ASTM E3219-20
(Guide)Standard Guide for Derivation of Health-Based Exposure Limits (HBELs)
Standard Guide for Derivation of Health-Based Exposure Limits (HBELs)
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-spe...
SCOPE
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 ...
General Information
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Standards Content (Sample)
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 − 20
Standard Guide for
1
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 (´) indicates an editorial change since the last revision or reapproval.
1. Scope 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
1.1 This guide describes the scientific procedures underly-
body weight.
ing the integrative interpretation of all data concerning an
1.7 The primary scope of this guide is to ensure the safety of
active pharmaceutical ingredient (API) taking into account
human patients exposed to residual active substances and
study adequacy, relevance, reliability, validity, and compound-
intermediates via medicinal products. The general principles of
specific characteristics (for example, potency, toxicological
this guide can also be applied to the manufacture of veterinary
profile, and pharmacokinetics) leading to a numerical value for
medicinal products. However, there may be certain unique
the API, which is used further in the quality risk management
toxicological and pharmacological species-specific differences,
(ICH Q9) of cross contamination during the manufacture of
such as metabolism and sensitivity, as well as assumptions
different products in the same manufacturing facilities.
such as body weight for veterinary medicines that are not
1.2 This guide describes general guidance for calculating
addressed in this guide.
and documenting a health-based exposure limit (HBEL). It
1.8 This guide may be used independently or in conjunction
should serve the involved qualified experts as a reference for
with other proposed E55 standards published by ASTM Inter-
HBEL derivations and should harmonize the different ap-
national.
proaches and nomenclature to the greatest extent possible.
1.9 Units—The values stated in SI units are to be regarded
1.3 This guide should be used for calculating and document-
as standard. No other units of measurement are included in this
ing an HBEL, when required or necessary, for APIs (including
standard.
biologics), intermediates, cleaning agents, excipients, and other
1.10 This standard does not purport to address all of the
chemicals (that is, reagents, manufacturing residues, and so
safety concerns, if any, associated with its use. It is the
forth) used for cleaning validation and verification (Guides
responsibility of the user of this standard to establish appro-
F3127 and E3106). In scope is the cleaning and cross contami-
priate safety, health, and environmental practices and deter-
nation of surfaces of manufacturing equipment and medical
mine the applicability of regulatory limitations prior to use.
devices but does not include leachables/extractables (21 CFR
1.11 This international standard was developed in accor-
211.67, 21 CFR 610.11, 21 CFR 820.70, and 21 CFR 111.27).
dance with internationally recognized principles on standard-
1.4 The principles in this guide may also be used as a basis
ization established in the Decision on Principles for the
for setting occupational exposure limits.
Development of International Standards, Guides and Recom-
1.5 The principles in this guide may be applied during the mendations issued by the World Trade Organization Technical
Barriers to Trade (TBT) Committee.
development and commercial manufacturing of small or large
molecular weight medicines as well as isolated pharmaceutical
2. Referenced Documents
intermediates.
2
2.1 ASTM Standards:
1.6 Subsequent-product HBEL values may be set for spe-
E1262 Guide for Performance of Chinese Hamster Ovary
cific routes of exposure (for example, oral, inhalation, and
Cell/Hypoxanthine Guanine Phosphoribosyl Transferase
parenteral) when necessary (for example, because of differ-
Gene Mutation Assay
ences in bioavailability) and for specific patient populations
E3106 Guide for Science-Based and Risk-Based Cleaning
(for example, children) if formulations are manufactured in
Process Development and Validation
1
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
2
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Subcommittee E55.14 on Measurement Systems and Analysis. contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Current edition approved Feb. 1, 2020. Published April 2020. D
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