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Integration of Risk Assessment and Chemical Characterization (MD&M Minn. 2017)

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The Toxicological Risk Assessment (TRA) is an important tool in the safety assessment of biomedical devices, providing a chemical-based approach which complements a traditional animal-based testing program. The need for TRA is growing and in some cases, may be considered as a means of circumventing animal testing in the safety evaluation of devices.
Based on results of the chemical characterization, the TRA provides context to the chemistry data and the leachable compounds identified therein, which includes compounds expected to be found and compounds that are unexpected. The objective of the chemical characterization study is to identify and quantify substances that may be released from the test article during clinical use and in practical terms, is comprised of incubations of the test article in various media, e.g., water, ethanol, or hexane, at specific temperatures and durations.

By considering the end use of the characterization data in the TRA during the design of the chemical characterization study it can be assured that the study provides the most useful and informative data. Considering the needs of the TRA can also help in determining appropriate detection limits for the analysis, which in turn can help in determining the amount of test material needed for the study. Further, coordinating with the risk assessment team during the design of characterization study helps ensure that the data are usable and presented in the most suitable manner. By working together, the TRA and chemical characterization study provide an understanding of the impact of potential exposures on the overall safety of a device.

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Integration of Risk Assessment and Chemical Characterization (MD&M Minn. 2017)

  1. 1. Integration of Risk Assessment and Chemical Characterization Russell Sloboda Senior Scientist and Risk Assessment Specialist
  2. 2. » Nearly 40 yrs of experience in Medical Device, Pharma, & Biotech Industry • Material Qualification • Biocompatibilty • Microbiology • Efficacy/ Surgical Research • Toxicology Testing • Extractables & Leachables • Risk Assessment • Consulting Services » FDA Registered » ISO 17025 Accredited » GLP & GMP Compliant testing » Global Organization 1 Toxikon Company Profile
  3. 3. Chemistry and Risk Assessment Capabilities Overview CONFIDENTIAL2 » Chemistry Staff (Stephen Doherty, Ph.D., Laboratory Director): 8 study directors (12 - 37 years experience); 16 research assistants and senior chemists; 3 Quality Assurance, protocol, and document control specialists » Toxicology Staff (Kevin Connor, Ph.D., DABT, TOX-SMART Director): 4 Toxicologists (each with 20+ years experience); 3 PhDs
  4. 4. Quality Credentials and Certifications CONFIDENTIAL3 » ISO/IEC 17025: 2005 Accredited » AAALAC Accredited » FDA Registered » USDA Registered » OLAW Assurance » MSPCA Permit » Nuclear Regulatory Commission (Radiolabel)
  5. 5. 4 CONFIDENTIAL State of the Art Analytical Instrumentation LC/MS Orbitrap LC/MS Quad GC/MS (autosampler injection) Headspace GC/MS & GC/FID Purge and Trap GC/MS LC/UV, -FLD, -RI, -ELSD ICP/MS ICP-OES
  6. 6. 5 CONFIDENTIAL State of the Art Analytical Instrumentation
  7. 7. 6 CONFIDENTIAL State of the Art Analytical Instrumentation In addition to instrumentation, Toxikon has extensive laboratory equipment for virtually any technique utilized in test article extraction
  8. 8. ANALYTICAL SCREENING TO IDENTIFY FULL RANGE OF UNKNOWNS » Mass Spectral (MS) Advanced Identification Methods: » TOXIKON chemists: Decades of experience in device characterization by HS-GC/MS, GC/MS and UPLC-HRAM (accurate mass LC/MS) » Custom libraries focus on compounds seen in elastomers/polymers » NIST, mzCloud, and proprietary in-house mass spectral libraries » Target compound databases - both spectrum & retention time match » Robust identification using LC-HRAM is more powerful, but more resource intensive Reliable & Comprehensive Identification of Organic Substances
  9. 9. INTRODUCTION » Purpose of chemical characterization & risk assessment » Evaluate safety of biomedical products using chemical analysis  Extractable chemical analysis data (medical devices)  Leachables data (drug product container closure systems) » Typical information used in a toxicological risk assessment  Clinical indications for use, patient age, dosage, & duration  Test article size & composition  Detected concentrations & analytical method details  Chemical structure analysis using QSAR software  Literature studies of toxicity (animal or human data)  Bioavailability (absorption, distribution, metabolism, and excretion)  Risk-benefit factors (treatment efficacy) 8
  10. 10. Chemical Characterization: What ISO 10993 Part 18 and Part 12 CAN offer? » A framework to ensure use of appropriate chemical characterization methods to evaluate device safety » Requires knowledge of: 1. What was introduced during manufacturing 2. What classes of chemicals may leach 3. Analytical methods that can identify all classes of chemicals & detect threshold levels of concern 4. Type of extraction best suited to generate representative data for estimating patient exposure & toxicological risks 9
  11. 11. Chemical Characterization: What ISO 10993 Part 18 and Part 12 CANNOT offer? » Does NOT provide a blanket assessment to eliminate biocompatibility testing » Study design not specified; details are key to ensure: 1. Thoroughness of analytical techniques to detect broad range of substance classes 2. Extraction conditions that allow data to be extrapolated to assess exposures during clinical use 3. Material properties can affect extraction success & must be taken into account in study design 10
  12. 12. Toxicological Risk Assessment: Regulatory Basis » Regulatory Basis: • ISO 10993-17 (2002) – Toxicological Risk Assessment. Establishment of Allowable Limits for Leachable Substances • Calculation of toxicological effects of chemical leachables & impurities • Calculation of thresholds to ensure adequate testing for evaluating safety • FDA/ICH ‘M7’ Guidance. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. 2015 • FDA Final Guidance (June 17, 2016). Use of ISO 10993-1, Biological Evaluation of Medical Devices – Part 1: Evaluation and testing within a risk management process » Other Guidance on the Risk Management Process: • ISO 14971 (2007) – Application of Risk Management to Medical Devices • ISO 15499 (2012) – Guidance on the conduct of biological evaluation within a risk management process 11
  13. 13. Toxicological Risk Assessment: Regulatory Basis 12 » FDA Final Guidance (June 17, 2016). Use of ISO 10993-1, Biological Evaluation of Medical Devices – Part 1: Evaluation and testing within a risk management process. » Increasing role for Risk Assessment (and Chemical Characterization) – possibly even a prerequisite to biocompatibility testing? Use Risk Assessment in the design of a biocompatibility testing program  No mutagens or carcinogens identified  No toxic leachables identified  Omit long-term tox and cancer studies?  Minimize genotoxicity testing?
  14. 14. Toxicological Risk Assessment - Objectives » For Medical Devices, the Risk Assessment is: 13 • A complementary approach to biocompatibility testing program • Based upon a chemical-specific toxicity evaluation • Relies on extractables/leachables data » What are the questions it hopes to answer? • What are residues, extractables, impurities of concern? • What are permissible levels for these analytes? • Could there be an unacceptable risk to the patient? essential component? -------------------------------- ^
  15. 15. Correctly Categorize the Body Contact of a Device » Surface Device • Does it contact intact skin? • Does it contact intact mucosal membranes? • Does it contact breached or compromised surfaces? » External Communicating Device (conduit) • Does it have indirect blood contact? • Does it contact tissue/bone/dentin? • Does it have contact with circulating blood? » Implant Device • Does it have contact with tissue/bone? • Does it have contact with blood? 14
  16. 16. Correctly Categorizing the Contact Duration of a Device » Limited Exposure • Less than 24 hours » Prolonged Exposure • 24 hours to 30 days » Permanent Exposure • Greater than 30 days 15 Longer exposure period can require more rigorous exhaustive extraction
  17. 17. The Ties that Bind: Chemistry and Risk Assessment CHEMISTRY: Extractions: » Conditions? » Extraction media? » Which components to include? Analysis: » AETs Data Reduction: » How to present data? 16 RISK ASSESSMENT: Understand the Device and Its Use Understand Frequency and Magnitude of Use Determine Data Needs
  18. 18. Basics of Extractables/Leachables (E&L) Chemical Characterization
  19. 19. EXTRACTABLES & LEACHABLES DEFINITIONS 18 » Extractables: Extractables are compounds that migrate from the contact surface under more aggressive conditions such as elevated temperature, extended contact time, or aggressive solvent system. Any component that is added to or pulled from the device or the materials used to make the device, including degradants and residuals. What CAN come out. » Leachables: Leachables are compounds that migrate from the contact surface under normal conditions of exposure. Leachables are usually subset of extractables. What DOES come out.
  20. 20. Extractable and Leachable (E&L) Analysis » What are the targets? • Chemical constituents of the device and its packaging • Impurities/Contaminants in the materials • Degradants of the material constituents » How are they measured? • Incubation of the representative device in a relevant medium • Using appropriate extraction media • Relevant, but rigorous conditions, e.g., 50ºC for 72 hrs • Inclusion of components making patient contact Chemical analysis should be – to the greatest extent possible – conducted on final, finished (sterilized and packaged) product. 19
  21. 21. Typical Extraction Conditions for E&L Analysis 20 Screening (Extraction) Refined (Leachability) Article: Media Ratio 3 or 6 cm2/mL, based on material thickness Other options: irregular shape/porous materials (0.1 - 0.2 g/mL) Extraction conditions 37, 50, 70°C 24 or 72 hrs 37°C for heat susceptible materials real-world shelf life, temperature Option to simulate accelerating aging Extraction media Polar: Saline, Purified water, Acidic or Alkaline pH water Non-polar: Hexane Mixed: An alcohol (20 - 50%) Depends on drug product formulation and excipients in contact with device: (aqueous, acidic, alkaline, nonpolar) Selection of components Components that make direct patient contact or which directly contact drug formulations/solutions administered to the patient
  22. 22. Extraction Methodology: Leachables Released vs. Time Take into account the duration of use, type of use • Single extraction vs. consecutive, exhaustive extractions • If a risk assessment uses the former to estimate recurrent daily exposures it most likely will yield an over-estimate: 21 0 2 4 6 8 10 12 14 0 50 100 150 200 250 300 350 Result(mg/device) Hours Extraction Leachable Mass From One Extraction Exhaustive 24 Hrs
  23. 23. Gas Flow Pathway Analysis: Volatiles Released vs. Time Simulated use, 48-hr. gas flow analysis by TD-GC/MS 22
  24. 24. ISO 18562: test for SVOC/NVOC extractables, VOC gas flow analysis Breathing Circuit Analysis: Extraction, Headspace, Gas Flow 23
  25. 25. What Can Affect Migration? Factors that affect leaching (rate/amount & final product) » Polymer type: Tg » Polymer crystalinity: > amorphous, ↑ migra on » Additive size: ↑ MW, ↓ rate of diffusion » Polarity: Like dissolves alike » Processes: Aging, Sterilization, Solvating steps » Temperature: ↑ temp, ↑ diffusion » Contact Solution/Environment » Environment of Concern: aqueous (polar), organic, apolar... » Solvatation 24 Diffusion
  26. 26. Analytical Evaluation Threshold » Analytical Evaluation Threshold = AET. » Translates the leachables threshold required for further toxicological evaluation into a concentration for analytical methods » Ensures the laboratory defines a minimum detection level to ensure adequate detectability for the assessment of material safety » The AET is a “cut-off” concentration level for analytical techniques 25
  27. 27. Analytical Evaluation Threshold » AET concept is not new, but has undergone refinement over last two decades » AET requires an anchor in an appropriate Safety Concern Threshold (SCT) » SCTs are derived for different routes of exposure to toxicants (oral, inhalation, and parenteral/systemic) » SCTs are based on Toxicological Thresholds of Concern (TTCs) and are distinct for genotoxicity (mutagenic carcinogens), chemicals that are sensitizers, & general (noncancer) toxicity 26
  28. 28. » SCT for genotoxicity (ICH M7): ranges from 1.5 to 120 µg/day. SCT is lowest for longer duration exposures (Haber’s rule) » SCT for sensitization (PQRI, 2013): 5 µg/day. SCT does not necessarily scale to a higher value for shorter duration exposures » SCTs for noncancer effects (general toxicity) depend on Hazard Class I, II, or III, as determined by chemical structure (Cramer, 1978) » Thresholds for adverse noncancer effects depend on toxicokinetics and toxicodynamics (absorption, distribution, metabolism, excretion). » Is 3 mg once every 3 days as potent as 1 mg daily doses for 3 days? Analytical Evaluation Threshold 27
  29. 29. Analytical Evaluation Threshold: Calculation 28 TTC VD D UFAET extc ext         AET Analytical evaluation Threshold (in µg/mL or mg/L) – based on the most stringent of the SCTs for mutagenicity, sensitization, or general (noncancer) toxicity TTC Threshold for further Toxicological Evaluation, as applicable for the Device exposure type (µg/day) UF Uncertainty Factor (a default value of 0.5 should be considered when utilizing semi-quantitative methods) Dext # of Devices present in the extraction volume of Vext Dc # of Devices clinically utilized in a day (Dc ≥ 1 unless study conditions provide adequate resolution in release kinetics of a prolonged or permanent exposure device and kinetics demonstrate linear release) Vext Extraction Volume (in mL) Note: Both Vext & Dext must be resolved accordingly to account for any extract modifications such as concentrations and/or dilutions prior to analysis
  30. 30. AET – Instrument Detection Threshold Illustrated 29 Requirement to detect levels > AET Note: Actual AET is often based on peak area, not height
  31. 31. Analytical Evaluation Threshold: Improvements What if method(s) is not sensitive enough to achieve AET? » Adjust extraction methodology (e.g., extraction ratio) » Increase the extract solvent concentration factor » Adjust Analytical Methods: • SIM – Selected Ion Monitoring – Can enable detection at levels 10-100X lower than standard screen • Method becomes targeted rather than screening 30
  32. 32. Extractable/Leachable Chemical Classes
  33. 33. Extractable/Leachable Chemical Classes 32 Potential Inorganic Chemicals of Concern Metals If you don’t look for it, you won’t find it!
  34. 34. 33 Compounds that may elicit effects include: Potential Sources of Leachables » Polymer oligomers » Polymer degradation products » Polymer/Rubber Additives Antioxidants Photostabilizers Plasticizers Lubricants Acid Scavengers Pigments/Colorants Carifying/Nucleating Agents Cross Linking Agents (Rubbers) Initiators (Rubbers) Accelerators (Rubbers) » Polymer additive degradation products » Impurities in polymer additives » Catalysts » Polymer residues (e.g. monomers) » Adhesives » Manufacturing impurities/residuals Extractables and Leachables Sources CH3H O H3C H3C CH3 OH H3C O H3C CH3 CH3 H3C CH3 O H3C OH O H3C O CH3 OO O OO O O O O O O O CH3 CH2 H3C CH3 CH3H3C CH2 H3C CH3 CH3H3C Br CH3 H3C CH3 CH3 CH2 H3C H3C CH3 CH3 Cl O O O O O O O O CH3 CH3
  35. 35. 34 Antioxidants Function: assuring protection against thermal and oxidative degradation during processing and during shelf life of polymer (Sterically Hindered Phenols & Organic Phosphites/Phosphonates are mostly used) European Pharmacopoeia lists a.o. the following Antioxidants: BHT Hostanox 03 Irganox 1010 Irganox 1330 Irgafos 168 Irganox 3114 Irganox 1076 OH CH3 O O O O OH OH O O O O HO HO CH3 CH3 H3C OH OH HO HO O O CH3 O P OO N N N O O O OH OH HO H3C O O O OH O CH3 HO OH OH Extractables and Leachables Sources
  36. 36. 35 Plasticizers Function: Gives the plastic flexibility and durability Plasticizer requirements: o Low Water solubility (low extractibility) o Stability to heat and light o Low Odor, taste and toxicity O O O O CH3 CH3 CH3 CH3 O O O O CH3 CH3 CH3 CH3 O OH3C H3CDiethylhexylphthalate (DEHP) TOTM O O O O O O O O O O O O ESBO OH O H3C Stearic Acid C4H9 O O C4H9 C2H5 O O C2H5 Diethylhexylsebacate H3C O O CH3 O O H3C CH3 Diethylhexyladipate Extractables and Leachables Sources
  37. 37. 36 Photostabilizers Function: Protects the Polymer from UV-Degradation (exposure to sunlight) Tinuvin 328 Tinuvin 770 N N N CH3 H3C HO CH3 H3C CH3 CH3 O ON H3C CH3 H H3C H3C O O N H3C CH3 H CH3 CH3 O O O N O O O O N O * * n Tinuvin 622 Extractables and Leachables Sources
  38. 38. 37 Slip Agents Function: reduce the “friction” or “film adherence”, important when producing bags from films Erucamide Oleamide CH3 NH2 O CH3 NH2 O Remark: because of their specific properties, Slip agents will be widely detected as Leachables! Extractables and Leachables Sources
  39. 39. 38 Acid Scavengers Function: Protects the polymer from “acid attacks” through conversion of strong acids (high degradation impact) to weak acids (low degradation impact) Examples: Ca(Stearate)2 + 2HCl  CaCl2 + Stearic acid strong acid weak acid Extractables and Leachables Sources
  40. 40. 39 Pigments / Colorants Function: Gives the polymer/rubber the desired color (cosmetic) Examples: Carbon Black (PAHs), TiO2 (white), Fe2O3 (red), Pigment Green 07 N N Cl Cl Cl Cl O Solvent Red N OH O O Solvent yellow 114 O O N N H H H3C H3C Solvent Green 03 Extractables and Leachables Sources
  41. 41. 40 Clarifying Agents (Nucleating Agents) Function: by controlling the crystallization (nucleation) when cooling off polymer, it becomes transparent. NC-4 Millad 3988 O O O O C2H5 C2H5 OH HO O O O O CH3 H3C OH HO H3C CH3 Extractables and Leachables Sources
  42. 42. Various residues from the production process: Solvents Monomers Catalysts 41 H3C CH3 H H H3C O CH3 CH3 H3C OH CH3 CH2 N O H CH3 O H2C O CH3 Styrene Hexane DHN MIBK IPA Cyclohexane Caprolactam Methyl methacrylate H2C CH2 CH3 Isoprene Titanium Zirconium Cobalt Aluminum ... Extractables and Leachables Sources
  43. 43. 42 OLIGOMERS: Examples PET PBT Nylon 6 Nylon 6.6 Butyl Rubber Polyester N N O H OH NHHN O O N N N O O O H H H HN HN O O NH NH O O HN H N H N N H N H NH O O O O O O O O O O O O O O OO O OO O O O O O O O CH3 CH2 H3C CH3 CH3H3C CH2 H3C CH3 CH3H3C Br CH2 H3C CH3 CH3H3C Cl CH3 H3C CH3 CH3 H3C CH2 H3C H3C CH3 CH3 CH3 H3C CH3 CH3 CH2 H3C H3C CH3 CH3 Cl CH3 H3C CH3 CH3 CH2 H3C H3C CH3 CH3 Br OO O O O O O O O O O O O O O O O O O O O O O O O O HO O O O O OH O O O O O O HO OH O O O O O O O O O O O O O CH3 O O O O CH3 CH3 O O O O O O O O O O O O O O O O H3C CH3 H3C CH3 O O O O O O O O CH3 CH3 adhesive Other typical oligomers from Silicone, PP, PE-adhesives ... Extractables and Leachables Sources
  44. 44. Polymer degradation Compounds Origin: Oxidative degradation of the polymers (when the polymer is not properly stabilized via antioxidants) Example of Polymer Degradation Compounds from Polypropylene 43 H OH O H3C OH O CH3H O H3C OH CH3 CH3 H3C OH H3C H3C CH3 OH H3C O H3C CH3 CH3 H3C CH3 O H3C OH O H3C O CH3 H CH3 O CH3 CH3CH3 H3C CH3H3C CH3CH3 CH3 H3C CH3 CH3 CH3CH3CH3H3C H3C CH3H3C CH3 CH3 Acids Aldehydes Alcohols Ketones Polymer Fragments Extractables and Leachables Sources
  45. 45. 44 O O O HO OH O OH O OH O HO O O CH3 O OH O O CH2 O O Irganox 1010 O O O O OH OH O O O O HO HO O O O O OH OH O O O O HO HO O O O OH O O O O HO HO O O O O O OH O O O O HO HO OH O O O O O OH O O O O HO HO .... Example Degradation of Irganox 1010 SMALL degradation Compounds LARGE degradation Compounds Extractables and Leachables Sources
  46. 46. » EXAMPLE: Degradation of Irgafos 168 (also other degradation compounds for Irgafos 168 are known) 45 O P OO O P OO O + ROOH + ROH HO Irgafos 168 Irgafos 168 Oxide Extractables and Leachables Sources
  47. 47. Toxicological Risk Assessment Applied to Chemical Characterization Data
  48. 48. Risk Assessment of Medical Devices Two complimentary, but not overlapping, areas that the FDA expects the Sponsor to evaluate via risk assessment: BIOLOGICAL ASSESSMENT (ISO 10993-1) Evaluation and testing within a risk management process TOXICOLOGICAL ASSESSMENT (ISO 10993-17) Establishment of Allowable Limits for Leachable Substances 47 CONFIDENTIAL
  49. 49. Toxicological Risk Assessment: Regulatory Basis 48 » FDA Final Guidance (June 17, 2016). Use of ISO 10993-1, Biological Evaluation of Medical Devices – Part 1: Evaluation and testing within a risk management process. » Increasing role for Risk Assessment (and Chemical Characterization) – possibly even a prerequisite to biocompatibility testing? Use Risk Assessment in the design of a biocompatibility testing program  No mutagens or carcinogens identified  No toxic leachables identified  Omit long-term tox and cancer studies?  Minimize genotoxicity testing?
  50. 50. Toxicological Risk Assessment First Step - Understand what is Delivered to Patient 49 1. Identification of compounds that leach from the device 2. Quantify compounds detected 3. Apply E&L data to estimate patient exposure
  51. 51. Estimating Exposure to Leachables Extrapolate E&L data to estimate patient exposure » Consider exposure type: contact route affects toxicity studies to select as relevant and need for oral bioavailability adjustment  Parenteral or systemic exposure (IV, subcutaneous, or implants)  Inhalation exposure (breathing gas ventilation or nebulized aerosols)  Oral exposure (oral medications or dental devices)  Dermal absorption (transdermal patches, wound dressings, gels) » Frequency of use (daily or intermittent) » Duration of use (short term, prolonged, or permanent) » Extrapolate release from test article size extracted to clinical device size » Convert analytical data units from µg/mL to µg/device 50
  52. 52. Establishing Chemical-Specific Toxicity Thresholds » Derive toxicity-based thresholds: Tolerable Intake (TI, µg/kg-day) and Tolerable Exposure level (TE, µg/day).  TI represents a maximal dose at which adverse effects are not expected (with a margin of safety)  Based on a toxicological “point of departure”, identified from a literature search of available toxicology studies. Expressed as a No Observed Adverse Effect Level (NOAEL) or Lowest Observed Adverse Effect Level (LOAEL).  Modifying Factor (MF) is applied with several Uncertainty Factors (UFs)  TI = (NOAEL or LOAEL) / Modifying Factor (MF)  Where, MF = (UF1 × UF2 × UF3) 51
  53. 53. Establishing Chemical-Specific Toxicity Thresholds » Tolerable Exposure level (TE, in µg/day) represents an adjusted tolerated exposure level of a chemical within a population subset, and incorporates a Utilization Factor (UTF).  TE = TI × mB × UTF  Where:  mB = Body Weight  UTF = Concomitant Exposure Factor (CEF) × Proportional Exposure Factor (PEF)  UTF account for variables potentially impacting clinical exposure, including frequency of exposure and potential exposure to similar extractables from other sources. » Note: FDA does not accept general use of the PEF as defined in ISO 10993-17. 52
  54. 54. Are Estimated Exposure Levels Safe? » TE is compared to the estimated daily exposure (in µg/day) » Comparison is expressed as a ratio, or Margin of Safety (MOS):  MOS = (TE) / (Daily Exposure)  A MOS greater than 1.0 indicates the estimated exposure is below the TE and unlikely to present any adverse effects » Hypothetical risk estimates typically will not represent actual risks of adverse effects in a patient population » Overestimation of risk is due to conservative aspects of risk analysis:  rigorous extraction conditions employed  conservative assumptions in exposure assessment 53
  55. 55. Optimizing Study Design for Risk Assessment
  56. 56. How to Optimize E&L Study Design for Risk Assessment 55 » Relevance of E&L test results depends on good study design » TOXIKON risk assessors provide input to study design to ensure useful data generated • Explore range of most appropriate extraction media • Optimize conditions and duration of extraction for device category » Where E/L analysis can go astray... • Objectives are not aligned to risk assessment goals • Incorrectly attempting to simulate aging/degradation of product • Inclusion of non-patient contacting surfaces
  57. 57. How to Optimize E&L Study Design for Risk Assessment WHAT DEVICE COMPONENTS SHOULD BE TESTED? Analyze Components Separately or as Combined System? (affects exposure estimate)  Separate chemical characterization analysis for components w/ different contact duration  Understand potential toxicity of new materials in modified components. If a new material is contemplated, can test it separately to demonstrate safety and suitability for an existing device  Combining multiple components into one extract for analysis might dilute the amount of individual components being extracted.  Relative proportion of extract that originates from each component should match clinical use Secondary packaging (e.g., ink label or pouch) - Likelihood of migration and relevance for testing with appropriate type(s) of analysis  Migration from secondary packaging into device (such as drug vial) more likely for VOCs  Secondary migration less likely if primary container highly impervious (e.g., glass vial), or if materials are not in close contact
  58. 58. How to Optimize E&L Study Design for Risk Assessment SELECTING APPROPRIATE E&L TESTING CONDITIONS Extraction solvent should contact surfaces that will directly contact the body or solutions introduced into the body  Fluid path extraction if inner vs. outer surfaces are different materials  One-sided extraction (example: leachables from a transdermal patch)  Traditional cut and cover extraction used for homogenous materials. Multiple Extraction Solvents: several solutions capture a larger range of leachables  ISO/FDA: Use nonpolar and polar solvents (more than one pH if clinically relevant)  Alcoholic mixtures mimic solution properties for clinical contact with blood or contact with a drug formulation of like polarity  A drug excipient solution can mimic solution contact during clinical use Extraction Temperatures/Duration:  Permanent implants – need exhaustive extraction duration to estimate total release  Aggressive conditions should not cause component material degradation  Leachables tests of drug stored in container system under shelf life conditions or accelerated  Flow-through simulation using realistic conditions: if drug merely flows through device
  59. 59. How to Optimize E&L Study Design for Risk Assessment ANALYTICAL METHODS- to maximize useful data Which Analytical Tests?  Many types of VOCs, SVOCs, NVOCs found in elastomers/polymers  Metallic substances - leachables in glass, metal, or polymer materials (less often high-risk)  Non-volatile residue (NVR) - surrogate endpoint to measure exhaustive extraction  FTIR indicates polymer type (not chemical-specific data for risk estimation) Mass Spectrometry Method Options:  High Resolution Accurate Mass (HRAM) – better able to ID unknowns vs. Low-Resolution MS  Mass spectral libraries: Fewer compounds for LC/HRAM (~2K to 5K) than for GC/MS (>200K).  Best accuracy using target compound analysis (requires calibration standards) vs. screening VOC options:  VOCs in extracts can be analyzed by GC/MS by (1) purging VOCs from extract then GC/MS, or (2) direct injection of headspace from extract vial (P&T better detection limits & accuracy)  Component material heated in sealed vial w/ injection of headspace can release greater total mass of VOCs than solvent extraction  ISO 18562 addresses devices that deliver gas into patient airways. Requires three methods: solvent extraction, gas flow sampling, & particulate testing. FDA hasn’t approved 18562.
  60. 60. How to Optimize E&L Study Design for Risk Assessment Options to enhance sensitivity:  Lower detection limits achievable by extract evaporation/concentration (to meet AET)  Selected Ion Monitoring (SIM) can achieve 10X to 100X improvement (to meet AET)  Chemical classes with low sensitivity: Nitrosamines, carboxylic acids, diols, and alcohols are derivatized with trimethyl silane for better detection. Not critical for compounds with low toxicity (fatty acids & simple alcohols) or degradants of rarely used additives (nitrosamines) Metals analysis – Specify target metals list up-front  Comprehensive target analyte list (USP List) often needed for testing drug container systems  ICP/MS has lower detection limits than ICP/OES. However, ICP/MS interferences can occur with high excipient levels, and in isolated cases causes bias (e.g., Si)
  61. 61. 60  Understanding a device’s intended use:  Facilitates proper study design for extractables/leachables testing  Provides key input used in the toxicological risk assessment  Coordination between chemists and toxicologists ensures that:  Analytical detection limits are adequate for a comprehensive risk assessment  The conditions of extraction are appropriate for estimating patient exposure  The scope of the analysis includes all compound classes of potential interest  Conducting a proper risk assessment for regulatory approval requires:  Consideration of intended use of the device (type of body contact, duration, etc.)  Knowledge of the potential patient population (age, body weight, etc.)  Research into available toxicity literature (chronic toxicity, mutagenicity, bioavail.)  Professional judgment to select appropriate NOAELs, uncertainty factors, etc.  Ability to weigh the relevance of different types of analytical data (solvents, etc.)  Consideration of risks vs. benefits in formulating a conclusion as to overall safety TOXIKON chemists and toxicologists work closely together in order to optimize E&L study design and ensure regulatory approval Conclusions – Key Elements in the Integration of Risk Assessment and Chemical Characterization
  62. 62. Questions and Comments 61 If you have any questions on the full range of chemistry and biocompatibility testing services offered by TOXIKON Corporation, *** Please stop by booth # 1929 *** Thanks for attending ! 15 Wiggins Ave, Bedford, MA 01730 Presenter: Russell Sloboda, Sr. Scientist and Risk Assessment Specialist Russell.Sloboda@Toxikon.com Stephen Doherty, Ph.D., Laboratory Director Stephen.Doherty@Toxikon.com Kevin Connor, Ph.D., DABT, TOX-SMART Director Kevin.Connor@Toxikon.com

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