ASTM E3418-23
(Practice)Standard Practice for Calculating Scientifically Justifiable Limits of Residues for Cleaning of Pharmaceutical and Medical Device Manufacturing Equipment and for Medical Devices
Standard Practice for Calculating Scientifically Justifiable Limits of Residues for Cleaning of Pharmaceutical and Medical Device Manufacturing Equipment and for Medical Devices
SIGNIFICANCE AND USE
4.1 Pharmaceutical Discussion:
4.1.1 The origins for the calculation of cleaning validation limits for pharmaceuticals date back to the 1980's with the publication of an article in 1984, that stated that "limits must be safe and acceptable and in line with residual limits set for various substances in foods" (7). A second article in 1989 expanded upon these ideas adding that an "effect threshold" should be established in collaboration with toxicology and medical authorities (or alternatively, an appropriate safety factor. For example, 10× or 100× could be superimposed) and finally that limits for surface residue levels could then be calculated based on a smallest batch size/maximum dose combination. This article further mentioned that this calculation leads to many limits that could be verified through visual inspection (8). A third article in 1993, proposed the use of a combination of limits suggesting that carryover of product residues needed to meet these three criteria:
(1) No more than 0.001 dose of any product will appear in the maximum daily dose of another product,
(2) No more than 10 ppm of a product will appear in another product, and
(3) No quantity of residue will be visible on the equipment after cleaning procedures are performed (9).
4.1.2 In 1993, United States Food and Drug Administration (USFDA) issued a guide for its inspectors requiring that "the basis for any limits must be scientifically justifiable" (6). In 1996, USFDA proposed that, in addition to penicillin, certain "classes" of compounds would also need to be manufactured in dedicated facilities and would expect manufacturers to identify any drugs that present the risk of cross-contamination and to implement measures necessary to eliminate that risk (10). Otherwise, nothing short of dedicated facilities or equipment would be sufficient. In 2005, the European Medicines Agency (EMA) similarly announced that it would require dedicated facilities for certain medicines in addition t...
SCOPE
1.1 This practice provides procedures for calculating safe and scientifically justifiable limits of residues for use in cleaning validation studies of pharmaceutical/biopharmaceutical/medical device manufacturing equipment surfaces and medical device surfaces.
1.2 The procedures in this standard practice for calculating safe limits of chemical residues are based on Guide E3219.
1.3 This practice applies to pharmaceuticals (including active pharmaceutical ingredients (APIs); dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) and medical devices following all manufacturing and cleaning. This practice is also applicable to other health, cosmetics, and consumer products.
1.4 This practice applies to all types of chemical residues (including APIs; intermediates, cleaning agents, processing aids, machining oils, etc.) that could remain on manufacturing equipment surfaces or on medical devices that have undergone all manufacturing steps including cleaning. This practice does not cover extractables and leachables (see ISO 10993-17).
1.5 This practice applies to microbiological residues that may be present on manufacturing equipment surfaces or on medical devices that have undergone all manufacturing steps including cleaning and does not cover disinfection or sterilization.
1.6 Exclusions—Medical devices that do not make patient contact; non-product contact surfaces (which are discussed in other existing guides: Ref (1)2, PDA TR 29, USP , Guide E2614, ISO 14698, and ISO 14937).
1.7 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
1.8 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 limit...
General Information
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: E3418 − 23
Standard Practice for
Calculating Scientifically Justifiable Limits of Residues for
Cleaning of Pharmaceutical and Medical Device
1
Manufacturing Equipment and for Medical Devices
This standard is issued under the fixed designation E3418; 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 1.7 The values stated in SI units are to be regarded as
standard. No other units of measurement are included in this
1.1 This practice provides procedures for calculating safe
standard.
and scientifically justifiable limits of residues for use in
1.8 This standard does not purport to address all of the
cleaning validation studies of pharmaceutical/
safety concerns, if any, associated with its use. It is the
biopharmaceutical/medical device manufacturing equipment
responsibility of the user of this standard to establish appro-
surfaces and medical device surfaces.
priate safety, health, and environmental practices and deter-
1.2 The procedures in this standard practice for calculating
mine the applicability of regulatory limitations prior to use.
safe limits of chemical residues are based on Guide E3219.
1.9 This international standard was developed in accor-
1.3 This practice applies to pharmaceuticals (including ac- dance with internationally recognized principles on standard-
tive pharmaceutical ingredients (APIs); dosage forms; and ization established in the Decision on Principles for the
over-the-counter, veterinary, biologics, and clinical supplies) Development of International Standards, Guides and Recom-
and medical devices following all manufacturing and cleaning. mendations issued by the World Trade Organization Technical
This practice is also applicable to other health, cosmetics, and Barriers to Trade (TBT) Committee.
consumer products.
2. Referenced Documents
1.4 This practice applies to all types of chemical residues
3
2.1 ASTM Standards:
(including APIs; intermediates, cleaning agents, processing
E2476 Guide for Risk Assessment and Risk Control as it
aids, machining oils, etc.) that could remain on manufacturing
Impacts the Design, Development, and Operation of PAT
equipment surfaces or on medical devices that have undergone
Processes for Pharmaceutical Manufacture
all manufacturing steps including cleaning. This practice does
E2586 Practice for Calculating and Using Basic Statistics
not cover extractables and leachables (see ISO 10993-17).
E2587 Practice for Use of Control Charts in Statistical
1.5 This practice applies to microbiological residues that
Process Control
may be present on manufacturing equipment surfaces or on
E2614 Guide for Evaluation of Cleanroom Disinfectants
medical devices that have undergone all manufacturing steps
F2847 Practice for Reporting and Assessment of Residues
including cleaning and does not cover disinfection or steriliza-
on Single-Use Implants and Single-Use Sterile Instru-
tion.
ments
E3106 Guide for Science-Based and Risk-Based Cleaning
1.6 Exclusions—Medical devices that do not make patient
Process Development and Validation
contact; non-product contact surfaces (which are discussed in
2
E3219 Guide for Derivation of Health-Based Exposure Lim-
other existing guides: Ref (1) , PDA TR 29, USP <1072>,
its (HBELs)
Guide E2614, ISO 14698, and ISO 14937).
E3263 Practice for Qualification of Visual Inspection of
Pharmaceutical Manufacturing Equipment and Medical
Devices for Residues
1
This practice is under the jurisdiction of ASTM Committee E55 on Manufac-
ture of Pharmaceutical and Biopharmaceutical Products and is the direct responsi-
bility of Subcommittee E55.13 on Process Evaluation and Control.
3
Current edition approved Nov. 1, 2023. Published November 2023. DOI: For referenced ASTM standards, visit the ASTM website, www.astm.org, or
10.1520/E3418-23. contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
2
The boldface numbers in parentheses refer to a list of references at the end of Standards volume information, refer to the standard’s Document Summary page on
this standard. the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
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E3418 − 23
F3127 Guide for Validating Cleaning Processes Used During 2.6 Other Standards:
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the Manufacture of Medical Devices PDA TR 29 Points to Consider for Cleaning Validation
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2.2 ICH Guideline
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