Cleaning Validation For Medical Device Manufacturing
alconox.comCritical Cleaning ExpertsSMAQUEOUS CRITICAL CLEANING: A WHITE PAPERWhat Is CleaningValidation? 1DefinitionsProduction andProcess ControlsInspection,Measuring, andTest Equipment 2Process Validation 3Validating the Useof a CleanerIdentifying CleanerResiduesSelecting andValidating a ResidueDetection Method 4Choosing a SamplingMethodConstructingRecovery StudiesSetting ResidueAcceptance Criteria 6Using Total OrganicCarbon to MeasureResidue AcceptanceCriteria 9Writing Proceduresand TrainingOperatorsFinal ValidationReportCleaning SupplierValidation Support 10Get ValidationSupport 11Cleaning Validation forMedical Device ManufacturingWhy Get Cleaning Validation Support From Your Cleaner Supplier?Cleaning validation or verification is a necessary regulatory compliance stepin medical device manufacturing and reprocessing. Support from the cleanermanufacturer can save time and money when establishing either cleaning validationor cleaning verification processes. This white paper outlines the basics of cleaningvalidation and how the cleaner manufacturer can help simplify and speed up theprocess, as well as support ongoing maintenance of the validated or verified state.What Is Cleaning Validation?Cleaning validation is documentation establishing thata cleaning process will consistently result in devicesthat are clean to a predetermined acceptable levelof cleanliness. In the medical device manufacturingindustry, cleaning validation is generally performedby examining the finished device itself rather than theequipment used to manufacture it.In addition to cleaning validation, sterilityvalidation is required for products sold sterile.Although sterility validation is beyond the scope ofthis paper, cleaning validation is important for anydevice sold sterile. (For more information aboutsterility validation, contact Alconox, Inc.)Validation concerns vary across the industry anddepend on the class of medical device. Devices areclassified according to the nature of patient contact.Re-usable examining devices with incidental patientcontact might be tested for function and, possibly,bioburden. Implantable medical devices with yearsof internal patient contact might also be tested forendotoxins, cytotoxicity, sterility, and proper devicefunction.The goal of validation is to prove that a system isfunctioning properly within established parameters toensure product, patient, worker, and environmentalsafety. To achieve this, manufacturers typicallyhave a validation committee with clearly definedCleaning Validation for Medical Device Manufacturing Alconox, Inc.1
responsibilities, consisting of these members: Validation Specialist — Writes andcoordinates the procedure Manufacturing — Writes SOPs and providestraining Quality Assurance/Control — Approvesand implements analytical methods Engineering — Communicates changes andevaluates equipment data R&D — Performs recovery studies, validatesand transfers methods, and selects newcleanersBefore:Blood dried ontoscalpel handles isdifficult to thoroughlyremove.After:Soaking inTERGAZYME,followed by gentlecleaning, preparessurgical instrumentsfor effectivesterilization andprolongs instrumentlife.The required cleaning validation documentationis specified in the relevant sections of themanufacturer’s Validation Master Plan, including: The objective Background Equipment/reagents Responsibilities Product Procedures Residue acceptance limits, with rationale Analytical methods Sampling procedures and recovery Cleaning process design Data analysis Assumptions Change control/maintenance ReferencesAll cleaning validation documents are subjectto an FDA inspection process known as the QualitySystem Inspection Technique (QSIT), defined inthe FDA “Guide to Inspections of Quality Systems”(FDA Center for Devices and Radiological Health[CDRH], August 1999). QSIT establishes a “topdown” approach for inspecting and managing thesesubsystems of a firm’s overall quality system: Corrective and Preventive Actions Management Controls Production and Process Controls Facility and Equipment Controls Records, Documents and Change Controls Material Controls Design ControlsThese subsystems must conform to current goodmanufacturing practice (cGMP) in accordance withthe Quality System regulations (21 CFR Part 820).The ISO medical device quality equivalent is ISO13485. The most relevant sections to critical cleaningand cleaning validation are listed below.§820.3 Definitions(p) Manufacturing material means any materialor substance used in or used to facilitatethe manufacturing process, a concomitantconstituent, or a byproduct constituent producedduring the manufacturing process, whichis present in or on the finished device as aresidue or impurity not by design or intent of themanufacturer.§820.70 Production and process controls(ISO 13485:2003 6.3 6.4 7.1 7.5.1 7.5.2 8.2.3)(e) Contamination control. Each manufacturer shallestablish and maintain procedures to preventcontamination of equipment or product bysubstances that could reasonably be expected tohave an adverse effect on product quality.(h) Manufacturing material. Where a manufacturingmaterial could reasonably be expected tohave an adverse effect on product quality, themanufacturer shall establish and maintainprocedures for the use and removal of suchmanufacturing material to ensure that it isremoved or limited to an amount that does notadversely affect the device’s quality. The removalor reduction of such manufacturing material shallbe documented.§820.72 Inspection, measuring, and testequipment(ISO 13485:2003 7.6)(a) Control of inspection, measuring, and testequipment. Each manufacturer shall ensure thatall inspection, measuring, and test equipment,including mechanical, automated, or electronicinspection and test equipment, is suitablefor its intended purposes and is capable ofproducing valid results. Each manufacturer shallestablish and maintain procedures to ensurethat equipment is routinely calibrated, inspected,checked, and maintained. The procedures shallCleaning Validation for Medical Device Manufacturing Alconox, Inc.2
include provisions for handling, preservation, andstorage of equipment, so that its accuracy andfitness for use are maintained. These activitiesshall be documented.Cleaningverification isdocumentedevidence thatan individualcleaning event hasproduced a devicethat is acceptablyclean.§820.75 Process validation(ISO 13485:2003 6.3 6.4 7.1 7.5.1 7.5.2 8.2.3)(a) Where the results of a process cannot be fullyverified by subsequent inspection and test, theprocess shall be validated with a high degree ofassurance and approved according to establishedprocedures. The validation activities andresults, including the date and signature of theindividual(s) approving the validation and whereappropriate the major equipment validated, shallbe documented.Furthermore, the FDA has been supporting arisk-based approach for medical device processvalidations. These types of risk-based approacheswould include something like a pFMEA (processfailure mode engineering analysis). This is aquantitative way of evaluating risk that can be usedas part of a design history file (DHF).The need for cleaning validation or cleaningverification comes from cGMP required productionand process controls, as well as design inputsand outputs. If cleaning verification is employed— commonly when small batches of devices aremanufactured or re-use devices are being cleaned —then verification must be done every time cleaning isperformed.Cleaning verification is documented evidence thatan individual cleaning event has produced a devicethat is acceptably clean. Verification tests may beperformed as deemed appropriate by hazard analysis,and may include demonstrating: A 2–4 log reduction of bioburden Levels of less than 10 colony forming units(CFU) per device Less than 20 endotoxin units (EU) per device Chemical residues shown to be below limitsaffecting biocompatibility, function and toxicityTIR 30, SECTION 6, TABLE 6: TEST SOILS FOR REUSABLE DEVICESAuthorsConstituents of SoilDeviceAAMI TIR12 (Hucker’s)Peanut butter, evaporated milk, butter, flour, lard,dehydrated egg yolk, saline, printer’s ink, bloodNot specifiedAlfa and Jackson (2001)ATS-B (bacteria, protein, carbohydrate, endotoxin, hemoglobin)Flexible colonscopeAnderson and Nwoguh (1991)Klebsiella aerogenesEnteral feeding tubesBar, et al. (2001)Mycobacterium tuberculosisBronchoscopeChartier, et al. (2001)Yeast extract, native human albumin, defibrinated nativesheep blood, bovine serum, fibrin, Tween 80, waterMicroplatesDonlan, et al. (2001)B. stearothermophilus spores, E. cloacae biofilmNeedleless connectors to centralvenous cathetersGreen, et al. (2001)Oils, calf serum, albumin, gelatin, hog mucin, egg whiteMicroplatesKozarek, et al. (2001)B. stearothermophilus sporesDouble-channel sphincterotomesMerrit, et al. (2000a)Bacteria, mammalian cells, albumin, bovine fibrin, bovine fibrogen MicroplatesMostafa and Chackett (1976)Radiolabeled human serum albuminSurgical instrumentsOrzechowski, et al. (2000)Bovine albumin, mucin, fibrogenDental handpiecesPenna and Ferraz (2000)B. subtilis in radioopaque iodine contrast, bovine blood with EDTAAngiographic catheters, spinalneedlesPfeifer (1998a, 1998b)Albumin, hemoglobin, fibrinogen, thrombinSurgical instrumentsRoth, et al. (1999b)a) Radioactive marked macroalbuminsb) S. aureus, P. aeruginosa, heparinized sheep blood, protamineBiopsy forceps, papillotome, DormiabasketRowan and Anderson (1998)Bacillus cereusInfant feeding bottlesSchrimm, et al. (1994)Radiolabeled marker macroalbuminsTubular instrumentsVerjat, et al. (1999)Human albumin solutionHemolysis glass tubes, surgical steelblades, ceramic penicylindersWorking group (1995)Microorganisms in oleic acid-albumin-dextrose catalaseEndoscopesCleaning Validation for Medical Device Manufacturing Alconox, Inc.3
To identify cleanerresidues, youneed to knowthe cleanerformulation. Thecleaner suppliershould be willingto disclose theingredients of theircleaner under anon-disclosureagreement.Further testing should be done to show nonviable residuals may be removed. This could be doneby applying soils such as those found in TIR12,or TIR 30, Section 6, Table 6 (shown previouspage). Examples of soils are Hucker’s or ATS-B soils.Another example of a test to demonstrate removalof soil contamination is the ProFormance TOSI (testobject surgical instrument) cleaning challenge (seeHealthmark Industries, 33671 Doreka, Fraser, MI48026. www.hmark.com. Phone: 800.521.6224).process operates within predetermined parameters.The performance qualification (PQ) portion of thevalidation should demonstrate at least three timesthat the cleaning process removes residues downto predetermined acceptable levels. Changing anysignificant part of the cleaning procedure, includingthe cleaner, mandates revalidation. This entails, at aminimum, first cleaning the new way, collecting data,then cleaning the prior way (validated) before usingany equipment for manufacturing.Validating the Use of a CleanerValidating the use of a cleaner requires demonstratingthat the cleaning process removes any cleanerresidues down to acceptable levels. This involvesseveral steps: Identifying cleaner residues Selecting a residue detection method Choosing a sampling method Validating residue detection methods Constructing recovery studies Setting residue acceptance criteria Validating the cleaning process with the newcleaner, including:—design of experiments for optimal process—three consecutive cleaning trials—creating the validation report Writing procedures and training operatorsIdentifying Cleaner ResiduesTo identify cleaner residues, you need to know thecleaner formulation. The cleaner supplier should bewilling to disclose the ingredients of their cleanerunder a non-disclosure agreement. Sometimessufficient information about cleaner ingredients canbe obtained from material safety data sheets (MSDS)and cleaning validation technical information suppliedby the cleaner supplier. Ask your cleaner supplierwhich ingredients are likely to be the last to rinseaway and which ingredients are best to analyze as amarker for the cleaner residue. After a residue markeris identified, a residue detection method can beselected and validated.The validation is done on critical cleaning stepsaffecting the quality or safety of the final productor device. Validation is achieved by proving that aSelecting and Validating a ResidueDetection MethodSelecting the appropriate detection method forcleaner residues begins with choosing a specific ornon-specific methodology, according to the criteriashown in Table 1.TABLE 1: SELECTING THE PROPER CLEANER RESIDUE DETECTION METHODSpecificNon-specificTests for:Individual ingredientBlend of ingredientsMethods:High-performance liquid chromatography (HPLC)Total organic carbon (TOC)Ultra performance liquid chromatography (UPLC)pH levelsGas chromatography/mass spectroscopy (GC/MS) ConductivityTitrationDirect UV spectroscopyAssayIon chromatography (IC)Preferred for: Initial validationBroad detection of any residueInvestigating failures or action levelsRetesting to maintain a validated stateMonitoringCleaning Validation for Medical Device Manufacturing Alconox, Inc.4
TABLE 2: CLEANER RESIDUE DETECTION METHODS FOR ALCONOX, INC. CLEANERSAlconox, Inc. AnionicBrandSurfactantCleanerby HPLCEDTAbyHPLCNonionicSurfactantby Deriv. yOrganicCarbonby TOCOrganic Acidby HPLC, PotassiumUV, orby flameConductivityAssayor TERGENT 8CITRANOXLUMINOXCITRAJETWhen performinga medicaldevice cleaningvalidation,analytical methodsfor detectingdetergent residuesmust be validatedalso.SOLUJETKEYLAJETDETONOXTERGAJETWhen performing a medical device cleaningvalidation, analytical methods for detecting detergentresidues must be validated also. Table 2 lists avariety of appropriate residue detection methods forAlconox, Inc. detergents and cleaners.The validation of the residue detection methodmay involve establishing accuracy, precision, linearity,reproducibility, selectivity, specificity (for specificmethods), detection and/or quantitation limits, as wellas robustness of the residue detection method. Onrequest, Alconox, Inc. can supply analytical methodsper Table 2 for use with the respective detergents.TOC and other non-specific methods areThe FDA often prefers use of specific methods,especially when investigating failures or action levels.Under specified usage conditions, these methodsare proven specific at a 95 percent confidencelevel, without significant bias or interferencefrom impurities, degredants, excipients, or otheringredients.However, non-specific methods may be accepted,provided a scientific rationale for their use isdetermined. Non-specific methods are commonlyused where the limit of quantitation is 50% ofthe residue acceptance levels and where the broaddetection of any residue is desired.TABLE 3: DATA ELEMENTS REQUIRED FOR VALIDATIONAnalyticalPerformance CharacteristicsCategory ICategory IIQuantitativeLimit TestsCategory IIICategory ityYesYesYes*YesDetection LimitNoNoYes*NoQuantitation * May be required, depending on the nature of the specific test.Cleaning Validation for Medical Device Manufacturing Alconox, Inc.5
When conductinga rinse extraction,to demonstrateexhaustiveextraction,successive rinsesmust be studiedto determine howmuch water orsolvent is neededand for how long.commonly used where the limits of detection andquantitation are well below residue acceptance levels.USP chapter 1225 , Validation of CompendialProcedures, provides information about validatingcompendial analytical procedures ranging fromexacting analytical determinations to subjectiveevaluations of various attributes. Within this range,tests are categorized as follows: Category I — Analytical procedures forquantitation of major components of bulk drugsubstances or active ingredients (includingpreservatives) in finished pharmaceuticalproducts. Category II — Analytical procedures fordetermination of impurities in bulk drugsubstances or degradation compounds infinished pharmaceutical products. Theseprocedures include quantitative assays andlimit tests. Category III — Analytical procedures fordetermination of performance characteristicssuch as dissolution, drug release, and others. Category IV — Identification tests.Table 3 shows the analytes being tested.Choosing a Sampling MethodResidual cleaner can remain on device surfaces aftercleaning. A sampling method needs to be establishedto sample for this. Available methods include: Rinse water sampling or solvent extraction Surface swabbingRinse water sampling requires taking asample of equilibrated post-final rinse water orsolvent recirculated over all device surfaces. Whenconducting a rinse extraction, to demonstrateexhaustive extraction, successive rinses must bestudied to determine how much water or solvent isneeded and for how long. Rinse samples should becorrelated to a direct measuring technique such asswabbing.Swab or wipe sampling for TOC involves aswab or wipe moistened with high-purity water suchas water for infection (WFI) drawn over a definedarea using a systematic, multi-pass technique,always moving from clean to dirty areas to avoidrecontamination. Then the swab head is cut off or thewipe is placed in a pre-cleaned TOC, or other sample,vial. TOC analysis requires the use of very clean lowbackground, water, swabs/wipes and sample vials.Constructing Recovery StudiesRecovery studies use selected sampling anddetection methods on residues that have been“spiked” on the device surfaces at known levels.Generally, spikes are set at 50, 100, and 150 percentof the acceptance criteria limit. This demonstratesand establishes linearity with documented percentrecovery, as analyzed, and helps determine the limitsof detection and quantitation. Ideally, the expectedvalues and limits should be multiples of the limits ofquantitation. The percent recovery is used to correlateamount detected with the amount of assumedsurface residue found acceptable.For example, if 100 µg of residue were spikedon the surface and after swabbing or extractingthe detection analysis yielded 90 µg, the calculatedpercent recovery would be 90%. For cleaningvalidation, any analytical results would have to beadjusted by this recovery factor. In this example,the resulting 90 µg per swabbed or sampled areaneeds to be interpreted as being actually 100 µgper swabbed or sampled area to adjust for the90% recovery. If the area is the entire device, thena detection of 90 µg in the extraction fluid can beinterpreted as 100 µg per device by the followingequation:Residue Detected / Per sampled area(or device) / % Recovery Adjusted Detected ResidueSolving for the example above, the equation would be:90 µg Detected / Device / 90% Recovery 100 µg / Device Detected ResidueSetting Residue Acceptance CriteriaResidue acceptance limits must be set for anyresidue according to its potential to affect the form,fit or function of the finished device in terms ofbiocompatibility, toxicity, or functionality. Typically,limits need to be set for contaminants such asprocess fluids, polishing compounds, mold releases,bioburden, and cleaning agents, as well as anydegradation or new products resulting from reactionsCleaning Validation for Medical Device Manufacturing Alconox, Inc.6
For a new device,where no history isavailable, a studycan be performedby cleaningand measuringthe cleanlinessof a series ofpredetermined andjustified worstcase devicesspiked withdifferent residueamounts on thesurface.or interactions with these compounds, fluids orcleaning agents and possibly endotoxins.Any applicable historical data on residues fromsuccessful manufacturing processes can be usedto set accept
industry, cleaning validation is generally performed by examining the fi nished device itself rather than the equipment used to manufacture it. In addition to cleaning validation, sterility validation is required for products sold sterile. Although sterility validation is beyond the scop
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that can affect the effective cleaning. So a master validation plan should be prepared, that will guide the cleaning validation step by step. While preparing cleaning validation protocol some points should be considered. 1. Disassembling of equipments, 2. The pre-cleaning method which is to be used 3.
cleaning validation, call 914-948-4040 for Malcolm McLaughlin (x160) mmclaughlin@alconox.com. References 1. Brewer, Rebecca Designing and Documenting Your Cleaning Validation Program to Meet FDA Requirements, Washington Group International , Philadelphia. presented at Cleaning Validation and Cleaning Processes Feb 1-2 Philadelphia, PA (2001) 2.
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