Russell Sloboda presented on toxicological risk assessment for medical devices. He discussed how risk assessment plays an increasing role in preclinical safety evaluation under ISO 10993-1. Key points included how chemical characterization data forms the basis for risk assessment, and how tools like threshold of toxicological concern, quantitative structure-activity relationship analysis, and permissible exposure thresholds can be applied to evaluate risks. The goal of risk assessment is to identify hazards, evaluate exposure levels, and characterize overall risks to determine if biological testing is needed.

1. Toxicological Risk Assessment For Medical Devices:
New Pathways to Success under ISO 10993-1
M edicalDeviceP reclinicalBootcamp– 02/13/2019
Russell Sloboda – S r.S cientist& R iskAssessmentS pecialist

2. Speaker Bio
•Analytical chemist and risk assessment specialist
•35 years’ experience
•Responsible for all aspects of toxicological risk
assessment as per ISO 10993-17 and ICH M7
guidelines, which includes:
•Exposure modeling
•QSAR models
•Toxicological profiles
•Calculation of tolerable intakes
•Study design and AET calculations

3. RISK Assessment Under ISO 10993-17
GreaterR oleinBiologicalS afety Assessment

4. FDA On ISO 10993-1: Increased Role For Risk Assessment
•Evaluation and testing “within a risk management process”
•FDA Final Guidance (June 17, 2016) solidified role of Toxicological Risk Assessment
(TRA)
•TRA (and Chemical Characterization) is described as a prerequisiteto
biocompatibility testing
•GreaterDemandforChemicalCharacterizationandT oxicologicalR iskAssessment
•Update to ISO 10993-1:2018 emphasizes this expanded role, with a tiered
approach to testing beginning with physical and chemical characterization,
followed by assessment of toxicological risks, and use of results to focus/limit the
scope of biological testing
•Traditional Biocomp testing is NOT going away; however, rote biocompatibility
analysis (“check-box” exercise) is getting more difficult
M orethoughtneededinthedesignofaS tudyP lan

5. Roles of Risk Assessment in Medical Device Testing & Approval
•Development of a biocompatibility testing plan based on assessing the potential for
toxicological hazards and given the exposure category of a device and its intended use
•Gap analysis determines if additional biological tests are needed, based on review of
existing test results for compliance (proper/current methodology and passing results)
•Assessment of modifications to an existing, approved device to determine if
component and material changes require further testing (justification letter)
•Toxicological Risk Assessment (TRA) of chemical characterization data to evaluate if the
leachable levels of compounds exceed toxicological thresholds, given the quantity,
frequency, and duration of patient contact with the device
T R A isincreasinglyview edasaprerequisiteforbiocompatibilitytestingbecause,ifall
detectedlevelsarelessthantoxicitythresholds,severalbiologicaltestscanbeomitted

6. Risk Assessment: Regulatory Basis
•Regulatory Guidance:
•ISO 10993-17 (2002) – Toxicological Risk Assessment. Establishment of
Allowable Limits for Leachable Substances
• Toxicological effects of chemical leachates or impurities
• Provide direction (thresholds) to ensure adequate testing and appropriate evaluation of safety
• Currently undergoing revision – may change with upcoming ISO guidance on Thresholds of
Toxicological Concern
•FDA/ICH ‘M7’ Guidance. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. 2018
•FDA/ICH ‘Q3D’ Guidance. Elemental Impurities. 2015
•ISO 18562. Biocompatibility evaluation of breathing gas pathways in healthcare
applications
•CAUTION: Several Similar Sounding Terms
•Risk Management: ISO 10993-1 - Evaluation and testing within a risk management process
•Risk Analysis under ISO 14971. Broader meaning, including all nature of hazards.

7. TRA per ISO 10993-1: Biological Safety Assessment
Evaluation Strategy ISO 10993–1:2018 BiologicalEvaluationofM edicalDevices: P art1:Evaluationandtesting w ithinariskmanagementprocess.
Test Methods
Part 5: Cytotoxicity
Part 10: Irritation & hypersensitivity
Part 11: Systemic toxicity
Part 3: Genotoxicity, carcinogenicity and reproductive toxicity
Part 6: Implantation and local effects
Part 4: Blood compatibility
Part 16: Toxicokinetic study design for leachables and degradation products
Part 20: Principles and methods for immunotoxicology testing
Reference Materials
Part 8: Selection of reference materials
Part 12: Sample preparation and reference materials
Animal Welfare
Part 2: Animal welfare requirements
Sterilization Residuals
Part 7: Ethylene oxide sterilization residuals
Degradation Products
Part 9: Framework for Identification and quantification of degradation
products
Part 13: Identification and quantification of polymeric degradation products
Part 14: Identification and quantification of ceramic degradation products
Part 15: Identification and quantification of metallic degradation products
Materials Characterization
Part 18: Chemical characterization of materials
Part 19: Physico-chemical, morphological and topographical characterization
Risk Assessment
Part 17: Establishment of allowable limits for leachables

8. Toxicological Risk Assessment - Objectives
•What is it?
•A complementary approach to traditional biocompatibility testing
•Often required by FDA
•It is built upon the chemical characterization
•For medical devices, it relies on extractability/leachability (E/L) data
•What are the questions it hopes to answer?
•What are constituents, additives, impurities of concern?
•What are the tolerable exposure levels for these impurities?
•Could there be an unacceptable risk to the patient?
For Medical Devices & Pharmaceuticals

9. What Are The Concerns Underpinning TRA?
•Constituent Materials
•Impurities/Contaminants
•Degradants
•Leachables/Extractables
•from constituent materials
•AND packaging
•Solvent residues
ACCORDINGLY, Analysis should be conducted on final, finished product.
…to capture chemical residues from processing, manufacturing, and packaging, as well as
leachable constituents
…totheextentthatthisispossible.

10. Toxicological Risk Assessment: Paradigm and Process
•HAZARD IDENTIFICATION
• C hemic alC harac terization
• Toxic ologic alC harac terization
•DOSE-RESPONSE EVALUATION
• D erive Tolerable Expos u re levels
•EXPOSURE ASSESSMENT
• N atu re ofd evic e/d ru gprod u c t
• Frequ enc y/D u ration ofUs e
•RISK CHARACTERIZATION
•Ford evic es , D A TA is typic ally from E/L A nalys is .
N O TE: O therforms ofd ata mays erve TRA !
•Toxic ityP rofile bas ed on literatu re s earc h
•Extrapolation ofanimald ata
•D ifferentrou tes ofad minis tration
•D ifferents tu d y d u rations (s u bac u te vs . c hronic )
•D es c ribe u s e ofd evic e/prod u c t, e. g. , natu re and
magnitu d e ofpatientc ontac t, patientpopu lation
•Explain u nc ertainties , margins ofs afety
•Therapeu tic benefits ofthe prod u c t?

11. TTC: Threshold Of Toxicological Concern
• TTCs are acceptable daily intakes intended to be protective of all toxicological
endpoints
• Not specific to any one chemical. A S afeDoseforAnyChemical!
• Chemical toxicity depends on how introduced into the body, so a TTC evaluation
can be specific to the route of exposure (e.g., oral, parenteral, or inhalation)
• Intended (originally) for daily exposureoveralifetime
• However, values have been established for less-than-lifetime exposures.
• S horterduration= HigherpermissibleDose
Duration of Exposure ≤1 month >1 – 12 months >1 – 10 years >10 years to
lifetime
Tolerable Intake
(µg/day)
120 20 10 1.5

12. Safety Concern Thresholds (SCTs) From PQRIǂ
ǂ For parenteral (systemic) exposures to organic chemicals
Class SCT
mg/day mg/kg/day
InitialClassification
1 (low toxicity) 150 3
2 (moderate toxicity) 50 1
3 (marked toxicity) 5 0.1
4 (genotoxicity) 0.15 0.003
CurrentClassification(2013)
1 (general toxicity, QT) 150 3
2 (sensitizers) 5 0.1
3 (genotoxicant, SCT) 1.5 0.03

13. TTC: Toxicological Threshold of Concern (cont.)
•May TTCs be used for SCREENING-LEVEL assessments?
•“T T C approachcanberecommendedasausefulscreeningtooleitherforprioritysettingor
fordecidingw hetherexposuretoasubstanceissolow thattheprobabilityofadversehealth
effectsislow andthatnofurtherdataarenecessary” (from EFSA Journal, 2012).

14. QSAR Analysis: Predicting Toxicity Of Unstudied Chemicals
•QSAR : Quantitative Structure-Activity Relationships
•Computational Models used to predict toxicology for chemicals
without any tox data (i.e., unstudied)
•Software packages:
•ICH M7 Guidance: For pharmaceutical impurities
•Focus is mutagenicity
•Must use dual model (Statistical-based + Knowledge based)
•Interpretation of model results is key part of the work
•ToxTree
•OECD Toolbox
•TOKAT
•Leadscope
•MultiCase
•DEREK/SARAH

15. QSAR: Additional Applications
ToxSmart Uses QSAR Models for Risk Assessment:
•Hazard Ranking / Chemical Categorization
• Cramer Classification: Grades 1 (low) , 2, and 3 (high)
•Surrogate Identification when No Data are Available for
Chemical of Interest
•Identify a chemical class
•Identify a very similar chemical (or analog) which has more
data

16. Risk Assessment: Turn-Around Time Is Important
Speeding up the process:
•Use screening evaluation in the face of many pages of data
•Make use of toxicity values from authoritative agencies
•EPA IRIS, EPA HEAST, ATSDR, ECHA, ESIS (EU), State Agencies, e.g., CAL-EPA, NJDEP,
Occupational Exposure Limits, TLVs, etc.
•ICH (Q3D), IOM (UL and RDA for elements)
•Library of Toxicity Profiles, Tolerable Exposures (TEs)
•The E/L Analyses for most medical devices identify similar constituents/additives.
•ToxSmart has toxicity profiles and route-specific toxicity values for >200 chemicals

17. Permissible Daily Exposures (PDEs) For Elementsǂ
ǂ Excerpt from ICH Q3D
Element Class
Oral PDE
(µg/day)
Parenteral
PDE (µg/day)
Inhalation
PDE (µg/day)
Cadmium 1 5 2 2
Lead 1 5 5 5
Arsenic 1 15 15 2
Cobalt 2A 50 5 3
Nickel 2A 200 20 5
Platinum 2B 100 10 1
Barium 3 1400 700 300
Copper 3 3000 300 30
Chromium 3 11,000 1100 3

18. Quantitative Risk Assessment Under ISO 10993-17
•TE = TI × mB × UTF; an adjusted tolerated exposure level of a chemical within a population subset
•where: mB = Body Weight and
UTF = Concomitant Exposure Factor ǂ (CEF) × Proportional Exposure Factor (PEF)
Uncertainty Factor Example Sources of Variation/Uncertainty
UF1 Intra-individual variation (in humans)
UF2 Inter-species variation (animal-to-human)
UF3
Overall study quality/relevance: Subchronic to chronic extrapolation, different experimental versus clinical
exposure routes, use of a LOAEL instead of a NOAEL, and other uncertainties
UF4 (optional) Toxicity data based on a surrogate compound
•Uses derived toxicity-based thresholds - Tolerable Intake level (TI, in µg/kg-day) and Tolerable
Exposure level (TE, in µg/day)
•Based on a toxicological “point of departure” (e.g. NOAEL) identified from a literature search
•TI = NOAEL / Modifying Factor (MF), which is made up of several Uncertainty Factors (UFs):
ǂ CEF applies if more than 1 device may be used concurrently

19. Risk Assessment At ToxSmart
• ToxSmart is embedded in one of the preeminent CROs in the U.S.:
• Surrounded by subject matter experts
• “In-house” chemistry lab
• We evaluate many, many devices and drug products
• A culture of QUALITY: Embedded in all operations at Toxikon.
• An SOP for Toxicological Risk Assessment
• Peer review and appropriate quality review is part of the system

20. Chemical Characterization for Risk
Assessment

21. Introduction
Extractables/Leachables (E/L) Analysis is the basis for most Toxicological Risk Assessments
for devices having direct patient contact
•Has a growing role in preclinical safety assessment, as per FDA (2016 “Use of ISO 10993-1” Guidance)
•Extractables analysis – incubation of a device in contact with a solvent, usually under elevated
temperature conditions – required by ISO 10993-17 for a TRA. Two subcategories:
•Exaggerated extraction – Fixed duration, designed to leach a greater amount versus simulated use
•Exhaustive extraction – Successive extractions repeated until virtually all leachable residue is removed
• Simulated use extraction – Extractions conducted under relatively mild conditions designed to closely
simulate clinical use of a device
• Leachables analysis - Analysis of a drug product solution after a prolonged storage period while in
contact with a container closure system, measured at intervals over a product’s shelf life
Gas flow simulation analysis measures the releasable amounts of volatile organic compounds and
particulates that may arise during use of a respiratory medical device, required by ISO 18562

22. Extraction Guidelines per ISO 10993-12: Biological vs. Chemical Tests
Biocompatibility Testing Chemical Characterization
T estarticlecondition Finished/sterilized/packaged device Same (Objective is the same)
Extractionratios ISO: 3 cm2/mL or 6 cm2/mL, based on
material thickness
Same (Objective is the same)
Extractionconditions ISO guidance: Several default
conditions, e.g., 50⁰C / 72 hrs or 70⁰C
/ 24 hrs; however, some biological
extractions (MEM) must be at 37⁰C
Exhaustive conditions should be used for permanent
contact devices, while exaggerated conditions are
intended for devices having a shorter clinical contact.
Resorbable devices are fully dissolved but not denatured
Extractionmedia Polar and non-polar vehicles which do
not adversely affect the biological test;
usually Saline and Cottonseed Oil
(CSO) or Sesame Oil
Implanted device: Purified Water, Ethanol, or Hexane
Indirect contacting device: Medium that is most relevant
to drug formulation or communicating medium
Blood contact: Ethanol/Water mixture
Componentsurfaces In practice, err on the side of inclusion Test components that actually make contact (direct or
indirect) with patient; e.g, fluid path vs. immersion

23. Analytical Requirements: ISO 10993-18 Versus ISO 18562
•ISO 10993-18:
•General guidance: E/L testing is
conducted with polar, semi-polar,
and nonpolar solvents to
determine leaching of organic
compounds (10993-12)
•Volatile Organic Compounds (VOC)
can be determined either by:
1) Analysis of aqueous extracts, or
2) Direct analysis of test article by
heated headspace (90 – 115◦ C)
•ISO 18562:
•E/L is conducted by solvent
extraction using water to simulate
humidified vapor condensate
(18562-4)
•VOCs are analyzed by gas flow
through the device under
simulated clinical use conditions
(temperature, gas flow rate,
duration), with analysis by GC/MS
(18562-3)
•Particulates analyzed (<2.5 µm,
<10 µm) (18562-2)

24. Comparison of Methods: Extraction, Headspace, Gas Flow
Higher temperature in headspace analysis exaggerates the release of VOCs
Choice of extraction solvent significantly affects
polymer swelling and extraction of nonpolar
compounds. Purified water is the most realistic
solvent to simulate humidified vapor condensate.

25. Risk Assessment Is Built Upon Chemical Characterization Data
•Applicable to container closure systems, processing equipment,
packaging, as well as medical devices
•A complementary approach to biocompatibility testing in the
preclinical safety assessment
•Identify material constituents, additives, impurities, contaminants,
degradants, and residues of concern
•Establish tolerable exposure (TE) levels for the chemicals/elements
identified
•Must consider nature and magnitude of patient exposure:
•Classification of the device
•Duration of contact
•Route of exposure

26. The Ties that Bind: Chemistry and Risk Assessment (TRA)
GOOD CHEMISTRY DEPENDS ON…
Extractions:
•Conditions?
•Extraction media?
•Which components to include?
Targeting Analysis:
•AETs
Data Reduction:
•How to present data?
…CONSIDERATIONS FOR THE TRA
Understand the Device
Understand Device Use
Determine Data Needs

27. E/L Analysis: Think About Patient Contact
•DO test the Final, Finished Product (as packaged and delivered)
•DO send lab the device in the form that it would be sent to a user
•DO help lab understand the nature of patient contact
•DON’T forget to tell the lab to remove components that should not
be included, e.g., needle guards, hose clamps
Q: What is the harm of including non-contacting components?
A: You may dilute out smaller components that matter more

28. Categorize the Device: Exposure Duration
•Limited Exposure
•Less than 24 hours
•Prolonged Exposure
•24 hours to 30 days
•Permanent Exposure
•Greater than 30 days

29. Categorize the Device: Nature of Contact
•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?

30. Risk Assessment Perspective On E/L Analysis
•E/L Analysis for risk assessment should emphasize the more relevant
conditions (e.g., leachables)
•Target normal (‘real-world’) conditions of exposure and migration from a
contact surface
•Where E/L analysis may go astray…
•Extraction to simulate aging/degradation of product may overshoot extent of
actual leaching
•Nonpolar extraction solvent swells and degrades polymer
•Non-patient contacting portions of a device may be included
•Although it is difficult to ignore data in hand, risks may be explained with a
caveat stating that these are ‘upper-bound’ estimates of risk, with little to no
relevance to clinical exposure

31. Risk Assessment Concerns With Combination Products
•Examples: pulmonary delivery device, drug-coated balloon catheter, prefilled syringe, transdermal
patch, wound dressing combined with drug product, or scaffold seed with cells
•Extractables testing is necessary to evaluate (1) leachables from device components, and
(2) leachables testing to assess stability/degradants in presence of drug product
•Study design involves input/review from multiple FDA agencies (CDRH, CDER, CBER, to be assigned
by the Office of Combination Products)
•Important to involve CRO’s toxicologists and chemists in study design and for consultation on any
FDA feedback, In particular,
•Customized extraction methods may be needed for gels, transdermal patches, etc.
•Time profile info on the in vivo absorption of resorbable products is important to risk
assessment
•FDA may have special concerns necessitating exhausting extraction
•FDA may want E/L even for transient drug-contacting components that provide drug delivery

32. Common Issues With Data Usability
•Exhaustive extraction not completed
•No information on time course of leachability
•Unidentified analytes (Chemical Unknowns)
•Components Included with Very Little or No Patient Contact
•Extraction Medium not Appropriate
•Detection Limits are Not Adequate (See AETs)

33. By Popular Demand… Is E/L Analysis Necessary?
•Is leachability the appropriate measure of exposure?
•Air pathway (respiratory) devices
•Resorbable materials?
•Predicate device assures safety
•No novel materials or chemicals
•Risks can be eliminated through a “worst-case” exposure
assessment

34. Analytical Evaluation Threshold (AET)
•Identifies analytes for further analysis or toxicological evaluation
•Defines a minimum threshold for adequate detectability for the lab
•Converts the µg/day (safety threshold) into a unit of concentration
(µg/unit) using information on the container volume, number of units
analyzed, the recommended (or maximum) dose
•May also be expressed in units of µg/mL of extract
“The threshold at or above which [the risk assessor] should
identify and quantify a particular extractable and/or leachable
and report it for potential toxicological assessment.”
– Prasad Peri, Ph.D., FDA, 2013

35. 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
•SCTs are based on Toxicological Thresholds of Concern (TTCs)
and are distinct for genotoxicity (mutagenic carcinogens),
chemicals that are sensitizers, and general (noncancer) toxicity

36. Analytical Evaluation Threshold
•SCT for genotoxicity (ICH M7): ranges from 1.5 to 120 µg/day. SCT is
lowest for longer duration exposures, and is based on cumulative days
of exposure
•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?

37. Toxicology Focus
•AET must correlate E&L data to the actual Patient Exposure
•Adapt safety thresholds (TTCs) to the E&L study considering:
•Patient exposure type (location)
•Duration of use
•Device size
•Dosing frequency (cumulative exposure)
•For drug products, the underlying TTC is based on a daily dose
•To adapt concept to implants, consider AET in terms of a daily rate of leaching that
equates to exposure to a fraction of total leachables (fraction of a test article/day)

38. Threshold Approach For Medical Devices
AET in µg/mL, or µg/unit if Vext is omitted
SCT Safety Concern Threshold for the device/exposure type (µg/day)
UF Uncertainty Factor
(shouldbeconsideredw henutilizingS emi-quantitativemethods)
Dext Number of devices present in the extraction volume of Vext
Dc # of Devices clinically utilized in a day (Dc≥ 1 unlessstudyconditionsprovideadequate
resolutioninreleasekineticsofaprolongedorpermanentexposuredeviceandkinetics
demonstratelinearrelease)
Vext [Optional] Extraction Volume (in mL)
Note: BothVext & Dext mustberesolved accordingly to account for any extract modifications
such as concentrations and/or dilutions prior to analysis
UF
VD
D
S C TA ET
extc
ext









39. Example 1: AET Determination For A Syringe
AET expressed in µg/unit; Vext is omitted
SCT 1.5 µg/day, assumes long term (>10 yrs. to lifetime daily use), based on stringent SCT for
mutagenic chemicals
UF Uncertainty Factor (shouldbeconsideredw henutilizingS emi-quantitativemethods)
Dext # of Devices present in the extraction volume of Vext
Dc 4 devices can be used clinically per day
S C T
VD
D
UFA ET
extc
ext








AET expressed in µg/mL; Vext = 10 mL
g/u nit0 . 191. 5
4
1
0 . 5A ET 







40. Example 2: AET Determination For An Artificial Disc Implant
AET in µg/mL
SCT 1.5 µg/day, assumes long term (>10 yrs. to lifetime), based on stringent SCT for mutagenic chemicals
UF Uncertainty Factor
Dext 2.47 Devices in extraction volume of Vext - Extract one 43 cm2 prototype; clinical device = 17.4 cm2
Dc 0.236 no. of devices used per day – equivalent fraction of total leached during first 24 hours of clinical use
(at 37◦ C). Model assumes 72-hour initial extraction NVR = 1.0 (nominal amount); 2nd extraction NVR = 0.3;
final extraction NVR = 0.1. Hence, total leached = 1.4; leachables in first 24 hours = 1/3 of 1.0 = 0.33, so
the fraction leached = 0.33/1.4 = 0.236.
Justified by ISO 10993-18: “Leachables can, in some cases, be determined by mathematical models as well
as tests.” Furthermore, draft ISO guidance for Application of the TTC states, “if sequential extractions
demonstrate that the amount of leachable chemicals change over time, then the 24-hour window with
peak exposure should be used.”
Vext 34.4 mL = 43 cm2 / 1.25* cm2/mL
*SA-Vol. ratio for an elastomer
S C T
VD
D
UFA ET
extc
ext









41. The Case for Worst-Case Risk Assessment:
W henExposureispredictablyT rivial

42. Screening TRA: A Worst-Case Exposure Assessment
•We don’t always need data …although a very conservative approach
•Conservative = Certain to overstate exposure and toxicity
•Useful for eliminating concern, where applicable
•Should have a sound basis for estimating an approximate release of
leachable chemicals, e.g., literature values?
•Utilizes the TTC (Toxicological Threshold of Concern): A safe dose for
any chemical
Concept: Small Device = Small Exposure
Sometimes TooS mallto be a Concern

43. Case Study: A Dental Cement Made From A Resin Composite
Background
•Cement applied in thin layers as a bonding agent for veneers, crowns, inlays, and onlays
•Device classification: Permanent implant
•Composition in mass percent: 13 ingredients, must assess each material for toxicity and history of safe use
Evaluation of a Worst-case Scenario
•Assume 150 mg of material is applied, which is comprised of 31% resin, or 47 mg.
•Cured resin - Literature studies report that ~2.5% of the total resin mass leaches over 30 days, or 1.2 mg
•Studies of resin toxicity report NOAEL of 100 mg/kg-day. Using BW = 70 kg & UF = 300, yield TE = 23 mg/day
•The calculated TE is 590X greater than estimated potential daily intake of 39 µg/day (1.2 mg resin/30 days)
•Non-resin ingredients – The highest non-resin ingredient is 1% of 150 mg, or 1.5 mg, 2.5% of which = 38 µg
•Dividing by 30 days exposure yields 1.3 µg/day exposure. This is less than the 1.5 µg/day most stringent TTC
Conclusion
•Risk from leachables released from any individual ingredient is unlikely to be of toxicological concern
•Leachability of 2.5% is based on previous studies with similar material

44. Case Study: An Optical Sensor On An Intravascular Pump
Background
•Device classification: External communicating device having direct contact with circulating blood
for a prolonged duration
•Total mass of a silicone coating: 3.1 µg
Evaluation of a Worst-case Scenario
•Part 1: Assume daily exposure to silicones as leachables is < 1% of the total mass (0.031 µg/day)
•Well below applicable TTC (150 µg/day)
•Part 2: Assume that the silicone contains a maximum plausible 10% level of a toxic leachable
•Assuming the same 1% leaching rate per day, this equates to 0.0031 µg/day; below the applicable
TTC of 5 µg/day
Conclusion
•Risk from leachables is unlikely to be of toxicological concern
•Leachability of 1% is based on NVR data, which was correlated with release of siloxanes

45. Resorbable Products: A Case For Bulk Material Analysis
•Test article: Polyglactin sutures
•Completely absorbed within 45 days
•Standard “extractables” study may not yield the right data
•Data will represent the initial (72-hour) release (X) from fresh material
•Will likely have to assume that a daily exposure of 1/3 of the measured
amount will continue for entire 45 days: Total exposure will be 15X ??
•Proposal: Exhaustive extraction, analyzing total content of target analytes
•Better measure of total patient exposure
•Total releasable amount is divided by 45 (days) to approximate
an average daily exposure. Exhaustive extraction will likely show
an asymptotic depletion curve, so this avoids over-estimating risks.

46. Case Study: Gas Flow Pathway - Volatiles Released vs. Time
Simulated use, 48-hr. gas flow analysis by GC/MS
ISO 18562 recommends
sampling at intervals
over the clinical
duration of use.
Results are used in the
Toxicological Risk
Assessment according
to ISO 18562-1.

47. Gap Analysis For Implanted Device
Sponsor wants to know if chronic toxicity and carcinogenicity studies
are necessary?
•Review biocompatibility data
•Are studies GLP compliant?
•Do they provide high-quality, relevant data?
•Evaluate device classification based on intended uses, nature of
patient exposure, and consult FDA biocompatibility test matrix
•E/L data: Consider toxicology of any known or identified constituents
•Make recommendations

48. ToxSmart: More Than Risk Assessment!
• Toxicological Risk Assessment
• Assistance with the design of E/L studies
• Toxicological Evaluations of Materials or Specific Additives/Impurities
• Literature search and review
• Biocompatibility Test Program Review
• Retrospective (Gap-Analysis)
• Forward-looking (Program design)
• Sponsor: “We have all this test data, but don’t know where we stand”
• Custom study design
• Third-party Review of E/L Data or Risk Assessments

49. Questions?
Thank You!