Plastics in Medical Devices || Material Requirements for Plastics used in Medical Devices

4 Material Requirements for Plastics used inMedical Devices

4.1 Introduction

Plastics used in medical device applications mustmeet stringent performance requirements throughproduction, packaging, shipping, end use, anddisposal. Many devices and device kits are sterilizedbefore they are shipped for use. Duringmanufacturing and during end use they also come incontact with various chemicals, solvents, bodilyfluids, skin, organs, and tissues. The materials used insuch devices must be resistant to the sterilizationmethods, chemicals, and fluids that they encounter,be compatible with bodily fluids, skin and tissues andstill maintain their safety, effectiveness, and func-tionality. Requirements for plastics used in medicaldevices include the following:

1. Material characterization,

2. Sterilization resistance,

3. Chemical and lipid resistance,

4. Extractables and leachables characterization,

5. Biocompatibility and hemocompatiblity, and

6. Shelf life and stability.

4.2 Material Characterization

Plastics used in medical device applications mustbe fully characterized with respect to the followingattributes as described in ISO 10993-18 (seeTable 4.10).

• Composition (identity and percent of all compo-nents in the formulation, spectroscopic and/orchromatographic analysis, and fingerprints);

• Mechanical properties (tensile strength, elonga-tion, flexural modulus, flexural strength);

• Thermal properties (melting point, softeningpoint, heat distortion temperature, glass transi-tion temperature, continuous temperature, ther-mogravimetric analysis);

Plastics in Medical Devices

Copyright � 2010, Vinny Sastri. Published by Elsevier Inc. All rights reserved

• Electrical properties (if applicable); and

• Trace metal analysis.

4.3 Sterilization

Many devices need to be packaged and sterilizedeither before distribution or before use. Examples ofsuch devices are exam and surgical gloves, cleanroom garments, specimen cups, wound care products,sutures, needles, syringes, catheters, drain bags, IVbags, fluid delivery systems, dialysis equipment,implants, surgical instruments, dental instruments,surgery supplies, and combination products.

All materials used in such medical devices,including the plastics used in them, must be capableof being sterilized without loss of performance.Sterilization can be defined as the removal ordestruction of all living organisms, including resis-tant forms such as bacterial or fungal spores [1].Bacterial spores are most resistant to destruction, andif the sterilization is effective in eliminating themthen it can generally be assumed that all other path-ogenic and non-pathogenic organisms have beendestroyed. It is important to reduce or eliminate thebioburden of certain medical devices and the mate-rials used in their manufacture before end use. Bio-burden is the concentration or the number ofmicroorganisms like pyrogens, viruses, molds, andfungi present in or on a material. Pyrogens aresubstances that can cause a fever. There are varioustests that can detect the number and kinds of micro-organisms including pyrogens and remnants ofbacteria. A product may be sterile but it still maycontain pyrogens. Use of high temperatures or radi-ation will typically kill pyrogens. It is important torealize that production in a ‘‘clean room’’ does notmake a device sterile; it simply reduces the initialbioburden and concentration of foreign particles in oron the material to make sterilization more effective.Cleanliness does not mean sterile.

After sterilization, samples are tested for sterility.Biological indicators are one way of assessing the

33

Table 4.1 Typical Steam Sterilization Conditions

Temperature (8C)Sterilization Time(minutes)—1 Cycle

132–134 3–10

121 8–30

115 35–45

111 80–180

34 PLASTICS IN MEDICAL DEVICES

effectiveness of sterilization. A biological indicatorcontains minute organisms and is placed along withthe devices at various locations in the sterilizationchamber. Death of the organisms in the biologicalindicator provide confirmation of the effectiveness ofthe sterilization procedure.

A second method to assess the effectiveness ofsterilization is by ‘‘parametric release’’. Parametricrelease is the tight control of the critical processparameters used in the sterilization. The criticalprocess parameters and their values are determinedby validating the appropriate sterilization method forthe specific devices and materials. For example, inethylene oxide sterilization, critical parametersinclude the concentration of the ethylene oxide gas,the relative humidity of the chamber, the temperatureof the chamber, and the residence time in thechamber. Various standards detail the needs forspecific types of sterilization [2–5].

Sterility is measured by the Sterility AssuranceLevel (SAL) of the device or the material. The SAL,expressed as 10�N, is the expected probability ofsurviving organisms. Typical SALs are 10�6

meaning that the expected probability of anysurviving microorganism after sterilization is 10�6.Some less critical or low-risk devices might needSALs less than 10�6. Sterilization conditions must beselected to achieve targeted SALs.

Sterilization can be achieved through a variety ofmethods. These methods will be described withparticular emphasis on their applicability to thesterilization of plastics. No matter which sterilizationmethod is used, the objective is to reduce the bio-burden to a safe SAL. The main sterilization methodsused in medical devices are:

1. Autoclaving (steam, dry heat)

2. Ethylene oxide (EtO)

3. Radiation (gamma radiation, electron-beamradiation)

4.3.1 Steam Sterilization

Autoclaving uses saturated steam in the steriliza-tion process [6]. Steam sterilization is generallycarried out at temperatures between 121 �C (250 �F)and 134 �C (273 �F), under 15 psi (0.5 bar) pressure,between 10-60 min, depending upon the material andneed. Table 4.1 gives typical steam sterilizationconditions. The lower the temperature, the longer the

exposure time required for sterilization. Multiple-usedevices are exposed to several sterilization cycles asthey are sterilized after each use. Materials used insuch devices must be able to withstand the number ofcycles specified to the device and still maintainperformance, safety, and effectiveness.

It is important to remove all the air from theautoclave before introducing steam as air is heavierthan steam and will reduce the steam concentrationand hence the effectiveness of the sterilization. High-speed steam sterilization is conducted at highertemperatures (134 �C/273 �F) and shorter cycle times(between 3 and 10 min). High temperatures alongwith moisture will kill microorganisms. High-pres-sure steam first condenses when it comes in contactwith the part/material while continuing to heat thepart/material. Appropriate time/temperature cyclesare developed based on the type and the amount ofload in the chamber to ensure complete sterilizationand destruction of microorganisms. Steam shouldpenetrate and reach all surfaces of the product forproper sterilization efficacy. Poor cleaning, impropermoisture, impermeable packaging, or over packingthe autoclave chamber can reduce the effectivenessof steam sterilization.

The critical factors in ensuring the reliability ofsteam sterilization are: (1) the right temperature andtime; and (2) the complete replacement of air withsteam (i.e., no entrapment of air). The use of appro-priate biological indicators at locations throughoutthe autoclave is considered as the best indicator ofsterilization. The biological indicator most widelyused for wet heat sterilization is Bacillus stear-othermophilus spores. More recently parametricrelease methods have been used to evaluate sterilityof devices [7].

Plastic materials that have a higher softeningtemperature than the sterilization temperature must beused when considering steam sterilization (Table 4.2).Plastics with lower softening points than the steam

Table 4.2 Autoclaving Capability and Heat Distortion Temperatures of Plastics used in Medical Applications

Polymer HDT (at

0.46 Mpa)

Steam

at 121°C

Dry Heat at

135°C

Hydrolytic

stability

Polyolefins HDPE 80 - 120 Fair Poor Good

LDPE 60 - 80 Poor Poor Good

UMHPE 60 - 80 Poor Poor Good

0 2 1 - 0 0 1 * P P Good Fair Good

PP copolymers 85 - 105 Good Fair Good

0 7 1 C O C Good Good Good

PVC PVC plasticized 60 - 80 Poor Poor Good

PVC unplasticized 90 - 115 Good Good Good

Polystyrene/StyrenicsPolystyrene 70 - 90 Poor Poor Good

5 9 - 0 8 S B A Poor Poor Good

SAN 95 - 105 Poor Poor Good

Acrylics 75 - 100 Poor Poor Fair

Polycarbonates 135 - 140 Fair Fair Fair

Polyurethanes 50 - 130 Poor Poor Poor

Acetals 145 - 160 Good Fair Good

Polyamides Nylon 6, Nylon 66 170 - 220 Fair Fair Poor

Aromatic 250 - 300 Good Good Good

Nylon 12, 10, 6/12 70 - 150 Poor Poor Fair

Polyesters PET/PBT 75 - 140 Fair Fair Poor

Copolyesters 60 - 80 Poor Poor Poor

High temperature thermoplastics

Polysulfones 170 - 215 Good Good Good

PPS 195 - 215 Good Good Good

LCP 200 - 300 Good Good Good

0 1 2 - 0 0 2 I E P Good Good Fair

0 61 K E E P Good Good Good

Fluoropolymers PTFE 75 - 130 Fair Fair Good

0 7 P E F Good Good Good

ECTFE/ETFE 115 Good Good Good

PVF/PVF2 140 - 150 Good Good Good

Biopolymers 25 - 80 Poor Poor Poor

Elastomers 20 - 40 Poor Poor Fair

Thermosets 150 - 300 Good Good Good

4: MATERIAL REQUIREMENTS FOR PLASTICS USED IN MEDICAL DEVICES 35

sterilization temperatures will warp and deform.Hydrolytic stability is another important considera-tion. Materials that have high heat distortiontemperatures (like polycarbonate, polyesters, andpolyamides) might be prone to hydrolysis. Steamsterilization might not be the best option for suchmaterials. Polymers like polycarbonates have highheat distortion temperatures but fair hydrolyticstability. They can thus be steam sterilized for 1-2cycles only.

Sometimes products that have a higher softeningtemperature than the autoclaving temperature canwarp or distort due to the release of molded-in stress[8]. Molded-in stress is caused by the rapid cooling orimproper design of the part. Heating the part relieves

the stress causing differential stress and hencedeformation. Where autoclaving is to be used, theeffect of multiple sterilization cycles needs to beconsidered to prevent cumulative effects of thetreatment on the plastic. If the devices are to bepackaged before autoclaving then the packagingmaterial and packaging method needs to be carefullychosen. The suitability of a package for autoclavingwill depend on the material, the size of the package,the wall thickness of the package, and the contents.Autoclaving is used significantly in hospitals for thesterilization of multiple-use articles. It is not thepredominant method in the commercial sterilizationof medical devices because of the difficultiesinvolved with autoclaving packaged products.


Most plastics will survive 1-5 cycles of steamsterilization. For those reusable devices, that need upto 100 sterilization cycles, polysulfones, polyethersulfones, polyetherimides, PEEK, and liquid crystalpolymers (LCPs) are generally used. For applicationsthat require greater than 100 cycles poly-phenylsulfones, PEEK (Polyether ether ketone), andLCPs can be used. Polyphenylene sulfones can beused for up to 1000 cycles of steam sterilization.

4.3.2 Dry Heat

Dry heat sterilization is not as effective and effi-cient as wet heat (steam) sterilization. Highertemperatures and longer times compared to steamsterilization are generally required. Temperaturesrange from 160 to 170 �C (320-338 �F) for periods of2-4 hours. The specific times, temperatures, and otherprocess parameters must be determined for each typeof material being sterilized and amount and config-uration of the load in the autoclave chamber. Highertemperatures and shorter times may be used for heat-resistant materials.

The advantage of wet heat (steam sterilization) isbetter heat transfer to the material or part resulting inoverall shorter exposure time and lower temperature.Dry heat is not generally regarded as being suitablefor plastics due to the low thermal transmissionproperties of plastics and the difficulty of insuringthat all parts of the product have been exposed to therequired temperature for an adequate time. Mostplastics will either warp or degrade during prolonged

XHR CC

O

H

H

H

H

-XH = -NH2, -OH, -SH, -COOH

+

Figure 4.2 Reaction of ethylene oxide with proteins.

CC

O

H

H

H

H

Figure 4.1 Structure of ethylene oxide.

dry heat sterilization (see Table 4.2 for the heatdistortion temperatures).

4.3.3 Ethylene Oxide (EtO)

Ethylene oxide (EtO)—Figure 4.1—has beenwidely used as a low-temperature sterilizing agentsince the 1950s [9]. Temperature-sensitive andmoisture-sensitive materials and devices typicallyuse ethylene oxide sterilization. EtO is supplied inthree basic forms for sterilization: 100% EtO, 10%EtO and 90% hydrochlorofluorocarbon (HCFC),and 8.6% EtO diluted in 91.4% carbon dioxide(CO2).

Pure ethylene oxide gas is flammable, explosive,and a very powerful alkylating agent. It is thusregarded by the EPA (Environmental ProtectionAgency) as a toxic and possibly a carcinogenic gas(exposure to EtO is regulated by the EPA and OSHA(Occupational Safety and Health Administration)).Proteins can react with ethylene oxide leading todenaturing of the protein (Figure 4.2) [10,11].

The efficacy of EtO sterilization is measured bybiological indicators. More recently parametricrelease methods have been developed to measure theeffectiveness of EtO sterilization. Parametric releaseremoves the need to send the biological indicatorsto a testing laboratory to evaluate sterilization levelsby measuring the microorganisms in the biologicalindicators.

Ethylene oxide sterilization depends upon thefollowing factors:

1. Chamber temperature;

2. Relative humidity of the chamber;

3. Concentration of the gas;

4. Time of exposure to the gas;

5. Compatibility of the material to EtO andpermeability of packaging material to EtO; and

6. Types of microorganisms.

XR CH2 CH2 OH


The first step in EtO sterilization involves pre-conditioning of the products in a chamber to specifiedtemperatures and relative humidity. This reduces theprocessing time in the sterilization chamber itself.After conditioning, the products are introduced intothe sterilization chamber which is first evacuated andthen heated to a temperature of 50-60 �C. Moistureand EtO gas are then introduced for a specifiedamount of time. Gas concentrations are typically200-800 mg/l. The internal pressure of the chamber iskept at less than the atmospheric pressure so that EtOgas does not diffuse or leak out into the atmosphere.After the specified exposure time, the EtO is removedand the chamber is flooded with filtered sterile air toaerate the products and remove any residual EtO toreach the acceptable levels. Thus the products aretested for sterility and residual ethylene oxide content.

Most plastics are unaffected by EtO sterilizationtreatment, but some can absorb EtO and must beaerated to eliminate any EtO before use. Some plasticsare relatively permeable to EtO and can be used aspackaging materials to sterilize fully packageddevices. Packaging films, such as polyethylene, allowEtO gas to enter the package and sterilize the contents.The packaging film must also be permeable to bothwater vapor (for bacterial growth) and air (for aerationand EtO removal) to be effective. Table 4.6 shows thecompatibility of various plastics to EtO sterilization.

Table 4.3 Radiation Dose Units and Conversions

1 Gray (Gy) 100 rads

1 kGy 100,000 rads

1,000,000 rads 1 Megarad (Mrad)

1 kGy 0.1 Mrads

10 kGy 1 Mrad

4.3.4 Irradiation

Irradiation is commonly used for sterilization andcan be generated by either gamma rays from a Cobalt(Co60) source or an electron beam (e-beam) [12].Plastic devices subjected to irradiation sterilizationcan be affected by the radiation and the environmentused during sterilization, and can degrade or cross-link[13]. These processes will lead to changes in thetensile strength, elongation at break, and impactstrength. The exact changes will depend both on thetype of polymer and any additives used. The changesin mechanical properties may not be immediatelyapparent and there can be some time delay in theirdevelopment. Stabilizers like antioxidants and freeradial scavengers can prevent degradation and cross-linking [13]. Discoloration and yellowing is also fairlycommon and in many cases fades with time. Discol-oration can be overcome by the use of tinting agentsthat compensate for the color change [14]. Irradiateddevices are completely safe to handle and can bereleased and used immediately after sterilization.

Dose levels for either process are measured inKiloGrays or Megarads. A dose is defined as theamount of energy deposited per unit mass. The unitused for measuring the absorbed dose, according tothe International System of Units (SI), is the gray(1 Gy ¼ 1 J/kg), where 1 J of energy is deposited on1 kg of material. Table 4.3 details the relationshipbetween these two units.

As a general rule, a radiation dose of 25 kGy (2.5Mrads) will sterilize most plastics in air. The requireddosage will be approximately twice as high inanaerobic conditions. It is important to recognize thatthis is the minimum dosage. The equipment is typi-cally set to ensure that at least the minimum dosage isdelivered. The actual delivered dosage is often muchhigher to achieve sterilization. The effect of radiationis cumulative and for items that must be repeatedlysterilized the total dosage can rise rapidly. Dosimeters(instruments used to detect dose levels) are used invalidated radiation processes to keep track of the dosereceived by the materials in the chamber. Irradiationis very effective for fully packaged and sealed single-use items where only one radiation dose is required.Most plastic films are transparent to radiation.

4.3.4.1 Gamma Radiation

Gamma rays are produced from a Co60 source andhave penetrating powers up to 50 cm. Figure 4.3shows where the high-energy gamma rays lie in theelectromagnetic spectrum.

Controlled exposure of the product to the radiationensures that specified doses are delivered to theproduct. The specified dose is defined as the amountof radiation required to reduce the bioburden to thedesired level while still maintaining the integrity,aesthetics, and performance of the device. Theminimum dosage (Dmin) is the dose that ensuresacceptable microbiological reduction, and themaximum dosage (Dmax) is the maximum dosage thatwill still maintain the quality, aesthetics, andperformance of the material or device.

10-6

nm

10-5

nm

10-4

nm

10-3

nm

10-2

nm

10-1

nm

= 1

Å

1 n

m

10 n

m

100

nm

103

nm

= 1

µm

10 µ

m

100

µm

103

µm =

1 m

m

10 m

m =

1 c

m

10 c

m

100

cm =

1 m

10 m

100

m

1000

m =

1 k

m

10km

100

km

Gam

ma rays

X-rays

Ultravio

let rays

Visib

le lig

ht

In

frared

Micro

waves

Rad

io

w

aves

Å = Angstromcm = Centimeternm = Nanometer

µm = Micrometerkm = Kilometer

mm = Millimeter

m = Meter

Figure 4.3 The electromagnetic spectrum.


The high penetrating power of gamma radiationallows for a high packing density of devices andproducts in the sterilization chamber. However,products at the outer edges of the packing load can besubjected to much higher radiation doses than thoseat the center of the packing load. Materials sterilizedby gamma radiation need to be rated at higher doselevels than those actually used in sterilization toensure that there is minimal degradation of thoseproducts at the outer edges of the packing load in thechamber. Gamma radiation can negatively affectplastics in the following ways:

1. Formation of radicals leading to chain scissionand degradation (Figure 4.4);

2. Formation of radicals leading to cross-linking;and

3. Color change and yellowing.

H

RO

RadicalFormation

CH3CH3CH3CH3

Continued radical formationand chain scission

leading to polymer degradation

Figure 4.4 Radical formation and chain scission using rad

Chain scission leads to degradation and reducestoughness, elongation, and impact strength. Thehigh-energy gamma radiation forms radicals alongthe polymer chain. These radicals subsequentlydegrade the polymer to lower molecular weightchains leading to reduced physical properties.

In general, polymers that contain aromatic ringstructures are more resistant to radiation effectscompared to aliphatic polymers. However, manystabilizers like phenolics, HALS (hindered aminelight stabilizers), phosphates, etc. have been used toabsorb the energy or quench and capture the freeradicals formed, thus preventing degradation [15].Color correction tints like ultramarine blue are usedto compensate for the color change and maintaina clear, transparent plastic after radiation. Thosepolymers that require stabilization are given below.Transparent polymers like polyvinyl chloride,

ChainScission

ROH+

CH3 CH3 CH3 CH3

CH3CH3CH3CH3

+

iation.


acrylics, polycarbonates, and polyurethanes typicallyhave a tinting agent and some polymers also requirefree radical scavengers or quenchers to preventdegradation (Table 4.4). The radiation stability ofcommon polymers is given in Table 4.6.

In choosing polymers that need to undergo gammaradiation sterilization, the following should be takeninto consideration:

1. Polymers stabilized with antioxidants andstabilizers can reduce the effects of radiation.

2. High-molecular weight polymers will maintainphysical properties better than lower molecularweight polymers if chain scission occurs.

3. Residual mold stress can accelerate chain scis-sion during radiation.

4. Highly oriented parts can become weaker inthe cross-flow direction after radiation.

5. Radiation doses are additive. For example, if amaterial is irradiated twice at 25 kGy, it is as ifthe material was irradiated with a 50 kGy dose.

Table 4.4 Radiation Stability of Various Plastics

Polymer Com

Polyolefins Polysuscpolygood

PVC Susbasedisc

Acrylics Muschan

Polycarbonates Muschan

Polyurethanes Som

Acetals Typi

Polyamides PolyPoly

Polyesters Arom

High-temperature thermoplastics PEK

Fluoropolymers TefloTeflofluor

Elastomers Gen

Thermosets The

Materials must be tested at their maximumpossible dose. Some suggest testing the mate-rials at twice the maximum possible dose.

4.3.4.2 Electron-beam (e-beam)Radiation

e-Beam sterilization uses an e-beam generator(between 1 MeVand 12 MeV. MeV¼Mega ElectronVolt. 1 MeV¼ 0.1.602� 10�13 J) to produce a beamof high-energy electrons that destroy organisms [16].The e-beam electrons have a much lower penetratingpower than gamma rays. A 10 MeV e-beam willpenetrate about 5 cm or 2 inches. This means that thepacking density of the load in the chamber must below to ensure that the electrons reach the center of thepacking load. As with gamma rays, products at theedges of the packing load are subjected to higherdoses than products at the center to ensure that fullsterilization is achieved. Like gamma radiation,effects on plastics from dose rates are cumulative.Twice the required dose rate is used to ensure

ment

ethylene can cross-link. Polypropylene is especiallyeptible to degradation and discoloration. Stabilizedpropylene and polypropylene copolymer grades are

ceptible to degradation and color change. Tint-d, stabilizers are incorporated into PVC to prevent

oloration and degradation

t be stabilized to prevent degradation and colorge

t be stabilized to prevent degradation and colorge

e discoloration that reverses over time

cally not used for gamma sterilization

amides containing aromatic rings are goodamides 10, 12, 6/10, and 6/12 are good

atic polyesters are radiation stable

, PEEK, PEI, Polysulfones—Good

n embrittles when exposed to gamma radiation.n and FEP must be stabilized. All other

opolymers are stable to gamma radiation

erally stable to gamma and e-beam radiation

rmosets typically are radiation stable


integrity and performance for the material and device.e-Beam sterilization can be harmful to productscontaining batteries or electronic components.

Table 4.5 compares the various sterilizationmethods and Table 4.6 is a matrix of commonly usedpolymers and their sterilization capability by thevarious methods discussed above. e-Beam sterilizationis the only continuous method available. All the othersterilization methods are batch processed. Most ster-ilization methods except for ethylene oxide steriliza-tion are safe. It is important to confine the ethyleneoxide gas in the chamber and ensure that the gas doesnot leak out of the chamber into the atmosphere. Low-temperature ethylene oxide sterilization is the mostreliable form of sterilization for combination products.High temperatures and high-energy radiationcan denature or destroy the drug in a combinationdevice. Steam is the most commonly used sterilizationmethod in hospitals for reusable devices.

One very important aspect to sterilization is thepermeability of the packaging material to the steril-ization method. Many devices are packaged and thensterilized. Packaging material must be permeable tomoisture for steam sterilization, ethylene oxide forEtO sterilization, and to radiation for gamma and e-beam sterilizations. In addition, they must also allowthe removal of moisture and EtO after those respec-tive sterilizations. Most importantly, the packagingmust maintain its integrity and functionality afterradiation, through storage, shipping, and distributiontill the device is finally used.

4.4 Chemical Resistance

Plastics used in medical devices can come intocontact with various types of solvents and chemicalseither during the manufacturing process or duringend use. The parts must maintain their integrity,performance, and aesthetics when exposed to suchsolvents and chemicals. The effect of solvents andchemicals on plastics is determined by:

1. The type of plastic;

2. The types of fillers in the formulated plastic;

3. The type of solvent or chemical; and

4. The processing history of the part.

Amorphous plastics tend to be less chemicallyresistant than crystalline materials as they absorbliquids or solvents more easily [17]. They are also

prone to molded-in stress during processing thusmaking them susceptible to environmental stresscracking when exposed to chemicals. Environmentalstress cracking (ESCR) is the formation of cracks ina part when exposed to chemicals, if the parts haveresidual stress in them after molding. The solventsdiffuse into the part and cause differential stressleading to hazing and cracking. Aggressive or strongsolvents can swell, dissolve, or react with the mate-rial causing it to warp and/or degrade. Chemicalscan also interact or react with the additives causingthem to leach out of the part or form unwantedby-products.

Chemicals typically used in a manufacturingenvironment include the following:

1. Acids,

2. Bases,

3. Solvents (methyl ethyl ketone—MEK, tetrahy-drofuran—THF, methylene chloride—MeCl2,ethylene oxide—EtO, alcohols, ethyl acetate),and

4. Processing aids—greases, oils, mold releaselike silicones, etc.

Solvents like MEK and THF are used in thejoining of plastics. Ethylene oxide (and ethyleneglycol) is used in the sterilization of plastics. Manyplastics are exposed to mold release agents like sili-cone sprays during production.

Chemicals used at point of care facilities includethe following:

1. Bleaches,

2. Disinfectants,

3. Detergents and cleaning agents,

4. Lipids,

5. Isopropyl alcohol, and

6. Betadine.

Bleaches typically contain hydrogen peroxideor chlorine in the form of sodium hypochlorite.Disinfectants are often dilute solutions of ammoniumchloride or phenol. Detergents and cleaning agentsare sodium salts of fatty acids. Detergents are verystrong bases and can be harsh on materials. The useof lipids continues to increase in the healthcareindustry. With the discovery of newer drugs thatcannot be dissolved in water, lipid emulsions are usedto dissolve the drugs to administer to patients. Lipidstend to be fatty acids and come in 20% fat/protein

Table 4.5 Comparison of Common Sterilization Methods

Sterilizationcharacteristic

Steam Dry heat Ethyleneoxide (EtO)

Gamma radiation Electron beam(e-beam)

Process type Batch Batch Batch Batch Continuous

Post-sterilizationtesting for SterilityAssurance Level(SAL)

Parametric release;biological indicators

Parametricrelease;biologicalindicators

Parametric release;biological indicators

Dosimetric release Dosimetric release

Post-sterilizationtreatment

Need to dry the product None Need to aerate product toremove residues

None None

Penetration Requires vapor permeablepackaging. Surfacepenetration

Goodpenetration

Requires gas-permeablepackaging; high pressure,temperatures for improvedpenetration

Excellent penetration Near completepenetration, needdosimeters; lowpenetration in high-density materials

Safety Almost no safety concerns Almost nosafetyconcerns

Considered a mutagen/carcinogen; need to removeresidual absorbed EtO

Minimal concern;environmentally safe;non-toxic (needprotection from radiation)

Almost no safetyconcerns

Reliability Excellent Good Good Excellent Excellent

Turnaround time Slow Slow Slow Fast Fast

ProcessParameterControls

Temperature, pressure,vacuum, relative humidity,time

Temperature,pressure,vacuum, time

Temperature, pressure,vacuum, relative humidity,gas conc., time

Time Time

Materialconstraints

Heat resistant andhydrolysis resistantmaterials only

Heat-resistantmaterials only

Polymers that do not absorbor degrade with EtO

Radiation stablepolymers; complex partsand kits not effectivelysterilized

e-Beam stablepolymers; low-density materialsonly

Relative cost Inexpensive Relativelyinexpensive

High capital investment High capital investment High capitalinvestment

Advantages Simple process, widelyused, excellent for reusabledevices, excellent for heat-stable liquids

Relativelysimple process

Well characterized, good forkits, combination products,parametric release

Simple, fast, excellentpenetration, doseuniformity

Simple, fast, lessmaterialdegradation

Disadvantages Comparatively hightemperatures, generally notappropriate for single-usedevices and large lots

Hightemperatures,limited use

Relatively complex process;some limits to penetration;need to remove EtO residuals

Limited applicability to kitsand complex designs/products; no drug/combination products;material degradation

Limited penetration,poor on high-densityproducts, dosimetricrelease is not veryuniform, affected bypart configuration

4:

MA

TE

RIA

LR

EQ

UIR

EM

EN

TS

FO

RP

LA

ST

ICS

US

ED

INM

ED

ICA

LD

EV

ICE

S4

1

Table 4.6 Sterilization Matrix of Plastics

Polymer Steam Dry Heat

Ethylene

Oxide

Gamma

Radiation e-beam

Polyolefins

HDPE Poor Poor Good Good Good

LDPE Poor Poor Good Good Good

UMHPE Poor Poor Good Good Good

PPa

Good Fair Good Fair Fair

PP copolymers Good Fair Good Fair Fair

COC Fair Fair Good Good Good

PVC

PVC plasticizeda,b

Fair Fair Good Good Good

PVC unplasticizeda,b

Poor Poor Good Fair Fair

Polystyrene/styrenics

Polystyrene Poor Poor Good Good Good

ABS Poor Poor Good Good Good

SAN Poor Poor Good Good Good

ASA Poor Poor Good Good Good

MABS Poor Poor Good Good Good

SBC Poor Poor Good Good Good

Acrylicsa,b

Poor Poor Good Good Good

Polycarbonatesa,b

Fair Fair Good Good Good

High heat

polycarbonates Good Good Good Good Good

Polyurethanes Poor Poor Good Good Good

Acetals Good Good Good Poor Poor

Polyamides

Nylon 6, Nylon 66 Fair Fair Good Fair Fair

Aromatic Good Good Good Good Good

Nylon 12, 10, 6/12 Poor Poor Good Fair Fair

Polyesters

PBT Fair Fair Good Good Good

PET Poor Poor Good Good Good

Copolyesters Poor Poor Good Good Good

High temperature

thermoplastics

Polysulfones Good Good Good Good Good

PPS Good Good Good Good Good

LCP Good Good Good Good Good

PEI Fair Fair Good Good Good

PAI Fair Fair Good Good Good

PEEK Good Good Good Good Good

Fluoropolymers

PTFEa

Fair Fair Good Poor Poor

FEP Good Good Good Fair Fair

PFA Good Good Good Good Good

ECTFE/ETFE Good Good Good Good Good

PVF/PVF2 Good Good Good Good Good

Elastomers

Silicones Good Good Good Good Good

TPU Poor Fair Good Good Good

TPC Poor Good Good Good Good

TPA Poor Poor Good Good Good

TPS Poor Poor Good Good Good

TPO Poor Fair Good Good Good

Biopolymers

PLLA Fair Good Good Good Good

PLA Poor Fair Good Good Good

PHB Poor Poor Good Fair Fair

PGA Good Good Good Good Good

PLGA Poor Poor Good Fair Fair

PCL Fair Good Good Good Good

Thermosets Good Good Good Good Good

a Radiation stable grades should be considered for gamma and e-beam radiation sterilization.b PVC, Acrylics, PC - require corrective tint to compensate for discoloration.



emulsions. Lipids are good solvents for plastics andcan cause them to swell, warp, and degrade. Asa result lipid-resistant plastics must be chosen, if thedevice or part will come into contact with lipids.

4.4.1 Test Method for ChemicalResistance

ASTM D543 and ISO 4599 are the test methodsused for chemical and lipid resistance. Test strips areexposed to (immersed in, wiped with, or wrapped ina gauze soaked with) the liquid under specifiedstrains (typically 0%, 0.5%, 1%, and 1.5%) for 72hours. Exposure to lipids is typically for 7 days. Thetest strips are then examined for visual changes(hazing, cracks) and also tested for physical proper-ties like tensile strength and elongation. These arecompared with controls subjected to the same strainsunder the same temperature and in air. Results arerecorded as percent retention of properties.

Figure 4.5 illustrates the fixture that is used fortesting of chemical resistance. Various levels of stresscan be applied to the test bars when exposed to thesolvents or chemicals.

Table 4.7 gives a summary of the chemical resis-tance of typical plastics to select chemicals. The hightemperature plastics (liquid crystalline polymers,PEEK, polysulfones) and fluoropolymers are resis-tant to most chemicals and solvents. Polyolefins(especially high-density polyethylene, ultra-highmolecular weight polyethylene) are resistant to mostchemicals except for some organic solvents. Most of

Figure 4.5 Three point bend (stress) test for chemi-cal resistance.

the other materials fare especially poorly withorganic solvents.

4.4.2 Leachables and Extractables

Another important criterion for the use of plasticsin medical device applications is quantifying the typeand amount of material that is leached out or ex-tracted from the plastic when in contact with chem-icals, reagents, or bodily fluids during the end use.This is especially important for combination productswhere drugs come into extended contact with plasticcontainers and fluid delivery systems [18].

Extractables are compounds that can be extractedfrom the elastomeric or plastic components, or coat-ings of the container closure system when in contactwith solvents at various temperatures of use andstorage.

Leachables are compounds that leach or migrateinto the drug or fluid from the elastomeric or plasticcomponents, or coatings of the container and closuresystem as a result of direct contact with the drugor fluid.

Extractables and leachables are affected by thetype and amount of additives in the formulationof the plastic. They are also dependent upon thetype of solvent, temperature, and exposure time.Sources of extractables include plasticizers, antioxi-dants, stabilizers, pigments, lubricants, vulcanizers,catalysts, residual monomers and oligomers, residualsolvents, and contaminants from fillers. Extractablesand leachables like N-nitrosoamines, polynu-clear aromatic hydrocarbons (PAHs or PNAs), and2-mercaptobenzothiazole in rubbers and elastomersrequire special monitoring and reporting [19].

The FDA has specific guidance for the followingtypes of devices:

• Metered Dose Inhaler (MDI) and Dry PowderInhaler (DPI) Drug Products [20]; and

• Nasal Spray and Inhalation Solution, Suspen-sion, and Spray Drug Products [21].

Table 4.8 lists the various solvents, conditionsused for extractions and the identification methodsthat can be used to identify and quantify them.

The results from the extraction study should detailthe following:

• Composition and identity of the extracts versusa control;

• Level of extract (quantified in mg/g);

Table 4.7 Chemical Resistance Matrix

Polymer Dilu

te A

cid

s

Dilu

te B

ases

TH

F

ME

K

MeC

L2

Aceto

ne

IP

A

Eth

ylen

e

oxid

e

Oils/G

reases

Silico

nes

Salin

e w

ater

Bleach

es

Hyd

ro

gen

Pero

xid

e

Disin

fectan

ts

So

ap

s/

Deterg

en

ts

Lip

id

s

Betad

in

e

Polyolefins

HDPE Good Good Poor Good Poor Good Good Good Good Good Good Good Good Good Good Good Good

LDPE Good Good Poor Fair Poor Good Good Fair Fair Good Good Good Good Good Good Fair Good

UHMWPE Good Good Fair Good Fair Good Good Good Good Good Good Good Good Good Good Good Good

PP Good Good Fair Good Fair Good Good Fair Good Good Good Good Good Good Good Good Good

PP copolymers Good Good Poor Fair Fair Good Good Fair Fair Good Good Good Good Good Good Fair Good

COC Good Good Poor Good Poor Good Good Good Poor Good Good Good Good Good Good Good Good

PVC

PVC plasticized Good Good Poor Poor Poor Poor Poor Poor Fair Good Good Good Good Good Good Fair Poor

PVC unplasticized Fair Good Poor Poor Poor Poor Good Fair Good Good Good Good Good Good Good Good Poor

Polystyrene/styrenics

Polystyrene Fair Fair Poor Poor Poor Poor Good Good Fair Fair Good Good Good Good Good Good Fair

ABS Good Good Poor Poor Poor Poor Fair Good Good Good Good Fair Fair Good Good Fair Fair

SAN Good Good Poor Poor Poor Poor Fair Good Good Good Good Good Good Good Fair Good Fair

ASA Good Good Poor Poor Poor Poor Good Good Good Good Good Good Good Good Good Good Fair

MABS Good Good Poor Poor Poor Poor Good Good Good Good Good Good Fair Good Good Good Fair

SBC Good Good Poor Poor Poor Poor Fair Good Good Good Good Good Good Good Good Good Fair

Acrylics Fair Fair Poor Poor Poor Poor Poor Good Poor Good Fair Good Good Good Fair Good Fair

Polycarbonates* Good Poor Poor Poor Poor Poor Good Good Fair Good Good Fair Good Good Fair Good Fair

Polyurethanes Poor Poor Poor Poor Poor Poor Fair Good Fair Good Fair Poor Fair Fair Fair Fair Fair

Acetals Poor Fair Good Good Fair Good Good Good Good Good Good Poor Fair Fair Good Fair Good

Polyamides

Nylon 6, Nylon 66 Poor Poor Good Good Poor Good Good Good Good Good Good Poor Poor Poor Fair Fair Poor

Aromatic Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

Nylon 12, 10, 6/12 Poor Poor Poor Poor Poor Poor Good Good Good Good Good Poor Poor Poor Fair Fair Poor

Polyesters

PBT Good Good Good Good Poor Fair Good Good Good Good Good Good Good Good Good Good Good

PET Fair Fair Fair Fair Poor Good Fair Good Good Good Good Good Good Good Fair Good Good

Copolyesters Poor Poor Fair Poor Poor Poor Good Good Good Good Good Fair Good Good Fair Good Fair

High temperature

thermoplastics

Polysulfones Good Good Fair Poor Poor Poor Fair Good Good Good Good Good Good Good Good Good Good

PPS Fair Good Good Good Good Good Good Good Good Good Good Fair Good Good Good Good Good

LCP Good Good Good Good Good Good Good Good Good Good Good Good Fair Good Good Good Good

PEI Fair Poor Good Poor Poor Poor Good Good Good Good Good Fair Fair Fair Fair Good Fair

PAI Good Fair Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

PEEK Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

Fluoropolymers

PTFE* Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

FEP Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

PFA Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

ECTFE/ETFE Good Good Fair Fair Fair Fair Good Good Good Good Good Good Good Good Good Good Good

PVF/PVF2 Good Good Good Fair Good Fair Good Good Good Good Good Good Good Good Good Good Good

Elastomers

Silicones Good Fair Fair Fair Poor Good Fair Good Good Good Good Fair Fair Good Good Good Good

TPU Poor Poor Poor Poor Poor Poor Fair Good Fair Good Fair Poor Fair Fair Fair Fair Fair

TPC Poor Fair Poor Good Fair Good Good Good Fair Good Good Poor Poor Good Fair Fair Fair

TPA Good Good Fair Fair Poor Good Good Good Fair Good Good Good Good Good Good Fair Good

TPS Good Good Poor Poor Poor Poor Fair Good Poor Good Good Good Good Fair Fair Fair Fair

TPO Good Good Poor Poor Poor Poor Fair Good Poor Good Good Fair Fair Fair Good Fair Good

Biopolymers

PLLA Good Poor Poor Poor Poor Poor Good Good Good Good Good Fair Fair Good Poor Good Poor

PLA Good Poor Poor Poor Poor Poor Fair Good Good Good Good Fair Fair Good Poor Good Poor

PHB Good Poor Poor Poor Poor Poor Fair Good Good Good Good Fair Poor Good Poor Good Poor

PGA Good Poor Good Good Good Good Good Good Good Good Good Fair Fair Good Poor Good Good

PLGA Good Poor Poor Poor Poor Poor Fair Good Good Good Good Fair Poor Good Fair Good Poor

PCL Good Poor Poor Poor Poor Poor Good Good Good Good Good Fair Poor Good Poor Good Poor

Thermosets Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good

All ratings at room temperature.


Table 4.8 Typical Experimental Conditions and Test Methods used for Extractables and Leachables Evaluation

Solvents Conditions Identification Methods

Saline solution(mimicking aqueous and buffersolutions)

121S�C for 1 hour Gas chromatography

Vegetable oil (mimicking lipids) 70�C for 24 hours GC/MS

Dimethyl sulfoxide (DMSO) 50�C for 72 hours LC/MS

Acetone:olive oil (4:1 v/v) 37�C for 24 hours Infrared spectroscopy

Alcohol:saline (1:20 v/v) 37�C for 72 hours FTIR

Isopropyl alcohol (IPA) Other specificConditions (justificationrequired)

NMR

Methylene chloride(mimicking aerosols)

LC/HPLC

n-Hexane Atomic absorptionspectroscopy

ICP/MS

ICP/AES


• Correlation with safety and safety qualificationstandards;

• Effects on long-term stability; and

• Effects on safety and effectiveness of device.

4.5 Biocompatibility

Biocompatibility is the interaction of (biologicalcompatibility of) a material when it comes in contactwith skin, tissues, or biological fluids for defined orextended periods of time. Biologically compatiblematerials must not have any effect on the composi-tion, function, or safety of the biological systems inthe patient. The biocompatibility of a materialdepends upon the nature and composition of thematerial, the design of the device, the nature ofcontact with the patient, the duration of time ofcontact, and the temperature during contact. Bio-logical effects include the following:

• Cytotoxicity,

• Sensitization,

• Irritation/intracutaneous,

• Systemic toxicity,

• Subchronic toxicity,

• Genotoxicity,

• Implantation, and

• Hemocompatibility.

4.5.1 Cytotoxicity

Cytotoxicity is the assessment of the (toxic) effectof chemicals on cells. There are three types ofcytotoxicity tests.

The Direct Contact test is typically used formaterials of low density (like polymers used forophthalmic or contact lenses) where the test materialis placed directly on the cells in the culture medium.During incubation, materials from the polymer leachinto the culture medium and onto the cells. Cells arethen evaluated for degeneration, malformation, andlysis. Lysis is the death or destruction of a cell causedby bacteria, viruses, or osmotic (pressure) mecha-nisms. A positive test indicates that the material iscytotoxic.

The Agar Diffusion test is typically used for high-density materials like elastomers for closures. In thistest, the test material or extract of the test material isplaced on top of a nutrient-supplemented agar layerthat has in turn been placed over the culture mediumand cells. Cells are then evaluated for degeneration,


malformation, and lysis. A positive test indicates thatthe material is cytotoxic.

The MEM Elution method uses extraction mediaand conditions comparable to the actual end useconditions. The extracts are then transferred to thecells and evaluated for cytotoxicity after incubation.

4.5.2 Sensitization

Sensitization tests determine the allergic orhypersensitivity reactions of skin and tissues whenexposed to materials or their extracts for prolongedperiods of time. Dermal sensitization is marked byredness and swelling of the skin. There are threetypes of tests.

The Guinea Pig maximization test uses materialsand their extracts on Guinea Pig skin. Sensitization isevaluated after the extracts are in contact with theskin for a specified length of time. The times arerelated to the duration in which the specific devicewill be in contact with the human body.

The Closed Patch test (for devices that come intocontact with broken skin) uses repeated applicationsof the chemicals or extracts to test animal’s skin andis evaluated for sensitization.

The Murine Local Lymph Node Assay (LLNA)evaluates the ability of the sensitizer to affect thelymph nodes.

4.5.3 Irritation

Irritation tests determine whether the part, mate-rial, or extract causes local irritation on skin ormucous membranes via exposure through skin, eye,or mucosa. The route of exposure and the duration ofcontact should mimic the actual end use. Testsinclude the intracutaneous test, the primary skinirritation test, and the mucous membrane test.

4.5.4 Acute System Toxicity

The Acute System Toxicity test evaluates whetherthe extracts cause toxicity effects on various systemsof the body when injected into the animal. Allmaterials that come in contact with blood or bloodcomponents or other internal tissues must be evalu-ated for acute system toxicity. The Material MediatedPyrogen test evaluates whether the material or extractcan cause a pyrogenic effect or fever when injectedinto an animal’s (typically rabbit’s) body.

4.5.5 Subchronic Toxicity

This test is used for all implants. The extract isinjected intraperitoneally (in the abdomen walls) orintravenously (in the veins) and evaluated for systemtoxicity effects.

4.5.6 Genotoxicity

Genotoxicity evaluates the genetic damage causedby the extracts. This test is required for all implants,for devices that contact internal tissues or organs formore than 24 hours and for some extracorporealdevices that have less than 24 hours exposure. Testsinclude the Ames Mutagenicity test, the MouseLymphoma Assay, the Chromosomal Aberration test,and the Mouse Micronucleus test.

4.5.7 Implantation

Implantation tests require the material to beimplanted into the body for a specified time andevaluate the contact tissue for the onset of disease orcancerous cells.

4.5.8 Hemocompatibility

Hemocompatibility evaluates the compatibility ofmaterials and their extracts with blood and bloodcomponents. Those devices (like intravenous cathe-ters, blood transfusion sets, hemodialysis sets, andvascular prosthesis) that come into contact with theblood or blood components must pass this test.Hemolysis measures the damage to blood and bloodplatelets. Coagulation assays evaluate the effect ofmaterials on human blood coagulation time.Thrombogenecity tests evaluate the capacity of thematerial or extract to form clots.

4.5.9 Supplemental Tests

Supplemental tests that might be required are:Carcinogenesis—Long-term tests for implants to

test for formation of cancerous cells.Reproductive—Long-term test on the effects of

the materials and extracts on the reproductive system.Biodegradation—Long-term evaluation of mate-

rial degradation in the body.There are two main standards for the biocompat-

ibility evaluation of medical devices and their rawmaterials and components. They are the UnitedStates Pharmacopoeia (USP) Class VI and the ISO10993 standards.


4.6 USP Class VI

USP Class VI is a battery of biological testsdefined in USP XXII, Part 88, which was primarilydesigned for evaluating plastics used in packagingdrugs. Any ‘‘Food Grade’’ material which willpass this test series can be called ‘‘USP Class VI’’.Extracts of materials soaked in saline, vegetable oil,alcohol and polyethylene glycol are evaluated in a5-day mouse or rabbit intramuscular implantationtest. While this level of testing is widely used andaccepted in the medical products business, themeaning of the results and the level of safetyassurance for medical devices are limited. Forinstance, it would be possible to pass the USP ClassVI test while still showing up as cytotoxic, muta-genic, hemolytic, or sensitizing in other biologicaltesting.

To test medical device biocompatibility, manu-facturers often use USP procedures such as the USP

Table 4.9 USP Classification Table

Device category Contact

Surface device Skin

Mucosal surfaces

Breached or compromsurfaces

External communicatingdevices

Blood path indirect

Tissue/bone/dentin co

Circulating Blood

Implant devices Implant devices

in vivo biological reactivity tests (Class I-VI plasticstests)—Table 4.9. All implantable devices are USPClass VI. Those devices that are in prolonged contactwith broken skin, tissue, and blood tend to be clas-sified as USP Class VI also.

USP Class VI typically requires the followingtests:

(1) Acute systemic toxicity,

(2) Intracutaneous toxicity, and

(3) Implantation test.

If one is required to adhere to ISO 10993, then theonly overlap between the two test methods/regimensis the Intracutaneous Toxicity test (for an ISO ClassA, skin contact device). One must still perform, ata minimum, cytotoxicity and sensitization tests as perthe ISO 10993 protocol.

Exposuretime USP class

Limited USP Class I

Prolonged USP Class I

Permanent USP Class I

Limited USP Class I

Prolonged USP Class III

Permanent USP Class V

ised Limited USP Class III

Prolonged USP Class V

Permanent USP Class VI

Limited USP Class IV

Prolonged USP Class V


mmunicating Limited USP Class IV

Prolonged USP Class VI


Limited USP Class IV

Prolonged USP Class VI


Permanent Class VI

Table 4.10 ISO 10993 Standards

Standard Description

ISO 10993-1:2003 Biological evaluation of medical devices Part 1: Evaluation and testing

ISO 10993-2:2006 Biological evaluation of medical devices Part 2: Animal welfarerequirements

ISO 10993-3:2003 Biological evaluation of medical devices Part 3: Tests for genotoxicity,carcinogenicity and reproductive toxicity

ISO 10993-4:2002 Amd 1:2006 Biological evaluation of medical devices Part 4: Selection of tests forinteractions with blood

ISO 10993-5:1999 Biological evaluation of medical devices Part 5: Tests for in vitrocytotoxicity

ISO 10993-6:2007 Biological evaluation of medical devices Part 6: Tests for local effectsafter implantation

ISO 10993-7:1995 Biological evaluation of medical devices Part 7: Ethylene oxidesterilization residuals

ISO 10993-8:2000 Biological evaluation of medical devices. Part 8: Selection andqualification of reference materials for biological tests

ISO 10993-9:1999 Biological evaluation of medical devices Part 9: Framework foridentification and quantification of potential degradation products

ISO 10993-10:2002 Amd 1:2006 Biological evaluation of medical devices Part 10: Tests for irritation anddelayed-type hypersensitivity

ISO 10993-11:2006 Biological evaluation of medical devices Part 11: Tests for systemictoxicity

ISO 10993-12:2007 Biological evaluation of medical devices Part 12: Sample preparationand reference materials (available in English only)

ISO 10993-13:1998 Biological evaluation of medical devices Part 13: Identification andquantification of degradation products from polymeric medical devices

ISO 10993-14:2001 Biological evaluation of medical devices Part 14: Identification andquantification of degradation products from ceramics

ISO 10993-15:2000 Biological evaluation of medical devices Part 15: Identification andquantification of degradation products from metals and alloys

ISO 10993-16:1997 Biological evaluation of medical devices Part 16: Toxicokinetic studydesign for degradation products and leachables

ISO 10993-17:2002 Biological evaluation of medical devices Part 17: Establishment ofallowable limits for leachable substances

ISO 10993-18:2005 Biological evaluation of medical devices Part 18: Chemicalcharacterization of materials

ISO/TS 10993-19:2006 Biological evaluation of medical devices Part 19: Physico-chemical,morphological, and topographical characterization of materials

ISO/TS 10993-20: 2006 Biological evaluation of medical devices Part 20: Principles and methodsfor immunotoxicology testing of medical devices



4.7 ISO 10993

ISO 10993 is a series of standards that detail allcharacterization and biocompatibility tests needed formedical grade materials and medical devices beforeclinical studies (Table 4.10). Before the ISO 10993standard came into being, the United States used theTripartite standard for the evaluation of biocompati-bility. The Tripartite guidance was replaced in July1995, when FDA issued a modified version of ISO10993-1, ‘‘Guidance on Selection of Tests’’ as a bluebook memorandum [22]. The ISO 10993 standards areused throughout Europe and the FDA version of ISO10993-1 is used in the United States. The blue bookmemorandum adopted the same ISO nomenclature fordevice categories but developed a modified flowchartassigning the type of testing needed for each device

Table 4.11 ISO Biocompatibility Matrix

category and added additional requirements in someof the device categories.

ISO 10993-1 is an important standard as it detailsall the relevant biological tests needed for the mate-rial evaluation protocols for medical devices.Subsequent ISO 10993 standards are more specific tothe type of biocompatibility or toxicity tests. ISO10993-18 is another important standard. It details thevarious material characterization tests needed forplastics used in medical devices.

Table 4.11 is used to identify the appropriatebiocompatibility tests required for a material ordevice depending upon its end use. There are simi-larities between this and the USP Classification givenin Table 4.9.

Figure 4.6 details the decision tree that can be usedto assess whether or not biocompatibility tests are

Start

Does thedevice/material

contact thebody?

Biocompatibilitytests not required

MaterialCharacterization

Is the material thesame as an existing

commercially availableproduct?

Does the devicehave similar

properties to anexisting commercial

product?

Sufficientjustification

and/or test dataavailable?

Final review andassessment

Perform appropriate biocompatibility tests as per ISO 10993

No

No No

NoYes

YesYes

Yes

Figure 4.6 ISO 10993 Biocompatibility evaluation decision tree.


required. Biocompatibility tests are required for mostdevices that come into contact with the human body.The type and degree of testing will differ dependingupon the extent and location of contact (Table 4.11).Existing data might be sufficient for submission ifthey are scientifically valid.

4.8 Shelf Life and Aging

Considering key variables at the beginning ofproduct specification is essential to guaranteeingmedical device integrity. Material aging information,including physical, thermal, and optical performanceover time, is imperative for ensuring product integrityto meet stringent FDA validation requirements,including evidence of sterility and fitness for use overa product’s life cycle.

As an example, in a case where a product needsa five-year shelf life to allow time for distribution,storage, and other constraints, the quality of thepackage/device combination should be evaluatedand monitored. Observing the effects of time,

temperature, and relative humidity through acceler-ated aging studies on the product/package combina-tion can decrease the time it takes to introducea product to the marketplace. Aging tests at elevatedtemperatures and shorter periods of time can simulatelong-term aging [23].

Accelerated aging tests are performed using theAmerican Society for Testing and Materials (ASTM) F1980-02 entitled ‘‘Standard guide for acceleratedaging of sterile barrier systems for medical devices’’for sterile packaging or ASTM D3045-92 (2003)entitled ‘‘Standard practice for the heat aging ofplastics without load’’ for plastic materials. Tests areperformed at elevated temperatures and selectedrelative humidities. The effect of physical aging onthermal and mechanical properties can often bemodeled as linear with the log of aging time. The agingprocess proceeds more quickly at higher temperatures.

The ASTM guideline suggests using an accel-erated aging (Q10) factor of 2.0 as a conservativeestimate for aging the device. The guideline alsostates that certain materials such as polycarbonates,PVC (polyvinyl chloride), and copolyesters have


a unique Q10 factor. Specific Q10 factors can andshould be used if they can be derived from properresearch and experimentation.

Accelerated Aging test parameters are based onthe Q10 thermodynamic temperature coefficient(Arrhenius Theory).

The Arrhenius Reaction Rate Theory states that ‘‘arise in temperature of 10 �C will roughly double therate of a chemical reaction’’ [24].

The accelerated aging rate is given by thefollowing equation:

AAR ðAccelerated Aging RateÞ¼ Q10ððTe � TaÞ=10Þ

WhereTa ¼ Ambient TemperatureTe ¼ Elevated TemperatureQ10 ¼ Reaction Rate ¼ 2The Accelerated Aging Time Duration (AATD) is

given by the equation:

AATD ¼ Desired Real Time Aging

AAR

For example, if the desired real time aging orexpiration date of the medical device is three years,and the test temperature is chosen to be 55 �C, Q10 is2; the AATD is determined as follows:

AAR ðQ10Þ ¼ 2ðð55� 22Þ=10Þ ¼ 9:85

AATD ¼ 3*365 days=9:85 ¼ 11:1 days

¼ 112 days ðrounded upÞ

In order to reduce the aging test time, the highesttemperature possible should be selected, with thefollowing limitation and constraints.

1. The temperature should not exceed the plasticmaterial’s glass transition temperature, heatdistortion temperature, and melting point.

2. The temperature should not exceed 60 �C asthe accuracy of the Arrhenius equation dimin-ishes and introduces a lot of error.

3. If humidity is included in the aging protocol,a humidity level greater than 85% should bechosen for the high level and a humidity levelof less than 20% must be chosen for the low level.

The physical, mechanical, chemical, andbiocompatibility characteristics are evaluated after

the aging time. Results are recorded as percentretention of properties compared to the unagedcontrol.

4.9 Joining and Welding

Finished medical devices need to be assembledtogether and in some cases, several parts andcomponents might be required. Subassemblies inmedical equipment and machines, disposable andreusable devices also need assembly. These assemblymethods can include mechanical joining andassembly, but in many cases require similar ordissimilar parts to be joined together for perfor-mance and function. Several joining techniques canbe used and may include mechanical methods, heatand friction methods and the use of solvents andadhesives [25].

4.9.1 Mechanical techniques

Mechanical methods of joining materials are usedto obtain a firm and strong connection and usingmaterials that can withstand the environments andstresses required for the specific application. Twomajor methods exist for mechanical joining. The firstis the use of fasteners like screws, bolts and rivets.The second method is the use of interference fit likesnap-fit and press-fit techniques.

Mechanical fasteners are well-known, cost-effective and reliable methods for joining parts thatneed to be disassembled and reassembled a few timesover the life of the device. Plastic parts can havemolded-in threads (where the threads are part of themold design), or can be self-threading or self-tapping. Molded-in threads can be used as a typicalscrew for joining two parts. Self-threading screwscan either be thread cutting or thread forming.Thread-cutting screws cut away and remove materialto form a mating thread. Thread-forming screwsdisplace material to create a mating thread. Materialsused for such methods must have good strength andan acceptable modulus of elasticity. Self-threadingscrews are typically not used in applications whererepeated disassembly is required.

In the press-fit method, a shaft of one material isjoined with the hub of another material by a dimen-sional interference between the shaft’s outsidediameter and the hub’s inside diameter using force orheat. This method is cost-effective and producesjoints with reliable, high strengths and can be used


for joining similar and dissimilar materials. Snap-fitjoints may be the most widely used way of joiningand assembling plastics because this method requiresflexible and tough parts. In this method, a specificpart of one component is ‘‘snapped’’ into a fit withanother component. Materials with good ductilityand recovery characteristics are required.

4.9.2 Heat and Friction

Several methods can be used to join plastics usingheat and friction. They include:

• High frequency or radio frequency (RF) welding

• Heated tool or plate welding

• Ultrasonic welding

• Vibration welding

• Infrared welding

• Spin welding

• Laser welding

High frequency welding

Intermolecular friction is generated by applyinga high-frequency alternating field. This friction thengenerates heat and localized melting which is used tojoin the two (similar or dissimilar) plastic partstogether. It is used for the joining of blood bags,infusion bags, colostomy bags and diagnostic filters.

Heated tool or plate welding

In this method, heated platen contact the twomaterials (typically film) directly or indirectly, untilthe joint areas melt and are pressed under slightpressure together to join. This is also very commonand inexpensive method to join films and packaging.

Ultrasonic welding

Ultrasonic welding is one of the more commonlyused methods for the joining of plastics. In thismethod electrical energy (15–20 kHz) are convertedto localized mechanical vibrations which in turnheats and melts the material. Once heated, the twoparts are pressed and held together and cooled toform the bond.

Vibration welding

Energy between 120–240 Hz is used in thisprocess. One part is fixed on a stationary head and thesecond part is attached to the movable welding head.The two parts are pressed together at pressuresranging from 0.0–8 MPa. The energy causes thematerials to vibrate against each other generatinglocalized heat. When the surfaces melt, the parts arepressed together for several seconds to join. Largeparts can be joined by this method.

Infrared Welding

Infrared radiation, typically supplied by heatedmetal plates can be focused on to the area that needsto be joined, generating localized heat and meltingthe plastic surface. The materials are pressed togetherand joined. Laser welding can be highly automatedand used in mass production.

Spin Welding

In spin welding, one part remains stationary whilethe other part spins at 300–500 rpm while pressure isapplied to the parts to keep them in constant contact.In this process there is a lot of friction that generatesthe heat required to join the parts together.

Laser Welding

In this method a laser is passed across the regionthat needs to be welded. The area is heated and whenthe surface melts, the second part is pressed on to it tojoin. The beam size/width in laser welding can bewell controlled to direct the exact area that needs tobe joined.

Solvent bonding

Solvent bonding is one of the least expensivemethods to joining plastics together. The processinvolves treating, applying or dipping the plastic partwith a solvent that will soften the surface. The secondpart is then clamped under pressure onto the areatreated with the solvent to bond them together. Theappropriate bonding solvents will vary with the typeof resins. Care must be taken not to use veryaggressive solvents as they tend to swell, crack,deform or even dissolve the part. Surfaces shouldalso be well cleaned before bonding. Environmental


effects should also be considered when using solventbonding and selecting a solvent.

Adhesive Bonding

Another common and versatile technique ofjoining both similar and dissimilar parts together isby using an adhesive. Adhesives produce bonds ofvery high strength and durability. Several types ofadhesives are available. When selecting an adhesive,consideration must be given to the adhesive’scompatibility with the substrate, the flexibility andrigidity requirements, the environmental and heatresistance requirements and the aesthetics.

4.10 Conclusion

Plastics used in medical devices will need tobe evaluated for material characteristics, sterilizationresistance, chemical and lipid resistance, extractablesand leachables, biocompatibility, hemocompatibility,toxicity, and shelf life stability. The degree and typeof test will depend upon the end use and risk level ofthe device. Material characterization includes thephysical, chemical, mechanical, and thermal prop-erties of the plastic. Sterilization methods includeautoclave (steam and dry heat), ethylene oxide, andradiation (gamma rays and electron beam). Plasticsmust maintain their performance, shape, aesthetics,and color after sterilization. Many different types ofstabilizers can be used to prevent polymer degrada-tion or color change. The ISO 10993 and USP ClassVI standards detail the types of biocompatibility andtoxicity tests required depending upon the length andarea of contact of the device with the human body.Aging and shelf life stability tests provide informationabout the integrity and performance of the device afterspecified periods of time. Several joining and weldingmethods can be used for the joining of plastics. Theyinclude mechanical methods, heat and frictionmethods and the use of solvents and adhesives. Devicedesign, material strength, ductility, heat resistance andchemical compatibility must be taken into consider-ation when selecting an appropriate joining or weld-ing technique. All the data and information about theplastic material provide the device manufacturera level of comfort in selecting the right material forthe right device and end use. It is the responsibility ofthe device manufacturer to evaluate the finisheddevice for performance, biocompatibility, safety, andeffectiveness after sterilization.

References

[1] S. Seymour, Block (Eds.), Disinfection Sterili-zation and Preservation, fifth ed. Lippincott,Williams and Wilkins, 2001, p. 25.

[2] ANSI/AAMI/ISO 17665-1:2006—Sterilizationof health care products—Moist heat—Part 1.Requirements for the development, validation,and routine control of a sterilization process formedical devices.

[3] AAMI/CDV-2 20857 (ISO/TC 198/DIS20857)—Sterilization of health care products—Dry heat—Requirements for the development,validation, and routine control of a sterilizationprocess for medical devices (Draft).

[4] ANSI/AAMI/ISO 11135-1:2007—Sterilizationof health care products—Ethylene oxide—Part1: Requirements for the development, valida-tion, and routine control of a sterilizationprocess for medical devices.

[5] ANSI/AAMI/ISO 11137-1:2006—Sterilizationof health care products—Radiation—Part 1:Requirements for the development, validation,and routine control of a sterilization process formedical devices.

[6] R. Wayne, Steam: uses and challenges fordevice sterilization, Med. Dev. Diagnost. Indus(March 2006) 80–87.

[7] Parametric release methods for steam.[8] H.B. Daly, K.T. Nguyen, B. Sanschagrin,

K.C. Cole, et al., J. Inject. Mold. Technol 2 (2)(1998) 59–85.

[9] G.C. Mendes, T.R. Brandao, C.L. Silva,Ethylene oxide sterilization of medical device:a review, Am. J. Infect. Control 35 (9)(November 2007) 574–581.

[10] R.E. Parker, N.S. Isaacs, Chem. Rev. 59 (1959)737.

[11] J.A. Haines, C.B. Reese, A.R. Todd, J. Chem,Soc. London (1962) 5281.

[12] P. Barry, Fairand, Radiation sterilization forHealthcare. Products CRC Press, 2001.

[13] A. Charlesby, The Effects of ionizing radiationon polymers. in: D.W. Clegg, A.A. Collyer(Eds.), Radiation Effects on Polymers.Springer, 1991, pp. 39–78.

[14] R.L. Clough, K.T. Gillen, M. Dole, Radiationresistance of polymers and composites. in:D.W. Clegg, A.A. Collyer (Eds.), RadiationEffects on Polymers. Springer, 1991, pp. 114–134.


[15] D. Dhara, K. Glasgow, V. Kumar, US Patent20070081918, April 12, 2007.

[16] O. James, ANTEC Proceedings 2004, pp.3676–3679.

[17] Encyclopedia of Polymer Science and Tech-nology, vol. 2, 2004, 309–310.

[18] Guidance for Industry and FDA Staff–EarlyDevelopment Considerations for InnovativeCombination Products (September 2006).

[19] FDA 21, CFR Parts 177, Indirect Food Addi-tives: Polymers, Section 2600 Rubber ArticlesIntended for Repeated Use.

[20] FDA Draft Guidance–Metered Dose Inhaler(MDI) and Dry Powder Inhaler (DPI) Drug

Products–Chemistry, Manufacturing, andControls Documentation (1998).

[21] FDA Guidance for Industry–Nasal Spray andInhalation Solution, Suspension and SprayDrug Products–Chemistry, Manufacturing, andControls Documentation (2002).

[22] Required Biocompatibility Training andToxicology Profiles for Evaluation of Medicaldevices, May 1, 1995 (G95–1)–FDA Bluebook.

[23] L.C.E. Strum, Polym. Eng. Sci. 17 (3) (2004)165–173.

[24] S. Arrhenius, Z. Phys. Chem 4 (1889) 226.[25] MJ Troughten, Handbook of Plastic Joining,

William Andrew, USA (2008).

Documents

Plastics in Medical Devices || Material Requirements for Plastics used in Medical Devices