practical guidance in selecting materials for product...

Practical Guidance in Selecting Materials for Product Functionality

Byron J. Lambert, Ph.D.Fellow, Sterilization Science

Abbott Vascular Temecula, CA USA

[email protected]

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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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Surviviing Fracction

(+ O2)

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DOSE


Surviviing Fracction

(+ O2) (- O2)liquid

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DOSE


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


(+ O2)Active

( 2)

AgentL

(- O2)solid

Loss

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DOSE


(+ 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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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


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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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.


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

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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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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


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)


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)


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)


20

16

18

EB - Inert - RT - DRUG ONLY


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 - 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)


35

25

30 EB - Inert - RT - DRUG ONLY; n=3


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 - Cold - DRUG IN PLA)

0

5Linear (EB - Inert - Cold - DRUG inFLUOROPOLYMER)

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0 25 50 75 100 125 150

Dose (kGy)

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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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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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Questions?

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