Material

Characterization

Overview
ISO10993-1:2003(E) Section 3.3
The following should be considered for their
relevance to the overall biological evaluation of
the device Material(s) of Manufacturer,
Intended additives, process contaminants, &
and residues, Leachable substances,
Degradation products, other components and
their interactions in the final product and the
properties and characteristics of the final
product

Our Goals
To assist in establishing biocompatibility of a
Medical Device by identifying and quantifying
the chemical constituents of the materials
Develop compliant & cost effective One Shot
Analyses meeting multiple requirements
outlined in the ISO10993 Standards
Minimize the number of devices for testing
Support process control in manufacturing

Importance of Testing
Demonstrate equivalency of proposed materials
to a clinically established material
Demonstrate equivalency of device to a
prototype
Material selection
Material degradation
Assessment of overall biological safety of a
medical device (ISO10993-1 & 14971)
Vendor changes
Quality control on incoming raw materials
Chemical correlation to physical testing
Process validations

Definitions
Exhaustive Extraction Extraction until the
amount of the residues in a subsequent
extraction is less than 10% of that detected in
the first extraction
Simulated-use Extraction Extraction for
evaluating the potential risk to the patient or user
during routine use of a device using and
extraction method with an appropriate medium
that simulates product use
Definitions from ANSI/AAMI BE83:2006 Biological Evaluation of Medical
Medical Devices
Part 18 Chemical Characterization of Materials

Definitions
Extractable Soluble substances removed from
material when treated with solvent
Leachable Chemical removed from a medical
device by the action of water and other liquids
related to the use of the device
Definitions from ANSI/AAMI BE83:2006 Biological Evaluation of Medical
Medical Devices
Part 18 Chemical Characterization of Materials

Information to Collect Before

Testing
Select the appropriate analytical method to provide
the required information for toxicological evaluation
qualitative or quantitative
Material Composition
- base material
- additives and processing aids
Polymerization / crosslinking / curing processes
Fabrication process and additives used to assist
fabrication
Cleaning & washing processes
Packaging & storage processes

Potential Sources of
Extractables/Leachables
Additives Stabilizers, Plasticizers, Modifiers
Process Mould Release Agents, Anti-static
and Anti-slip agents
Lubricants Oils and Degreasing Agents
Accelerators
Monomers and Higher MW Oligomers from
incomplete polymerization
Residual Solvents
Degradation Products Temperature,
Absorption, Hydrolysis, Oxidation, Corrosion or
Dissolution

Examples of Qualitative &

Quantitative Parameters

Qualitative Test Methods

If extractables / leachables are not known,
perform screening methods to assess
materials
- USP<661> Physicochemical Test (NVR, Residue on
Ignition, Heavy Metals, Metals <231>, and Buffering Capacity)

- GCMS Searchable Libraries

- FTIR Low Resolution
- Headspace Technology
GCMS
FTIR High Resolution

Physicochemical Test
Good Starting Point
A group of tests to characterize plastic
components of pharmaceutical containers
and medical devices
Perform extractions with polar and nonpolar solvents (e.g. H2O, IPA, & heptane)
Determines presence of soluble
substances without regard to the identity
Volatiles are not detected

FTIR Low Resolution

Fingerprints Materials
When compared to a
known standard can
be used to identify a
material
Provides Qualitative
not Quantitative

FTIR Static Headspace (SHS):

Outgassing Profile
FTIR Static HS Gas Cell
IR Source

Total Cumulative
Outgassing vs Time

SAMPLE

Absorbance Units

FITR Spectra

Concentration

IR Detector

Time

Dynamic Headspace
Volatile and SemiSemiVolatile Compounds
Residuals

Oven (25 oC to 250 oC)

Contaminants

N2 Flow
SemiVOCs

Sample is placed inside

the oven manifold

Resulting
Chromatogram

VOCs

VOCs

SemiVOCs

Sample is sealed in a leak free

Teflon Sample Chamber

Thermal Desorption
(TD)
Trapping Tube

TD Tube
is Analyzed

Advantages of Headspace
Analytes are concentrated No Solvents
Ability to analyze Volatiles and non-Volatiles
(including acid and bases)
-Residuals Solvents
-Plasticizers
-Additives
-Phthalates
Shorter testing times than solvent extraction
Good Searchable Libraries
Methods can be validated for quantification

Quantitative Test Methods

If extractables / leachables are
known, quantitative methods provide
actual concentrations
Methods must be validated
- ICH Q2(R1)
- USP <1225>

Search literature for published

methods

Example of Extractable Analysis

Polymer A + Chemical B Yields
Finished Product C
Need to quantify the residuals from
polymer A and Chemical B to
demonstrate purity.

Approach
Search literature, which reveals that aldehydes, organic
acids, oligomers, and polymer may be present as
residuals
Screened samples using FTIR (high resolution)
Extract finished product at 37oC for 24 Hours in Water,
IPA, and Heptane (ISO10993-12)
Develop GC-ECD method for residual aldehydes
Developed Static GCMS method for residual organic
acid
Run Gel-permeation chromatography GPC to look for
MW distribution of residual polymer
Run LCMS to look for high MW oligomers
Total time ~2 to 3 weeks

Database of Materials

Example of Leachable Analysis

A proposal to reduce the allowable limit of
ethylene oxide residuals by a factor of 5
was made to the ISO community.
Current analytical challenge: The current
analytical technology is not sensitive to
support the limit change
Current technology will increase the
analysis cost to manufacturer by up to 5X
for devices alone.

Approach
Evaluated sensitivity Static of FTIR
Demonstrated equivalency of GC-FID
SPEMI and FTIR (SS, PeBax,
Polyproplyene, multicomponent polymer)
Performed exhaustive and simulated use
comparison
Presented to AAMI for approval
Currently validating the method

FTIR Advantages
FTIR Provides simultaneous analysis EO,ECH, EG (ISO
10993-018)
Increased sensitivity

EO sensitivity to ~3ug
ECH sensitivity to ~8ug

Reduced testing time for exhaustive analysis

Rate of release can be measured, calculated
Other leachables are quantifiable in gas phase
Non-destructive, vapor can be purged from system for
further analysis, and Device may be used for additional
extractions.
Minimal handling and the entire device is sampled

Analytical Capabilities
GCMS, GCFID, GCECD, GCTCD
HPLC-UV,-RI,-DAD, LCMS, LCMSMS
FTIR Liquid and Gas Phase
Headspace Dynamic and Static
Ion Chromatography
Inherent Viscosity
GPC
Permeability Testing
Dissolution