1、Designation: F3127 16Standard Guide forValidating Cleaning Processes Used During the Manufactureof Medical Devices1This standard is issued under the fixed designation F3127; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year
2、of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide provides considerations for validating clean-ing processes for medical devices during initial fabricatio
3、n andassembly prior to initial use. Validated cleaning processes areimportant for achieving consistency in function and consis-tency in biocompatibility. The considerations include but arenot limited to, validation approach, equipment design, proce-dures and documentation, analytical methods, sampli
4、ng, devel-opment of limits, and other issues.1.2 Inclusions:1.2.1 This guide describes the validation of critical cleaningprocesses for medical devices to reduce contaminants toacceptable levels prior to packaging.1.3 Exclusions:1.3.1 Reusable medical devices.1.3.1.1 Validation of cleaning operation
5、s for reusable medi-cal devices is not within the scope of this standard guide.Although cleaning of reusable medical devices is beyond thescope of this guide, many of the principles outlined in thisguide may be applicable to the validation of cleaning opera-tions for reusable devices.1.3.2 Cleaning
6、of medical devices in health care facilities.1.3.2.1 Validation of cleaning processes in patient/healthcare facilities is not within the scope of this standard guide.1.4 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of t
7、he user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2D543 Practices for Evaluating the Resistance of Plastics toChemical ReagentsE2857 Guide for Validating Ana
8、lytical MethodsF619 Practice for Extraction of Medical PlasticsF2459 Test Method for Extracting Residue from MetallicMedical Components and Quantifying via GravimetricAnalysisF2847 Practice for Reporting and Assessment of Residueson Single Use ImplantsG121 Practice for Preparation of Contaminated Te
9、st Cou-pons for the Evaluation of Cleaning AgentsG122 Test Method for Evaluating the Effectiveness ofCleaning AgentsG131 Practice for Cleaning of Materials and Components byUltrasonic Techniques2.2 ANSI/AAMI/ISO Standards:3ISO 10993-5 Biological Evaluation of Medical DevicesPart 5: Tests for Cytotox
10、icity, In Vitro MethodsISO 10993-11 Biological Evaluation of Medical DevicesArt 11: Tests for Systemic ToxicityISO 10993-17 Biological Evaluation of Medical DevicesPart 17: Establishment of Allowable Limits for LeachableSubstancesISO 11737-1 Sterilization of Medical DevicesMicrobiological MethodsPar
11、t 1: Determination of aPopulation of Microorganisms on ProductsISO 14971 Medical DevicesApplication of Risk Manage-ment to Medical DevicesAAMI ST72 Bacterial EndotoxinsTest Methodologies,Routine Monitoring, and Alternatives to Batch TestingAAMI TIR30 A Compendium of Processes, Materials, TestMethods
12、, and Acceptance Criteria for Cleaning ReusableMedical Devices2.3 United States Pharmacopoeia (USP) General Chap-ters:USP Bacterial Endotoxins TestUSP Biological Reactivity Tests, In VitroUSP Biological Reactivity Tests, In VivoUSP Validation of Compendial Procedures1This guide is under the jurisdic
13、tion of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.15 on Material Test Methods.Current edition approved April 1, 2016. Published May 2016. DOI: 10.1520/F3127-162For referenced ASTM standards, visit the ASTM website, www.astm.or
14、g, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.C
15、opyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States12.4 International Conference on Harmonization of Techni-cal Requirements for Registration of Pharmaceuticals forHuman Use (ICH):ICH Q2 Validation ofAnalytical Procedures: Text and Meth-od
16、ologyICH Q9 Quality Risk Management3. Terminology3.1 Definitions:3.1.1 analyte, na substance (usually a residue) for whichan analysis is being performed. The residue determination maybe qualitative, quantitative, specific, non-specific, and/or it mayinvolve compositional identification. The analyte
17、may bedetermined as an extract or directly on the surface of the deviceor portion (subassembly) of the device.3.1.2 blank, nan analytical sample taken to establish thebackground value for an analytical measurement which may besubtracted from an experimental value to determine the “true”value.3.1.3 c
18、lean, nhaving an level of residues and environmen-tal contaminants which do not exceed a maximum permissiblelevel for the intended application.3.1.4 cleaning, vremoval of potential contaminants froman item to the extent necessary for further processing or forintended use.3.1.5 cleaning process, na p
19、rocess that is used to removeany product, process-related material and environmental con-taminant introduced as part of the manufacturing process.3.1.6 cleaning validation, nthe documented evidence pro-viding a high degree of assurance that a cleaning process willresult in products consistently meet
20、ing their predeterminedcleanliness requirements.3.1.7 cleaning verification, na one-time sampling andtesting to ensure that a medical device has been properlycleaned following a specific cleaning event.3.1.8 contaminant, nany material that potentially ad-versely impacts the assembly, the functioning
21、 of the device,and/or shows undesirable interaction with the host. A contami-nant may be a single component or any combination ofcomponents. Examples of possible types of contaminantsinclude: (1) biological or non-biological in nature; (2) living ordead; (3) particles or thin films; (4) solid, liqui
22、d, or vapor; (5)organic or inorganic.3.1.9 first use, nthe initial contact with biological materi-als or fluids.3.1.10 installation qualification (IQ), nestablishing byobjective evidence that all key aspects of the process equip-ment and ancillary system installation adhere to the manufacut-ers appr
23、oved specification and the recommendations of thesupplier of the equipment are suitably considered.3.1.11 lowest observed adverse effect level (LOAEL),nlowest concentration or amount of a substance found byexperiment or observation which causes detectable adversealteration of morphology, functional
24、capacity, growth,development, or life span of the target organism under definedconditions of exposure.3.1.12 monitoring, vverification testing at predefined in-tervals.3.1.13 no observed adverse effect level (NOAEL),ngreatest concentration or amount of a substance found byexperiment or observation w
25、hich causes no detectable adversealteration of morphology, functional capacity, growth,development, or life span of the target organism under definedconditions of exposure.3.1.14 operational qualification (OQ), nestablishing byobjective evidence process control limits and action levelswhich result i
26、n product that meets all predetermined require-ments.3.1.15 process qualification (PQ), nestablishing by objec-tive evidence that the process, under anticipated conditions,consistently produces a product which meets all predeterminedrequirements.3.1.16 recovery study, na laboratory study combining t
27、hesampling method and analytical method to determine thequantitative recovery of a specific residue for a defined surface.3.1.17 residue, na substance present at the surface of animplant or embedded therein that is not explicitly recognizedand defined as part of the implant specification. It include
28、sprocessing-based residues as well as contamination by envi-ronmental factors (adsorbates).3.1.18 tolerable intake (TI), nestimate of the averagedaily intake of a substance over a specified time period, on thebasis of body mass, that is considered to be without appreciableharm to health.4. Summary o
29、f Practice4.1 This guide provides an approach for validating theremoval of contaminants and residues introduced during theintermediate process steps so that the terminal cleaning processcan result in a consistently clean medical device.5. Significance and Use5.1 This guide describes an approach to v
30、alidate a cleaningsystem for a medical device. It is based on the manufacturersaccurate and comprehensive understanding of their internalmanufacturing and cleaning processes.5.2 This guide is not intended to provide a detailed plan orroad map, but will provide considerations that can be used bythe d
31、evice manufacturer to develop a detailed plan for perform-ing cleaning validation.5.3 In cleaning validation, as with other types of validations,there are multiple ways to achieve a compliant, scientificallysound and practical cleaning validation program.5.4 There are several reference documents ide
32、ntified inAppendix X3 that describe cleaning validation approaches fornon-medical devices (including cleaning for oxygen-enrichedenvironments, pharmaceuticals, semiconductors). Any of thesereference documents could provide guidance for a well definedprocess for establishing a manufacturers minimum e
33、xpecta-tion of a specific cleaning validation program.5.5 This guidance specifically targets cleaning validation formedical devices, in-process and at terminal cleaning so that theF3127 162result is a consistently clean medical device that meets theperformance expectations for that device.6. General
34、 Requirements6.1 This guidance for the validation of cleaning processes isdivided into 3 sets of activities: understanding the upstreammanufacturing process, documenting the cleaning process, andestablishing the measurement tools used to evaluate cleanlinessand to establish the cleaning performance
35、criteria.6.2 Preliminary process characterization, whether in thelaboratory or on the manufacturing floor, provides the datanecessary to establish cleaning parameter control ranges.7. Cleaning Validation Approach7.1 A typical approach to a cleaning validation includes:7.1.1 An assessment of the risk
36、s and benefits of the cleaningprocess and the impact of the cleaning processes on themedical device and on downstream processes.7.1.2 Identification of contaminants from raw materials andmanufacturing and processing operations (e.g. machine oils)that could be residuals on the medical device.7.1.3 Es
37、tablishment of allowable limits for contaminants(determining “How clean is clean?”) based on the product andprocess needs. Acceptance criteria for “clean” should be statedwith scientific justification for the criteria.7.1.4 Avalidation of the analytical methods used to measurethe residues or contami
38、nants.7.1.5 A qualification or determination of the samplingtechniques used for evaluating the cleanliness of a medicaldevice.7.1.6 A determination that statistical requirements anddocumentation are adequate to conclude that the result oftesting meets the output specification of the process.7.2 A ge
39、neral process flow for a cleaning validation pro-gram is represented by the Fig. 1:7.3 Definition of the Cleaning Process:7.3.1 The definition of the process should include an evalu-ation of the device, the equipment to be used for the cleaningprocess, the process parameters, the process chemicals,
40、and themanufacturing materials that should be removed by the pro-cess.7.3.2 Device Design:7.3.2.1 The design, material composition, and intended enduse of the device have a significant impact on the suitability ofa cleaning process. A non-exhaustive list of examples areprovided:(1) A cleaning proces
41、s that will not reach a blind hole in amedical device will not get the blind hole clean.(2) Densely populated electronics assemblies may not bereadily accessed by cleaning chemistries. As a result, conduc-tive and non-conductive residue may remain.(3) The cleaning process should not have an adverse
42、effecton the materials of construction of the medical device, thecleaning equipment, or the functionality of the medical device.For example, for plastic devices, ASTM D543 may be used forguidance on how to determine the suitability of specificcleaning agents to medical devices. Chemical compatibilit
43、y ofthe cleaning process should be determined prior to cleaningprocess validation.(4) In some instances, the structure of the device or thesurface of the device may cause liquid or vapor-phase residueto be entrapped. Such occurrences are generally not consideredto constitute a materials compatibilit
44、y problem, if the residue isreadily removed with extensive rinsing and/or drying (bake-out). However, given the potential negative impact on perfor-mance and/or interaction with the host, the design and mate-rials of construction may qualitatively and quantitativelyimpact the rinsing and/or drying p
45、ortions of the cleaningprocess.7.3.2.2 While the discussion of device design (design forcleanability) is critical to a cleaning validation, a full discus-sion is not within the scope of this guide.7.3.3 Risk Analysis:7.3.3.1 The risks and benefits associated with a specificcleaning process should be
46、 addressed. There are a numberapproaches to evaluating the risks associated with a cleaningprocess, including those described in ISO 14971 and ICH Q9.7.3.3.2 The process risks evaluated should include the riskto the patient.7.3.3.3 All cleaning operations should be considered, in-cluding processes c
47、onducted by contract manufacturers.(1) Some cleaning operations may not be termed cleaning;and the terminology may be specific to a given technical field.Passivation, surface preparation, and surface modification mayor may not have a cleaning function. The manufacturer shoulddetermine the function a
48、nd efficacy of each process.(2) If an in-process cleaning operation is considered to becritical and therefore should be validated, acceptance limits forthis in-process operation may be established by considering theeffect of residue levels after this operation on the final residuelevels of the devic
49、e following the final cleaning step. Forexample, a manufacturer may perform an OQ on this in-process step to see what in-process residue levels start toimpact the final residue levels beyond their acceptable levels.By reducing the in-process residue levels below this limit, themanufacturer can establish the process conditions for validat-ing this in-process operation.7.3.3.4 Risks that should be considered include the impacton the subsequent process yields or the potential for carryoverof residue to the next process or the final product.7.3.4 In-process
