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Practical Guidance in Selecting Materials for Product Functionality
Byron J. Lambert, Ph.D.Fellow, Sterilization Science
Abbott Vascular Temecula, CA USA
www.doubleia.org
Agendage da
1. Material Compatibility Guidancel G id2. Protocol Guidance
3. Industry Guidance
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1. Material Compatibility Guidance
A i fA. Build on fundamentals
• The foundation of successful sterilization strategies are the fundamentals of radiation chemistry and biochemistry:chemistry and biochemistry:• Radiation yields (G-values)
Di t i di t ff t• Oxygen effects
M i t ff t• Direct vs indirect effects• Free radical species & scavengers
• Moisture effects• Thermal effects
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• Guidance can only give general rules of thumb (based on fundamentals like those presented by Dr. Parsons)
– Irradiate in the solid / frozen state, when feasible, to avoid secondary chemistry
– Select appropriate scavengers when irradiating in the liquid state to minimize degradation outside the cell
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IMRP’08 A T ll ti Mi bi l R di ti RA. Tallentire – Microbial Radiation Response
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IMRP’08 A T ll ti Mi bi l R di ti RA. Tallentire – Microbial Radiation Response
Surviviing Fracction
(+ O2)
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DOSE
IMRP’08 A T ll ti Mi bi l R di ti RA. Tallentire – Microbial Radiation Response
Surviviing Fracction
(+ O2) (- O2)liquid
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DOSE
IMRP’08 A T ll ti Mi bi l R di ti RA. Tallentire – Microbial Radiation Response
Surviviing Frac (- O2)solidction
(+ O2)
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DOSE
Analogous Effects on Active Agents?a ogous ects o ct ve ge ts?
(+ O2)Active
( 2)
AgentLLoss
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DOSE
Analogous Effects on Active Agents? a ogous ects o ct ve ge ts?
(+ O2) ( O )Active
( 2) (- O2)liquid
AgentLLoss
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DOSE
Analogous Effects on Active Agents? a ogous ects o ct ve ge ts?
(+ O2)Active
( 2)
AgentL
(- O2)solid
Loss
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DOSE
Analogous Effects on Active Agents? a ogous ects o ct ve ge ts?
(+ O2)Active
( 2)
(+ O2 + H2O)AgentL
2 2
Loss
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DOSE
Experiments can optimize the application and processingExperiments can optimize the application and processing range of a combination device drug*
1) I d h i t i t t?1) Is secondary chemistry important? 2) Is the release polymer important?3) Is oxygen or water important? 4) Is temperature important?
* You also need to answer a similar list of questions to unravel radiation effects on thedevice and on the release polymer …
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1. Material Compatibility Guidance
B L i ti idB. Leverage existing guidance
R l ti di ti t bilit di l d i• Relative radiation stability – medical device polymeric materials - AAMI TIR17
Rules of thumbs– Rules of thumbs– General principles
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5004003002001000
Relative Radiation Stability of Medical Polymer "Families"Dose (Kilogray) in Ambient Air at which Elongation Decreases by 25%
kGy25 50
Polystyrenes
Polyethylenes
Polyesters
Thermosets
1
2
High Performance
Polycarbonate/
Polyurethanes
PVC
Engineering Resins
Polysulfone
2
3
PVC
Fluoropolymers
Elastomers
High Performance
ABS
5
4
6
879
Acrylic (PMMA) &
Nylon(PolyAmides)
Cellulose &
Polypropylene(Radiation Grades)
Co-Polymers
Co-Polymers
This chart represents the best available data as of this date,NOTE:
(1) Residual & Functional Stress,(2) Section Thickness
10
12
13
14
11
and is intended as a guidance, specific resin formulationsmust be evaluated in the intended application for the effectsof radiation and;
Polymethylpentene
FEP
Polypropylene
A t l
(Natural)
(4) Morphology
(6) Dose Rate
(3) Molecular Weight & Distribution,
(5) Environment (Oxygen/Temperature
REFERENCES:
* Polymer Manufacturers Data
1 - HDPELegend*
2 - PBT3 - Aromatic4 - Rigid/Semi-Rigid PVC5 - ETFE (Tefzel) 6 - Hi-Impacy ABS7 - Butyl Rubber
14
15
* NASA/Jet Propulsion Laboratories, "Effects of Radiation on Polymers & Elastomers", 1988100 200 300 400 500
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Acetals
PTFE* Ley, "The Effects of Irradiation on Packaging Materials", 1976
Ageless Processing Technologies, KJH 12/96
8 - Silicone/Neoprene9 - EPDM
10 - Nylon 6 & 12
12 - Cellulose/Paper13 - PMMA 14 - Varies by Mfgr/Grade 15 - Homopolymer
11 - Amorphous Nylon
* - Within each family is a range of radiation stabilities, the "steps" are intended to show significant family members
* Kiang, "Effect of Gamma Irradiation on Elastomeric Closures, PDA, 1992
* Skeins & Williams,"Ionizing Radiation Effect on Selected Biomedical Polymers"Dose (kGy)
Association for the Advancement of Medical Instrumentation, AAMI TIR 17
1. Material Compatibility Guidance
C R ibl h lf lif ti tiC. Responsible shelf-life estimation
Medical Device Accelerated Aging (AAMI TIR 17-1997; ASTM F1980-2007)
Pharmaceutical Accelerated Stability (ICH G id li )(ICH Guidelines)
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1. Material Compatibility Guidance
D ESR R di l t bilitD. ESR – Radical stability
• Answers question: have free radical active species q pfrom the radiation sterilization process finished reacting?
• Provides confidence going into aging studies that d d i idegradation rates are representative
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ESR – Introduction
• Electron Spin Resonance (ESR) 90
100
I)( )• Magnetic field
scanned in a given i f
60
70
80
90
cent
ratio
n (D PLA* - Typical free radical
decay curve* t lli it i tlmicrowave frequency
• Concentration of active species (free 20
30
40
50
e R
adic
al C
on *crystallinity varies greatly
ac ve spec es ( eeradicals) from radiation sterilization are measured
0
10
20
0 10 20 30 40 50
Free
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are measuredTime (hour)
ESR Free Radical Stability – PLATime 0
1.0 hr
2.0 hr
4.0 hr6.0 hr
10.0 hr
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Data on file at Abbott Vascular.
PLA - Radical Decay – 2nd Order
Ti DI 1/DI 0 250Time DI 1/DI0.0 28.4 0.035
0.5 21.4 0.0470.200
0.250
entra
tion)
1.0 15.9 0.063
2.0 12.5 0.080
3.0 9.6 0.104
R2 = 0.9885
0.100
0.150
ree
radi
cal C
once
4.0 9.1 0.110
6.0 6.4 0.155
10.0 4.8 0.2110.000
0.050
0 2 4 6 8 10
1/(F
r
20.0 3.9 0.257
98.0 4.4 0.229
Time (hour)
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Data on file at Abbott Vascular.
1. Material Compatibility Guidance
E G E bE. Gamma vs E-beam
• ISO 11137, Sterilization of health care products – Radiation,ISO 11137, Sterilization of health care products Radiation, groups gamma, e-beam and x-ray sterilization modalities
• Gamma sterilization is approximately 90% of the market;
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pp y ;X-ray is a negligible fraction of the market
E-beam: Mechanism of Energy Deposition b Hi h E El tby High Energy Electrons
e-≈ 60 eV
• 0.5 – 10 MeV electrons are blasted into material
• Energy is deposited through glancing ionic interactions≈ 60 eV is lost during each ionic interaction until the electron runs out of energy
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out of energy
Gamma: Mechanism of Energy Depositionb C 60by Co-60 gamma rays
1 2• 1.25 MeV gamma rays are blasted into material
Energ is deposited thro gh• Energy is deposited through Compton Scattering≈ 0.5 MeV recoil electrons …
• Ionic interactions of high energy electrons are again the primary
d f d i i
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mode of energy deposition
Gamma & E-beam - same mechanism of d itienergy deposition
Differences between Gamma and E-beam• Penetration is different• Dose rate is different
Material Compatibility• For many materials – material compatibility is equivalentFor many materials material compatibility is equivalent
• For borderline materials, dose rate makes a difference:– Oxidative degradation: 4 hour process vs 4 second process
Temperature: short spike in temperature during e beam vs
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– Temperature: short spike in temperature during e-beam vs long elevation of temperature during gamma
Agendage da
1. Material Compatibility Guidancel G id2. Protocol Guidance
3. Industry Guidance
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2. Protocol Guidance
A Clinical StressesA. Clinical StressesCase Study # 1• PTFE is on the bottom of everyone’s list of radiationPTFE is on the bottom of everyone s list of radiation
compatible materials• An e-beam sterilized PTFE coating on a stainless steel wire
does not faildoes not fail… What are the clinically relevant stresses?
Case Study # 2Case Study # 2• Polyamide / Polyether blends are relatively high on the list
of radiation compatible materials• An e-beam sterilized polyester blend balloon catheter fails
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An e beam sterilized polyester blend balloon catheter fails because design requirements for wall thickness are severe.
B. Clinically relevant testing - basic mechanical and …micro and nano-scale characterization for controlled release ofpharmaceutical & biologic agents
1. Drug distribution and coating thickness uniformity using imaging FTIR
4. Thermal transition and analysis using μTA
FTIR
2. Surface (swelling) analysis using 5 Chemical component structure andSu ace (s e g) a a ys s us gAFM
5. Chemical component, structure, and conformation usingLCR, ATR,FTIR, and NMR
3. Microstructure and phase dispersion using AFM and LCR
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2. Protocol Guidance
C Screen earlyC. Screen early• Dose ranging experiments (drug and delivery system)• Temperature and environment
Look for clues relative to the fundamentals– E.g., Does drug degradation change in different matrices? This is a
clue relative to primary vs secondary chemistry …p y y y
– Note: rapid R&D sterilization allows for product iterations to be evaluated with the inclusion of the sterilization process
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p
2. Protocol Guidance
D Evaluate full range of parametersD. Evaluate full range of parameters
P i t D• Primary parameter: Dose
S d• Secondary parameters: – dose rate
i t ( d t )– environment (oxygen and water)– temperature– additives
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additives
Experiments can optimize the application and processing range of a combination device drug
1) Is secondary chemistry important? 2) Is the release polymer important?2) Is the release polymer important?3) Is oxygen or water important? 4) Is temperature important? ) p p
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Effects of E-beam on Drug # 1
20
16
18
10
12
14
Loss
- TC
EB - Inert - RT - DRUG ONLY; n=3Linear (Drug only; 0-60 kGy)
6
8
Dru
g L Poly. (EB - Inert - RT - DRUG ONLY; n=3)
0
2
4
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0 25 50 75 100 125 150
Dose (kGy)
Effects of E-beam on Drug # 1
20
16
18
10
12
14
rug
Loss
- TC EB - Inert - RT - DRUG ONLY; n=3
EB - Inert - RT - DRUG in PLGA; n=5+
Poly ( EB - Inert - RT - DRUG ONLY; n=3)
6
8
Rel
ativ
e D Poly. ( EB Inert RT DRUG ONLY; n 3)
Linear (EB - Inert - RT - DRUG in PLGA;n=5+)
0
2
4
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0 25 50 75 100 125 150
Dose (kGy)
Effects of E-beam on Drug # 1
20
16
18
EB - Inert - RT - DRUG ONLY
10
12
14
rug
Loss
- TC
EB Inert RT DRUG ONLY
EB - Inert - RT - DRUG in PLGA
EB - Inert - Cold - Early data - DRUG in PLA
Poly. (EB - Inert - RT - DRUG ONLY)
6
8
Rel
ativ
e D Poly. (EB Inert RT DRUG ONLY)
Linear (EB - Inert - RT - DRUG in PLGA)
Linear (EB - Inert - Cold - Early data - DRUG inPLA)
0
2
4
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0 25 50 75 100 125 150
Dose (kGy)
Effects of E-beam on Drug # 1
20
16
18
EB - Inert - RT - DRUG ONLY
EB - Inert - RT - DRUG in PLGA
10
12
14
rug
Loss
- TC
EB Inert RT DRUG in PLGA
EB - Inert - cold - Early data - DRUG in PLA
EB - Inert - cold - Early data - DRUG in FLUOROPOLYMER
Poly (EB - Inert - RT - DRUG ONLY)
6
8
Rel
ativ
e D Poly. (EB Inert RT DRUG ONLY)
Linear (EB - Inert - RT - DRUG in PLGA)
Linear ( EB - Inert - cold - Early data - DRUG in PLA)
Linear ( EB - Inert - cold - Early data - DRUG in
0
2
4Linear ( EB Inert cold Early data DRUG inFLUOROPOLYMER)
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0 25 50 75 100 125 150
Dose (kGy)
Effects of E-beam on Drug # 1
35
25
30 EB - Inert - RT - DRUG ONLY; n=3
EB - Inert - RT - DRUG in PLGA
20
25
rug
Loss
- TC EB - Inert - Cold - DRUG IN PLA
EB - Inert - Cold - DRUG in FLUOROPOLYMER
EB - AIR - RT - DRUG in FLUOROPOLYMER
10
15
Rel
ativ
e D
Poly. (EB - Inert - RT - DRUG ONLY; n=3)
Linear (EB - Inert - RT - DRUG in PLGA)
Linear (EB - Inert - Cold - DRUG IN PLA)
0
5Linear (EB - Inert - Cold - DRUG inFLUOROPOLYMER)
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0 25 50 75 100 125 150
Dose (kGy)
Agendage da
1. Material Compatibility Guidancel G id2. Protocol Guidance
3. Industry Guidance
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3. Industry Guidance
A AAMI TIR 17 1997 to TIR17 2008A. AAMI TIR 17-1997 to TIR17-2008
From sterilization of polymeric materials used in medical devices with radiation sterilization …
to six sterilization modalities:
– Radiation – Dry heatRadiation– EO– Steam
Dry heat– Hydrogen peroxide– Ozone
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3. Industry Guidance
B From TIR17 2008 to ???B. From TIR17-2008 to … ???
From six sterilization modalities with a focus on polymeric materials in medical devices …to pharmaceuticals and biologics?p g
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Agendage da
1. Material Compatibility Guidancel G id2. Protocol Guidance
3. Industry Guidance
Questions?
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