Practical Guidance in Selecting Materials for Product Functionality

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1 Practical Guidance in Selecting Materials for Product Functionality Byron J. Lambert, Ph.D. Fellow, Sterilization Science Abbott Vascular Temecula, CA USA

2 Agenda 1. Material Compatibility Guidance 2. Protocol Guidance 3. Industry Guidance

3 1. Material Compatibility Guidance A. Build on fundamentals The foundation of successful sterilization strategies are the fundamentals of radiation chemistry and biochemistry: Radiation yields (G-values) Direct vs indirect effects Free radical species & scavengers Oxygen effects Moisture effects Thermal effects

4 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

5 IMRP 08 A. Tallentire Microbial Radiation Response

6 IMRP 08 A. Tallentire Microbial Radiation Response Surviving Fraction (+ O 2 ) DOSE

7 IMRP 08 A. Tallentire Microbial Radiation Response Surviving Fraction (+ O 2 ) (- O 2 ) liquid DOSE

8 IMRP 08 A. Tallentire Microbial Radiation Response Surviving Frac ction (+ O 2 ) (- O 2 ) solid DOSE

9 Analogous Effects on Active Agents? (+ O 2 2) Active Agent Loss DOSE

10 Analogous Effects on Active Agents? Active (+ O 2 2) (- O 2 ) liquid Agent Loss DOSE

11 Analogous Effects on Active Agents? (+ O 2 2) Active Agent L Loss (- O 2 ) solid DOSE

12 Analogous Effects on Active Agents? (+ O 2 2) Active Agent L Loss (+ O 2 + H 2 O) 2 2 DOSE

13 Experiments can optimize the application and processing range of a combination device drug* 1) Is secondary chemistry important? t? 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 the device and on the release polymer

14 1. Material Compatibility Guidance B. Leverage existing guidance Relative radiation stability medical device polymeric materials - AAMI TIR17 Rules of thumbs General principles

15 Relative Radiation Stability of Medical Polymer "Families" Dose (Kilogray) in Ambient Air at which Elongation Decreases by 25% kgy Thermosets Polystyrenes Polyethylenes Polyesters 1 Engineering Resins High Performance Polycarbonate/ Polysulfone 2 Polyurethanes 3 PVC Fluoropolymers High Performance 4 5 ABS 6 Elastomers Nylon(PolyAmides) 11 Cellulose & Co-Polymers Acrylic (PMMA) & Co-Polymers Polypropylene (Radiation Grades) Polymethylpentene FEP Legend* NOTE: 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 (3) Molecular Weight & Distribution, (4) Morphology (5) Environment (Oxygen/Temperature (6) Dose Rate 1 - HDPE REFERENCES: Polypropylene 2 - PBT 3 - Aromatic (Natural) * Polymer Manufacturers Data 4 - Rigid/Semi-Rigid PVC 5 - ETFE (Tefzel) * NASA/Jet Propulsion Laboratories, "Effects of Radiation on Hi-Impacy ABS Polymers & Elastomers", Butyl Rubber Acetals 8 - Silicone/Neoprene * Skeins & Williams,"Ionizing Radiation Effect on Selected 9 - EPDM 10 - Nylon 6 & 12 Biomedical Polymers" 11 - Amorphous Nylon * Kiang, "Effect of Gamma Irradiation on Elastomeric Closures, PTFE Dose (kgy) 12 - Cellulose/Paper 13 - PMMA PDA, Varies by Mfgr/Grade * Ley, "The Effects of Irradiation on Packaging Materials", Homopolymer * - Within each family is a range of radiation stabilities, the "steps" are intended to show significant family members Ageless Processing Technologies, KJH 12/96 Association for the Advancement of Medical Instrumentation, AAMI TIR 17

16 1. Material Compatibility Guidance C. Responsible shelf-life lif estimation Medical Device Accelerated Aging (AAMI TIR ; ASTM F ) Pharmaceutical Accelerated Stability (ICH Guidelines)

17 1. Material Compatibility Guidance D. ESR Radical stability Answers question: have free radical active species from the radiation sterilization process finished reacting? Provides confidence going into aging studies that degradation rates are representative

18 ESR Introduction Electron Spin 100 Resonance (ESR) 90 Magnetic field scanned in a given microwave frequency I) centration (D Free e Radical Con Concentration of active species es (free 20 radicals) from 10 radiation sterilization 0 are measured PLA* - Typical free radical decay curve *crystallinity it varies greatly Time (hour)

19 ESR Free Radical Stability PLA Time hr 2.0 hr 4.0 hr 6.0 hr 10.0 hr Data on file at Abbott Vascular.

20 PLA - Radical Decay 2nd Order Time DI 1/DI /(Fr ree radical Conce entration) R 2 = Time (hour) Data on file at Abbott Vascular.

21 1. Material Compatibility Guidance EG E. Gamma vs E-beam Eb 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; X-ray is a negligible fraction of the market

22 E-beam: Mechanism of Energy Deposition by High henergy Electrons 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 e - 60 ev

23 Gamma: Mechanism of Energy Deposition by Co-60 gamma rays 1.25 MeV gamma rays are blasted into material Energy is deposited through Compton Scattering 0.5 MeV recoil electrons Ionic interactions of high energy electrons are again the primary mode of energy deposition

24 Gamma & E-beam - same mechanism of energy deposition Differences between Gamma and E-beam Penetration is different Dose rate is different Material Compatibility For 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 long elevation of temperature during gamma

25 Agenda 1. Material Compatibility Guidance 2. Protocol Guidance 3. Industry Guidance

26 2. Protocol Guidance A. Clinical Stresses 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 does not fail What are the clinically relevant stresses? CaseStudy#2 Polyamide / Polyether blends are relatively 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.

B. Clinically relevant testing - basic mechanical and

release of pharmaceutical & biologic agents 1.

Surface ace(swelling) analysis ayssusing 5.

27 B. Clinically relevant testing - basic mechanical and micro and nano-scale characterization for controlled release of pharmaceutical & biologic agents 1. Drug distribution and coating thickness uniformity using imaging FTIR 4. Thermal transition and analysis using μta 2. Surface ace(swelling) analysis ayssusing 5. Chemical component, structure, and AFM conformation using LCR, ATR, FTIR, and NMR 3. Microstructure and phase dispersion using AFM and LCR

28 2. Protocol Guidance C. 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 Note: rapid R&D sterilization allows for product iterations to be evaluated with the inclusion of the sterilization process

29 2. Protocol Guidance D. Evaluate full range of parameters Pi Primary parameter: Dose Secondary parameters: dose rate environment t( (oxygen and water) temperature additives

30 Experiments can optimize the application and processing range of a combination device drug 1) Is secondary chemistry important? 2) Is the release polymer important? 3) Is oxygen or water important? 4) Is temperature important?

31 Effects of E-beam on Drug # Drug Loss - TC EB - Inert - RT - DRUG ONLY; n=3 Linear (Drug only; 0-60 kgy) Poly. (EB - Inert - RT - DRUG ONLY; n=3) Dose (kgy)

32 Effects of E-beam on Drug # rug Loss - TC Relative D EB - Inert - RT - DRUG ONLY; n=3 EB - Inert - RT - DRUG in PLGA; n=5+ Poly. ( EB - Inert - RT - DRUG ONLY; n=3) Linear (EB - Inert - RT - DRUG in PLGA; n=5+) Dose (kgy)

33 Effects of E-beam on Drug # rug Loss - TC Relative D 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) Linear (EB - Inert - RT - DRUG in PLGA) Linear (EB - Inert - Cold - Early data - DRUG in PLA) Dose (kgy)

34 Effects of E-beam on Drug # rug Loss - TC Relative D EB - Inert - RT - DRUG ONLY 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) Linear (EB - Inert - RT - DRUG in PLGA) Linear ( EB - Inert - cold - Early data - DRUG in PLA) Linear ( EB - Inert - cold - Early data - DRUG in FLUOROPOLYMER) Dose (kgy)

35 Effects of E-beam on Drug # 1 35 rug Loss - TC Relative D EB - Inert - RT - DRUG ONLY; n=3 EB - Inert - RT - DRUG in PLGA EB - Inert - Cold - DRUG IN PLA EB - Inert - Cold - DRUG in FLUOROPOLYMER EB - AIR - RT - DRUG in FLUOROPOLYMER Poly. (EB - Inert - RT - DRUG ONLY; n=3) Linear (EB - Inert - RT - DRUG in PLGA) Linear (EB - Inert - Cold - DRUG IN PLA) Linear (EB - Inert - Cold - DRUG in FLUOROPOLYMER) Dose (kgy)

36 Agenda 1. Material Compatibility Guidance 2. Protocol Guidance 3. Industry Guidance

37 3. Industry Guidance A. AAMI TIR to TIR From sterilization of polymeric materials used in medical devices with radiation sterilization to six sterilization modalities: Radiation Dry heat EO Hydrogen peroxide Steam Ozone

38 3. Industry Guidance BFromTIR B. TIR to??? From six sterilization modalities with a focus on polymeric materials in medical devices to pharmaceuticals and biologics?

39 Agenda 1. Material Compatibility Guidance 2. Protocol Guidance 3. Industry Guidance Questions?

Sterilization & Chemical Resistance of Healthcare Polymers

Sterilization & Chemical Resistance of Healthcare Polymers Key Terms & Definitions Sterilization - A process that eliminates or kills all forms of life, including transmissible agents, on a medical device;