Colorants in Medical Devices:

Colorants in Medical Devices: The Spectrum of Current Regulatory Expectations John Iannone Program Manager/ Technical Specialist

Overview» Company Introduction» Why use Colorants in Devices?» Regulatory Testing Considerations» So now What s the Big Deal, again?» Meeting Regulatory Expectations 1

TOXIKON COMPANY PROFILE» C.R.O. Headquarters: Bedford, MA» European Lab Facility: Leuven, Belgium» Nearly 40 yrs of experience in Medical Device & Pharma Industry Biocompatibility Material Characterization (E&L) Toxicology Microbiology» FDA Registered» ISO 17025 Accredited» GLP & GMP Compliant testing» > 150 Researchers 2

Colorants in Medical Devices

Colorants in Devices 4 CONFIDENTIAL

Colorants in Medical Devices» Medical Device Manufacturers have many uses for including Pigments & Colorants in Medical Devices.. Improvement on Ease of use Identification of product type/ size/ etc. Marketing and visual appeal Opacity/visualization» FDA requires all Devices to be Safe Biocompatibility (ISO 10993)» Any change in additives can have an impact on Biocompatibility Why? 5

Biocompatibility» Simplest Viewpoint: Material is biologically compatible by not eliciting a local or systemic response from a living system or tissue.» Regulatory Viewpoint: Series of tests used to identify potentially adverse reactions of material/device contacting the body. The leachates of a device, or the device itself, should not produce adverse local, systemic, tumorgenic, reproductive, or developmental effects. 6

Test Article Preparation for Biocompatibility Testing» In biocompatibility testing for regulatory submission, test articles should be finished devices ready for the market» Most tests are performed with extractions created from the finished device (ISO 10993-12)» Extractions should occur at the highest feasible temp/time condition the regulations provide as options (ie. 70⁰C/24 hrs)» Polar & non-polar extraction vehicles are required (solubility) Utilized to mimic various environments in the body 7

Biocompatibility of Material/Devices ISO 10993» Cytotoxicity» Sensitization» Irritation & Intracutaneous Reactivity» Acute Systemic Toxicity» Subacute & Subchronic Systemic Toxicity» Genotoxicity» Implantation Reactivity» Hemocompatibility» Chronic Systemic Toxicity» Carcinogenicity 8

Leachate Migration/ Extraction Polymer Migration Extraction Solution Environment of Concern 9

Biocompatibility & Material Characterization» Biocompatibility per ISO 10993-1 Assess Specific Mechanisms for Biological Reactivity Material Focused Typically polymeric devices are extracted in assay Extractables/Leachables Determine leachates pre/post interactions between material, sterilization, aging, environmental effects Characterize WHAT may be of a safety concern - Material Selection - Submission Support» Toxicology per OECD, ISO etc. Toxicological effects of drug, biologic, chemical entity Evaluation of leachates found during product use to demonstrate safe and allowable limits 10

So what is the Big Deal?

FDA Position on Color Additives for Medical Devices» Under certain conditions, color additives in medical devices are subject to the same provisions that apply to color additives in foods, drugs and cosmetics. The Food, Drug and Cosmetic (FD&C) Act states that devices containing a color additive are considered unsafe, and thereby adulterated, unless a regulation is in effect listing the color additive for such use. The FD&C Act limits applicability of these provisions to color additives that directly contact the body for a significant period of time. At the present time, the term a "significant period of time" is not defined by FDA regulation.» For the purposes of enforcing adulteration provisions under the FD&C Act, unless the color additive and its use conform to a listing regulation under Title 21 of the Code of Federal Regulations (CFR) Parts 73 and 74, including any provision of such regulation prescribing the conditions under which the color additive may be safely used. The color listing regulation may permit use of the color additive in a generic type of device, such as contact lenses, or may place limitations on its use, such as polypropylene nonabsorbable sutures for general surgical use but not for ophthalmic surgical use.» A color additive subject to the provisions under section 721 of the FD&C Act is deemed unsafe The 21 CFR Parts 1 to 99 (includes Parts 70,71,73,74 & 80) 12

FDA Position on Color Additives for Medical Devices» Draft Guidance for Industry and Food and Drug Administration Staff issued in April of 2013 Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing Section 7: Assessment of Known or Potentially Toxic Chemical Entities For chemicals used in a device for the first time, or for chemicals with known or potential toxicities (e.g., color additives, or drugs used in combination products), additional information should be provided to determine whether toxicology information beyond standard biocompatibility testing is needed 13

Extractables and Leachables Sources COMPOSITION OF COMMERCIAL POLYMERS o Additives o Residues o Oligomers o Degradation Compounds from Polymers o Degradation Compounds from Polymer Additives 14

Extractables and Leachables Sources Anti-Oxidants Plasticizers Photostabilizers Slip Agents Antiozonants Coupling Agents Lubricants Acid Scavengers Peroxides / Crosslinkers Blowing Agents Pigments/Colorants Antistatic Agents Metal Chelators Adhesives Bactericides Clarifying Agents Antifogging agents Fillers (Red: coming with some examples) 15

Extractables and Leachables Sources Pigments / Colorants Function: Gives the polymer/material the desired color Carbon Black (PNA s!) TiO 2 (white) Fe 2 O 3 (red) Pigment Green 07 Solvent Red Solvent yellow 114 Solvent Green 03 Colorants have unique formulations: Include Ink/Pigment, Carrier, etc 16

Leaching of Additives Diffusion 17

Understanding Extractables & Leachables

MATERIAL QUALIFICATION/BIOCOMPATIBILITY/E&L SOURCES OF LEACHATES» Polymer Additives Antioxidants, Slip Agents, UV Stabilizers, Plasticizers, Colorants» Polymer Degradation Products Sterilization, Storage, Processing» Residues Monomers, Catalyst, Solvents» Manufacturing Impurities Cleaners, Hydrocarbons» Migration from Secondary Contacting Material Adhesive, Ink, Multi-film, Nonhomogeneous Material, Packaging 19

Extractable/Leachable Sources Potential Inorganic Compounds of concerns Metals If you don t look for it, you won t find it! 20

Analytical Methods for E&L Determination FIRST PASS Testing for Extractable Studies Try to Fully Characterize the Extraction Profile of material, using: Standard Analytical Equipment, e.g. 1. Headspace GC/MS 2. GC/MS 3. LC/MS 4. ICP 5. Ion Chromatography Optimized Procedures & Procotols» Leverage Compound Database (ie:tox-ray) for First Pass Analytical Techniques built on expertise & high volume of studies allows high level ID in First Pass Standardized Methods combined with Targeted Analysis Efficiency/Cost effectiveness is Key in FIRST PASS Experiments

Understand what is happening Extractable Testing» Identify the potential compounds extracted into model solvents under aggressive conditions» Determine which, if any, compounds may affect patient or product Leachable Testing» Measure actual amount of leached compounds as a function of time» Determine How Much of What is present and: Does exposure to the patient affect safety? Tox Assessment 22

Risk Assessments

Risk Assessment of Medical Devices 2 complimentary, but not overlapping, areas that the Sponsor is expected to evaluate via risk assessment ISO 10993-1 (2009) Evaluation and testing within a risk management process ISO 10993-17 (2002) Establishment of Allowable Limits for Leachable Substances 24 CONFIDENTIAL

Risk Assessment of Medical Devices ISO 10993-1 Determines safety of proposed device & recommends testing as needed from ISO/FDA requirements» Evaluate device materials (component breakdown)» Consider history of clinical use» Identifies data gaps Performed at the beginning of device development, often to guide material selection & test program 25 CONFIDENTIAL

Risk Assessment of Medical Devices ISO 10993-17 Used as a follow-up to extractables and/or leachables testing (ISO 10993-18)» Review safety information for all identified compounds» Set limits of safe exposure» Compare limits to amounts seen in E&L data Can be used to give a green light to continued product development once extractables are identified 26 CONFIDENTIAL

So which Colorants are considered acceptable? Approved for Specific Uses with Batch Certification 27 CONFIDENTIAL

So which Colorants are considered acceptable? Approved for Specific Uses Batch Certification Exempt 28 CONFIDENTIAL

Options in Meeting Regulatory Expectations» Full Biocompatibility on each Device Configuration (every color) & Technical Evaluation of each Colorant» Full Biocompatibility on 1 Device Configuration with Chemical Characterization of each Device Configuration (each color) & Toxicological Risk Assessment of the full package» Full Biocompatibility on 1 Device Configuration with a Toxicological Risk Assessment of additives (each of the colors)» Conduct pooled Biocompatibility on Multiple Device Configuration, with a modified (more aggressive) Extraction ratio that ensures individual configurations are not diluted & Technical Evaluation of each Colorant 29

Conclusion Colorants, Inks, & Pigments, are considered additives in Medical Devices Understanding & full characterizing these additives through Identification, Elution Characterization, & Patient Safety determination will satisfy regulatory expectations/ requirements. Biocompatibility may be leverage along with Chemical Characterization to evaluate more than one device configuration (when only a single difference exists) Toxicological Risk Assessment of Device additives can be sufficient with good info & exaggerating conditions of use. 30

Thank you John Iannone Program Manager john.iannone@toxikon.com 15 Wiggins Ave, Bedford, MA 01730 800-458-4141 x7142 31