluating Acute Systemic Toxicity of

Material Extracts by Systemic Injection in the Mouse

F756 Practice for Assessment of Hemolytic Properties of

Materials

F763 Practice for Short-Term Intramuscular Screening of

Implantable Medical Device Materials

F813 Practice for Direct Contact Cell Culture Evaluation of

Materials for Medical Devices

F895 Test Method for Agar Diffusion Cell Culture Screening

for Cytotoxicity

F981 Practice for Assessment of Muscle and Bone Tissue

Responses to Long-Term Implantable Materials Used in

Medical Devices

F1408 Practice for Subcutaneous Screening Test for Implant

Materials

F1439 Guide for Performance of Lifetime Bioassay for the

Tumorigenic Potential of Implant Materials

F1903 Practice for Testing for Cellular Responses to Par-

ticles in vitro

F1983 Practice for Assessment of Selected Tissue Effects of

Absorbable Biomaterials for Implant Applications

F2382 Test Method for Assessment of Circulating Blood-

Contacting Medical Device Materials on Partial Throm-

boplastin Time(PTT)

F2808 Test Method for Performing Behind-the-Knee(BTK)

Test for Evaluating Skin Irritation Response to Products

and Materials That Come Into Repeated or Extended

Contact with Skin

F2888 Practice for Platelet Leukocyte Count—An In-Vitro

Measure for Hemocompatibility Assessment of Cardio-

vascular Materials

F2901 Guide for Selecting Tests to Evaluate Potential Neu-

rotoxicity of Medical Devices

F3127 Guide for Validating Cleaning Processes Used During

the Manufacture of Medical Devices

2.2 ISO Standards:³

ISO 10993-1 Biological evaluation of medical devices-Part

1:Evaluation and testing within a risk management

process

ISO 10993-4 Biological evaluation of medical devices-Part

4:Selection of tests for interactions with blood

ISO 10993-6 Biological evaluation of medical devices-Part

6:Test for local effects after implantation

³Available from American National Standards Insitute(ANSD),25W.43rd St.,

4th Floor,New York,NY 10036,http://www.ansi.org.

ISO 10993-10 Biological evaluation of medical devices-

Part 10:Tests for skin sensitization

ISO 10993-11 Biological evaluation of medical devices -

Part 11:Test for systemic toxicity

ISO 10993-17 Biological evaluation of medical devices -

Part 17:Toxicological risk assessment of medical device

constituents

ISO 10993-23 Biological evaluation of medical devices -

Part 23:Tests for irritation

ISO 17664 Processing of health care products -Information

to be provided by the medical device manufacturer for the

processing of medical devices

2.3 ICH Guidelines:⁴

ICH M7(R2) Guideline:Assessment and Control of DNA

Reactive(Mutagenic)Impurities in Pharmaceuticals to

Limit Potential Carcinogenic Risk -Questions and An-

swers

ICH M7(R2)Addendum Application of the Principles of the

ICH M7 Guideline to Calculation of Compound-Specific

Acceptable Intakes

ICH Q3A(R2) Impurities in New Drug Substances

ICH Q3B(R2) Impurities in New Drug Products

ICH Q3C(R9)Impurities:Guideline for Residual Solvents

ICH Q3D(R2) Guideline for Elemental Impurities

ICH Q9(R1)Quality Risk Management

ICH S9 Nonclinical Evaluation for Anticancer Pharmaceu-

ticals

2.4 Federal Regulations:⁵

21 CFR 111.27 What requirements apply to the equipment

and utensils that you use?

21 CFR 211.42(d) Design and Construction Features

21 CFR 211.46(d) Ventilation,air filtration,air heating and

cooling

21 CFR 211.67 Equipment cleaning and maintenance

21 CFR 211.176 Penicillin contamination

21 CFR 610.11 General safety

21 CFR 820.70 Production and process controls

2.5 Other Documents:

WHO 2021 Annex 2:Points to consider when including

Health-Based Exposure Limits(HBELs)in cleaning

validation,TRS 10336

3.Terminology

3.1 Definitions:

3.1.1 acceptable daily exposure,ADE,n—this term for a

health-based exposure limit(HBEL)is synonymous with the

term permitted daily exposure(PDE);see HBEL for details.

3.1.2 accumulation,n—progressive increase in the amount

of a substance in an organism or part of an organism that

4Available from International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use(ICH),ICH

Secretariat,9,chemin des Mines,P.O.Box 195,1211 Geneva 20,Switzerland,

http://www.ich.org.

5Available from U.S.Government Printing Office,Superintendent of

Documents,732 N.Capitol St.,NW,Washington,DC 20401-0001,http://

www.access.gpo.gov.

⁶Available from World Health Organization(WHO),Avenue Appia 20,1211

Geneva 27,Switzerland,https://www.who.int.

E3219-25

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occurs because the rate of intake from all routes of exposure

from repeated dosing exceeds the organism's ability to remove

the substance from the body,ultimately leading to a steady-

state tissue concentration higher than that associated from a

single dose.

3.1.3 adjustment factor;AF,n—numerical factor used in a

quantitative risk assessment to represent or allow for the

extrapolation,uncertainty,or variability of an observed expo-

sure concentration and its associated health outcome in a

particular laboratory species or exposed population to an

exposure concentration for the target population (for example,

from animals to human patients and short-term exposure to

chronic exposure)that would be associated with the same

deivered dose.

3.1.3.1 Discussion—Synonymous with the terms uncer-

tainty factor(UF),modifying factor(MF),and safety factor

(SF).Ideally,AFs are based on quantitative chemical-specific

toxicokinetic(TK)or toxicodynamic(TD)data or both and

consider factors such as interspecies extrapolation,duration of

exposure,intraspecies variability,severity of effect,and others.

Often,default AF values are used because of the absence of

chemical-specific TK and TD data.For the purposes of this

guide,the terms “pharmacokinetic(PK)”and “pharmacody-

namic(PD)"are essentially synonymous to “toxicokinetic"and

"toxicodynamic"in the context of HBEL setting.

3.1.4 adverse effect,n—test-item-related change in the

morphology,physiology,growth,development,reproduction,

or life span of an animal that likely results in an impairment of

functional capacity to maintain homeostasis or an impairment

of the capacity to respond to an additional challenge or both

(1-4 ).?

3.1.4.1 Discussion—A biologically significant pharmaco-

logical effect should be considered adverse when establishing

an HBEL for an unintended contaminant or residue.

3.1.5 benchmark dose/benchmark concentration,BMD/

BMC,n—mathematically derived dose of a substance that

produces a predetermined change in the response rate of an

adverse effect relative to the background response of this effect

(5-7).

3.1.5.1 Discussion—The BMD or BMC refer to central

estimates.The benchmark dose lower limit(BMDL)and

benchmark lower concentration(BMCL)refer to the corre-

sponding lower limit of a one-sided 95%confidence interval

on the BMD or BMC,respectively.

3.1.6 benchmark response,BMR,n—predetermined change

in the response rate of an adverse effect relative to the

background response rate of this effect (for example,10 %

response for quantal(“yes/no”)or continuous data)(5-7).

3.1.6.1 Discussion—The BMR is the basis for deriving

BMDs and BMCs

3.1.7 bioavailability,n—fraction of a substance that reaches

the systemic circulation after administration or exposure.

7 The boldface numbers in parentheses refer to a list of references at the end of

this standard.

3.1.8 carcinogen,n—agent that is capable of increasing the

incidence of malignant neoplasms,reducing their latency,or

increasing their severity or multiplicity.

3.1.8.1 Discussion—The induction of benign neoplasms

may,in some circumstances,contribute to the judgment that

the agent may be carcinogenic.The terms "neoplasms"and

“tumor”are used interchangeably (8).Carcinogens that are

likely causing tumors by interaction with deoxyribonucleic

acid(DNA)(genotoxic)are distinguished from carcinogens

causing tumors by other mechanisms not involving genotoxic-

ity(non-genotoxic).

3.1.9 clinically relevant,adj—biologically meaningful

change in patient health in response to exposure.

3.1.10 critical effect,n—first adverse effect,or its known

precursor,that occurs in the increasing dose/concentration

scale after appropriate adjustment for interspecies differences

and interindividual variability (9).

3.1.10.1 Discussion—The effect shall be relevant for the

target population(for example,unintended exposure to a

patient or a healthy employee),that is,it is both statistically

significant and clinically relevant.In this context,"critical

effect"means the lead effect is undesired but not necessarily

harmful in nature.The critical effect may result in the lowest

HBEL;however,there are exceptions.

3.1.11 drug allergy,n—immunologically mediated drug hy-

persensitivity reaction.

3.1.11.1 Discussion—Of the four types of hypersensitivity

reactions,Type I,an immediate IgE-mediated,hypersensitivity

reaction is the most common and is a true allergic reaction(10,

11).T-cell mediated (Type IV)hypersensitivity reactions are

delayed-type reactions and are the second most common.

3.1.12 genotoxicity,n—also genetic toxicity;the effect that

results from damage to DNA and altered genetic expression.

3.1.12.1 Discussion—The four types of genetic change are

gene mutation(change in DNA sequence within a gene),

chromosome aberration(changes in the chromosome

structure),aneuploidy/polyploidy(increase or decrease in the

number of chromosomes),and epigenetics(external changes to

DNA such as methylation).

3.1.13 general assessment factors,n—factors used to evalu-

ate the quality and relevance of scientific and technical

information.

3.1.13.1 Discussion—Five general assessment factors in-

clude soundness,applicability and utility,clarity and

completeness,uncertainty and variability,and evaluation and

review( 12),with the level of quality assurance applied to the

information is commensurate with the intended use of the

information and the degree of confidence necessary in that

information( 13).

3.1.14 generic drug,n—drug product that is comparable to

a brand/reference listed drug product in dosage form,strength,

route of administration,quality and performance

characteristics,and intended use.

3.1.14.1 Discussion—Biosimilars are generic biologics.

ASTM E3219-25 基于健康的暴露限值（HBEL）推导指南

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