Legacy Evaluations. Ensuring your commercialized products meet the current regulations

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Frederick Hoover
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1 Legacy Evaluations Ensuring your commercialized products meet the current regulations

legacy evaluations: the process Gap Evaluation Testing Risk ssessment Scalable Programs Proven Performance TRINING Team training and cross-training to maximize

2 legacy evaluations: the process Gap Evaluation Testing Risk ssessment Scalable Programs Proven Performance TRINING Team training and cross-training to maximize flexibility and meet project timing. OPERTIONS Performance metrics to ensure best practices and consistency. PITY Proactive planning to achieve program goals. 2

gap evaluation METHOD vailable data/reports review urrent standards compared to work performed DELIVERLE: Final Report Summary table of work performed Gap analysis by section Summary table of gaps

3 gap evaluation METHOD vailable data/reports review urrent standards compared to work performed DELIVERLE: Final Report Summary table of work performed Gap analysis by section Summary table of gaps found Recommendation for remediation example Test Test rticle Name Final Report Number ISO Standard References urrent ISO Version ISO L929 MEM Elution ytotoxicity Test : : : :2012 STM Hemolysis ssay Direct ontact Method :2002 STM F : : :2012 ISO Intracutaneous Reactivity Test : : : :2012 ISO Guinea Pig Maximization Sensitization Test : : : :2012 I. Gap nalysis of ISO ISO :2009, Tests for in vitro cytotoxicity is the current version of the standard. The requirements of ISO : 2009 place emphasis on quantitative evaluation of cytotoxicity, the normative section of the standard references the MEM Elution ytotoxicity test. ccording to ISO , extractions are to be conducted per ISO new version of ISO was released in There are many editorial changes implemented in the newer version that have no impact on testing. There were a few changes that were substantive. In reference to cytotoxicity testing, Section now states For medical devices which are in short-term contact with intact skin or mucosa and which are not implanted, extraction times of less than 24 h, but not less than 4 h are acceptable (see ISO ). This now allows for shorter extraction periods for cytotoxicity testing of certain devices. None of the recommendations for extract ratios or conditions have changed. In project reports, the extract ratio and conditions meet the requirements of ISO :2012. No gaps were identified in cytotoxicity testing. II. Gap nalysis of ISO No changes have been made to ISO :2002 since testing was completed. However, this standard does expect use of the most current version of STM Hemolysis standard. The STM standard F was updated in Many of the changes to the method were editorial in nature and did not specifically impact assay performance. The revised document did suggest the use of a cyanmethemoglobin reagent versus the use of Drabkin s for measuring hemoglobin. oth are still considered acceptable, though Drabkin s could have a slightly lower sensitivity to binding hemoglobin. Further, the 2008 version is stronger in its recommendation to test materials in both direct and indirect hemolysis assays. The project was performed as a direct contact assays using Drabkin s reagent. From a technical perspective, the direct contact assay was performed in a manner consistent with the 2008 revision. However, an extract (indirect) version was not performed. The results from the direct contact assay were clearly negative. ased on intended clinical use, the direct method is an appropriate evaluation methodology. 3

4 testing biocompatibility METHOD ased on gap evaluation, select appropriate tests DELIVERLE: Individual Final Reports Methods summary Results Evaluation biocompatibility test matrix DEVIE TEGORIES IOLOGIL EFFET Initial Other SURFE DEVIES ody ontact EXTERNL OMMUNITING DEVIES IMPLNT DEVIES Skin Mucosal Membranes reached or ompromised Surfaces lood Path, Indirect Tissue /one/ Dentin ommunicating irculating lood Tissue / one lood ontact Duration Limited [ 24 hrs] Prolonged [>24 hrs to 30 days] Permanent [>30 days] ytotoxicity Sensitization Irritation Systemic Toxicity (cute) Subchronic Toxicity (Subacute) Genotoxicity Implantation Hemocompatibility hronic Toxicity arcinogenicity TESTS FOR ONSIDERTION Per ISO10993 and FD Guidances = ISO Evaluation Tests for onsideration = dditional tests that the FD considers may be applicable 4

$Methods summary Results chromatograms, spectra, calculated data Evaluation data examples b u n d a n c e 1 6 0 0 0 0 0 T I : 0 9 1 0 1 3 _ R e s e a rc h _ 0 0 4.D \ d a ta.$

5 testing materials characterization METHOD Design extractables study based on product risk Utilize multiple extracts hoose analytical methods based on expected chemicals DELIVERLE: Final Report Methods summary Results chromatograms, spectra, calculated data Evaluation data examples b u n d a n c e T I : _ R e s e a rc h _ D \ d a ta.m s T I : _ R e s e a rc h _ D \ d a ta.m s (*) T im e --> S Name Formula RT Mass Score (MFG) ug/ device Triethylene glycol 6H14O ,6-Diisopropyl-4-((dimethylamino)methyl)phenol 15H25NO arbamic acid, [3-(methylthio)propyl]-, 1,1- dimethylethyl ester 9H19NO2S Phosphorous acid, 2-(2-butoxyethoxy)ethyl 2-(2- ethoxyethoxy)ethyl2-ethoxyethyl ester 18H39O8P is(2-butoxyethyl)ether 12H26O Ethanol, 2-[2-[2-(dodecyloxy)ethoxy]ethoxy]-, hydrogen sulfate 18H38O7S Sulfanyl-3,6,9,12,15-pentaoxaheptadecan-1-ol 12H26O6S Pentacyclo[ ,7.19,13.1,15,19]octacosa (25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-50H70O4P dodecaene-25,26-diol, 5,11,17,23-tetrakis(1, dimethylethyl)-27,28-bis[(dimethylphosphino)methoxy] tri(2-butoxyethyl) phosphate 18H39O7P H54O na Polyethylene glycol (PEG) related fragments (0 28H58O DE) 1 30H62O H66O Octadecanamide 18H3NO

6 risk assessment METHOD Review available data/reports Review literature and databases alculate risk factors DELIVERLE: Final Report Summary opinion Extractable/leachable data Potential breakdown products, and mechanism by which they are formed omplete chemical formulations Final toxicological evaluation of all available data example of report content Table of ontents pprovals:... 1! 1.0! Executive Summary... 3! 2.0! ackground and Purpose... 3! 3.0! Test rticle / Device Identification... 3! 4.0! Test rticle / Device lassification... 3! 5.0! Test rticle / Device Description... 4! 6.0! hemical haracterization... 4! Table 1: hemical haracterization nalysis Summary... 4! 7.0! General Toxicological Risk ssessment pproach... 4! 7.1! Determination of Tolerable Intake (Hazard Identification and Dose Response ssessment) (General pproach)... 5! Table 2: Use of Modifying Factors (ISO )... 6! 7.2! Exposure ssessment... 6! 7.3! Risk haracterization... 6! 8.0! Databases... 7! 9.0! Risk ssessment of Extractable hemicals... 7! 9.1! Extractables hemicals by G-MS (Hexane Extract)... 8! Table 3: Risk ssessment of Extractable hemicals by G-MS (Hexane Extract)... 25! 9.2! Extractable hemicals by L-MS (IP/Water Extract)... 29! Table 4: Risk ssessment of Extractables by L-MS (IP/Water Extract)... 43! 9.3! Extractable Metals by IP-MS (5% Nitric cid (HNO3) Extract)... 49! Table 5: Risk ssessment of Extractable Metals by IP-MS (5% Nitric cid (HNO3) Extract).. 52! 9.4! Extractable hemicals by HS/G/MS (Water Extract)... 53! Table 6: Risk ssessment of Extractable hemical by HS/G/MS (Water Extract)... 54! 10.0!iocompatibility Testing... 55! Table 7: Summary of iocompatibility Testing... 55! 11.0! Discussion and onclusion... 56! 12.0! References... 57! 13.0! cronyms and bbreviations... 66! 6

examples of typical programs Typical Program for Long-Term Implant in one IOOMPTIILITY ytotoxicity Genotoxicity mes Mouse Lymphoma Mouse Micronucleus Irritation Intracutaneous Sensitization Guinea

7 examples of typical programs Typical Program for Long-Term Implant in one IOOMPTIILITY ytotoxicity Genotoxicity mes Mouse Lymphoma Mouse Micronucleus Irritation Intracutaneous Sensitization Guinea Pig Maximization cute Toxicity Subacute/Subchronic 14-day/14-dose Implantation 2-week, 13-week, 26-week MTERILS HRTERIZTION Extractables Non-Polar Mid-Polar Polar Leachables Dependent on extractables results RISK SSESSMENT Evaluation of iocompatibility Toxicological Evaluation of hemistry Typical Program for Instruments IOOMPTIILITY ytotoxicity Irritation Intracutaneous Sensitization Guinea Pig Maximization cute Toxicity MTERILS HRTERIZTION Extractables Non-Polar Mid-Polar Polar RISK SSESSMENT Evaluation of iocompatibility Toxicological Evaluation of hemistry 7

and timeline management Internal monitoring and troubleshooting Status reporting Quote, budget and invoice management ST.

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MICA Freeform MATERIALS DOSSIER M A T E R I A L S D O S S I E R. Rev.B 1

MICA Freeform MATERIALS DOSSIER M A T E R I A L S D O S S I E R. Rev.B 1 MI Freeform MTERILS DOSSIER Rev. 1 Table of ontents Material Properties page 3 iocompatability page 8 Manufacturing Processes page 33 MTERILS DOSSIER Rev. 2 M T E R I L P R O P E RT I E S Material Data