Satisfying ISO and US FDA Biocompatibility requirements for Breathing Gas Pathways in Healthcare Application

Satisfying ISO 18562 and US FDA Biocompatibility requirements for Breathing Gas Pathways in Healthcare Application Audrey Turley, B.S., RM (NRCM), CBA Biocompatibility Expert 801-290-7907 aturley@nelsonlabs.com

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ISO 18562 Standards for Presentation Biocompatibility evaluation of breathing gas pathways in healthcare applications ISO 10993 Suite US FDA guidance document Standards that cover all testing under Biological evaluation of medical devices Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1 (June 16, 2016) 4

Biological Safety Evaluation Biological Evaluation Plan (BEP): What are your risks and how do you plan to mitigate them? Testing and risk assessments Biological Evaluation Report (BER): Is the device safe? 5

Analyzing RISK ISO 18562 is intended as a guidance to determine the potential biological risks. Meaning, what is the risk of the materials and processes to the patient? ISO 18562 Part 1: Evaluation and testing within a risk management process 6

Section III. Risk Management for Biocompatibility Evaluations Such a process should generally begin with assessment of the device, including the material components, the manufacturing processes, the clinical use of the device Considering this information, the potential risks from a biocompatibility perspective should be identified. Considering the potential biological impact, a plan should be developed either by biocompatibility testing or other evaluations that appropriately address the risks. 7

Incorporating Risk What is Risk? ISO 14971 Definition: Combination of the probability of occurrence of harm and the severity of that harm. 8

Biological Evaluation Plan (BEP) Identify Risks Use Figure 1 in ISO 10993-1 9

Device Categorization US FDA Indirect contact term used for a device or device component through which a fluid or gas passes, prior to the fluid or gas coming into physical contact with body tissue (in this case the device or device component itself does not physically contact body tissue). ISO 18562 Testing under indirect tissue contacting categorization according to ISO 10993-1 leads to insufficient assessment of gas pathway devices (Introduction, pg. v). 11

ISO 18562 Biocompatibility evaluation of breathing gas pathways in healthcare applications ISO 18562-1: Evaluation and testing within a risk management process ISO 18562-2: Test for emissions of particulate matter ISO 18562-3: Tests for emissions of volatile organic compounds (VOCs) ISO 18562-4: Tests for leachables in condensate RISK EVALUATION PARTICULATES VOCs CONDENSATE 12

ISO 18562 Additional risks covered in ISO 18562 (Figure 1). 13

Biological Evaluation Plan (BEP) What should be included in a BEP? Material Characterization Suppliers Patient contact Specification sheets Testing information on raw materials Device description and categorization Puts everyone on the same page Include pictures Special Test Sample Preparations Master product Absorption capacity Parts to include or exclude Cut/don t cut Testing and risk assessments Identify tests to perform based on risk to patient Include conversation of areas where there is no risk 14

Test Selection Dry Air Pathway Humidified Air Pathway 18562-2: Particulates in air 18562-3: VOCs in air SVOCs in air may be required* 18562-4: Condensate VOCs in water Metals in water 17

Test Sample Selection Processes and sterilization ISO 10993-1, 6.2.1 a) Testing shall be performed on the sterile final product, or representative samples from the final product or materials processed in the same manner as the final product (including sterilization). Raw Material Finished device 18

Particulates ISO 18562-2: Tests for emissions of particulate matter Required for Dry Air pathway devices 3 test options Single particle filter Inertial particle separators Particle counter FDA has requested NIOSH Manual of Analytical Methods (NMAM) 0500 (with 2.5 µm filter) 19

Particulates Limits set according to US EPA 40 CFR Part 50 SIZE LIMIT 2.5 µm (0.2-2.5 µm. Does not address nanoparticles) 12 µg/m 3 10 µm 150 µg/m 3 *smaller particles are more toxic and penetrate further can even be absorbed into the blood stream.

Volatile Organic Compounds ISO 18562-3: Tests for emissions of volatile organic compounds (VOCs) Required for Dry Air Pathway devices FDA requests TO-15 (EPA Canister method analyzed by GC/MS) 21

Volatile Organic Compounds Reference ASTM D5466-01 Test method to determine VOCs in atmospheres (canister sampling) Acceptance Criteria Need a toxicologist to assess results TTC: Threshold of Toxicological Concern 22

Condensate ISO 18562-4: Tests for leachables in condensate Required for all humidified air gas pathway devices Test methods is 18562 This section is anticipated to be rewritten Recommend to run a full extractables and leachables (E&L) panel according to ISO 10993-18 *Testing approach can be verified through a BEP 23

How Does E&L Work: Extraction Conditions Extraction conditions are per ISO 10993-12 standards: Temperature and time: 50 C for 72 hrs Extract solvent: water

How Does E&L Work: What are we looking for? Inorganic (not carbon based) ANY Substance Organic (carbon based) We cast a wide net, looking for a variety of compounds Metals Do not evaporate easily, great for LC Volatile Organics (VOCs) Semi-Volatile Organics (SVOCs) Non-Volatile Organics (NVOCs) Evaporates easily, great for GC

How Does E&L Work: Chromatography Gas chromatography (GC) and liquid chromatography (LC)

How Does E&L Work: Mass Spectroscopy USP 29 monographs 27

Analysis of Results

Toxicological Risk Assessment According to ISO 10993-17 Determine chemistry results in mg/device Research the tox data available for each compound (NOAEL or LOAEL) Per ISO 10993-17, calculate TI TE MOS NOAEL/LOAEL: No Adverse Effect Level / Lowest Adverse Effect Level TI/TE: Tolerable Intake / Tolerable Exposure MOS: Margin of Safety

Example Calculations TTTT = NNNNNNNNNN UUFF 1 UUFF 2 UUFF 3 = XXXX µg/m 3 day TTTT = TTTT iiiiiiiiiiiiiiiiiii rrrrrrrr UUUUUU = XXXX µg/day Margin of Safey = TE Exposure = XXXX NOAEL/LOAEL: No Adverse Effect Level / Lowest Adverse Effect Level TI/TE: Tolerable Intake / Tolerable Exposure µg day XXXX µg day = XXXX MOS >1 low toxicological hazard UF1: Inter-individual variation among humans (default 10) UF2: Extrapolation of effects between animals and humans (default 10) UF3: Quality and relevance of experimental data 30

Conclusion This risk assessment was supported by information gathered from chemical characterization testing data on the device, published literature, and the derived margins of safety of the compounds detected from the device. This risk assessment indicates that the likelihood of adverse effects from the device is considered low for all compounds.

Additional Considerations Possible follow up analytical testing needed to demonstrate safety of the device For components that touch the skin of the patient, test according to ISO 10993-1 categorization: surface device, skin contact. Testing includes cytotoxicity, irritation, and sensitization.

Cytotoxicity Results Negative Score 0 33

Cytotoxicity Results Positive Score 4 34

Cytotoxicity GRADE REACTIVITY DESCRIPTION 0 1 2 3 4 None Slight Mild Moderate Severe Discrete intracytoplasmic granules, no cell lysis. Not more than 20% of the cells are rounded, loosely attached, and without intracytoplasmic granules; occasional lysed cells are present. Not more than 50% of the cells are rounded and devoid of intra cytoplasmic granules; no extensive cell lysis and empty areas between cells. Not more than 70% of the cells are rounded and/or lysed. Nearly complete destruction Pass Fail

Irritation Injection Extracts on 5 sites on right (test) and 5 other sites on left (control) Observation Data Interpretation Results Sites are observed for 24, 48, and 72 hours post injection and given an irritation score (0-4) or erythema and oedema. After the 72 hours, all the scores are added then divided by 15 (3 time points X 5 injection sites); then the scores from the rabbits will be added and divided by 3 The test article is considered a non-irritant if the difference between the test article and control mean score is 1.0 or less 36

Guinea Pig Maximization Sensitization Local Lymph Node Assay (LLNA) Buehler method (direct) 37

Sensitization LLNA TAT of 6 weeks Objective, quantitative data Not recommended for metals or known irritants Guinea Pig Maximization TAT of 8 weeks Subjective, qualitative data Use for metals and high molecular weight substances that do not penetrate the skin 38

Biological Evaluation Report CONCLUSION: Based on the testing results and information summarized in this report, the DEVICE is biocompatible and meets the requirements of ISO10993-1:2009: Biological evaluation of medical devices Part 1.

THANK YOU! Audrey Turley, B.S., RM (NRCM), CBA Biocompatibility Expert 801-290-7907 aturley@nelsonlabs.com