ASTM E3418-23

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

• Status: Published
• Publication Date: 31-Oct-2023
• Technical Committee: E55 - Manufacture of Pharmaceutical and Biopharmaceutical Products
• Drafting Committee: E55.13 - Process Evaluation and Control

Overview

ASTM E3418-23 is a standard practice developed by ASTM International for calculating scientifically justifiable limits of residues following cleaning in pharmaceutical and medical device manufacturing equipment, and for finished medical devices. This standard offers a structured approach to establish residue limits that are both scientifically defensible and aligned with international regulatory expectations, supporting thorough cleaning validation practices.

The standard is tailored for use in pharmaceutical, biopharmaceutical, and medical device industries and extends to health, cosmetic, and consumer product manufacturing. It ensures that all equipment and product contact surfaces meet stringent residue criteria to minimize the risk of cross-contamination, safeguard consumer health, and comply with regulatory requirements.

Key Topics

• Scientific Basis for Residue Limits
  Emphasizes the derivation of cleaning limits based on health-based exposure limits (HBELs), toxicity, pharmacology, potency, and risk factors.
• Comprehensive Applicability
  Covers active pharmaceutical ingredients (APIs), intermediates, cleaning agents, processing aids, machining oils, and microbiological residues remaining on equipment or devices after cleaning processes.
• Regulatory Alignment
  Considers guidelines from agencies such as the US FDA, EMA, and references international standards, ensuring that residue limits are globally relevant and acceptable.
• Calculation Procedures
  Provides methods to calculate Maximum Safe Carryover (MSC) and Maximum Safe Surface Residue (MSSR) using parameters such as batch size and maximum daily dose.
• Visual and Analytical Limits
  Integrates statistical and risk-based approaches to ensure that residue is not only below calculated safety thresholds but, where feasible, not visible to qualified inspectors.
• Risk Management and Control
  Encourages risk assessment methodologies as part of limit determination, decision-making, and validation processes.

Applications

• Cleaning Validation
  Used in designing, executing, and validating cleaning processes for pharmaceutical and medical device manufacturing to ensure that surfaces are sufficiently clean for reuse.
• Regulatory Compliance
  Supports compliance with FDA, EMA, and international standards by providing scientifically justifiable data for residue limits.
• Equipment and Device Safety
  Minimizes cross-contamination risks and supports patient safety by establishing robust cleaning acceptance criteria.
• Process Optimization
  Assists manufacturers in identifying which equipment or areas require more stringent cleaning based on residue risk and in establishing monitoring plans.
• Risk Assessment for New Products
  Facilitates integration into quality risk management systems for new or modified products/processes, where established residue limits may need reassessment.
• Training and Documentation
  Serves as a foundational reference for developing internal SOPs, training materials, and documentation to demonstrate compliance during inspections or audits.

Related Standards

• ASTM E3219 – Guide for Derivation of Health-Based Exposure Limits (HBELs)
• ASTM E3106 – Guide for Science-Based and Risk-Based Cleaning Process Development and Validation
• ASTM E3263 – Practice for Qualification of Visual Inspection of Equipment and Devices for Residues
• ASTM E2476 – Guide for Risk Assessment and Risk Control in Pharmaceutical Manufacturing
• ISO 10993-17 – Biological Evaluation of Medical Devices: Allowable Limits for Leachable Substances
• ISO 13485 – Medical Devices – Quality Management Systems
• 21 CFR 211.67 – US FDA requirements for Equipment Cleaning and Maintenance
• Relevant USP Chapters – e.g., <1072> Disinfectants and Antiseptics; <61>, <62>, <85> Microbiological Assessments

Practical Value

ASTM E3418-23 provides manufacturers and quality professionals with a rigorous, risk-based framework for setting cleaning validation residue limits. By ensuring that residual substances are controlled within scientifically defensible thresholds, the standard helps safeguard patient safety, maintain product quality, and demonstrate regulatory compliance. Its clear procedures and reference to other international standards support streamlined implementation across diverse manufacturing contexts, making it an indispensable resource in the pharmaceutical, biopharmaceutical, and medical device industries.

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
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
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
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
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.
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 [e-mail]. For Annual Book of ASTM
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
E3418 − 23
F3127 Guide for Validating Cleaning Processes Used During 2.6 Other Standards:
the Manufacture of Medical Devices PDA TR 29 Points to Consider for Cleaning Validation
2.2 ICH Guidelines:
3. Terminology
ICH Q9 Quality Risk Management
3.1 Definitions:
2.3 ISO Standards:
3.1.1 acceptable daily exposure, ADE, n—represents a dose
ISO 10993-1 Biological Evaluation Of Medical Devices—
that is unlikely to cause an adverse effect if an individual is
Part 1: Evaluation and testing within a risk management
exposed, by any route, at or below this dose every day for a
process
lifetime.
ISO 10993-12 Biological Evaluation Of Medical Devices—
3.1.1.1 Discussion—This is the term used in the Interna-
Part 12: Sample Preparation And Reference Materials
tional Society of Pharmaceutical Engineers (ISPE) Risk-MaPP
ISO 10993-17 Biological Evaluation of Medical devices—
Guide (1) and is equivalent to the acceptable daily intake (ADI)
Part 17: Establishment of allowable limits for leachable
but is associated with any route of administration.
substances
3.1.2 action limit, n—an established value that, when
ISO 13485 Medical Devices – Quality management sys-
exceeded, indicates a process is outside of its normal operating
tems – Requirements for regulatory purposes
conditions.
ISO 14644-2 Part 2: Monitoring to provide evidence of
3.1.2.1 Discussion—A response to such an excursion re-
cleanroom performance related to air cleanliness by par-
quires a documented investigation, product impact assessment,
ticle concentration
and corrective actions based on the results of that investigation
ISO 14698 Cleanrooms and associated controlled environ-
(PDA TR 29). Action level of a parameter set by the user
ments
which, when exceeded, requires immediate intervention, in-
ISO 14937 Biocontamination control—Part 1: General prin-
cluding investigation of cause, and corrective action (ISO
ciples and methods
14644-2). An established microbial or airborne particle level
ISO 19227 Implants for Surgery—Cleanliness of orthopedic
that, when exceeded, should trigger appropriate investigation
implants
and corrective action based on the investigation (2).
ISO 21726 Biological Evaluation of Medical devices—
3.1.3 alert limit, n—an established value that, when
Application of the threshold of toxicological concern
exceeded, provides an early warning of a potential drift from
(TTC) for assessing biocompatibility of medical device
the normal operating conditions and validated state.
constituents
3.1.3.1 Discussion—This type of warning does require an
2.4 Federal Regulations:
appropriate documented investigation (for example, trend
21 CFR 211.67 Equipment Cleaning and Maintenance
analysis) and may require corrective actions depending on the
21 CFR 820 Quality System Regulation
results of the investigation (PDA TR 29). The alert limit is the
level of a parameter set by the user giving early warning of a
2.5 United States Pharmacopoeia:
drift from normal conditions, which, when exceeded, should
USP <61> Microbiological Examination Of Nonsterile—
result in increased attention or corrective action (ISO 14644-2).
Products: Microbial Enumeration Tests
An established microbial or airborne particle level giving early
USP <62> Microbiological Examination Of Nonsterile
warning of potential drift from normal operating conditions
Products: Tests For Specified Microorganisms
and triggers appropriate scrutiny and follow-up to address the
USP <85> Bacterial Endotoxins
potential problem. Alert limits are always lower than action
USP <161> Transfusion and Infusion Assemblies and Simi-
limits (2).
lar Medical Devices
USP <771> Ophthalmic Products—Quality Tests 3.1.4 analyte, n—a substance (usually a residue) for which
USP <1072> Disinfectants and Antiseptics
an analysis is being performed.
USP <1085> Guidelines on Endotoxins Test 3.1.4.1 Discussion—The residue determination may be
USP <1111> Microbiological Examination Of Nonsterile
qualitative, quantitative, specific, non-specific, and/or it may
Products: Acceptance Criteria For Pharmaceutical Prepa- involve compositional identification. The analyte may be
rations And Substances For Pharmaceutical Use determined as an extract or directly on the surface of the device
or portion (subassembly) of the device.
3.1.5 cleaning limit, n—highest level of residue that is
acceptable for exposure to the patient or on the medical device.
Available from International Council on Harmonisation of Technical Require-
ments for Registration of Pharmaceuticals for Human Use (ICH), ICH Secretariat,
3.1.5.1 Discussion—Cleaning limits are used to evaluate
9, chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland, http://
www.ich.org
cleaning process performance for pharmaceutical manufactur-
Available from International Organization for Standardization (ISO), ISO
ing equipment or medical device surfaces.
Central Secretariat, Chemin de Blandonnet 8, CP 401, 1214 Vernier, Geneva,
3.1.6 cleaning performance limit, n—performance-based
Switzerland, https://www.iso.org.
limit derived from the cleaning process data.
Available from U.S. Government Printing Office, Superintendent of
Documents, 732 N. Capitol St., NW, Washington, DC 20401-0001, http://
www.access.gpo.gov.
7 8
Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook Available from Parenteral Drug Association (PDA), 4350 East West Highway,
Pkwy., Rockville, MD 20852-1790, http://www.usp.org. Suite 600, Bethesda, MD 20814, www.pda.org.
E3418 − 23
3.1.6.1 Discussion—The HBEL-based limit can be used as be short-term (acute exposure), of intermediate duration, or
an action limit when this limit is low with appropriate scientific long-term (chronic exposure).
justification based on the level of risk. With low risk products
3.1.16 health based exposure limit, HBEL, n—represents a
the HBEL may be too high and alternative limits should be
dose that is unlikely to cause an adverse effect if an individual
identified (see Guide E3106).
is exposed, by any route, at or below this dose every day for a
3.1.7 cleaning process residue, n—any residue, including,
lifetime (see Guide E3219).
but not limited to, APIs, cleaning agents, degradation products,
3.1.16.1 Discussion—This is the term used in the European
intermediates, excipients, and microbes remaining after a
Medicines Association (EMA) Guideline on health based
cleaning process (see Guide E3106).
exposure limits (3) and is equivalent to the acceptable daily
3.1.7.1 Discussion—Residues may be physical, chemical, exposure (ADE) and the permitted daily exposure (PDE).
bioburden, endotoxin, and even visual. For medical devices, a
3.1.17 maximum safe carryover, MSC, n—maximum
residue is a substance present at the surface of an implant or
amount of carryover of a residual cleaning process residue
embedded therein that is not explicitly recognized and defined
(API, cleaning agent, degradant, and so forth) into the next
as part of the implant specification. It includes processing-
product manufactured without presenting an appreciable health
based residues as well. A residue may or may not pose a risk to
risk to patients (see Guide E3106).
patients.
3.1.17.1 Discussion—The MSC is calculated from the
3.1.8 cleaning qualification, n—a cleaning qualification HBEL (ADE/PDE) and the total number of doses in a
subsequent batch.
confirms the cleaning process design and demonstrates that the
commercial cleaning process performs as expected (see Guide
3.1.18 maximum safe surface residue MSSR, n—maximum
E3106).
amount of residual residue cleaning process residue (API,
cleaning agent, degradant, and so forth) that may remain on
3.1.9 cleaning validation, n—collection and evaluation of
manufacturing equipment or medical device surfaces without
data, from the cleaning process design stage through cleaning
presenting an appreciable health risk to patients (see Guide
at commercial scale, which establishes scientific evidence that
E3106).
a cleaning process is capable of consistently delivering clean
3.1.18.1 Discussion—The MSSR is calculated from the
equipment (see Guide E3106).
MSC and the total shared product contact surface area of the
3.1.10 cleaning verification, n—confirmation, through the
equipment or total surface area of the device that may result in
provision of objective evidence, that specified cleaning re-
2 2
patient exposure and is expressed in μg/cm , mg/in. , and so
quirements have been fulfilled (see Guide E3106).
forth. The MSSR is widely used in cleaning validation
3.1.11 contaminant, n—any material that potentially ad-
programs, such as cleaning process development studies,
versely impacts the assembly, the functioning of the device,
cleaning verification or qualification studies, analytical method
and/or shows undesirable interaction with the host.
validation recovery studies, as well as for qualification of
visual inspection.
3.1.11.1 Discussion—A contaminant may be a single com-
ponent or any combination of components. Examples of
3.1.19 permitted daily exposure, PDE, n—represents a
possible types of contaminants include: (1) biological or
substance-specific dose that is unlikely to cause an adverse
non-biological in nature; (2) living or dead; (3) particles or thin
effect if an individual is exposed at or below this dose every
films; (4) solid, liquid, or vapor; (5) organic or inorganic (see
day for a lifetime.
Guide F3127).
3.1.19.1 Discussion—This is the term used in ICH Q3C and
by the European Medicines Agency (EMA) and is equivalent to
3.1.12 control limits, n—limits on a control chart that are
both the ADE and ADI (4).
used as criteria for signaling the need for action or judging
whether a set of data does or does not indicate a state of
3.1.20 qualified expert, n—individual with specific
statistical control based on a prescribed degree of risk (see
education and training in toxicology/pharmacology/
Practice E2587).
pharmacotherapy and risk assessment methods that can apply
3.1.12.1 Discussion—Control limits can be used as "alert" the principles of toxicology to deriving an HBEL (see Guide
or "action" limits. Alert limits can be set at two standard E3219).
deviations and action limits can be set at three standard
3.1.20.1 Discussion—The European Medicines Agency
deviations.
states that health based exposure limits should be determined
by a person who has adequate expertise and experience in
3.1.13 decision interval, H, n—the distance between the
toxicology/pharmacology, familiarity with pharmaceuticals as
center line and the control limits (see Practice E2587).
well as experience in the determination of health-based expo-
3.1.14 decision interval multiplier, h, n—multiplier of stan-
sure limits such as occupational exposure levels (OEL) or
dard deviation that defines the decision interval, H (see
permitted daily exposure (PDE) (3).
Practice E2587).
3.1.21 recovery study, n—laboratory study combining the
3.1.15 exposure, n—process by which a human or animal
sampling method and analytical method to determine the
can come into contact with a hazard.
quantitative recovery of a specific residue for a defined surface
3.1.15.1 Discussion—Exposure may occur through any (see Guide F3127). Laboratory study evaluating a sampling
route (oral, inhalational, dermal, and so forth). Exposure may method (for example, swab, rinse, visual examination, and so
E3418 − 23
forth) in combination with an analytical method (for example, other conditions, or in the cure, mitigation, treatment, or
TOC, HPLC, visual inspection, and so forth) to determine the prevention of disease, in man or other animals, or intended to
quantitative recovery of a specific residue (see Guide E3106). affect the structure or any function of the body of man or other
3.1.21.1 Discussion—Recovery studies are performed by animals, and which does not achieve its primary intended
purposes through chemical action within or on the body of man
spiking specific residues onto a defined surrogate surface
(coupon) or onto surfaces of actual processing equipment or or other animals and which is not dependent upon being
metabolized for the achievement of any of its primary intended
onto actual medical devices and sampling these surfaces.
Adequate recovery should be defined and demonstrated to purposes (6).
3.2.5.1 Discussion—Instrument, apparatus, implement,
justify the appropriateness of the method (see Practice F2847).
Recovery should be shown to be possible from all product machine, appliance, implant, reagent for in vitro use, software,
contact materials sampled in the equipment with all the material or other similar or related article, intended by the
sampling methods used (5). If a reduction in the number of manufacturer to be used, alone or in combination, for human
product contact materials on which recovery studies should be beings, for one or more specific medical purpose and does not
performed is desired this may be possible if justified through a achieve its primary intended action by pharmacological, im-
risk assessment (for example, consider patient exposure from munological or metabolic means, in or on the human body, but
which may be assisted in its intended function by such means
product contact surface).
(ISO 13485).
3.1.22 surrogate surface, n—part that is used as a substitute
for a piece of manufacturing equipment or a medical device
3.2.5.1 Discussion—ISO 13485 states that the organization
surface (see Guide E3106).
shall establish documented requirements for cleanliness of
3.1.22.1 Discussion—For pharmaceuticals, surrogate sur-
product. Each manufacturer shall establish and maintain pro-
faces are typically "coupons" which are typically a rectangular
cedures to prevent contamination of equipment or product by
piece of a material of construction on which a known amount
substances that could reasonably be expected to have an
of a compound is deposited to simulate a cleaning process
adverse effect on product quality (21 CFR 820). These require-
residue. For medical devices, surrogate surfaces may be in the
ments would include the setting of acceptance criteria.
form of "coupons" but are often parts of a medical device, or
3.2.6 scientifically justifiable, adj—able to be shown to be
the entire medical device itself.
defensible based on solid scientific evidence.
3.1.23 visual residue limit (VRL), n—lowest level of a
3.2.6.1 Discussion—The FDA 1993 Cleaning Validation
2 2
cleaning process residue on a surface (in μg/cm or μg/in. ) that
Guidance Section IV Evaluation of Cleaning Validation (6)
is visible to a qualified inspector under defined viewing
specifies that "the objective of the inspection is to ensure that
conditions (see Practice E3263).
the basis for any limits is scientifically justifiable," and ". the
3.2 Definitions of Terms Specific to This Standard:
test of any validation process is whether scientific data shows
3.2.1 maximum daily dose, MDD, n—the highest dose that a that the system consistently does as expected and produces a
patient may be administered in one day (that is, 24 hours) and
result that consistently meets predetermined specifications."
is a daily dose limitation on certain drugs imposed by the Therefore, cleaning data should support a conclusion that
regulatory agencies for safety reasons. residues have been reduced to an "acceptable level." This
indicates that the data must be assessed for patient risk and
3.2.1.1 Discussion—The MDD is determined from the Dos-
evaluated. Within this context, residue limits based on HBELs
age and Administration (D&A) section of the reference listed
and residue limits based on statistical process control (SPC) are
drug (RLD) or reference standard (RS) labeling.
scientifically justifiable.
3.2.2 maximum number of applications, MNA, n—the maxi-
3.2.7 smallest batch size, n—batch size with the smallest
mum number of applications per day or the maximum number
volume or weight manufactured on shared equipment.
of times a product can be administered per day.
3.2.7.1 Discussion—The smallest batch size is an important
3.2.3 maximum number of units, MNDU, n—maximum
parameter in the calculation of safe limits as the smallest batch
number of units administered/day.
would have the highest concentration of residue carryover
3.2.4 maximum quantity, MQ, n—maximum quantity ad-
resulting in highest level of exposure to patients.
ministered in each dose/application.
4. Significance and Use
3.2.4.1 Discussion—This could be in the form of the weight
of a single unit (mg/unit); the maximum volume administered
4.1 Pharmaceutical Discussion:
in a single dose (in mL/dose); the volume of a drop (mL/drop); 4.1.1 The origins for the calculation of cleaning validation
the amount applied in each application (g/application or
limits for pharmaceuticals date back to the 1980’s with the
mL/application). publication of an article in 1984, that stated that "limits must be
3.2.5 medical device, n—an instrument, apparatus, safe and acceptable and in line with residual limits set for
implement, machine, contrivance, implant, in vitro reagent, or various substances in foods" (7). A second article in 1989
other similar or related article, including a component part or expanded upon these ideas adding that an "effect threshold"
accessory which is: recognized in the official National should be established in collaboration with toxicology and
Formulary, or the United States Pharmacopoeia, or any supple- medical authorities (or alternatively, an appropriate safety
ment to them, intended for use in the diagnosis of disease or factor. For example, 10× or 100× could be superimposed) and
E3418 − 23
finally that limits for surface residue levels could then be and median lethal dose (LD ) should no longer be used and
calculated based on a smallest batch size/maximum dose should be replaced with the limits based on the ADE (12-15).
combination. This article further mentioned that this calcula-
4.1.4 In 2015, EMA issued a guidance requiring the use of
tion leads to many limits that could be verified through visual
health based exposure limits (HBELs) for use in calculating
inspection (8). A third article in 1993, proposed the use of a
cleaning limits (2). This requirement has now been incorpo-
combination of limits suggesting that carryover of product
rated into the European and Pharmaceutical Inspection Co-
residues needed to meet these three criteria:
operation Scheme Good Manufacturing Practices (5 and 16)
(1) No more than 0.001 dose of any product will appear in
and has been adopted by Health Canada (17) and the World
the maximum daily dose of another product,
Health Organization (18).
(2) No more than 10 ppm of a product will appear in
4.2 Medical Device Discussion:
another product, and
(3) No quantity of residue will be visible on the equipment
4.2.1 The medical device industry is very broad and in-
after cleaning procedures are performed (9).
cludes many diverse devices that have been handled differently
4.1.2 In 1993, United States Food and Drug Administration
than pharmaceuticals.
(USFDA) issued a guide for its inspectors requiring that "the
4.2.2 For example, cleaning acceptance limits for implant-
basis for any limits must be scientifically justifiable" (6). In
able medical devices have been based historically on testing
1996, USFDA proposed that, in addition to penicillin, certain
after the cleaning process is completed by doing biological
"classes" of compounds would also need to be manufactured in
safety assessments that show that the final packaged product is
dedicated facilities and would expect manufacturers to identify
safe and effective (ISO 19227, ISO 10993-1). Initial cleaning
any drugs that present the risk of cross-contamination and to
limits might be derived from historical data on the same types
implement measures necessary to eliminate that risk (10).
of devices using the same manufacturing processes and mate-
Otherwise, nothing short of dedicated facilities or equipment
rials as a starting point and coupling that with clinical history
would be sufficient. In 2005, the European Medicines Agency
that shows the devices produced using this methodology are
(EMA) similarly announced that it would require dedicated
safe and effective. Then biological safety testing, including
facilities for certain medicines in addition to potent sensitizers
extractables, is performed on devices exposed to the validated,
(11).
controlled cleaning process.
4.1.3 In response to these pending regulatory requirements,
4.2.3 The extractables testing also shows that the limits that
a guideline was published in 2010 by ISPE which introduced
were established for other manufacturing residuals that carry
the concept of a health-based limit for calculating cleaning
through on the part after cleaning are also at levels low enough
limits known as the Acceptable Daily Exposure (ADE) (1). The
to mitigate any local or systemic adverse reaction (this may be
demonstration of adequate cleaning and control against ADE
derived limits could avoid facility or equipment dedication. toxicological risk assessment of the extractables test data as
Several articles were published discussing why the dose-based well as biological testing).
All medicinal products must have HBEls determined (2). Other chemical compounds identified as hazards to patients in the risk (hazard) identification step that cannot
be eliminated or replaced should have HBELs determined if acceptable safety assessments or risk assessments are not available (see Guide E3219). After HBELs have
been determined, manufacturing parameters such as batch sizes, maximum daily doses, total share surface areas, etc. are documented in the risk analysis step and used
to calculate safe limits for swab and rinse samples.
FIG. 1 ASTM E3106 Risk (Hazard) Identification and Risk Analysis Steps (modified from FIG. 3 in E3106)
E3418 − 23
4.2.4 While many medical devices use the approach de- determined for all compounds identified during the hazard
scribed above, some medical devices can benefit from using an identification of the cleaning risk assessment as shown in Fig.
HBEL approach similar to pharmaceuticals. If an HBEL 1 unless they can be excluded by available safety assessments
approach is used with a medical device, a risk assessment (this or risk assessments (see Guide E3219 and (19)). Guide E3219
could be the HBEL monograph (see Guide E3219)) should provides guidance for setting HBELs from investigational new
address other potential risks (for example, patient exposure at products to products in commercial distribution. HBELs
the tissue level) from residue levels on the device beyond the should be determined by qualified experts following Guide
general toxicological risk assessments typically performed for E3219 and in accordance with regulatory guidance and expec-
pharmaceuticals. tations (19 and 20).
4.2.5 Application of the approach described within this
5.2.1 Use of Substitute Limits—In certain cases, such as
guide applies science-based and risk-based concepts and prin-
with older drugs with limited toxicological/clinical data or
ciples for calculation of cleaning validation safe limits and
investigational new medicines in early phase clinical trials, as
performance-based limits (for example, statistical process con-
well as the raw materials used in many of the machining fluids
trol) introduced in Guide E3106.
and other processing aids used to produce a medical device,
there may be insufficient data to support the calculation of an
NOTE 1—All limit calculations in this standard assume there will be
HBEL. In these circumstances, scientifically justified limits
homogeneity of residue levels on equipment and device surfaces achieved
after an effective and consistent cleaning as per Guide E3106. may be used in place of a calculated HBEL. There are several
different approaches for establishing an HBEL that have been
4.2.6 Application of the approach described within this
used in the past, such as the thresholds of toxicological concern
guide applies the science-based and risk-based concepts and
(TTCs). TTCs have been determined through statistical analy-
principles for derivation of health based exposure limits
sis for several types of compounds (see ISO 21726 and Guide
introduced in Guide E3219.
E3219 Section 7: Incomplete Datasets with a High Level of
4.2.7 Application of the approach described within this
Uncertainty).
guide applies the science-based and risk-based concepts and
5.2.1.1 Substitute limits should not be seen as permanent or
principles for derivation of visual residue limits introduced in
as a replacement for a scientifically derived HBEL. As infor-
Practice E3263.
mation becomes available, appropriate HBELs should then be
4.2.8 Key Concepts—This guide applies the following key
determined.
concepts: (1) health based exposure limits, (2) quality risk
management, (3) science-based approach, (4) statistics-based
5.3 Calculation of the Maximum Safe Carryover (MSC) of
approach, (5) visual residue limits, and (6) statistical process
Residue into Next Product Batch—After the determination of
control (SPC) limits.
the HBELs, the next step is the calculation of the maximum
safe carryover (MSC) of the residue into the batch of the
5. Procedure
subsequently manufactured product. For chemical residues
5.1 Users of this standard should define what equipment
(such as the drug active or cleaning agent, etc.), this is the
should be included in the calculation of limits (for example,
maximum amount of residue carryover into the next batch that
single pieces of equipment vs. equipment trains). This decision
is considered safe and is typically given in milligrams or
should be based on a risk assessment of the cleaning process.
grams. MSC is calculated by multiplying the HBEL by the
This standard does not recommend calculating a single limit
smallest batch size (SBS) of the next product divided by the
for all cleaning processes for all equipment and manufacturing
maximum daily dose (MDD) of the next product. The SBS
trains within a facility.
divided by the MDD provides the total number of daily doses
5.1.1 For pharmaceuticals and those medical device prod-
in the batch of the next product. Multiplying the total number
ucts that use the HBEL, the equations used for calculating safe
of daily doses in the batch of the next product by the HBEL
and scientifically justified swab and rinse sample limits are
(maximum daily exposure that is safe) gives the maximum
comprised of three sub-equations:
amount of residue carryover on the equipment that is consid-
(1) HBEL,
ered to be safe.
(2) Maximum safe carryover (MSC), and
The MSC is calculated using the following equation:
(3) Maximum safe surface residue (MSSR).
SBS
5.1.2 The following sections will discuss the parameters
MSC 5 HBEL × (1)
MDD
used in the calculation of these sub-equations, how these
parameters should be determined or derived, and how they
5.3.1 The SBS is determined from the master batch records
interact with each other. The first three sub-equations are
of the products processed in the equipment under consider-
generally combined into one general equation that calculates
ation. The SBS should be used for calculating safe limits for
down to a safe analytical limit, usually a swab or rinse limit
each cleaning process under investigation.
(see 5.6).
5.3.2 Maximum Daily Dose (MDD)—The MDD may be
5.2 Calculating Health Based Exposure Limits (Guide determined from several sources. The simplest source is the
E3219)—The first step in the calculation of safe limits for medication package insert/outsert for the product (for example,
residues is the determination of the HBEL. HBELs are based ‘United States Package Insert’ or the ‘Summary of Product
on substance-specific properties (toxicity, type of effect, sever- Characteristics’ in the EU) which typically list specific maxi-
ity of effect, pharmacology, potency, etc.). HBELs should be mum daily dosing. The MDD may be given as "No more than
E3418 − 23
TABLE 1 Batch Sizes of Various Products Processed and
selection of the MDD should be made on a case-by case basis
Smallest Batch Size
and requires consideration of all current data for each IMP.
Products in Blender 3 Batch Size Selected Batch
5.3.4.1 Batch Size / Daily Dose Ratio (BS / DD) using
Q
Product A 500 kg
Quantities—When the batch size is the smallest batch size this
Product D 250 kg Smallest Batch Size
Product E 400 kg
refers to the smallest quantity (weight or volume) of the final
Products in Mixer 2 Batch Size Selected Batch
mix/blend of the subsequent product processed in the
Product P 125 Liters
equipment/equipment train. The BS can be expressed in kg or
Product Q 200 Liters Q
Product T 100 Liters Smallest Batch Size
L depending on the type of formulation. When the DD is the
Products in Tablet
Batch Size Selected Batch maximum (daily) dose this refers to the maximum dose of the
Packaging Line 4
subsequent product processed in the equipment/equipment
Product A 250 kg
Product F 100 kg Smallest Batch Size
train that can be administered in a day. It is generally expressed
Product G 150 kg
in mg/day or mL/day.
Product I 200 kg
Products in Liquid Filling
MDD 5 MNA × MQ (2)
Batch Size Selected Batch
Line 2
Example calculations are shown in Appendix X1.
Product S 75 Liters
Product T 50 Liters Smallest Batch Size
5.3.4.2 Where MNA is the maximum number of
Product U 100 Liters
administrations/applications per day or the maximum number
of times a product can be administered per day and MQ is the
maximum quantity administered in each dose/application. The
MDD used for the calculation of safe limits must include the
6 tablets a day" or "No more than 3 fl oz per day". If the
total weight of the unit dose (weight of API + weight of
medication package insert does not contain the MDD it may be
excipients) and not just the weight of API. Table 2 provides
necessary to contact the clinician(s) involved in the clinical
some examples of MNA and MQ values for the different
studies to obtain this value.
dosage forms.
5.3.3 Ratios of batch size to daily dose can be calculated in
three different ways in 5.3.4.1 – 5.3.4.4. 5.3.4.3 Batch Size / Daily Dose Ratio using Dosage Units
5.3.4 For investigational medicinal products (IMPs) when (SBS /MNDU)—SBS refers to the smallest number of
DU DU
the product is manufactured on the equipment, if the subse- dosage units manufactured per batch and is expressed in
quent product’s MDD is known it can be used in the product’s units/batch. MNDU is the maximum number of dosage units
MSC calculation and a limit derived. For IMPs lacking an administered per day and is expressed in units/day. This ratio is
MDD, a qualified toxicologist and the clinician responsible for the simplified form of the ratio discussed in 5.3.4.1. It can be
the IMP should be consulted to determine an appropriate used as an alternative to the SBS /M(D)D ratio for the
Q
MDD. Parameters the toxicologist and the clinician may calculation of MSC. The advantage of using this ratio is that it
consider include, for example, subject body weight, the HBEL does not require the estimation of weight or volume of a unit
if known, first-in-human doses, maximum tolerated dose, as dose or the entire batch. For products manufactured/
well as the steepness of the dose-response curve if known. The administered in dosage units, the total number of dosage units
TABLE 2 Examples of MNA and MQ for the Different Dosage Forms (21)
Dosage form MNA MQ Example
Solids – single dosage units (for The maximum number of The weight of a single unit (mg/ Dosage: One or two capsules orally every 6 to 12 hours.
example, tablet, capsule) dosage units that can be unit) Maximum number of capsules administered per day: 2 units ×
administered in a day (units/ (24 hours/day ÷ 6 hours) = 8 units ⁄day; Capsule weight:
day) 295 mg ⁄unit; MDD = 295 × 8 = 2360 mg/day
Liquids – oral, injectable The maximum number of times The maximum volume Dosage (cough syrup): 5 mL to 10 mL three or four times a day.
the product can be administered in a single dose Maximum number of times cough syrup administered per day:
administered in a day (in mL/dose) 4 administration ⁄day; The maximum quantity of a single dose:
10 ml ⁄administration; MDD = 4 × 10 = 40 mL/day Dosage
(Injectable): 10 mL four times a day. Maximum number of
injections per day: 4 injections ⁄day; The maximum quantity of a
single dose: 10 ml ⁄injection; MDD = 4 × 10 = 40 mL/day
Liquids – ophthalmic/otic drops The maximum number of Volume of a drop (mLs/drop) Dosage: One or two drops into each eye five (5) times daily.
drops that can be instilled in a Maximum number of drops instilled per day: 2 drops/application/
day (drops/day) eye × 2 eye × 5 application ⁄day = 20 drops/day; Volume of one
drop: 0.5 mL/drop MDD = 20 × 0.5 = 10 mL/day
Topicals (for example, topical The maximum number of Amount applied in each Dosage (topical ointment): 3 to 5 times daily with a maximum 2
cream, ointment, gel) applications per day application (g/application or mL/ finger tip units (FTUs) per application (21-23). Maximum number
A
(applications/day) application) of FTUs per application: 2 FTU/application; Maximum number of
applications per day: 5 application/day; Weight of 1 FTU:
0.5 g ⁄FTU; MDD = 2 × 5 × 0.5 = 5 g/day
A
The maximum quantity per application of many topical formulations (for example, shampoo, lotion, mouthwash) can be obtained from the Scientific Committee on
Consumer Safety notes (24).
E3418 − 23
in a batch can be calculated by dividing the quantity (weight or MSSR, which may be expressed for chemical residues in mass
volume) of the final mix by the quantity of a unit dose. That is, units per surface area (for example, μg/cm ), is expressed in the
following equation:
SBS ~units ⁄ batch! 5 SBS ~mg ⁄ batch or mL ⁄ batch!
DU Q
MSC
÷Unit Dose Quantity
MSSR 5 (4)
TSSA
mg ⁄ unit or mL ⁄ unit! (3)
~
Example calculations are shown in Appendix X1. This ap-
5.4.1 Total Shared Surface Area (TSSA)—The TSSA is the
proach is most applicable in packaging operations where
total area of the equipment that is shared between products.
batch sizes are typically expressed in dosage units rather That is, the surface area of a piece of equipment that more than
than kilograms. one product comes in contact with during processing.
NOTE 2—Areas identified as risks should be sampled during the
5.3.4.4 Batch Size / Daily Dose Ratio using API Quantities
validation.
(SBS )—SBS refers to the smallest batch size of the
Q-API Q-API
5.4.1.1 An alternative to the TSSA is when the concern is
API or the smallest batch quantity (weight or volume) of the
for carryover into a single, or several, unit doses rather than
API produced. This ratio is typically used for calculating the
into a full scale batch. This can be a concern for a filler nozzle,
MSC in API manufacturing setting. For finished products, it
or a tablet punch, where the risk of carryover may be primarily
can be used as an alternative to the ratios discussed in 5.3.4.1
at the start of vial filling or tablet compression and concern a
and 5.3.4.3. In the case of drug products, SBS refers to the
Q-API
single unit dose and not necessarily the entire batch. In these
quantity (weight or volume) of the API in the smallest batch
cases the TSSA may be set to the total inner surface area of the
size of the final mix of Product B. SBS is expressed in
Q-API
filler nozzle or the surface area of the punch head of the tablet
kilograms or liters.
punch. The batch size (BS) is then set to the size of the single,
5.3.4.5 MDD is the maximum daily dose of the API and
API
or several units being filled or to the weight of the tablet being
refers to the maximum dose of the API that can be administered
compressed. In general though, the initial units of a filling
daily or in a single (intermittent or lifetime) administration by
batch or compression batch are discarded due to production
a particular route of administration. When the information
issues (low fill volume, low tablet weight, etc.) and this
about the route of administration and dosage form of the
analysis may not be critical. However, this analysis addresses
product for which the API can be used is not available, then the
whether product residues are an issue for discarding initial
MDD should be defined based on a formal risk assessment.
API
units.
5.3.4.6 For finished products, it is the quantity of the API in
5.4.1.2 The MSSR is widely used in cleaning validation
the maximum daily dose of Product B. It is expressed in
programs, such as in cleaning process development/
mg/day or mL/day. When the maximum daily dose is given in
verification/validation studies, analytical method validation,
dose per kilogram body-weight (for example, mg/kg-bw/day),
swab/rinse sample recovery studies, as well as for qualification
it can be converted to the daily dose in mg/day by multiplying
of visual inspection (see Practice E3263).
the dose by the body-weight (in kilograms) of the population
5.5 Safe Limit in Analytical Samples—Once the MSSR is
that is expected to receive larger dose of the API. When a
determined, the safe limit in swab or rinse analytical samples
finished products consists of multiple APIs, the SBS and
Q-API
can be calculated. It should be noted that some of the sampling
MDD values of any API can be used for the calculation of
API
the ratio.
5.3.4.7 Device / Residue per Device for Medical Devices—
For products (for example, implants) that are not administered
TABLE 3 PDE Values for Class 2 Solvents in Pharmaceutical
on a daily basis, the administered dose should not be scaled-
Products from ICH Q3C
down to a daily dose. In such cases, the HBEL value of the
Solvent PDE (mg/day) Solvent PDE (mg/day)
cleaning process residue should be adjusted to a one time Acetonitrile 4.1 Methanol 30.0
Chlorobenzene 3.6 2-Methoxyethanol 0.5
exposure over the lifetime of the device and the largest possible
Chloroform 0.6 Methylbutyl ketone 0.5
patient exposure. For products that are administered on a
Cumene 0.7 Methylcyclohexane 11.8
Cyclohexane 38.8 Methylisobutylketone 45
replicate exposure (multiple times in a day), the administered
1,2- 18.7 N-Methylpyrrolidone 5.3
exposure should not be scaled to a daily exposure. In such
Dichloroethene
cases the value of the cleaning process residue is used as
Dichloromethane 6.0 Nitromethane 0.5
1,2- 1.0 Pyridine 2.0
calculated.
Dimethoxyethane
N,N- 10.9 Sulfolane 1.6
5.4 Maximum Safe Surface Residue (MSSR)—Because the
Dimethylacetamide
MSC is the total amount safe to carryover into the next
N,N- 8.8 Tetrahydrofuran 7.2
Dimethylformamide
manufactured product, it is also the total amount safe for
1,4-Dioxane 3.8 Tetralin 1.0
carryover onto shared equipment surfaces (that is, shared
2-Ethoxyethanol 1.6 Toluene 8.9
between the cleaned product and the next manufactured
Ethylene Glycol 6.2 1,1,2- 0.8
Trichloroethene
product). The maximum safe surface residue (MSSR) is
Formamide 2.2 Xylene 21.7
calculated by dividing the MSC by the total shared product
Hexane 2.9
contact surface of the equipment between the two products.
E3418 − 23
FIG. 2 Example Drawing of (V( Blender Showing Product Contact Areas
This Kettle has three different batch sizes but each batch size will have a different
product contact area. The 1500 gal batches may not contact the dome and upper
areas of the mixer shafts. All surfaces areas within the red outlined area must be
included in the total surface area calculation. As a worse case, some companies use
the total surface area of the equipment regardless of the batch size but it should be
understood that this will lower the safe limits. Although some companies may use
these lower surfaces area a risk assessment should be performed to identify any
points of concern where cleaning process residues may occur from the areas outside
the calculated area (for example, ve
...