December 11 th, 2013 Richard W. Hutchinson, DVM, PhD, DABT Johnson & Johnson Global Surgery Group

Transcription

1 December 11 th, 2013 Richard W. Hutchinson, DVM, PhD, DABT Johnson & Johnson Global Surgery Group

2 Agenda Background on Risk Assessment of Medical Devices based on Analytical Characterization Background on TTC Draft Standard Practical application of the TTC approach for compounds released from devices Comparison of SAR packages

3 ISO Part 1 - Evalua7on & Tes7ng within a Risk Management Process The role of this part of ISO is to serve as a framework in which to plan a biological evaluation which, as scientific knowledge advances our understanding of the basic mechanisms of tissue responses, minimizes the number and exposure of test animals by giving preference to chemical constituent testing and in vitro models, in situations where these methods yield equally relevant information to that obtained from in vivo models.

4 ISO

5 FDA- CDRH

6 ISO

7 Threshold Of Toxicological Concern The Threshold of Toxicological Concern is used where there are limited or no data on the compound, but the human exposure is so low that undertaking toxicity studies is not warranted (Renwick, 2004)

8 How TTC Values are calculated

9 Published guidance

10 ICH M7 Less than Life7me Exposure

11 ICH M7 Less than Life7me exposure

12 Pavia Italy April 2013

13 Proposed Default Threshold of Toxicological Concern Values ISO Contact Category Dura7on of treatment Daily intake [μg/day]- any one chemical Daily intake [μg/day]- total exposure to mul7ple chemicals Limited (<24 hr) Prolonged (24 hr to 30 days) Permanent (>30 days) < 1 month >1-12 >1-10 >10 years to months years life7me

14 Hypothe7cal example Supplier A of Component X just went out of business, Supplier B is being considered as an alternative. Component X is made from pure polypropylene Clinically it is placed in contact with open wound Changed every week for up to 6 weeks Both claim to be 95% pure Polypropylene, but will not disclose the other 5 % All other processes and additives will be identical What do you do?

15 FDA- CDRH

16 Hypothe7cal example con7nued Compare a new plastic to a predicate plastic Exhaustive extraction/exaggerated extraction conditions Qualitative/Quantitative analytical analysis LC MS, GC MS, HPLC, NMR Report all new leachables > TTC TTC= 20 ug per individual chemical 60 ug total Sort by concentration and report all above these limits For this example select 15 by random # Generator Jenke 2009 list {656 leachables from medical plastics}

17 Hypothe7cal example con7nued CAS# Common Name IARC Class GRAS Benzene Group 1: Carcinogenic to humans no N- butyl stearate na no ctadecanoic acid na yes Diethylene glycol na no Ethyl palmitate na no ctanone na no ,6,10- Trimethylpentadecane na no Methyl- 4- methylene- hexane- 2- one na no Propionic acid na yes Di- (2- ethylhexyl) phthalate Group 2B: Possibly carcinogenic to humans no Hexanone na no Tricosane na no Bisphenol A glycerolate dimethacrylate na no Bisphenol A bis(2,3- dihydroxypropyl)ether na no ,6,10,14- Tetramethylhexadecane na no

18 ChemID

19 DEREK

20 Tox Tree

21 QSAR Toolbox

22 ToxTree (Genotoxic/ nongenotoxi c Hypothe7cal example 6: DEREK Alert (s) Mutagenicity QSAR Toolbox (in vitro SARAH Tox Tree (In QSAR Genetox vitro Tox Tree (in QSAR QSAR Toolbox (in mutagenicity Alert (100% Tox Tree mutagenicity vivo Toolbox Toolbox vitro - confidence (Cramer (Ames test) carcinogenici micronucleu (Carcinogeni (Ames, MN, mutagenicity micronucleu CAS of nega7ve) Class) alerts by ISS) ty by ISS) s) city) CA by OASIS) - ames) s) Carcinogenic ity 100 III no nega7ve no no no no no no none 99 I no nega7ve no no no no yes no none 100 I no nega7ve no no no no yes no Bone Marrow Tox, Nephrotoxici ty 100 I no nega7ve yes no no no yes no none 99 I no nega7ve no no no no yes no none 77 II no nega7ve no no no no no no alpha 2 glob 38 I no nega7ve no no no no no no chromosoma l damage 1 I yes genotoxic Carcinogen yes yes no yes yes yes Carcinogenic ity, GI Irrita7on 100 I no Teratogenicit y, tes7culat toxicity 100 I no QSAR Toolbox (Oncologic) non- genotoxic Carcinogen no no no no yes no non- genotoxic Carcinogen yes yes no no yes no none 77 I no nega7ve no no no no no no none 97 I no nega7ve no no no no no no Chromosom al Damage, Eye irrita7on, Skin Irrita7on, Sensi7za7on 100 III no nega7ve yes no no no yes yes Nephrotoxici ty 100 III no nega7ve yes no no no yes no alpha 2 glob 38 I no nega7ve no no no no no no

23 Hypothe7cal example con7nued CAS Tox Tree (Cramer Class) Tox Tree Tox Tree (Skin (Skin QSAR Toolbox Irrita7on) Sensi7za7on) (eye irrita7on) QSAR Toolbox (Sensi7za7on) III unknown no no no no I irrita7ng no no no yes I irrita7ng no no no no I irrita7ng no no no no I irrita7ng no no no yes II irrita7ng no no no yes I unknown no no no no I irrita7ng yes no no yes I irrita7ng no no no yes I no no no yes no I irrita7ng no no no yes I unknown no no no no QSAR Toolbox (Skin Irrita7on) III no yes no yes no III no no no no no I unknown no no no no

24 Hypothe7cal Example Conclusions Known Human Carcinogen only flagged by DEREK and Cramer Models {Tox Tree} GRAS Compounds overpredicted #1: QSAR Toolbox predicted was mutagenic #2: DEREK, Tox Tree and QSAR Toolbox all predicted was carcinogenic Skin Irritation molecules not very discriminating up to 12/15 positives- dose response QSAR Toolbox models tended to be all positive or all negative DEREK and Tox Tree modules tended to have similar results

25 Hypothe7cal example next steps CAS DEREK Alert (s) Carcinogenicity III none I none I Bone Marrow Tox, Nephrotoxicity I none I none II alpha 2 glob I chromosomal damage I Carcinogenicity, GI Irrita7on I Teratogenicity, tes7cular toxicity I none I none I Tox Tree (Cramer Class) Next steps- Individual risk assessment for each as per ISO E.g. for benzene the cancer slope factor is 77.5 mg/kg/day Chromosomal Damage, Eye irrita7on, Skin Irrita7on, Sensi7za7on III Nephrotoxicity III alpha 2 glob I

26 Conclusions Chemical Characterization is a useful tool for Risk Assessment of Medical Devices ICH M7 TTC values are the most current and widely accepted ISO TC 194 has drafted an international standard describing this process DEREK and Tox Tree- Cramer Class seem to be the most useful SAR packages for medical devices.