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8/12/2019 Cleanliness Validation White Paper Medical Device
1/17
v1 Dec 2013
MEDICAL DEVICES CLEANLINESS
VALIDATION
Dr Chris Pickles
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INTRODUCTION
Residues on the surface of medical devices can
cause implant failure and poor device
performance. The main source of these residues
is from materials used in the manufacture of thedevice, although contamination during the
storage, cleaning and handling of the device is
also known to occur. Small amounts of these
surface residues can cause deleterious effects in
patients, because the residues are in direct
contact with body tissues and patients often
have compromised immune systems (Beal,
2009). In addition, residues may often alter the
surface chemistry and geometry of the device, so
even inert residues can be a problem. For
example, small amounts of non-toxic cutting fluid
on an implant limit the ability of surrounding
tissues to attach to the implant (Jackson and
Ahmed, 2007).
In order to minimise contamination, the Federal
Drug Administration (FDA) stipulates that
medical device manufacturers follow specific
cleanliness validation procedures (FDA, 2003).
Firstly, they must identify all possible residues
present on the device and set an acceptable
residue limit (Luginbuehl et al, 2006). Then, they
must use a cleaning regime that reduces residue
levels below this limit, without leaving significant
levels of cleaning agent behind. Finallydocumentation to verify that residue limits are
not exceeded must be submitted to the FDA
before the device can go on the market
(Luginbuehl et al, 2006).
Despite these procedures being in place, some
medical devices are failing to meet FDA
requirements for cleanliness verification and
validation. Since 2001, 173 medical devices have
been recalled, some due to contamination issues
(Medical Device Recalls, 2009). In just one year of
sterility inspections, more than 483 FDA
observations related to validation deficiencies -more than any other deficiency (Booth, 1999).
Part of the problem for medical device
manufacturers and device cleaners is that there
are no official residue limits or specified analytical
techniques to measure residue levels. Therefore,
the manufacturers have to base their judgments
on existing medical devices on the market, which
may not be possible if the device has a novel use
or uses different materials or manufacturing
processes to devices currently on the market.
Another issue is that the surfaces of medical
devices are becoming more complex in terms of
their geometry and chemistry, making cleaning
more difficult. Recently there has been a rise in
the use of combination devices (devices with
both a drug or biologic component and a device
component) which creates even more challenges
for effective device cleaning. These combo
devices need to simultaneously meet quality
regulations for both the device and drugscomponent, but the FDA has yet to issue
guidance for cleanliness validation for these
devices (Kanegsberg et al, 2008; Staff Report,
2007).
Furthermore, highly aggressive cleaning of the
device may produce undesirable surface
modifications and inadequate cleaning may leave
residues that interact with therapeutic chemicals
(Kanegsberg et al, 2008).
In light of the challenges facing the medicaldevice industry, this paper will cover the
following:
1. Guidance from regulatory bodies on
cleanliness validation
2. Residues and sources of contamination
3. Residue limits
- Risk categories for medical devices
- Combination devices
4. Analytical methods to validate cleanliness:
description, and pros and cons of each
method
- Direct surface analysis
- Residue analysis
- Gravimetric
5.
Benefits of cleanliness validation
The advice in this document is intended for
manufacturers of implantables, combo products
and of any device that comes into contact with
the inside of the body, e.g., theatre instruments,
and users of reusable instruments or companies
that clean them. Biological contaminants and
bioburden analysis are not covered in this white
paper.
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GUIDANCE FROM REGULATORY
BODIES ON CLEANLINESS
VALIDATION
None of the regulatory bodies for medical
devices stipulate residue limits for medicaldevices, as absolute cleanliness is unobtainable,
nor do they specify the cleanliness validation
methods to be used. All of the regulatory bodies
stipulate a requirement to identify possible
residues, establish a residue limit and to not
exceed this limit, and to document and validate
cleanliness as part of an ongoing process (Daniel
et al, 2008). For example, ISO 14969 requires
documented and validated cleaning methods for
production facilities, manufacturing equipment,
and for the medical devices themselves (Daniel et
al, 2008). According to EN ISO 17664, medicaldevice manufacturers are obliged to provide
validated and documented methods of
reprocessing (cleaning and disinfection) for
reusable medical devices (Daniel et al, 2008).
The UKs BS EN46002 standard, a specification
for application of ENISO9002, stipulates the
following requirements for cleanliness of medical
devices: cleanliness of product and validated
sterilisation process (Daniel et al, 2008).
According to the FDA Guide to Inspections of
Validation of Cleaning Processes and The PDA
Technical Report No. 29, Validated cleaning
requires a procedure whose effectiveness has
been proven by a documented program
providing a high degree of assurance that a
specific cleaning procedure, formed
appropriately, will consistently clean a particular
piece of equipment, device, or area, to a
predetermined level of cleanliness - a level
objectively substantiated by specific chemical
and microbiological tests (Brunklow et al, 1996).
RESIDUES AND SOURCES OFCONTAMINATION
A problem for manufacturers is that there are a
wide range of possible contaminants/residues for
a medical device (table A). These residues can
react with drug components and other residues
to create new, potentially toxic compounds, or
can alter the surface geometry of the device by
corrosion or by creating layers on the surface of
the device (figure A) (Kanegsberg and
Kanegsberg, 2006).
Contaminants usually fall into one of three
categories: water soluble residue, non water-
soluble residue and non soluble debris. Water-
soluble residues are usually ionic compounds
such as detergents and salts. Non water-soluble
residues, such as oils, greases, and other
hydrocarbons, are soluble in solvents other than
water. Non-soluble debris includes residues such
as metals, organic and inorganic solids, andceramics.
Table A. Types of Residues Found on the Surface
of Medical Devices with Examples
Residues and Source
of Residue
Examples
Cleaning Agents
Detergents, IonicCompounds, Acids,Alkalis, Solvents
Chlorinated cleaners,ethyl and isopropylalcohol, methylchloroform (1,1,1-trichloroethane), andtricholoroethyleneAnionic and non-ionicsurfactants
Sterilising Agents Especially EthyleneOxide (Estrin, 1990)
Plastic medicalequipment retainformaldehyderesidues after low-temperature steamand formaldehyde
(LTSF) sterilization(NEWS, 2005)
Packaging
Debris, Extractablecompounds(plasticizers)
Handling equipment
Gloves, Lotions,Skin/Oil
Dithiocarbamatevulcanizationaccelerators on latexproducts (FDA,Technical Guide)
Oils/lubricants
hydrocarbon-based)
Alkanes, olefins,
additives
Lubricants aqueous-
based)
Emulsifiers
Inorganics
Grit blast compoundsLoose metal grainsSalt/ionic speciesHeavy metals
Silicon, Aluminium,Iron
Processing Aids
Polishing compounds(lipid-based)
Dye penetrantsMoulding aids
Mould releasingagents can often befound on plastic
devices.Silicones,fluorocarbons
(Luginbuehl et al, 2006; Speigelberg, 2003)
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Figure A. Composition of an Initially Contaminated and then Cleaned Surface (Riechl, 2003)
Residues present as irregular-shaped particles
have few attachment points with the surface of
the medical device and can be easily removed
during cleaning (figure B) (Hazell et al, 2007).
Residues that form a single layer on the surface
of a device have many more attachment points
with the surface of the device and are not so
easily removed (figure B) (Hazell et al, 2007).
However, in the saline environment of the body
these residues can be liberated through corrosion
reactions and become a potential problem for
medical device manufacturers (Hazell et al,
2007).
Figure B. Comparison of Bonding Sites for a Particle and the Same Volume of Residue Adsorbed onthe Surface of a Metallic Medical Device
Arrow representing bonding sites -
not to scale and not representative of the number
of bonding sites (Hazell et al, 2007)
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The chemical properties of residues present on
the surface of a device help determine the type
of analytical method used to validate cleanliness.
Residues are sub-divided into different categories
(Table B):
Table B. Chemical Classifications of Different
Residues
Residue
Classification
Examples
Inorganic Salts
Ceramics
Metals
Organic (includingpolymers)
Polar (soluble in water)
Apolar (insoluble inwater)
Biological Natural macromolecules
Bacterial or viral
(Luginbuehl et al, 2006)
RESIDUE LIMITS
After identifying the potential residues present, it
is the role of the manufacturer to set residue
limits and validate that these limits are not
exceeded in the manufacturing process. The roleof cleaners of reusable devices is to ensure
residue limits are not exceeded. Although there is
no official residue limit, there are guidelines for
setting residue limits based on the current
product qualities: the risk classification of the
device*, size of the device and the possible
residues present (LeBlanc, 2006). For cleanliness
validation of a process, the FDA wants to see
evidence that the residue limits are logical,
practical, achievable and verifiable (Booth, 1999).
If the device or similar devices are already on the
market, it is recommended that manufacturers
look at the devices history of acceptable
performance then use a mean level of residue
plus 3 standard deviations for particulates and
other types of residue (Broad and Kanegsberg,2007).
For new devices, a series of residue spiking
biocompatibility studies need to be performed at
different levels to determine the failure point of
the device (Broad and Kanegsberg, 2007). At
half the failure point, analysis can be performed
to demonstrate that device performance was not
affected by the residues present and toxicity
levels were not exceeded (Broad and
Kanegsberg, 2007). If the expected level of
residue is known, the device can be spiked at ahigher residue level and then evaluated for
biocompatibility and functionality. This higher
residue level is the maximum allowable residue
limit.
It is also recommended that manufacturers
estimate the acceptable daily intake (ADI) for a
cleaning fluid or residue, if systemic toxicity
based limits are not known. The ADI can be
calculated using the LD50 (lethal dose for 50% of
the population by compatible route of exposure
depending on device) and a conversion factor
(usually a value from 100 to 100,000):
ADI = LD50 (mg/kg) x body weight (kg) /
conversion factor (LeBlanc, 2006)
* The Medical Devices Directive (MDD) includes a
classification system whereby the level of
regulatory control applied to devices is
proportionate to the degree of risk associated
with the device (www.MHRA.gov.uk)
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Table C. Risk Classifications of Medical Devices Used by the Medical Device Directives (the system
used in the EU)
Classification Risk
Nature of
Contact and
Tissue Type
Duration of
Contact
Types of Device
Conformity
Assessment Process
including cleanliness
validation)
Conducted By
Class I Low Surface -skin,mucous,membranes
Limited Examinationgloves, tape,blood-pressurecuff, dentaldams,endoscopes
Manufacturer/NotifiedBody**
Class IIa Medium Externalcommunication- Blood,indirect
Prolonged Dialysis,cardiopulmonarybypass
Notified Body**
Class IIb Medium
Class III High Implant direct,blood andtissue contact
Permanent Shunts or grafts,orthopaedicimplants
Notified Body**
(Booth, 1999; Riechl, 2003; Albert, 2004, www.MHRA.gov.uk)
** The Notified Body is an independently verified body and is required for medical device approval in
the EU.
N.B. The FDA system differs from the EU system in that the devices are classified as I, II, III and IV
devices rather than I, IIa, IIb and III.
For combination devices, setting residue limits is challenging and a good understanding of the
chemical properties (especially stability) of the biological component of the device is needed; see
table D below for the issues concerning cleanliness validation for combo devices.
Table D. Issues Concerning Cleanliness Validation of Combination Devices
Cleaning or Assembly Issue Comments
Areas proximal to the drug Cleaning of the device may compromise drug activity
Consider materials compatibility
Technical support from cleaning agent supplier is optimal
Corrosion Avoid chlorine-containing agents with iron-containing alloys
Thin films Films can interfere with drug release or action
Particulates Could interfere with drug delivery
Out gassing Porous materials can absorb and retain cleaning chemicals withunintended slow release
Cleaning Process Design Balance cleaning action and product modification from wash rinseand dry
Product design Design for manufacturability including cleaning
Be aware of complexities that can trap water or other
contaminants
Sterilisation Heat or radiation may compromise drug portion of the device
(Kanegsberg, et al., 2008)
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The therapeutic surface chemicals often used to
minimise the risk of rejection of implants, for
example hydroxyapatite, present an opportunity
for interactions between therapeutic surface
chemicals and residues (Jackson and Ahmed,
2007).
ANALYTICAL METHODS TO
VALIDATE CLEANLINESS:
DESCRIPTION AND PROS AND CONS
OF EACH METHOD
The challenge for the medical device industry inverifying the cleanliness of their devices andvalidating the performance of their cleaningprocesses is to identify one or moremeasurement techniques that detect the
contaminants present on a sample at the requiredsensitivity (Booth, 1999). The FDA prefers specificmethods, although considers any validationmethod acceptable if it can be justified(McLaughlin and Zisman, 2002).
Once possible contaminants are known andresidue limits are set, analysis method (s) must bechosen that measure the analyte (s) at and belowthe residue acceptance limits. For this, the Limitof Detection (LOD) (lowest amount of acompound that can be detected) and the Limit ofQuantitation (LOQ) (lowest amount ofcompound that can be quantified) of the
analytical tool need to be established. Theresidue acceptance limit should be well above theLOQ, so that the residue can be accuratelyquantified (Kaiser and Minowitz).
In order to satisfy the FDAs cleanliness validationcriteria, the FDA needs to be assured that thevalidation process is repeatable, the process doesnot adversely affect the product or thepackaging, and the process meets the sterilityassurance limit (SAL) in the worst case scenario.(The SAL is the probability that an implant willremain non-sterile following sterilisation - one in amillion) (Booth, 1999; Arscott et al., 1996). TheFDA recommends that the following four criteria
are considered before implementing an analyticalprocedure for a cleaning validation application(Booth, 1999):
Sensitivity - the method is appropriate for theresidue limits in terms of sensitivity and LOD ofthe device (mentioned previously).
Practicality- the method is practical and rapidand, if possible, uses established pre-existingtechniques and equipment.
Validation Scheme- the method is readilyvalidated in accordance with regulatoryrequirements for instrumentation.
Successful Recovery Study- the method should
include compound recovery studies thatchallenge the sampling and testing methods
(Booth, 1999).
The analytical methods can be subdivided intotwo categories: direct and indirect. Directmethods detect the residue directly on thesurface of the device; indirect methods requireresidues to be extracted prior to analysis. Forindirect methods, residues are extracted bywashing the device with water, aqueous solutionor an organic solvent and then collecting therinse water, or by direct surface sampling with aswab. Exceptions to this are volatile organics or
absorbed gases, e.g. ethylene oxide, which areextracted via thermal evaporation using aheadspace sampling technique.
At the very minimum, the method requires twodifferent analysts, instruments, columns (ifchromatography is being used), days forexperimentation, and the use of preparedsamples and standards (Kaiser and Minowitz).
The different cleanliness validation methods aredivided into three main categories: direct surfaceanalysis, residue analysis and gravimetric analysis.Both gravimetric analysis and residue analysis areindirect methods; of course, direct surface
analysis is a direct method. The choice of methoddepends not only on the anticipated residuespresent and residue acceptance limits, but alsoincludes a consideration of the pros and cons ofthe methods, along with cost considerations(Table E). Usually more than one method is usedto validate the cleanliness of the device to ensurethat the entire range of possible contaminants isdetected.
Of all of the methods, surface analysis techniques
are the only methods that can identify the
location of the contaminant on the device and
detect extremely low levels of residue. So, the
surface analysis techniques can potentially beused to identify the manufacturing stage or
process in which contamination has occurred.
Two surface analysis techniques that are often
used to validate cleanliness are ToF-SIMS and
XPS because they analyse the outermost surface
layers and therefore directly measure residual
contamination (Hazell et al., 2007).
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Table E. Comparison of the Three Major Cleanliness Validation Method Categories - Including theResidues Detected, Cost Considerations and Pros and Cons of the Technique
Analysis
Technique
Residues
Detected or
Ideal Device
Material
Costs
per
Sample
Initial
Investment
Pros Cons
DirectSurfaceAnalysis
Metals,ceramics,
plastics
High High - Location ofcontaminants on thedevice is known
- Used at each step inthe manufacture ofthe device
- Used for insolubledried-out residues
- Identifycontaminantspresent
- Can detect verysmall levels ofresidue
- Can assess sub-surface contamination
- Lab setting is needed
Gravimetric Non-volatileresiduesincludingnon-watersolublecontaminants
Low Low - Sensitive
- Simple
- Robust
- Little preparation isneeded
- Broad range ofcontaminants can betested
- Can use extractionsolvents other thanpurified water
- Human error is likely
- Easy to contaminatethe sample
- Easy to obtainmisleading data dueto differences inparticle size anddistribution betweenthe residues in thesample and referenceresidues
- Excludes residuesmore volatile than theextraction solvent
- Does not identify theresidues present
ResidueAnalysis(requiresextractionmedia)
Porousmaterials,materialswith acomplexsurfacegeometry
Low Low - Can capture residuestrapped in pores inthe device
- Measure high levelsof contamination
- Done in a hospitalsetting
- Some techniques can
identifycontaminantspresent, some cannot
- Location ofcontaminants is notknown
- Does not captureadsorbed contaminant
- Some residues may beleft on the medicaldevice
- Residues may not behomogenouslydistributed in theeluant therefore theeluant sampleanalysed may nottruly represent thelevels of contaminantpresent on the device
- Difficult to assess sub-surface contamination
(Beal, 2006)
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All of the direct surface analysis techniquesexamine the top few layers of the devicessurface by irradiating the sample with x-rays orion beams and analysing the emitted electrons orsecondary ions. In contrast, the indirect residueanalysis methods use a variety of techniques to
detect residues present on the surface of thedevice. Descriptions of how the differentmethods work are detailed in tables F and Gbelow.
Gravimetric analysis is an indirect analysis
technique. The device is placed in an extraction
media and the resulting eluant is passed through
a pre-weighted membrane filter. The filter is then
dried and re-weighed. It is assumed that any
difference in mass is due to particles present onthe surface of the medical device and these
particles are of the same density and size as the
original tests used to set acceptable mass levels
for the residues.
Table F1. Descriptions of the Most Commonly Used Direct Surface Analysis Methods
MethodDescription
Method Abbreviation
X-Ray PhotoelectronSpectroscopy
(Also known as ElectronSpectroscopy for ChemicalAnalysis (ESCA)
XPS The medical device is irradiated with x-rays causingthe emission of particles called photoelectrons. Theenergy of the emitted photoelectrons is specific toelements on the surface of the medical device.
Time-of-Flight SecondaryIon Mass Spectrometry
ToF-SIMSA pulsed beam of primary ions is focused onto thesurface of the medical device producing particlescalled ions. These ions are analysed providinginformation about the molecules and elementspresent on the surface of the sample.
3D Non-contact profiling 3D-NCP This technique involves irradiating the sample withtwo or more white-light lasers and analysing thepattern of interference of the light waves. A detailedmap of the outer nanometers of the medical devicessurface can be obtained showing height variation inthe sample
Transmission electronmicroscopy
TEM This technique involves passing a high energy (200-300 keV) electron beam through a thinned section ofthe specimen to produce very high-resolution imagesof the material.
Scanning ElectronMicroscopy
SEM Rasters a focused electron beam across a samplesurface, providing high-resolution and long-depth-of-field images of the sample surface.
Laser Ionisation MassAnalysis
LIMA A high performance reflectron ToF massspectrometer which uses an Nd:YAG laser as its
primary ionising beam. Uses a finely focussed probe -in this case a laser - for analysis.
Fourier Transform Infra-RedSpectroscopy
FTIR Chemical bonds vibrate at characteristic frequencies,and when exposed to infrared radiation, they absorbthe radiation at frequencies that match their vibrationmodes. Measuring the radiation absorption as afunction of frequency produces a spectrum that canbe used to identify functional groups andcompounds.
Raman Spectroscopy Raman Raman Spectroscopy (Raman) enables you todetermine the chemical structure of a sample andidentify the compounds present by measuringmolecular vibrations, similar to Fourier TransformInfrared Spectroscopy (FTIR). However, the method
used with Raman yields better spatial resolution andenables the analysis of smaller samples.
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Table F2. Descriptions of the Most Commonly Used Residue Analysis Methods
Method Abbreviation Description
Total Organic
Carbon
TOC Residuals are extracted from the devices in a known amount of
purified water and the extract is analyzed on a TOC instrument.The TOC is determined by the oxidation of an organic compoundinto carbon dioxide. This oxidation can occur through a numberof mechanisms depending on the instrument being used. Thecarbon dioxide that is produced from these oxidations is eithermeasured using conductivity or infrared techniques (Kaiser andMinowitz).
Capillary ZoneElectrophoresis
CZE A high voltage source is used to apply a potential across twosolutions. One of the solutions contains the analyte and thepotential applied to the solutions causes the analyte to migratethrough the capillary, through the detector, and into the othersolution (Kaiser and Mirowitz).
GasChromatography-MassSpectroscopy
GC/MS Identifies and separates volatile and semi-volatile compoundsinto individual components using a temperature-controlled gaschromatograph. During the process, a sample is injected into thechromatograph (or it may come from another sampling device)and passes through the chromatography column, whichseparates mixtures into individual components as they passthrough at different rates. The result is a quantitative analysis ofthe components, along with a mass spectrum of eachcomponent.
(Zurbruegge, 2006; Speigelberg, 2003; Kaiser and Aiche, 2005)
Table F3. Gravimetric: Comparison of Specific, Common Cleanliness Validation Techniques - ResiduesIdentified, Pros and Cons
Analysis
Method
Residues Pros Cons
Detection
Limits
Other
Information
Gravimetric Same Non-volatileresiduesand abroadrange ofresidues
- Sensitive
- Simple
- Robust
- Littlepreparation isneeded
- Broad rangeofcontaminantscan be tested
- Can useextractionsolventsother thanpurifiedwater
- Human error islikely
- Easy tocontaminate thesample
- Easy to obtainmisleading datadue to differencesin particle sizeand distribution
between theresidues in thesample andreference residues
- Excludes residuesmore volatile thanthe extractionsolvent
- Does not identifythe residuespresent
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Table G: Indirect Residue Analysis (Requires extraction media): Comparison of Specific, CommonCleanliness Validation Techniques - Residues Identified, Pros and Cons
Analysis
Method
Residues Pros Cons
Detection
Limits
Other
Information
IonChromatography
Ionizableorganic acids(cleaningfluidscontainingsodium andpotassiumions)
- Very low levels ofcleaning agent canbe detected
- Assumes the rinse
- Water contains nopotassium
Specific
CapillaryElectrophoresis
Analyseorganic acids,inorganic andtrace drug
residues
- Detection limits arehigher than withHPLC
- All commondetection can be
used in capillaryelectrophoresisdetection.
Specific
GasChromatography-MassSpectroscopy
(GC-MS)
Solid, liquid,gas
Organicsolvents(volatileorganiccompounds)and semi-volatileorganiccompounds(plasticizers,
phenols, etc.)volatile andsemi-volatilecompounds
- QuantificationIdentifies very small(trace-level)quantities of aresidue
- Identifies residues
- Good for residualsolvents and residueson plastics
- Elements notdetected, samplemust be volatile
ppb-ppm
ng-ug/device
TOC Ideal for polarorganiccompounds(soluble in thelow ppmrange)
- Detects residues atlower levels thangravimetry.
- Faster processingtime than HPLC
- Does not take long todevelop a method
- Many possiblesources ofcontamination
- Organic solventscannot be used
- No identification ofthe residues
- The extraction ratioof eluant to residuemust be carefully
controlled foraccurate analyticalresults.
0.2mg/device
Non-specific
- Quick rapid results
- A level has beenestablished forpurified water whichrepresents a goodtarget level forresidual analysis.
- Residue mustcontain significantamounts of organiccarbon, it must bepossible to oxidizethe carbon and theresidues must bewater soluble. Notgood for lubricantsand coolants mineral oil-basedprocessing aids
- Does not detectinorganiccontamination
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Analysis
Method
Residues Pros Cons
Detection
Limits
Other
Information
HPLC Can detectany type of
compound
- Easy detection ofimpurities or
potentialcontaminants withinpeaks.
- Ultraviolet detectionusually requires noadditional reagentsor post column orpre-column reactions.
- UV detectors are notharmful to thesample, areinexpensive andreadily available
- Simple
technique
- No baseline drift dueto mobile phase
- Long set up andanalysis time
- Often requiring oneor two days ofdowntime beforeprocessingequipment can becertified forcleanliness
- Is not inherentlyspecific
UV/VisSpectroscopy
Compoundsthat absorbUV and visiblelight
Detergents
- Quantitative - The extraction ratiomust be controlledfor accurateanalytical results
- Not qualitative
LCMS Anionic
- carboxylates
- sulphates
Cationic
- amines
- quaternaryammoniumcompounds
Non-ionic
- glucosides
- alkylethoxylates
- Small sample
size
- Sample must beliquid or solid
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Table H. Direct Surface Analysis: Comparison of Specific, Common Cleanliness Validation Techniques Residues Identified, Pros and Cons
Direct
Surface
Analysis
Method
Residues Pros Cons
Detection
Limits
Other
Information
ToF-SIMS Inorganic andorganicmolecularspots >0.01um
Solidcontaminants
Localisedresidues
Dry staining
residues
- Does not destroy themedical device sample
- Produces surface areamap - identifying thelocation of thecontaminants at aresolution
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Direct
Surface
Analysis
Method
Residues Pros Cons
Detection
Limits
Other
Information
FTIR Organic andinorganics,particles >10um
Solids/liquidsor bothdepending onthe technique
Best for non-polar organicresidues (dueto required
solvents) -lubricants,coolants,greases, andeven forresidues fromfingerprints.
- Detect residues at muchlower levels thangravimetric analysis
- Sensitivity of 1000ppm
- Obtain informationabout molecular groups
- Semi-quantitative
- Detects all elementspresent
- Good recovery ofmineral oil-based
processing aids on PETand metal.
- Capable of identifyingorganic functionalgroups and oftenspecific organiccompounds
- Extensive spectrallibraries for compoundidentification
- Ambient conditions (notvacuum; good forvolatile compounds)
- Typically non-destructive Minimumanalysis area: ~15 micron
- Uses chlorinated orchlorofluorinatedozone depletingsolvents, whichrequires special safetyprecautions
- Limited surfacesensitivity (typicalsampling volumes are~0.8 m)
- Minimum analysisarea: ~15 micron
- Limited inorganic
information
- Typically notquantitative (needsstandards)
>1%
1000ppm
It can beused as ascreen toidentifypotentialcleaningagents
SEM/EDX
SEM:
spots >5nm
Solids
EDX: particles,spots >1um
Localizedresidues
- Depth of focus
- Produce high-resolutionimages giving structuraland morphologicalinformation
- Rapid results- Identifies the elementspresent above Carbon inthe periodic table
- Cant quantify amountof contaminantpresent
- No depth profiling
- Elements of lowatomic number aredifficult to detect byEDX.
- SEM may spoil samplefor subsequentanalyses
- Vacuum compatibilitytypically required
- Ultimate resolution is astrong function of thesample andpreparation
- May need to etch forcontrast
EDA -
EDX: 0.1 -0.5%
Can becombinedwithEnergydispersiveanalysis toquantifyamount ofresiduepresent
and giveelementalinformation
Light
Microscopy
Solids - Create Images - No quantification and
no elements aredetected
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Direct
Surface
Analysis
Method
Residues Pros Cons
Detection
Limits
Other
Information
Visualexamination
Visibleorganic andorganicparticles,
spots > 20um
- Cheap
- Quick
- Inexpensive
- Not specific
- Not quantitative
- Can only be used formedical devices with alarge surface area withlarge quantities ofcontaminants
1-4mcg/cm2(Booth,1999)
TEM Solid
Atomic layer
- Produces high-resolutionimages giving structuraland morphologicalinformation
- Does not producequantified andelemental information.
- Requires a very thinsample
- Expensive
Canproducequantifiedandelementalinformationifcombinedwith EEL
3D NonContactSurfaceProfiling
Solid - Produce an image withtopographicalinformation such asroughness, peak height,valley depth plus surfaceimages
- Quantification
xyresolution
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Class I and II medical devices are exempt frompremarket review or are subject to the 510(K)premarket notification process (FDA, 2003).Under the 510 (K) process, a device can becleared for marketing based on demonstration bythe manufacturer that the device is substantially
equivalent to one or more legally marketedpredicate devices that dont require a PMA(Hogan and Hartson, 2009).
Class III devices require a premarket application(PMA) providing evidence demonstrating thesafety and effectiveness of the product prior tomarketing (FDA, 2003).
Depending on the use of a combo device, it mayrequire either PMA or 510K approval prior toentering the market (FDA, 2003).
510(K) fees are $3693 as a standard fee and
$1847 for small businesses (FDA, 2003).
PMA fees range from $200,725 to $599,366, withlower fees for small businesses (FDA, 2009). Thefees are even higher for combination devicesbecause an efficacy supplement for the biologiccomponent needs to be submitted to the FDA,raising the application fee by an additional$200,725 (FDA, 2009).
Once the device is on the market, periodicreporting, including cleanliness validationreporting, for the device is needed costing $7.025per annum (FDA, 2009)
The regulatory system in the EU for medicaldevices is similar to the FDA process. However,independent bodies are often hired to carry outvalidation processes and there is no requirementfor prospective, randomized controlled clinicaltrials for PDA applications. Therefore, theapproval process for drugs in the EU is oftenshorter than the approval process in the US.
For manufacturers and cleaners of medicaldevices, Ceram offers a range of independently-verified cleanliness analysis techniquesparticularly focusing on surface analysismeasurements. With more than twenty five yearsexperience, Cerams materials and surfaceanalysis group is Europes leading surfacecharacterisation company. Ceram has developedthe unique Validata cleanliness index (CI) whichexpresses surface cleanliness as a single figureranging from 0 to 100% derived from a complexcombinatorial algorithm (Pickles, 2008). Thisindex enables a simple comparison betweensamples and permits the monitoring of processtrends; the index also enables the easycommunication of surface cleanliness validationfindings.
CASE STUDIES
Ceram analysed metered dose inhaler (MDI)barrels using XPS and ADXPS. Using thesetechniques, they found significant silicone
contamination of some of the barrel surfaces,thought to have originated from a lubricantapplied to the barrel assembly duringconstruction or filling of the device. Theinvestigation also identified thinning of thefluorinated surface coating on the device.
Two direct surface analysis methods were alsoused by Ceram to analyse a stain on the outersurface of Aluminium Metered Dose Inhaler (MDI)cans. Using both XPS and ToF-SIMS, Ceram wasable to characterise the stain and identify it asorganic in nature containing fatty acids oftenfound in lubricating oils.
The validation methods offered by Ceram havebeen used to verify that changes to cleaningprocesses and revised manufacturing methodsfor a medical device did not detrimentally affectthe cleanliness of the device. For example, Ceramused SEM/EDX to verify for Joint ReplacementIndustries (JRI) that residues limits of embeddedparticulates from the polishing and blastingprocesses in the manufacture of orthopaedicimplants had not been exceeded. Ceram alsoused XPS to compare the elemental andoxidation-state composition of the devicessurface before and after the implementation ofthe new cleaning and manufacturing processesfor the device. Using this information fromCeram, the medical device manufacturer was ableto demonstrate that its new productionprocesses produced cleaner medical devices thanbefore and ensured that a break in productiondid not occur.
CONCLUSION
Of the various analytical methods available tomeasure device cleanliness, and thereby trulyvalidate the cleaning process, only surfaceanalysis can inform the level of adsorbedcontaminants.
Ceram offers a unique form of surface analysistailored for cleanliness process validation for anytype of cleaning method.
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ABOUT LUCIDEON
Lucideon is a leading international provider of
materials development, testing and assurance.
Through its offices and laboratories in the UK, US
and the Far East, Lucideon provides materials
and assurance expertise to clients in a wide range
of sectors, including healthcare, construction,
ceramics and power engineering.
The company aims to improve the competitive
advantage and profitability of its clients by
providing them with the expertise, accurateresults and objective, innovative thinking that
they need to optimise their materials, products,
processes, systems and businesses.
ABOUT THE AUTHOR
DR CHRIS PICKLES - CONSULTANT
TO LUCIDEON
EXPERTISE IN: AUTOMOTIVE; POLYMERS;SURFACES & COATINGS
Chris holds a Degree in Chemistry, a PhD in
Polymer Science, and a Postdoctoral Fellowship.
AEROSPACE
Chris has been supplying surface analysis
capabilities to the aerospace industry for over
three years with particular emphasis on carbon
reduction programmes involving composite
developments, coating analysis and lubricant
developments in relation to the introduction of
biofuels.
AUTOMOTIVE
Chris has worked in both the aftercare sector as a
Company Technical Manager and in tier one
supply chain manufacturing as Managing
Director.
Chris has been responsible for the plasticinjection moulding and blow moulding
manufacture of automotive component systems
including highly technical mouldings such as fuel
tanks and 3D spoilers. In addition Chris has alsomanaged an integral supply chain utilising Toyota
production system protocols.
POLYMERS
During his career, Chris has spent four years
researching copolymer design for bulk property
manipulation and the statistical mechanics of
PVC to determine conformational sequencing.
Chris's knowledge also encompasses plastics
manufacturing, including injection moulding of
glass-filled nylon and co-extrusion blow moulding
of complex 3D components.
SURFACES AND COATINGS
In the field of surface science, Chris has
conducted research projects on alternative
material sources for surfactants and detergent
product re-formulation. These include the re-
launch of a branded fabric washing product in
Brazil and the design of a surfactant system
utilising renewable resources. As Technical
Manager in the automotive aftercare industry he
has managed the development and qualitycontrol of spray paints for high speed aerosol
filling.