ASTM F3127-22

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: F3127 − 22
Standard Guide for
Validating Cleaning Processes Used During the Manufacture
of Medical Devices
This standard is issued under the fixed designation F3127; 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 Development of International Standards, Guides and Recom-
mendations issued by the World Trade Organization Technical
1.1 This guide provides considerations for validating clean-
Barriers to Trade (TBT) Committee.
ing processes for medical devices during initial fabrication and
assembly prior to initial use. Validated cleaning processes are
2. Referenced Documents
important for achieving consistency in function and consis-
tency in biocompatibility. The considerations include but are
2.1 ASTM Standards:
not limited to: validation approach, equipment design, proce- D543 Practices for Evaluating the Resistance of Plastics to
duresanddocumentation,analyticalmethods,sampling,devel-
Chemical Reagents
opment of limits, and other issues. E1766 Test Method for Determination of Effectiveness of
Sterilization Processes for Reusable Medical Devices
1.2 Inclusions:
E2857 Guide for Validating Analytical Methods
1.2.1 This guide describes the validation of critical cleaning
E3106 Guide for Science-Based and Risk-Based Cleaning
processes for medical devices to reduce contaminants to
Process Development and Validation
acceptable levels prior to packaging.
E3219 GuideforDerivationofHealth-BasedExposureLim-
1.3 Exclusions—The following items / medical devices /
its (HBELs)
processes are excluded from the scope of this document:
E3263 Practice for Qualification of Visual Inspection of
1.3.1 Reusable medical devices.
Pharmaceutical Manufacturing Equipment and Medical
1.3.1.1 Validation of cleaning operations for reusable medi-
Devices for Residues
cal devices is not within the scope of this standard guide.
F619 Practice for Extraction of Materials Used in Medical
Although cleaning of reusable medical devices is beyond the
Devices
scope of this guide, many of the principles outlined in this
F2459 Test Method for Extracting Residue from Metallic
guide may be applicable to the validation of cleaning opera-
Medical Components and Quantifying via Gravimetric
tions for reusable devices.
Analysis
1.3.2 Cleaning of medical devices in health care facilities.
F2847 Practice for Reporting and Assessment of Residues
1.3.2.1 Validation of cleaning processes in patient/health
on Single-Use Implants and Single-Use Sterile Instru-
care facilities is not within the scope of this standard guide.
ments
1.4 This standard does not purport to be a replacement for G121 Practice for Preparation of Contaminated Test Cou-
biological safety testing. pons for the Evaluation of Cleaning Agents
G122 Test Method for Evaluating the Effectiveness of
1.5 This standard does not purport to address all of the
Cleaning Agents and Processes
safety concerns, if any, associated with its use. It is the
G131 PracticeforCleaningofMaterialsandComponentsby
responsibility of the user of this standard to establish appro-
Ultrasonic Techniques
priate safety, health, and environmental practices and deter-
mine the applicability of regulatory limitations prior to use. 2.2 ANSI/AAMI/ISO Standards:
1.6 This international standard was developed in accor-
ISO 10993-5 Biological Evaluation of Medical Devices—
dance with internationally recognized principles on standard- Part 5: Tests for Cytotoxicity, In Vitro Methods
ization established in the Decision on Principles for the
1 2
This guide is under the jurisdiction of ASTM Committee F04 on Medical and For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Surgical Materials and Devices and is the direct responsibility of Subcommittee contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
F04.15 on Material Test Methods. Standards volume information, refer to the standard’s Document Summary page on
Current edition approved Oct. 1, 2022. Published October 2022. Originally the ASTM website.
approved in 2016. Last previous edition approved in 2016 as F3127 – 16. DOI: Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St.,
10.1520/F3127-22. 4th Floor, New York, NY 10036, http://www.ansi.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F3127 − 22
ISO 11737-1:2018 Sterilization of Health Care Products— 3.1.5 cleaning process, n—a process that is used to remove
Microbiological Methods—Part 1: Determination of a any product, process-related material, and environmental con-
Population of Microorganisms on Products taminant introduced as part of the manufacturing process.
ISO 14971 Medical Devices—Application of Risk Manage-
3.1.6 cleaning validation, n—the documented evidence pro-
ment to Medical Devices
viding a high degree of assurance that a cleaning process will
ISO 17025 General Requirements for the Competence of
result in medical devices consistently meeting their predeter-
Testing and Calibration Laboratories
mined cleanliness requirements.
ISO19227 ImplantsforSurgery—CleanlinessofOrthopedic
3.1.7 cleaning verification, n—a one-time sampling and
Implants—General Requirements
testing to ensure that a medical device has been properly
AAMI ST72 Bacterial Endotoxins—Test Methodologies,
cleaned following a specific cleaning event.
Routine Monitoring, and Alternatives to Batch Testing
3.1.8 contaminant, n—any material that potentially ad-
2.3 United States Pharmacopoeia (USP) – General Chap-
versely impacts the assembly, the functioning of the device,
ters:
and/or shows undesirable interaction with the host.Acontami-
USP<61> Microbiological Examination of Nonsterile Prod-
nant may be a single component or any combination of
ucts: Microbial Enumeration Test
components. Examples of possible types of contaminants
USP<62> Microbiological Examination of Nonsterile Prod-
include: (1) biological or non-biological in nature; (2) living or
ucts: Test for Specified Microorganisms
dead; (3) particles or thin films; (4) solid, liquid, or vapor; and
USP <85> Bacterial Endotoxins Test
(5) organic or inorganic.
USP <161> Transfusion and Infusion Assemblies and Simi-
lar Medical Devices
3.1.9 first use, n—the initial contact with biological materi-
USP <1225> Validation of Compendial Procedures
als or fluids.
2.4 International Conference on Harmonization of Techni-
3.1.10 installation qualification (IQ), n—establishing by
cal Requirements for Registration of Pharmaceuticals for
objective evidence that all key aspects of the process equip-
Human Use (ICH):
ment and ancillary system installation adhere to the manufac-
ICHQ2 ValidationofAnalyticalProcedures:TextandMeth-
turer’s approved specification and the recommendations of the
odology
supplier of the equipment are suitably considered.
ICH Q9 Quality Risk Management
3.1.11 monitoring, v—verification testing at predefined in-
2.5 FDA Guidance Documents:
tervals.
FDA Guidance Pyrogen and Endotoxins Testing: Questions
and Answers, issued June 2012 3.1.12 operational qualification (OQ), n—establishing by
objective evidence process control limits and action levels
2.6 European Standards and Pharmacopoeia:
which result in product that meets all predetermined require-
EN 13018 Non-Destructive Testing—Visual Testing—
ments.
General Principles
European Pharmacopoeia
3.1.13 process qualification (PQ), n—establishing by objec-
tive evidence that the process, under anticipated conditions,
3. Terminology
consistently produces a product which meets all predetermined
3.1 Definitions:
requirements.
3.1.1 analyte, n—a substance (usually a residue) for which
3.1.14 recovery study, n—a laboratory study combining the
an analysis is being performed.The residue determination may
sampling method and analytical method to determine the
bequalitative,quantitative,specific,non-specific,and/oritmay
quantitativerecoveryofaspecificresidueforadefinedsurface.
involve compositional identification. The analyte may be
3.1.15 residue, n—a substance present at the surface of an
determinedasanextractordirectlyonthesurfaceofthedevice
implant or embedded therein that is not explicitly recognized
or portion (subassembly) of the device.
and defined as part of the implant specification. It includes
3.1.2 blank, n—an analytical sample taken to establish the
processing-based residues as well as contamination by envi-
backgroundvalueforananalyticalmeasurementwhichmaybe
ronmental factors (adsorbates).
subtracted from an experimental value to determine the “true”
value.
4. Summary of Practice
3.1.3 clean, n—having a level of residues and environmen-
4.1 This guide provides an approach for validating the
tal contaminants which does not exceed a maximum permis-
removal of contaminants and residues introduced during the
sible level for the intended application.
intermediateprocessstepssothattheterminalcleaningprocess
3.1.4 cleaning, v—removal of potential contaminants from
can result in a consistently clean medical device.
an item to the extent necessary for further processing or for
intended use.
5. Significance and Use
5.1 This guide describes an approach to validate a cleaning
Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook
system for a medical device. It is based on the manufacturer’s
Pkwy., Rockville, MD 20852-1790, http://www.usp.org.
accurate and comprehensive understanding of their internal
Available from U.S. Food and Drug Administration (FDA), 10903 New
Hampshire Ave., Silver Spring, MD 20993, http://www.fda.gov. manufacturing and cleaning processes.
F3127 − 22
5.2 This guide is not intended to provide a detailed plan or 7.3.2 Device Design:
road map, but will provide considerations that can be used by 7.3.2.1 The design, material composition, and intended end
thedevicemanufacturertodevelopadetailedplanforperform-
use of the device have a significant impact on the suitability of
ing cleaning validation. a cleaning process. A non-exhaustive list of examples is
provided:
5.3 Incleaningvalidation,aswithothertypesofvalidations,
(1) Acleaning process that will not reach a blind hole in a
there are multiple ways to achieve a compliant, scientifically
medical device will not get the blind hole clean.
sound, and practical cleaning validation program.
(2) Densely populated electronics assemblies may not be
5.4 There are several reference documents identified in
readily accessed by cleaning chemistries. As a result, conduc-
Appendix X3 that describe cleaning validation approaches for
tive and non-conductive residue may remain.
non-medical devices (including cleaning for oxygen-enriched
(3) The cleaning process should not have an adverse effect
environments, pharmaceuticals, and semiconductors). Any of
on the materials of construction of the medical device, the
these reference documents could provide guidance for a
cleaning equipment, or the functionality of the medical device.
well-defined process for establishing a manufacturer’s mini-
For example, for plastic devices, Practice D543 may be used
mum expectation of a specific cleaning validation program.
for guidance on how to determine the suitability of specific
5.5 Thisguidancespecificallytargetscleaningvalidationfor cleaning agents to medical devices. Chemical compatibility of
medicaldevices,in-processandatterminalcleaningsothatthe
the cleaning process should be determined prior to cleaning
result is a consistently clean medical device that meets the process validation.
performance expectations for that device. (4) In some instances, the structure of the device or the
surface of the device may cause liquid or vapor-phase residue
6. General Requirements
to be entrapped. Such occurrences are generally not considered
6.1 This guidance for the validation of cleaning processes is
toconstituteamaterialscompatibilityproblem,iftheresidueis
dividedintothreesetsofactivities:understandingtheupstream
readily removed with extensive rinsing and/or drying (bake-
manufacturing process, documenting the cleaning process, and
out). However, given the potential negative impact on perfor-
establishingthemeasurementtoolsusedtoevaluatecleanliness
mance and/or interaction with the host, the design and mate-
and to establish the cleaning performance criteria.
rials of construction may qualitatively and quantitatively
impact the rinsing and/or drying portions of the cleaning
6.2 Preliminary process characterization, whether in the
process.
laboratory or on the manufacturing floor, provides the data
7.3.2.2 While the discussion of device design (design for
necessary to establish cleaning parameter control ranges.
cleanability) is critical to a cleaning validation, a full discus-
7. Cleaning Validation Approach
sion is not within the scope of this guide.
7.1 A typical approach to a cleaning validation includes: 7.3.3 Risk Analysis:
7.1.1 Anassessmentoftherisksandbenefitsofthecleaning
7.3.3.1 The risks and benefits associated with a specific
process and the impact of the cleaning processes on the
cleaning process should be addressed. There are a number of
medical device and on downstream processes.
approaches to evaluating the risks associated with a cleaning
7.1.2 Identification of contaminants from raw materials and
process, including those described in ISO 14971, ISO 19227,
manufacturing and processing operations (for example, ma-
Guide E3106, and ICH Q9.
chine oils) that could be residuals on the medical device.
7.3.3.2 The process risks evaluated should include the risk
7.1.3 Establishment of allowable limits for contaminants
to the patient.
(determining “How clean is clean?”) based on the product and
7.3.3.3 All cleaning operations should be considered, in-
process needs.Acceptance criteria for “clean” should be stated
cluding processes conducted by contract manufacturers.
with scientific justification for the criteria.
(1) Some cleaning operations may not be termed cleaning,
7.1.4 Avalidationoftheanalyticalmethodsusedtomeasure
and the terminology may be specific to a given technical field.
the residues or contaminants.
Passivation, surface preparation, and surface modification may
7.1.5 A qualification or determination of the sampling
or may not have a cleaning function. The manufacturer should
techniques used for evaluating the cleanliness of a medical
determine the function and efficacy of each process.
device.
(2) If an in-process cleaning operation is considered to be
7.1.6 A determination that statistical requirements and
critical and therefore should be validated, acceptance limits for
documentation are adequate to conclude that the result of
thisin-processoperationmaybeestablishedbyconsideringthe
testing meets the output specification of the process.
effect of residue levels after this operation on the final residue
levels of the device following the final cleaning step. For
7.2 A general process flow for a cleaning validation pro-
example, a manufacturer may perform an OQ on this in-
gram is presented in Fig. 1.
process step to see what in-process residue levels start to
7.3 Definition of the Cleaning Process:
impact the final residue levels beyond their acceptable levels.
7.3.1 The definition of the process should include an evalu-
By reducing the in-process residue levels below this limit, the
ation of the device, the equipment to be used for the cleaning
manufacturer can establish the process conditions for validat-
process, the process parameters, the process chemicals, and the
ing this in-process operation.
manufacturing materials that should be removed by the pro-
cess. NOTE 1—In-process cleaning validations may also apply if cleaning is
F3127 − 22
FIG. 1 Process Flow for a Cleaning Validation
critical to a subsequent process step, such as bonding or inspection steps
7.3.4 In-process cleaning operations that are not critical to
requiring a clean part.
subsequent processes or the final product could be included in
7.3.3.4 Risks that should be considered include the impact other process validation activities or, if appropriately justified,
on the subsequent process yields or the potential for carryover may not need to be validated.
of residue to the next process or the final product. 7.3.5 Cleaning Process Development:
F3127 − 22
7.3.5.1 The process development should include the devel- (5) The procedures for documenting and approving the
opment of a process flow chart. qualification.
7.3.6.2 The qualification plan should also include the re-
7.3.5.2 Theprocessflowchartshouldbeginwiththeprocess
quirements for the evaluation of changes. Qualification activi-
steps immediately after the previous validated cleaning step
ties should be documented and summarized in a report with
(allstepssubsequenttothepreviousvalidatedcleaningstepare
conclusions that address criteria in the plan.
residue inputs to the current cleaning step). The process flow
7.3.6.3 Installation qualifications (IQ) should be performed
chart should end after the cleaning operation and should
on all equipment used in the cleaning process prior to any OQ
includeanevaluationoftheimpactofthecleaneddeviceonthe
or PQ execution. At a minimum the IQ should include
subsequent operations.
verifications that utility systems and equipment are built and
7.3.5.3 The process flow chart and an appropriate list of
installed in compliance with the design specifications (for
materials should be detailed enough to identify all of the
example, built as designed with proper materials, capacity, and
materials (including metalworking fluids, polishing
functions, and properly connected and calibrated).
compounds, glove contaminants, cleaning agents, etc.) that
come in contact with the in-process component or medical
NOTE 2—Tests for equipment safety, functional features, training of
personnel, software validation, and other necessary tests to ensure quality
device. Without knowing the contact materials, the definition
and traceability have been performed prior to OQ execution, and the
of an adequate cleaning process is incomplete.
results remain at pre-defined requirements until the conclusion of the OQ.
(1) The device manufacturer should work with the suppli-
7.3.6.4 The operational qualification (OQ) establishes the
ers of process materials to ensure that a consistent composition
ability of the processing equipment to execute the cleaning
is obtained. Identifying the composition of process materials
operation within the allowable process parameters. At a
includes,ataminimum,obtainingaMaterialSafetyDataSheet
minimum, the OQ should include verification that utility
(MSDS). However, the focus of an MSDS is worker safety
systems and equipment operate in accordance with the process
issues and therefore may not reveal ingredients that may have
requirements in all anticipated operating ranges. This should
an undesirable interaction with the process, with the device, or
include challenging the equipment or system functions while
with the patient. Further, many process materials, notably
under load comparable to that expected during routine produc-
metalworking fluids and cleaning agents, may be complex
tion. It should also include the performance of interventions,
blends where individual components are present at levels that
stoppage,andstart-upasisexpectedduringroutineproduction.
do not have to be listed on the MSDS.
Operating ranges should be shown capable of being held as
7.3.5.4 The device manufacturer should work with the
long as would be necessary during routine production. Worst-
suppliers of process materials to develop a plan for managing
case product should be tested at the process challenge condi-
product changes. Any changes to product design or manufac-
tions.
turing process or processing materials have the potential to
7.3.6.5 Cleaning processes are generally comprised of mul-
adversely impact final product efficacy, and thus, must be
tiple steps. Each critical step of the process shall have a
assessed.
function and a set of parameters that are controlled within
7.3.5.5 Based on the process flow and the risk analysis, a
defined ranges to ensure effective residue or contaminant
validation plan that identifies all validation activities required
removal. The process parameters for each critical step of the
to demonstrate the suitability and effectiveness of the cleaning
process shall be identified and specified in detail and should be
process should be developed. The validation plan should
based on empirical evidence.
provide rationale for product type groupings, process
7.3.6.6 Factors to identify and specify in detail may include
definition, sample size selection, numbers of runs, types of
the use and type of detergents, solvent grade and lot
analyses, and acceptance criteria. Validation bracketing or
information, the presence of an acid cleaning step, the concen-
grouping approaches may be utilized. Possible criteria for
tration of cleaning agents, the contact time of cleaning agents,
defining cleaning groups should be but are not limited to:
feed pressure or flow rate, cleaning temperature, sonication
cleaning equipment, cleaning program, process flow, device
energy, ultrasonic frequency, spray pressures, required length
characteristics (such as such as geometry, base material,
or volume of rinse steps, required conditions for drying and/or
surface finish, mated components, functionality, critical
bake-out, length of time or number of parts between tank
features), and contact materials.
clean-out cycles, and the wait time between cleaning steps in
7.3.6 Process Qualification:
addition to other process specific parameters.
7.3.6.1 The plan should consider the requirements of use 7.3.6.7 Each cleaning process line should be considered
and can incorporate risk management to prioritize certain independently. The burden of validation for multiple cleaning
activities and to identify a level of effort in both the perfor- lines might be reduced based on identical cleaning equipment
and processes (that is, process equivalency). Each firm is
mance and documentation of qualification activities. The plan
should identify the following items: responsible for determining and justifying the specific criteria
for cleaning equivalency between cleaning processes.
(1) The studies or tests to use,
(2) Acceptance criteria,
7.3.6.8 The process qualification (PQ) combines the actual
(3) The timing of qualification activities, facility, utilities, equipment (each now qualified), and the
(4) The responsibilities of relevant departments and the
trained personnel (including required training programs) with
quality unit, and the commercial manufacturing process, control procedures,
F3127 − 22
and components to produce commercial batches. A successful 7.3.8.2 Any changes in the process flow (addition of new
PQ should confirm the process design and demonstrate that the equipment, changes to the process parameters, changes to
cleaning process performs as expected. The decision to begin
upstream processes or processing materials, changes to the
manufacturing should be supported by data from commercial-
cleaning agents, etc.) should be assessed. The necessity of
scale batches.
re-validation or verification and the extent of it should be
7.3.6.9 Laboratory data from pilot studies performed prior
risk-based.
to the qualification can provide assurance that the process
7.3.8.3 Routine monitoring data used with periodic reviews
qualification will demonstrate adequate performance.
could provide data to justify continued processing without
7.3.6.10 The approach to PQ should be based on sound
revalidation.
science,theoveralllevelofproductandprocessunderstanding,
7.3.9 Documentation:
and demonstrable control. The cumulative data from all rel-
7.3.9.1 The process inputs for the cleaning process should
evant studies (for example, designed experiments; laboratory,
be defined and documented.
pilot, and commercial batches) should be used to establish the
7.3.9.2 The documentation of the cleaning process should
process conditions for the PQ. To understand the production
include, but not be limited to, documenting all critical, vali-
cleaning process sufficiently, the manufacturer will need to
dated parameters. Following is a list of examples:
consider the effects of scale. However, it is not typically
(1) Water quality (and conditioning/treatment),
necessary to explore the entire operating range at production
scale if assurance can be provided by process design data. (2) Solvent quality,
Previous credible experience with sufficiently similar devices (3) Makes, models, and serial numbers of the equipment,
and processes can also be helpful. In addition, objective
(4) Verification of preventative maintenance of tanks to
measures (for example, statistical metrics) are strongly recom- prevent contamination buildup,
mended wherever feasible and meaningful to achieve adequate
(5) The concentration of cleaning agents,
assurance.
(6) Cleaning agent type (brand and manufacturer),
7.3.6.11 In most cases, PQ will have a higher level of
(7) The contact time of cleaning agents,
sampling, additional testing, and greater scrutiny of process
(8) Feed pressure or flow rate of cleaning agents,
performance than would be typical of routine production. The
(9) Cleaning temperature,
level of monitoring and testing should be sufficient to confirm
(10) Cleaning agitation requirements,
uniform product quality throughout the batch. The sample size
(11) Verified delivered ultrasonic power (when used),
should be statistically justified for each objective acceptance
(12) Bubbling parameters,
criterion. A minimum of three production lots should be
(13) Spray parameters (when used),
evaluated to capture production variation prior to cleaning.
(14) Current density in electrolytic descaling systems,
7.3.7 Routine Monitoring:
(15) Required length or volume of rinse steps, and change-
7.3.7.1 An output of the cleaning validation should include
out cycle (max number of parts cleaned or cleaning cycles
establishment of ongoing routine process monitoring at prede-
performed prior to a change),
termined intervals.
(16) Required drying conditions,
7.3.7.2 The collection and evaluation of information and
(17) Rack configurations,
data about the performance of the cleaning process should
(18) Rack quantities (min and max quantities in the racks,
allow detection of undesired process variability. Evaluating the
and min and max quantities of racks should be considered for
performance of the cleaning process can identify problems and
validations. Standard loading conditions will be defined, along
determines whether action should be taken to correct,
with worst-case loading conditions. Note that there should be
anticipate, and prevent problems so that the cleaning process
evidence to justify worst case conditions), and
remains in control.
(19) Wait times between process steps.
7.3.7.3 An ongoing program to collect and analyze product
7.3.9.3 Thedocumentationofthecleaningvalidationshould
and process data that relate to product quality should be
include:
established. The data collected should include relevant clean-
(1) Process flow diagrams,
ingprocessparametermonitoring,trendsandqualityofincom-
(2) Process risk assessments,
ing materials or components, in-process material, and cleanli-
(3) Validation plans (including, but not limited to: catego-
ness of finished devices.
rization of devices, sample size selection and rationale, num-
7.3.7.4 The data should be statistically trended and re-
bers of runs, types of analyses, positive and negative controls
viewed.Theinformationcollectedshouldverifythatthedevice
used in analytical methods, analytical method validation, and
cleanliness is being appropriately controlled throughout the
acceptance criteria),
process.
(4) IQ, OQ, and PQ protocols and reports,
7.3.7.5 The methods used for monitoring the cleaning pro-
(5) A written statement providing a conclusion about the
cess should be included in the cleaning validation process.
suitability of the process to clean effectively,
7.3.8 Re-Validation:
(6) Criteria for routine monitoring, and
7.3.8.1 Another output of the validation activities should be
(7) Criteria for re-validation.
a schedule for periodic consideration of re-validation of the
cleaning processes. 7.4 Acceptance Limits:
F3127 − 22
7.4.1 Theprocesscleanlinessrequirementshouldbedefined Answers for endotoxins and for guidance on methods to
and documented. The process output requirement as well as evaluate biological contamination.
expected end use and risk analysis factor into the definition of 7.4.6 Notethatthereareconditionsandcleaningparameters
cleanliness. in which the cleaning agent itself can leave or create unaccept-
able residues/contaminants or alter the surface of the compo-
7.4.2 The output requirements (measurements of residue
nent. The cleaning agent should be treated exactly like any
levels) of the cleaning process should be determined,
other process residue or contaminant. Acceptance criteria for
established, and justified by the manufacturer. These criteria
residual cleaning agents should be established just as they are
for “clean” or acceptance limits should be stated with scientific
for any process material, and analytical techniques shall be
justification (see Appendix X1).
established for measuring the residual cleaning compounds.
7.4.3 Therearemanywaystoestablishacceptancelimitsfor
Manufacturers of cleaning agents can sometimes contribute
a cleaning process.
appropriate certification and testing or testing methods. The
7.4.3.1 For existing processes, analysis of current compo-
composition of some complex cleaning agent blends may have
nents or product, analysis of product taken from the field,
to be changed in response to safety and/or environmental
and/or analysis of product returned due to expiration can be
regulatory considerations, and such changes may result in
helpful in establishing a baseline result that reflects the current
undesirable cleaning and/or unacceptable surface residue.
state. The current state may provide an acceptable rationale of
Therefore, part of the quality program should include provi-
suitability, assuming no associated complaints or adverse
sions for notification of such changes by suppliers.
events that can be tied to manufacturing material residues or
contaminants.
8. Analytical Methods
7.4.3.2 For new processes, or processes with limited prod-
uctclinicalhistory,severaltechniquescanbeusedtodetermine 8.1 Use of appropriate analytical methods is essential to any
the suitability of cleaning including quantifiable specific and cleaning validation program. Analytical methods shall be
non-specific methods and qualitative methods. demonstrated to adequately detect the residues of concern at or
preferably below the acceptable limits. Additionally, adequate
7.4.3.3 Limits should be established using a risk-based
recovery shall be defined and demonstrated to justify the
approach. Guide E3219 provides a scientifically justified,
appropriateness of the method (see Practice F2847). Selection
data-driven approach to deriving health-based exposure limits
of an analytical method depends on the nature and level of the
forunintendedexposurestoindividualsubstances.Theselimits
expected residue after the cleaning process.
may then be further used to calculate cleaning limits used in
quality risk assessment for medical devices.
8.2 If a method results in a “non-detectable” or “non-
7.4.3.4 For manufacturing materials that do not have well-
quantifiable” response at a level that is higher than the
studied toxic responses, appropriate data may need to be
acceptable limits, then it is not an appropriate method.
developed to justify the suitability of residue limits. ANSI/
8.2.1 The limit of detection (LOD) is generally defined as
AAMI/ISO 10993-5 and Guide E3219 provide guidance on
three times the standard deviation of the blank.
either limits or methods to establish suitable limits for manu-
8.2.1.1 For instrumental methods, this limit is often consid-
facturing materials that are not well studied.
ered to be three times the average value of the noise.
7.4.4 Visual inspection techniques, which should be the first
8.2.1.2 An alternative method for determining the LOD is
cleanliness inspection step, are often used to evaluate the
basedondetectabilitythroughanalysisofserialdilutionsofthe
aesthetics like “visually clean” (at some defined level of
residues in questions. Using this method the LOD can be
magnification and under defined lighting conditions), visible
calculated from the regression curve:
debrisorresidue,consistentcolor,discoloration,orpresenceof
LOD 5y-intercept13*SE standard error of the regression line
~ !
surface imperfections. See Practice E3263 or EN 13018 for
(1)
guidance on visual methods and validation.
7.4.5 Microbiological control is not required for cleaning 8.2.1.3 Samples that are at a level at or below the limit of
validation unless it is a final cleaning process before packaging detection are referred to as “non-detectable.”
in a clean room. The microbiologically clean requirements are 8.2.2 Thelimitofquantitation(LOQ)isgenerallydefinedas
associated with bioburden limits of the finished device. ten times the standard deviation of the blank.
However, it may also be applied to in-process cleaning 8.2.3 For instrumental methods, this is often considered to
operations to minimize the carryover of microbial contamina- be ten times the average value of the noise.
tion to subsequent operations. In that respect, the differentia- 8.2.4 An alternative method for determining LOQ is based
tion between viable populations of microorganisms (biobur-
on detectability through analysis of serial dilutions of the
den) and residue of microorganisms (endotoxins) should be residues in question. Using this method the LOQ can be
considered. Endotoxin evaluation could be considered part of a
calculated from the regression curve:
validated cleaning process depending on the intended use of
LOQ 5y-intercept110*SE ~standard error of the regression line!
the device and for devices with specific patient contact. See for
(2)
example ISO 11737-1, Test Method E1766, USP <61> for
bioburden; ANSI/AAMI ST72, USP <85>, USP <161>, Sec- 8.2.5 Samples that are at a level at or above the limit of
tion 2.6.14 of the European Pharmacopoeia, and FDA Guid- detection, but below the limit of quantitation, are referred to as
ance on Pyrogen and Endotoxins Testing: Questions and “non-quantifiable.”
F3127 − 22
8.3 The specificity and limit of detection (sensitivity) of the 8.9.3.5 Gel electrophoresis (sodium dodecyl sulfate (SDS)
analytical method used to detect residues or contaminants polyacrylamide gel electrophoresis (PAGE)),
should be determined. 8.9.3.6 Inductively coupled plasma (ICP), and
8.9.3.7 X-ray photoelectron spectroscopy (XPS)/electron
8.4 If levels of contamination or residue are not detected, it
spectroscopy for chemical analysis (ESCA).
does not mean that there is no residual contaminant present
8.10 Non-Specific Analytical Methods:
after cleaning. It only means that the levels of contaminant
greater than the sensitivity or detection limit of the analytical 8.10.1 There are several non-specific analytical methods
that can be useful for detecting the presence of residues or
method are not present in the sample.
contaminants.
8.5 All methods of evaluation of process output (whether
8.10.2 Non-specific methods measure a general property
quantitative or qualitative, or specific or non-specific) should
which could be a combination of residues or contaminants.
be evaluated to establish method suitability (adequate limits of
8.10.3 The advantage of non-specific methods is that they
detection and quantitation), accuracy, precision, linearity,
provide a measurement of total levels of residues or contami-
range, reliability, and robustness. For example, visual exami-
nants of a given type: organic, inorganic, biologic, particulate,
nation may not be adequate to identify the presence of
etc.
microgram quantities of aqueous cleaning agent residue. Test
8.10.4 Examples of methods that are not specific to a
suitability should be demonstrated and justified based on data.
particular contaminant include:
Guide E2857, USP <1225>, ICH Q2, and ISO 17025 are
8.10.4.1 Gravimetric analysis (non-volatile residuals—
standards that describe analytical method validations.
NVR),
8.6 The analytical method should be challenged in combi-
8.10.4.2 Total organic carbon (TOC),
nation with the sampling method used to show that contami-
8.10.4.3 Particulate analysis,
nants can be recovered from the device and at what level (for
8.10.4.4 Conductivity,
example, 50 % recovery; 90 % recovery) they can be recov-
8.10.4.5 Visual inspection, and
ered.
8.10.4.6 Water contact angle.
NOTE3—TestMethodF2459requires75 %recoveryonthegravimetric
8.11 Microbiological Test Methods:
analysis.
8.11.1 Control of the bioburden and endotoxin in a cleaning
8.7 Inspection processes that only yield a pass/fail result
process is important to ensure that subsequent sterilization or
cannot be qualified using standard repeatability and reproduc-
sanitization procedures achieve the necessary sterility assur-
ibility testing (R&R) techniques, so in these cases fault seed
ance. Methods to evaluate residual bioburden include ANSI/
testing (or other options for qualifying pass/fail testing) can be
AAMI ST72, USP <85>, and ANSI/AAMI/ISO 11737-1.
used. Fault seed testing can be conducted by randomly testing
8.11.2 Depending on the medical device, both bioburden
both acceptable and unacceptable product, and verifying that
and endotoxin are monitored and controlled during the manu-
the inspection process yields the desired disposition. The
facturing and/or cleaning processes.
inspector should not know which product is acceptable, and
8.12 Biocompatibility Testing:
ideally should be unaware that the process is being tested.
8.12.1 Biocompatibility testing (for example, cytotoxicity
Acceptance criteria are then based on the criticality of the
attribute being inspected. For automated processes, generally as described in ISO 10993-05) may be appropriate for deter-
mining if the output of a cleaning process meets its specified
all fault-seeded product should be rejected.
requirements.
8.8 It is important to establish analytical method suitability
8.13 Sampling:
before any conclusions can be made about a cleaning valida-
8.13.1 Preparation of samples of residues and contaminants
tion based on the sample results. It is up to the user to
forcleaningvalidationtestingforanalyticaltestingisascritical
determine and justify method suitability to screen for unspeci-
as the test itself. If a sample is prepared inappropriately, the
fied analytes as well as test for specified analytes.
resultwillalsonotbeappropriate.Samplesshouldrepresentall
8.9 Specific Analytical Methods:
aspects of the manufacturing process that are being evaluated
8.9.1 Specificanalyticalmethodsarethosewhichmeasurea
as part of the cleaning validation.
specific residue in the presence of expected interferences.
8.13.2 The analytical method validation should include the
8.9.2 The advantage of a specific analytical method is that it
sampling technique as a confounding factor for interference
provides specific measurements of the major residue of con-
determination and for recovery studies.
cern.
8.13.3 Direct Surface Sampling:
8.9.3 Examples of methods that can be specific are:
8.13.3.1 Direct surface sampling using surface analytical
8.9.3.1 Gas chromatography with a mass spectrometer de-
techniques like photoelectron spectroscopy (PES), time-of-
tector (GC/MS),
flight secondary ion mass spectroscopy (TOF-SIMS), energy
8.9.3.2 Infrared spectroscopy, including micro-Fourier
dispersive spectroscopy (EDS), and micro-FT-IR can provide
transform infrared (FTIR) spectroscopy,
direct sampling of surfaces. These techniques can have the
8.9.3.3 High pressure liquid chromatography (HPLC),
advantage that they provide immediate results about specific
8.9.3.4 Enzyme-linked immunosorbent assay (ELISA) sites on surfaces. They also can provide direct evidence at the
assays, worst-case locations or at the best-case locations. While there
F3127 − 22
are no specific recovery issues, direct surface sampling can 8.13.5.3 The method validations should consider the impact
have the disadvantage that the techniques may not provide an of volume reductions (evaporation of solvent to increase the
overall picture of the device. It may lead to erroneous conclu- concentration of the analyte) of the extracting solvents to
sions because of sampling bias. Direct surface sampling is ensure that the concentration of the extracting solvent does not
dependent on how and where sampling sites are chosen. contribute to the result. Documentation of extraction process
Imaging techniques, based on direct surface sampling, can also should include specifying the appropriate quantity and the
provide an overall view of the relative distributions of residues appropriate quality of water and/or one or more of the correct
and contaminants. Each of these techniques has technique- qualityofextractionsolvent(s).Theextractionprocess(includ-
specific requirements for the sample surface such as a require- ing temperature, force, and time) should also be developed and
ment for surface flatness, the ability to withstand high vacuum, documented so that the residue is identifiable. In other words,
depth of penetration, and access to the desired sample location the residue cannot be swamped by artifactual interferences
due to equipment limitations. from the extraction media or the extraction process.Appropri-
8.13.4 Swab sampling is also a direct surface sampling ate controls to establish the suitability of the solvent to extract
technique that is reasonably cost-effective. It provides infor- the residue should be evaluated and considered in a recovery
mation about the specific sites selected and swabbed. Swab- study. Potential interferences from the solvent should be
bing protocols that reduce swab sampling bias should be considered and minimized. Both positive (recovery) and nega-
developed. A limitation of swab sampling is that the swab tive controls should be specified.
should “release” the residue or contaminant. The ability of the
8.13.5.4 In some instances, a volatile residue should be
swab to release the residue should be considered in the considered. In such an instance, rather than an extraction in a
recovery study. There are also potential interferences from the
liquid,extractioninthevaporphasecombinedwithhead-space
swab (based on swab material composition) that should be gas chromatography (GC) may be appropriate.
considered and minimized. Swabbing is a manual operation so
8.13.5.5 Certain types of devices (for example, porous
procedures should be established to develop sampling consis-
devices and some coatings) may not be suitable for surface
tency.
detections methods.
8.13.5 Rinse sampling and extraction by immersion in-
8.13.5.6 There are available standards for some rinse sam-
volves the use of a solvent to contact all surfaces of a sampled
pling techniques, including Practice F619 and Test Method
item to quantitatively remove the residue or contaminant. The
F2459.
solventcanbewater,water-based,ororganic,dependingonthe
relative solubility of the residue or contaminant and the
9. Sample Size
composition of the medical device. Different solvents can be
9.1 The sample size required to reach a justifiable conclu-
used to evaluate residues of different solubility on the same
sion for a given cleaning validation is dependent on a valid
sample groups.
statistical approach, the analytical technique, the variability of
NOTE 4—If a sample is used for one rinse or extraction, the exact same
the analytical technique, and the desired outcome of the test.
part should not be used again with a different solvent.
Factors that should be considered include the following:
Sampling and extraction can be assisted by ultrasonic
9.1.1 Will the results of the process evaluation be compared
agitation, reflux, bubbling, or
...