Biomaterials: Sjsu Mate 175

SJSU MatE 175
Biomaterials
Sterilization Technologies
and
Their Effects on Materials
Byron J. Lambert, Ph.D.
Advisor, Sterilization & Materials
Guidant Corporation
Temecula, CA
blambert@guidant.com
Guidant 2003
Class Outline
Introduction to medical device sterilization
Why sterilize?
Sterility definitions and concepts
Regulations and Standards
Sterilization technologies and their material effects
Steam
Radiation: Gamma and E-beam
Ethylene Oxide (EO)
Other gases, plasma and liquid chemical
Biomaterial engineers design considerations
SJSU MatE 175 Biomaterials Summer '05
Guidant 2003
Why Sterilize?
Joseph Listers germ theory
90% mortality rates Who? Me?
J&Js Heritage
The real world today microbial contamination
in manufacturing cleanrooms
the good, the bad and the ugly (part 1)
Guidant 2003
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 Contaminants
Non-Viable Particulate (Dirt, Dust, etc.)
Viable Particulate (Skin, Bacteria, Viruses, etc)
Chemical (Residuals, Oils, Lotions, Make-up, etc.)
Static (Charged Materials, etc.)
Guidant 2003
Basic Contamination Control

Sources of Contamination
Raw Material
Equipment and Instruments
Manufacturing Process
Containers and closure systems
Manufacturing environment
People
Guidant 2003
Sources of Contamination
People Are The Greatest Source
Sneezing produces 100,000 - 200,000 aerosol droplets

which can then attach to dust particles. These contaminated
particles may be present in the air for weeks.
Guidant 2003
Contamination Radiation
Minimal Activity Particle Generation (0.3 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
Guidant 2003
Contamination controls - Gowning
Guidant 2003
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?
Guidant 2003
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
Gamma and E-beam: radiation dose to get a
The following is an example of using d-values in a
sterilization model to achieve an SAL of 10-6
Guidant 2003
Microbial log reduction as a function of

dose of sterilization agent
"Sterility" - the probability concept
Probability of a bug on a device // # bugs/device
1.E+03
1.E+02
1.E+01
1 bug per device
1.E+00
1.E-01
1.E-02
1.E-03
1.E-04
1.E-05
1.E-06
1.E-07
0
10
Quantity of sterilization agent
Guidant 2003
Graphical representation: SAL = 10E-06

(see Excel sheet for the ISO radiation sterilization model)
Probability of a bug on a device // # of bugs per device
Sterility Assurance Level (SAL)

1.E+03
1.E+02
1.E+01
1 bug per device

1.E+00
With an initial
bioburden of 1000
bugs per device, 9
'units' of
sterilization agent
are required to
achieve an SAL of
10E-06
1.E-01
1.E-02
1.E-03
1.E-04
1.E-05
SAL = 10E-06
1.E-06
1.E-07
0
10
Quantity of sterilization agent (units)
Guidant 2003
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:
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
Pyronema cotton from China
Guidant 2003
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.
Guidant 2003
Sterilization validation per standards

The other of the story
1st leg: Validated dose required to get microbial kill
2nd leg: Validated process to reproducibly provide the
validated dose to all parts of the
validated product configuration.
Example: Radiation sterilization

1st leg: Dose setting
2nd leg: Dose mapping
Guidant 2003
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 GMPs
is good for the patient and good for the business. It
requires effort to make and maintain a compliant
culture.
Guidant 2003
Overview of Sterilization Technologies

Steam
Radiation
Gamma
Electron beam (E-beam)
X-ray
Ethylene Oxide (EO, EtO)

Other
Other gases
Plasma
Liquid chemical
Guidant 2003
Lab / Office Autoclave
Guidant 2003
Autoclave picture
Guidant 2003
Steam sterilization (autoclaving)

Process
Expose all surfaces to saturated steam at 121-133C
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
Guidant 2003

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.
Guidant 2003

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.
Guidant 2003
Gamma processing plant
Guidant 2003
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 configurations
around the source.
Exposure time and path of travel define dose.
Absorbed dose of ionizing radiation is the key
parameter (dose; kGy or Mrad).

Break DNA and other cellular bonds
Guidant 2003
Radiation sterilization microbial kill

Microbial kill
Ionizing radiation
break down DNA
bond of
microorganisms
into fragments
and prevent their
reproduction.
Guidant 2003

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
Guidant 2003

Radiation Effects on Polymeric Materials
Primary chemistry
High 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.
Guidant 2003

Radiation Effects on Polymeric Materials
Guidant 2003
AAMI TIR 17 Radiation Sterilization

Material Qualification
Relative Radiation Stability of Medical Polymer "Families"
Dose (Kilogray) in Ambient Air at which Elongation Decreases by 25%
0
25
100
50
200
300
400
500
kGy
Thermosets
Polystyrenes
Polyethylenes
1
Polyesters
2
Engineering Resins
High Performance
Polycarbonate/
Polysulfone
Polyurethanes
3
PVC
4
Fluoropolymers
High Performance
ABS
6
Elastomers
9
11
Nylon(PolyAmides)
10
Cellulose &
Co-Polymers
NOTE:
12
Acrylic (PMMA) &

Co-Polymers
13
Polypropylene
This chart represents the best available data as of this date,

and is intended as a guidance, specific resin formulations
must be evaluated in the intended application for the effects
of radiation and;
(1) Residual & Functional Stress,
(2) Section Thickness
(Radiation Grades)
14
(3) Molecular Weight & Distribution,
Polymethylpentene
(4) Morphology
15
(5) Environment (Oxygen/Temperature
FEP
(6) Dose Rate

Legend*
Polypropylene
(Natural)
Acetals
PTFE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
HDPE
PBT
Aromatic
Rigid/Semi-Rigid PVC
ETFE (Tefzel)
Hi-Impacy ABS
Butyl Rubber
Silicone/Neoprene
EPDM
Nylon 6 & 12
Amorphous Nylon
Cellulose/Paper
PMMA
Varies by Mfgr/Grade
Homopolymer
REFERENCES:
* Polymer Manufacturers Data
* NASA/Jet Propulsion Laboratories, "Effects of Radiation on
Polymers & Elastomers", 1988
* Skeins & Williams,"Ionizing Radiation Effect on Selected
Biomedical Polymers"
* Kiang, "Effect of Gamma Irradiation on Elastomeric Closures,
PDA, 1992
* Ley, "The Effects of Irradiation on Packaging Materials", 1976
* - Within each family is a range of radiation stabilities, the "steps" are intended to show significant family members
Ageless Processing Technologies, KJH
12/96
Guidant 2003
Radiation Sterlization
Radiation Tolerance Level of Polymeric Materials
Material
PET (Aromatic Polyester)
PE (Polyethylene)
Nylon-12 (Aliphatic Polyamide)
Aromatic Polyamide
PTFE (Teflon, Polytetrafluoroethylene)
PCTFE (Polychlorotrifluoroethylene)
PVDF (Polyvinyl Fluoride)
Radiation Tolerance Level

(kGy)
1000
1000
50
10000
5
200
1000
Guidant 2003
Basic rules for radiation material selection
z
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 semicrystalline 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
Guidant 2003
For example, to improve material compatibility
with radiation:
Stabilizer (antirad, antioxidant, radical scavenger)
Quenching
Blending
Guidant 2003

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
Guidant 2003
E-beam plant, self-shielded design
Guidant 2003
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).

Break DNA and other cellular bonds
Guidant 2003
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 ebeam come from the secondary electrons generated
by the high energy primary electrons.
Difference in material effects between gamma and ebeam result from the process cycle times in air (hours
versus seconds) and temperature effects from
processing.
Guidant 2003
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
Guidant 2003
Ethylene Oxide (EtO, EO) Chamber
Guidant 2003
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 arent so great either.
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
Guidant 2003
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.
Guidant 2003
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
Guidant 2003
Sterilization using gases other an EtO

Vaporized Hydrogen Peroxide
Main application is barrier isolators
Protein oxidation
No toxic residues
Severe on materials
Guidant 2003
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
Guidant 2003
Gas Plasma Sterilizer (ASP)
Guidant 2003
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 (< 50C)
Guidant 2003
Gas Plasma Sterilization; E.g., H2O2

Materials of concern:
Hydrophilic
materials
Cellulosics
Collagens
Natural rubber
Copper / brass
proteins
Butyl acetate
Guidant 2003
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.
Guidant 2003
Material Effects - Summary

Steam
Heat resistant materials only

Corrosion concerns with metals
Not compatible
Radiation
with biologics
Many polymers compatible up to 50 kGy

Careful: PTFE, polyacetal, unstabilized PP
Not compatible with active electronics
EtO
Most polymers compatible

Humidity effects hydrophilic coatings
Some temperature effects with sensitive materials
Residues may be toxic; requires degassing process
Plasma
Materials of concern: Hydrophilic materials,

Cellulosics, proteins, Butyl acetate, Collagens,
Natural rubber, Copper / brass
Other Gases
Strong oxidizing agents impact many materials
Guidant 2003
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)
Guidant 2003
Rules of thumb versus reality Radiation sterilization Case Studies

Case Study # 1
PTFE is on the bottom of everyones 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.
Guidant 2003
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.
Guidant 2003
The Biomaterial Engineers 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
Guidant 2003
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.
Guidant 2003

Biomaterials: Sjsu Mate 175

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SJSU MatE 175

SJSU MatE 175 Biomaterials Summer '05

SJSU MatE 175 Biomaterials Summer '05

Basic Contamination Control

SJSU MatE 175 Biomaterials Summer '05

Basic Contamination Control

SJSU MatE 175 Biomaterials Summer '05

People Are The Greatest Source

Sneezing produces 100,000 - 200,000 aerosol droplets

Motionless Standing or Sitting

Hands, Forearms, Neck & Head Motion

Sitting to Standing or Vice Versa

Walking From 2 to 5 Mph

Increased Activity (Personnel)

Times Increased Over Normal

Rubbing Skin on Hands and Face

Breathing of Smoker 20 Min. After Smoking

SJSU MatE 175 Biomaterials Summer '05

Contamination controls - Gowning

SJSU MatE 175 Biomaterials Summer '05

Sterility Assurance Level (SAL)

SJSU MatE 175 Biomaterials Summer '05

SAL Concepts: D-values

SJSU MatE 175 Biomaterials Summer '05

Microbial log reduction as a function of

Probability of a bug on a device // # bugs/device

Quantity of sterilization agent

SJSU MatE 175 Biomaterials Summer '05

Graphical representation: SAL = 10E-06

Probability of a bug on a device // # of bugs per device

Sterility Assurance Level (SAL)

1 bug per device

Quantity of sterilization agent (units)

SJSU MatE 175 Biomaterials Summer '05

Why sterilize # 2: Resistance of bugs

SJSU MatE 175 Biomaterials Summer '05

Regulations and Standards

SJSU MatE 175 Biomaterials Summer '05

Sterilization validation per standards

Example: Radiation sterilization

SJSU MatE 175 Biomaterials Summer '05

SJSU MatE 175 Biomaterials Summer '05

Overview of Sterilization Technologies

Ethylene Oxide (EO, EtO)

Lab / Office Autoclave

SJSU MatE 175 Biomaterials Summer '05

SJSU MatE 175 Biomaterials Summer '05

Steam sterilization (autoclaving)

Mode of microbial kill

Steam sterilization (autoclaving)

SJSU MatE 175 Biomaterials Summer '05

Steam sterilization (autoclaving)

SJSU MatE 175 Biomaterials Summer '05

Gamma processing plant

SJSU MatE 175 Biomaterials Summer '05

Radiation sterilization - Gamma

Mode of microbial kill

Radiation sterilization microbial kill

SJSU MatE 175 Biomaterials Summer '05

Radiation sterilization - Gamma

SJSU MatE 175 Biomaterials Summer '05

Radiation sterilization - Gamma

SJSU MatE 175 Biomaterials Summer '05