cleanliness validation white paper medical device

8/12/2019 Cleanliness Validation White Paper Medical Device

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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.

cleanliness validation white paper medical device

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