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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 ( and guidance from the International Society of Pharmaceutical Engineers (ISPE) , )( 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 ( (see ) ).
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.
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 and ). 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.
2. Referenced Documents (purchase separately) The documents listed below are referenced within the subject standard but are not provided as part of the standard.
E1262 Guide for Performance of Chinese Hamster Ovary Cell/Hypoxanthine Guanine Phosphoribosyl Transferase Gene Mutation Assay
E3106 Guide for Science-Based and Risk-Based Cleaning Process Development and Validation
F619 Practice for Extraction of Medical Plastics
F719 Practice for Testing Biomaterials in Rabbits for Primary Skin Irritation
F748 Practice for Selecting Generic Biological Test Methods for Materials and Devices
F750 Practice for Evaluating Material Extracts by Systemic Injection in the Mouse
F756 Practice for Assessment of Hemolytic Properties of Materials
F763 Practice for Short-Term Screening of Implant 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 Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Insertion into Bone
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 Particles 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 Thromboplastin 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 CountAn In-Vitro Measure for Hemocompatibility Assessment of Cardiovascular Materials
F2901 Guide for Selecting Tests to Evaluate Potential Neurotoxicity of Medical Devices
|Link to Active (This link will always route to the current Active version of the standard.)|
ASTM E3219-20, Standard Guide for Derivation of Health-Based Exposure Limits (HBELs), ASTM International, West Conshohocken, PA, 2020, www.astm.orgBack to Top