Sterilization Technologies and Their Effects on Materials

© Guidant 2003

SJSU MatE 175

Biomaterials

Sterilization Technologies and

Their Effects on Materials

Byron J. Lambert, Ph.D.Advisor, Sterilization & Materials

Guidant CorporationTemecula, CA

[email protected]

SJSU MatE 175 Biomaterials Summer '05 © Guidant 2003

Class Outline

Introduction to medical device sterilizationWhy sterilize? Sterility definitions and conceptsRegulations and Standards

Sterilization technologies and their material effectsSteamRadiation: Gamma and E-beamEthylene Oxide (EO)Other gases, plasma and liquid chemical

Biomaterial engineer’s design considerations


Why Sterilize?

Joseph Lister’s germ theory

90% mortality rates … Who? Me?

J&J’s Heritage

The real world today … microbial contamination in manufacturing cleanrooms

… the good, the bad and the ugly (part 1)


Basic Contamination Control

• What is a contaminant ?

Any unwanted substance present in or on a material or surface within a controlled environment or clean room.

• Potential ContaminantsNon-Viable Particulate (Dirt, Dust, etc.)

Viable Particulate (Skin, Bacteria, Viruses, etc)

Chemical (Residuals, Oils, Lotions, Make-up, etc.)

Static (Charged Materials, etc.)


Basic Contamination Control

Sources of Contamination• Raw Material• Equipment and Instruments• Manufacturing Process• Containers and closure systems• Manufacturing environment• People


Sources of Contamination

People Are The Greatest SourcePeople Are The Greatest Source

Sneezing produces 100,000 Sneezing produces 100,000 -- 200,000 aerosol droplets200,000 aerosol dropletswhich can then attach to dust particles. These contaminated which can then attach to dust particles. These contaminated

particles may be present in the air for weeks.particles may be present in the air for weeks.


Contamination Radiation

Minimal Activity Particle Generation (0.3µ and Larger) per Minute

• Motionless Standing or Sitting ~ 100,000

• Hands, Forearms, Neck & Head Motion ~ 500,000

• Sitting to Standing or Vice Versa ~ 2,500,000

• Walking From 2 to 5 Mph ~ 10,000,000

March 2004

Increased Activity (Personnel) Times Increased Over Normal

• Rubbing Skin on Hands and Face 1 to 2

• Breathing of Smoker 20 Min. After Smoking 2 to 5

• Sneezing 5 to 20


Contamination controls - Gowning


Sterility Assurance Level (SAL) Definition and Concept

Consensus Standards – ISO/EN/ANSI/AAMI:• 11134 Steam• 11135 Ethylene Oxide• 11137 Radiation• 14937 General Requirements (e.g., Plasma)

How many microorganisms (bugs / germs) are on a device after it is manufactured?

What is the probability of a bug on a device after terminal sterilization?


SAL Concepts: D-values

D-values (D10)• Quantity of a sterilization agent/process to achieve a

one log reduction in bioburden

• Gas sterilization agents: time of exposure to get a one log reduction in bioburden

• Gamma and E-beam: radiation dose to get a one log reduction in bioburden

• The following is an example of using d-values in a sterilization model to achieve an SAL of 10-6


Microbial log reduction as a function of ‘dose’ of sterilization agent

"Sterility" - the probability concept

1.E-07

1.E-06

1.E-05

1.E-04

1.E-03

1.E-02

1.E-01

1.E+00

1.E+01

1.E+02

1.E+03

0 2 4 6 8 10Quantity of sterilization agent

Pro

babi

lity

of a

bug

on

a de

vice

//

# b

ugs/

devi

ce

1 bug per device


Graphical representation: SAL = 10E-06(see Excel sheet for the ISO radiation sterilization model)

Sterility Assurance Level (SAL)

1.E-07

1.E-06

1.E-05

1.E-04

1.E-03

1.E-02

1.E-01

1.E+00

1.E+01

1.E+02

1.E+03

0 2 4 6 8 10

Quantity of sterilization agent (units)

Prob

abili

ty o

f a b

ug o

n a

devi

ce

// #

of b

ugs

per d

evic

e

SAL = 10E-06

1 bug per device

With an initial bioburden of 1000 bugs per device, 9 'units' of sterilization agent are required to achieve an SAL of 10E-06


Why sterilize # 2: Resistance of bugs

Characterization of microorganisms involves both:

• Number of organisms and

• Type of organisms, which defines the resistance of the bug to the given sterilization agent (d-value).

• Some bugs are very nasty:

• Pyronema – cotton from China

D10 kGy 1,0 1,5 2,0 2,5 2,8 3,1 3,4 3,7 4,0 4,2 Probability % 65 22 6,2 3,2 1,2 0,8 0,4 0,1 0,07 0,007


Regulations and Standards

• To label an implantable device with biomaterials as ‘sterile,’ an SAL of 10-6 is mandatory.

• ‘Consensus standards’ provide methods for achieving statutory regulations• ANSI gives U.S. authority to Association for Advancement

of Medical Instrumentation (AAMI) to develop sterilization standards

• Industry users, manufacturers and regulators develop standards together – great forum.

• If you claim compliance to a voluntary standard, you simply have to prove that you are indeed following the standard

• You can choose not to follow a standard, but the device manufacturer has the burden to prove that the method achieves the desired SAL.


Sterilization validation per standards

The other ½ of the story …• 1st leg: Validated “dose” required to get microbial kill

• 2nd leg: Validated process to reproducibly provide thevalidated dose to all parts of the validated product configuration.

Example: Radiation sterilization• 1st leg: Dose setting

• 2nd leg: Dose mapping


Why sterilize # 3

Avoid regulatory risk that can delay getting a product to market or cause a product to be pulled from the market.

• A few basic sterilization methods are common across hundreds or thousands of devices. Hence, regulators tend to be very familiar with the methods and can identify if a manufacture compliant.

• This is a subset of good manufacturing practices (GMPs, cGMPs for drug products). Following GMPsis good for the patient and good for the business. It requires effort to make and maintain a compliant culture.


Overview of Sterilization Technologies

SteamRadiation

• Gamma• Electron beam (E-beam)• X-ray

Ethylene Oxide (EO, EtO)Other

• Other gases• Plasma• Liquid chemical


Lab / Office Autoclave


Autoclave picture


Steam sterilization (autoclaving)

Process• Expose all surfaces to saturated steam at 121-133°C

for 15-30 minutes. Time and temperature are the key parameters.

• Packaging must allow for steam penetration

• Batch process: pressure rated sterilization chamber accommodates validated configurations of product

• Boiler water additives to limit corrosion are regulated by the FDA

Mode of microbial kill• Denaturation of proteins



Material Effects• Only compatible with metallic devices and limited

heat-resistant textiles and polymers.

• Packaging materials are normally not compatible

• Deposition of hydrophobic organics and hygroscopic salts on implants has been indicated.

• These surface contaminants can negatively impact adhesion to implants.

• They can have a positive effect on applications such as heart valves that seek to avoid adhesion.



Advantages:• short cycle times;

• simplicity of the process (high uptimes; low cost);

• lack of toxic residuals

Disadvantages: • Limited polymeric device application due to material

effects

• Great for re-usable metal surgical instrumentation and heat resistant surgical supplies, e.g., drapes and dressings.


Gamma processing plant


Radiation sterilization - Gamma

Process (typical industrial process)

• Radioactive gamma source (typically Co-60) is stored in a 20-25 foot pool of water in a large concrete vault.

• Continuous process: source is raised into the room and product is circulated in validated configurationsaround the source.

• Exposure time and path of travel define dose. Absorbed dose of ionizing radiation is the key parameter (dose; kGy or Mrad).

Mode of microbial kill• Break DNA and other cellular bonds


Radiation sterilization – microbial kill

Microbial kill

Ionizing radiation break down DNA bond of microorganisms into fragments and prevent their reproduction.



Material Effects• Compatible with a large cross-section of engineering

polymeric materials with notable exceptions

• Guidance is availability on where materials fall on the spectrum of bulk property compatibility (AAMI TIR 17)

• Leaves no residue or cleaning effect; negligible effect on surface properties, reactivity or bioadhesion



Radiation Effects on Polymeric Materials

Primary chemistryHigh energy electrons break down the chemical bonds or excite the molecules to produce reactive species (charged species, free radicals and excited molecules) in close proximity to the point of origination.

Secondary chemistry

The high energy species return to lower energy states with the final effect of molecular cross-linking and chain scission.



Radiation Effects on Polymeric Materials


AAMI TIR 17 Radiation Sterilization Material Qualification

Polystyrenes

Polyethylenes

Polyesters

High Performance

Polycarbonate/

Polyurethanes

Thermosets

PVC

Fluoropolymers

Elastomers

Acrylic (PMMA) &

Nylon(PolyAmides)

Cellulose &

Polymethylpentene

Polypropylene

FEP

Polypropylene

Acetals

PTFE

5004003002001000

Relative Radiation Stability of Medical Polymer "Families"

High Performance

(Radiation Grades)

(Natural)

Engineering Resins

Polysulfone

ABS

Dose (Kilogray) in Ambient Air at which Elongation Decreases by 25%kGy25 50

Co-Polymers

Co-Polymers

This chart represents the best available data as of this date,NOTE:

(1) Residual & Functional Stress,

(4) Morphology

(2) Section Thickness

(6) Dose Rate

(3) Molecular Weight & Distribution,

(5) Environment (Oxygen/Temperature

REFERENCES:

* Ley, "The Effects of Irradiation on Packaging Materials", 1976

Ageless Processing Technologies, KJH 12/96

* Polymer Manufacturers Data

5

1 - HDPELegend*

2 - PBT3 - Aromatic4 - Rigid/Semi-Rigid PVC5 - ETFE (Tefzel) 6 - Hi-Impacy ABS7 - Butyl Rubber8 - Silicone/Neoprene9 - EPDM

10 - Nylon 6 & 12

12 - Cellulose/Paper13 - PMMA

4

1

2

3

6

87

10

12

13

14

15

14 - Varies by Mfgr/Grade 15 - Homopolymer

11 - Amorphous Nylon

11

* - Within each family is a range of radiation stabilities, the "steps" are intended to show significant family members

9

* Kiang, "Effect of Gamma Irradiation on Elastomeric Closures, PDA, 1992

* Skeins & Williams,"Ionizing Radiation Effect on Selected Biomedical Polymers"

* NASA/Jet Propulsion Laboratories, "Effects of Radiation on Polymers & Elastomers", 1988

and is intended as a guidance, specific resin formulationsmust be evaluated in the intended application for the effectsof radiation and;


Material Qualification –Radiation Sterlization

Material Radiation Tolerance Level(kGy)

PET (Aromatic Polyester) 1000PE (Polyethylene) 1000Nylon-12 (Aliphatic Polyamide) 50Aromatic Polyamide 10000

PTFE (Teflon, Polytetrafluoroethylene) 5PCTFE (Polychlorotrifluoroethylene) 200PVDF (Polyvinyl Fluoride) 1000

Radiation Tolerance Level of Polymeric Materials



Basic rules for radiation material selection

Use highest molecular weight and narrow molecular weight distribution materials

Aromatic materials are more radiation resistant than aliphatic materials

Amorphous materials are more radiation resistant than semi-crystalline materials

Materials with small side groups are more radiation resistant

For semi-crystalline materials, the lower the crystalline, the greater the radiation resistant

Avoid Polyacetal (Delrin), PTFE (Teflon), unstabilized Polypropylene

Use high dose rate (e-beam) to avoid oxidation



For example, to improve material compatibility with radiation:

• Stabilizer (antirad, antioxidant, radical scavenger)

• Quenching

• Blending



Advantages: • reasonably short cycle times (hours)

• single parameter process (dose)

• dose can be measured directly and easily controlled

• Simplicity of the sterilization process

• Material compatibility with a large range of materials

Disadvantages:• Radiation shielding and safety issues

• Capital costs for facility, infrastructure and source replenishment


E-beam plant, self-shielded design


Radiation sterilization – E-beam

Process (typical industrial process)• Electrons are accelerated from 200 eV to energies up

to 10 MeV. Various technologies, with a broad range of complexity, are used to accelerate the electrons.

• Continuous process: product, in validated configurations, pass in front of a scanned beam of the accelerated electrons.

• Exposure time (and path of travel) define dose. Absorbed dose of ionizing radiation is the key parameter (dose; kGy or Mrad).

Mode of microbial kill• Break DNA and other cellular bonds


Radiation sterilization - E-beam

Material Effects• All gamma ‘lists’ apply to e-beam. Similar material

compatibility, but slightly better compatibility than gamma.

• Gamma rays actually produce high energy primary electrons as they deposit energy (Compton scattering). Material effects in both gamma and e-beam come from the secondary electrons generated by the high energy primary electrons.

• Difference in material effects between gamma and e-beam result from the process cycle times in air (hours versus seconds) and temperature effects from processing.


Radiation sterilization - E-beam

Advantages: • shortest cycle times (seconds / minutes); high

flexibility for special processing

• radiation dose (the singe parameter) can be measured directly and easily controlled

• Material compatibility with a large range of materials

Disadvantages:• Radiation shielding and safety issues

• Complexity of the sterilization equipment

• Capital costs for facility and ongoing maintenance


Ethylene Oxide (EtO, EO) Chamber


Ethylene oxide

Process

• Batch process: product in validated configurations are placed in a chamber and pressure cycled to be humidity and temperature conditioned, exposed to EtO, and degassed. EtO concentration, humidity, temperature, pressure cycles and time are all key parameters.

• EtO in the process and EtO residuals in the product must be managed; EtO is a nasty gas (explosive and toxic), and its process byproducts aren’t so great either.

Mode of microbial kill

• Alkylation of amine groups on the nucleic acid

• Epoxide and alkylating agent – reacts with proteins and DNA; compromises metabolism and reproduction of the bacterial cell


Ethylene oxide

Material Effects• Compatible with the largest cross-section of engineering

polymeric materials with minor exceptions

• Material compatibility exceptions may include hydrophobic coatings and very temperature sensitive materials, e.g., drug release polymers

• Residuals must be managed, especially in porous ceramics and adsorbing polymers. With all materials, process and residuals can negatively impact adhesion to implants.

• Diffusion limited products need to be managed.

• Sparking potential in electronics needs to be managed.


Ethylene oxide (EO; EtO)

Advantages:• Broadest material compatibility

• Disadvantages:• Relatively long cycle times (hours / days)

• Residues need to be managed

• Explosion and worker safety issues


Sterilization using gases other an EtO

• Vaporized Hydrogen Peroxide• Main application is barrier isolators

• Protein oxidation

• No toxic residues

• Severe on materials


Sterilization using gases other an EtO

• Chlorine dioxide• Non-flammable and non-ozone depleting

• Generated at time of use

• Oxidation of materials

• Ozone• Generated from air at time of use

• No toxic residues

• Oxidation of materials


Gas Plasma Sterilizer (ASP)


Gas Plasma Sterilization; E.g., H2O2

• Initially researched for surface cleaning of biomaterials; Hence, beneficial for implant adhesion and not good for heart valves

• ASP system: vacuum, inject Hydrogen peroxide liquid and allow diffusion, electromagnetic field that breaks apart the H2O2 and produces a plasma cloud containing free radicals and UV light; (repeat); vent.

• Relatively cold process (< 50°C)


Gas Plasma Sterilization; E.g., H2O2

Materials of concern:

Collagens

Natural rubber

Copper / brass

Hydrophilic materials

Cellulosics

proteins

Butyl acetate


Liquid chemical sterilization

• Sporicidal ‘active ingredient’ together with inert ingredients such as buffers, anti-corrisive agents and detergents

• Qualitative process: dip devices for given time at a given temperature. High level disenfection in healthcare facilities allows for short turn around time of high cost reusable devices.

• Applied commonly for animal and human tissue that are not compatible with other terminal sterilization processes. Devices may be packaged with the sterilization agent and rinsed prior to use.


Material Effects - Summary

Strong oxidizing agents impact many materialsOther Gases

Materials of concern: Hydrophilic materials, Cellulosics, proteins, Butyl acetate, Collagens, Natural rubber, Copper / brass

Plasma

Most polymers compatible•Humidity effects hydrophilic coatings•Some temperature effects with sensitive materials•Residues may be toxic; requires degassing process

EtO

Many polymers compatible up to 50 kGy•Careful: PTFE, polyacetal, unstabilized PP•Not compatible with active electronics

Radiation

Heat resistant materials only•Corrosion concerns with metals•Not compatible with biologics

Steam


Foundations for successful design of compatible materials

GENERAL• Understanding clinical stresses on the material,• Clinically relevant test methods, • Material selection and • Responsible shelf-life estimation model

STERILIZATION• Screen materials for sterilization effects early• Iterate product with all manufacturing steps, including

sterilization

PACKAGING• Assure that packaging is appropriate (protect the product,

compatible with sterilization method)


Rules of thumb versus reality -Radiation sterilization Case Studies

Case Study # 1• PTFE is on the bottom of everyone’s list of radiation

compatible materials

• An e-beam sterilized PTFE coating on a stainless steel wire will not fail.… What are the clinically relevant stresses?

Case Study # 2• Polyesters are high on the list of radiation compatible

materials

• An e-beam sterilized polyester blend balloon catheter fails because design requirements for wall thickness are severe.


Sterilization and Material R&D

Example of Radiation: • Dose ranging experiments

Example of Ethylene Oxide:• R&D engineers often look at EtO sterilization as a

black box.

• Small R&D chambers (e.g., 3M 8XL chambers):

• Allows for the effects of parameters to be differentiated: Temp, RH, time, EtO and pressure

• Allows product design iterations to be done with sterilization for integrated development.


The Biomaterial Engineer’s Opportunity:Optimizing for Outrageous Success

Material R&D• Robust understanding and design

Process Optimization • Compliance: assuring the appropriate SAL using

appropriate standards can bring great value by avoiding months of delay in getting product to market

• Cycle times: Sterilization cycle times are often the longest part of the process. “JIT” sterilization can bring enormous value in development and production

• Cost: Often dwarfed by cycle time considerations, especially for high value devices, but always a valued if optimized


References

• J.B. Kowalski and R.F. Morrisey, “Sterilization of Implants,” section 9.2 of “Biomaterials Science,” Edited by B.D. Ratner et al, Academic Press, p. 415.

• B.J. Lambert, F.W. Tang and V.C. Chamberlain, “Sterilization Effects,” chpt 15 in “Handbook of Biomaterials Evaluation,” Edited by A.F. von Recum, Taylor and Francis, Columbus OH, 1999, pp. 253-261.

• B.J. Lambert, F.W. Tang and W.J. Rogers, “Polymers in Medical Applications,” RAPRA Review Reports, Vol 11 (7), 2001, 35 pp.

• Association for the Advancement of Medical Instrumentation, TIR 17, “Radiation Sterilization – Material Qualification,” 1997, www.aami.org.

Sterilization Technologies and Their Effects on Materials

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