Most medical device manufacturersmust first receive approval from the

U.S. Food and Drug Administration(FDA) before they can market a medicaldevice. Device manufacturers mustdemonstrate that their device is safe andeffective for the intended application.The tests that must be performed varywith the device, application of thedevice, and components of the device,such as coatings, as well as the length oftime that the device may be used in apatient. To prevent delays in the FDAreview process, manufacturers mustensure that they complete the necessarytests and avoid wasting time on tests thatare not required or do not add to theassurance of safety of the product.

The best strategy to streamline FDAapproval begins by formulating a detailedtesting plan, then having the FDA reviewthe plan. This approach permits theagency to offer guidance, if necessary.

A provider of full, life-cycle testingservices for medical devices, such as

Nelson Laboratories of Salt Lake City,UT, can help formulate this plan todetermine which tests a specific type ofdevice may need. Many medical devicesare unique and could require individu-alized or niche testing to get to market.The tests listed in this article are someof the most widely used.

BiocompatibilityBiocompatibility analyses consist of sev-

eral defined tests including: sensitization,cytotoxicity, hemocompatibility, irrita-tion, and systemic toxicity. These preclin-ical biocompatibility tests provide adegree of confidence about how a devicewill react when used in the human body.

Sensitization: The sensitization test eval-uates whether or not the device, or a deviceextract, will elicit an immune system reac-tion from repeated exposures. The testuses guinea pigs, the animal model thatmost closely mirrors the reaction ofhumans to an immunizing substance. Thetest is performed by repeatedly exposing

the animals to device or device extracts fol-lowed by a rest period to allow antibodyproduction, and then a challenge to deter-mine the presence of antibodies.

Examples of materials that can causeallergic reactions from second or subse-quent exposures include detergents, sol-vents, adhesives, and biodegradablepolymers. Initial exposure produces noresponse, but after the body has beenexposed to an allergen, it makes an anti-body that can cause dangerous, evenlife-threatening reactions from subse-quent exposures.

Cytotoxicity: Cytotoxicity is arguablythe most sensitive of the biocompatibil-ity tests. It is a basic in vitro test that usesmammalian cells in culture to respondto any cytotoxic material present in thedevice or that can be extracted fromthe device. Cytotoxicity tests mayinclude elution tests, which employdevice extracts, or may be performeddirectly on cells with the agar overlayprocedure. The cytotoxicity test is usedas a finished device test as well as adevice component screen, and is oftenused for monitoring each incoming lotof raw material.

Irritation: Irritation tests are per-formed on rabbits. Extracts of the deviceare injected into the skin and monitoredfor irritation reactions, typically redness,swelling, or both. This test allows manu-facturers to determine if any toxic mate-rials are leaching off their devices at lev-els that can be detected in a live mam-malian system.

Hemocompatibility: If a device isdesigned for direct or indirect contactwith circulating blood, it needs to be test-ed for blood compatibility. Hemolysistests are performed by exposing thedevice or device extract to mammalian(typically human or rabbit) red bloodcells. Blood cells and test samples areincubated together for sufficient time toallow any hemolysis to occur. The cellNelson Labs scientist removing extraction media while performing a Cytotoxicity test.

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containing liquid is then analyzed for thepresence of hemoglobin that cannot beremoved by centrifugation. If the cellswere unaffected by the device or extract,centrifuging the cells from the mixturewill result in little or no hemoglobin inthe supernatant fluid. This is a passingresult. If hemolysis occurs, manufactur-ers must determine if the level of hemol-ysis is significant. This often requirescomparison of the device under test to apredicate (already on the market) prod-uct with the same claims or usage.

Based on device design and applica-tion, additional blood compatibilitytests may be required; including coagu-lation/thrombogenicity, complementactivation, implantation, systemic toxici-ty, cytogenetic tests such as Ames,mouse lymphoma, or chromosomalaberration tests. Devices used in specificareas of the body often need testsdesigned to simulate the intended use.These would include eye irritation ormucosal irritation tests.

ChemistryChemistry tests are usually basic and

are designed to determine if the poly-meric or other device componentreceived is the one that the FDA was toldwould be in the device. Chemistry testsare also valuable to characterize newmaterials to determine the level ofextractables or residual manufacturingmaterials present.

USP Physicochemical series: This series oftests is used to characterize leachablesubstances. These tests include heavymetals, non-volatile residues, residueson ignition and materials that may

change the pH in the body (bufferingcapacity). These tests are described inthe compendia and have defined accept-ance criteria. Their intent is to reducerisk when employed in new applications.

Identification tests: Identification testsinclude Fourier Transform Infrared(FTIR) and differential scanningcalorimetry (DSC). FTIR is used to con-firm the identity of a polymeric materialand DSC characterizes the thermalevents that may be significant such as theglass transition point (Tg).

Packaging ValidationA manufacturer’s device master plan

should consider the environment inwhich the device will be used. This willhelp to design the proper packaging.Products that will be used in an emer-gency vehicle normally require morerobust packaging than items dispensedfrom a shelf pack in a clinic. Productsthat need to be delivered sterile to apatient in surgery need two packages sothat the outer contaminated packagecan be removed before the inner pack-age is moved to the surgical suite. Theseal strengths of the packages shouldnot be too low, which would result in lossof package integrity; or too high, whichwould cause issues with opening thepackage at the point of use. Devices withsharp or irregular surfaces often failshipping and packaging tests due towear or damage on the package materi-al. Density, number of units per package,device mobility inside a package, andmany other factors can delay the projectand cause test failures. Preliminary tri-als, or feasibility studies, should be

included in any plan. Careful attentionto packaging design can minimize test-ing failures and prevent extra costs andlost time.

Strength Tests: Strength tests are impor-tant to make sure packaging is strongenough to protect the device from theintended environmental conditions.Burst: The burst test determines packag-ing strength by pressurizing a packageand measuring the pressure inside thepackage system until the seals or thepackage bursts. Seal Peel: This test determines packageseal strength by cutting and inserting asegment of the package seal into a phys-ical test apparatus and recording theforce needed to pull the seal apart. Thetest also determines the package’s maxi-mum load.

Integrity, Permeability, and Stability Tests:Accelerated Aging: This test simulates theaging process, and allows a package to beevaluated prior to completion of real-time aging. The duration required forsimulated aging depends on the temper-ature at which the products are stored.Aerosol Challenge: This test is intendedto challenge the entire package to deter-mine the microbial barrier properties ofthe package. The finished, packageddevice is placed in a chamber andexposed to an aerosol of bacterial sporesto determine if the microbial spores canpenetrate the packaging system.Dye Migration: The dye migration testinvolves injecting dye into the packageand placing the weight of the solutionagainst each package seal for a specificduration. The package is examined forevidence of seal failure demonstrated bydye migrating through a seal.Bubble Emission: Bubble emission is avisual test. The whole package isimmersed in water and observed for thepresence of bubbles. Evidence of bubbleemission through the package is consid-ered a failure. This test has the addition-al advantage of identifying where thefailures occur and is often used as a testfor failure investigations.

Bacterial EndotoxinsMedical devices and pharmaceutical

products can introduce bacterial endo-toxins to the human body through theblood, lymph nodes, or cerebral spinalfluid if they are not properly manufac-tured or cleaned, causing fever andpotentially death.

Endotoxin-producing bacteria aredangerous to the human body whetherdead or alive. Sterilization does not elim-

Nelson Labs scientist loading samples for sterilization.

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inate endotoxins. Medical device manu-facturers must conduct bacterial endo-toxin testing on their medical devices iftheir product will contact blood orspinal fluid. Some medical devices thatdo not contact blood or spinal fluidmust also be tested. Examples includesurgeon’s gloves and some oculardevices. This test is performed on allparts of the device that are designed tocome in contact with the blood or spinalfluid. Endotoxin tests are simple, rapid,and use an enzymatic reagent to detectcontamination. Endotoxin tests mustalso be performed on the final productafter all manufacturing processes havebeen completed.

SterilizationIf a medical device must be sterile,

manufacturers will need to define anddesign a sterilization process. It is mostefficient to determine the sterilizationmode early in the development process.Preliminary tests should be conducted toidentify problems that would otherwiserequire a change in process or a repeat ofcompleted tests. The best sterilizationoptions include dry heat, steam, radiation(gamma or e-beam), ethylene oxide, andvaporized hydrogen peroxide.

BioburdenBioburden testing determines the

number of microorganisms on devicesprior to sterilization. The number ofmicroorganisms on the device indicatesthe level of microbial control of themanufacturing process and can help

determine which sterilization processmay be required and the dose of steri-lant necessary. Normally, the lower thebioburden, the lower the sterilizationcosts. For most sterilization processes itis also important to perform organismidentification tests to characterize theorganisms on a device. Knowing thetypes of microorganisms on a device ishelpful in determining the source ofmicroorganisms and thus how to reduceor control them.

ParticulatesThe FDA has increasingly been requir-

ing particulate tests for critical blood con-tact (intravascular) devices. Particulatetesting is advisable for all products todetermine the potential particulate risk.Some manufacturers have been surprisedby high particulate levels, but have beenable to control them once they wereaware. Regardless, most devices that havedirect intravascular blood contact and alldevices that have either substantial in -travascular blood contact or involve anextracorporeal circuit should be evaluat-ed for particulate counts.

Particulate tests simply quantify thenumbers of particles present on the inter-nal or external surfaces of a device. Thesetests are performed using product washesthat are either counted in an automatedliquid particle counting instrument ormanually with a microscope.

SummaryManufacturers should first identify

the tests that they think are important

to ensure that their device is safe andeffective. If the product must be ster-ile, they should select the mode ofsterilization. The proposed tests mustbe discussed with the FDA divisionthat will review the submission to getfeedback on the plan. They shouldreview the test list to determine theorder in which the tests must be per-formed. For example, biocompatibili-ty tests must be performed on anyproduct that has been subjected to thesterilization process. Otherwise, bio-compatibility tests will need to berepeated. Often multiple exposures tothe sterilization process may be neces-sary to account for worst-case process-ing situations. Packaging must beselected and preliminary tests runbefore bioburden and particulate testscan be performed.

Once the testing sequence is deter-mined, it is wise to re-evaluate riskassessment and consider any final addi-tions or deletions. Remember that risksmay include safety, efficacy, cost, andtime. Manufacturers should review thefinal plan with a laboratory testing part-ner to ensure a common vision for exe-cution. An experienced partner willhelp greatly in adjusting to currenttrends and changing expectations fromregulatory agencies.

This article was written by Jerry Nelson,Ph.D., Chief Science Officer, and AmyKarren, Microbiology Section Leader atNelson Labs, Salt Lake City, UT. For moreinformation, visit http://info.hotims.com/28055-160.

Medical Device Testing

Reprinted from Medical Design Briefs, July 2010. On the web at www.techbriefs.com.© 2010. All Rights Reserved. Foster Printing Service: 866-879-9144, www.marketingreprints.com.

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