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V.

Physical and Chemical Testing

According to the harmonized standard EN ISO 10993-1 "Biological evaluation of medical devices -
Part 1: Evaluation and testing" the evaluation of the biological risk of medical devices must also take
into account the non-biological attributes and properties of any materials used in a particular medical
device. This includes chemical, physical, electrical, morphological and mechanical properties.

For the material characterization of new medical devices EN ISO 10993-18 "Biological evaluation of
medical devices - Part 18: Chemical characterization of materials " was issued as a guideline. The
material characterization supports the manufacturer at an early stage to evaluate the critical proper-
ties or chemical substances. Furthermore, during the development of new products an identification
and quantification of possible degradation products has to be performed in accordance with EN ISO
10993-9, EN ISO 10993-13 (polymers), EN ISO 10993-14 (ceramics) and EN ISO 10993-15 (metals
and alloys).

After launching new devices accompanying inspections are necessary. This may include inspections
of raw materials, in-process controls, final inspections of the product (e.g., residual monomer content,
'fingerprint' of extractable substances, sterilization residues) as well as tests of packaging materials.

Subsequently we have provided an overview for several physico-chemical tests which are stipulated in
the aforementioned standards. The main focus of this overview is the material characterization ac-
cording to EN ISO 10993-18.

1. Material Characterization of Medical Devices

'mdt' developed a matrix (see table below) which helps to determine a suitable series of tests which
need to be performed in order to appropriately characterize newly developed materials. This matrix
shows similarities with the matrix for the biological evaluation of medical devices according to EN ISO
10993-1 (see Chapter I). The matrix for the material characterization is intended as a guide. However,
the actual tests to be performed have to be identified with the medical device and its intended use.

According to EN ISO 10993-18 the material characterization helps the manufacturer to collect impor-
tant information with the following goal:
• Assessment of the overall biological safety of the medical device

• Identification and, if applicable, quantification of all extractable substances in order to allow a toxi-

cological risk assessment

• Judging equivalence of a proposed material to a clinically established material

• Judging equivalence of the final device to the already tested prototypes

• Screening and selection of potential new materials with special technical or clinical properties

• Identification of batch-to-batch material variations and comparison of raw material of different sup-

pliers

In principal, material characterization may include investigations of the raw materials and the final
products. Physical and mechanical tests as well as surface analyses are carried out directly on the
product. The chemical composition analysis and the determination of the molecular weight parame-
ters are performed after dissolving the material in a suitable solvent. In order to determine the extract-
able substances the product must be extracted with suitable solvents (e.g., according to EN ISO
10993-12 or USP) and these extracts are finally analyzed.

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Medical Device Category

Material Characterization Test Procedure

Analysis of

O

rganic

Substances

Analysis of

Inorganic

Substances

Physical/

Mechanical

Tests

Molecular

Weight

Distributions

Morphological

Thermal

Ana

ly

s

is

Nature of Body Contact

Physicochemical Tests

FT-IR

GC/

M

S

HPLC/DAD

FT-IR

ICP

XPS / AES

Mechanical Tests

Specific G

ravity

H

a

rdness

GPC

Viscosity

SEM

or SEM

-EDX

DSC

E

M

E

1

E

1

E

1

E

1

E

1

Skin

E

1

E

M

E

1

E

1

E

1

E

1

E

1

Mucosal Mem-

brane

E

1

E

M

E

1

E

1

E

1

E

1

E

1

Surface Device

Breached or

Compromised

Surfaces

E

1

E

M

E/M E/M E/M E/M

M

M

E/M

M

2

M

Blood Path Indi-

rect

E/M

M

E

M

E/M E/M E/M E/M

M

M

E/M

M

2

M

Tissue, Bone,

Dentin

E/M

M

E

M

E/M E/M E/M E/M

M

M

M

M

M

M

M

E/M

M

2

M

M

External

Communicating

Device

Circulating Blood

E/M

M

M

E

M

E/M E/M E/M E/M

M

M

M

M

M

M

M

E/M

M

2

M

M

Tissue, Bone

E/M

M

M

E

M

E/M E/M E/M E/M

M

M

M

M

M

M

M

E/M

M

2

M

M

Implant Device

Blood

E/M

M

M

Polymeric Material

Metal

Ceramic

E

Extractables, quantitative determination

E

1

Extractables, qualitative 'Fingerprint'

M Material

M

2

Material, only present as coating

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The aforementioned material characterization test procedures include the following tests:

Physicochemical Tests:

These tests, which are performed according to USP and Pharmcopeial Forum, supply first non-
specific information with regard to the amount of water-soluble substances (extraction with water) and
solvent-soluble substances (extraction with isopropanol). These tests are also suitable to compare
materials of different manufacturers or different production lots.

FT-IR (Fourier-Transformed Infrared Spectroscopy):

This technique is useful to identify organic substances or to prepare a product fingerprint.

Analysis of Organic Substances:

Non-extractable organic substances can be identified and, if applicable, quantified after dissolving the
polymer in a suitable solvent using the following analysis techniques:

-

Gas chromatography equipped with a mass selective detector (GC/MS): separation technique
for volatile and semi-volatile organic substances

-

High performance liquid chromatography equipped with a diode array detector (HPLC/DAD):
separation technique for non-volatile and thermally fragile organic substances

-

Fourier-transformed infrared spectroscopy (FT-IR)

Extractable organic substances are analyzable after a suitable extraction with one of the aforemen-
tioned analysis techniques.

Analysis of Inorganic Substances:

The composition of metals and ceramic materials can be determined using an ICP spectrometer (in-
ductive coupled plasma). With this spectroscopic analysis technique it is also possible to determine
even small amounts of inorganic substances (like metal ions) present in polymers or their extracts.
The surface analysis of metal-coated materials can supply useful information when this surface is
analyzed using X-ray photoelectron spectroscopy (XPS) or Auger-electron spectroscopy (AES).

Physical Respectively Mechanical Analysis:

Mechanical investigations of materials are necessary in order to evaluate these materials under a va-
riety of loading conditions (stresses and strains). Hardness test are performed with metals and poly-
meric materials in order to determine the indentation resistance, scratch resistance, or rebound resil-
ience. These investigations are useful in order to identify insufficient material properties or to compare
different production lots. Specific gravity determinations are applied for the characterization of identity,
purity and concentration of materials.

Molecular Weight Distribution:

For the characterization of polymeric materials the determination of the molecular weight distribution
using gel permeation chromatography (GPC) or the determination of the solution viscosity using an
Ubbelohde viscosimeter are important analytical tools.

Morphological Characterization:

Scanning electron microscopy can be used to obtain important information with regard to the surface
integrity of materials. The smoothness or roughness of a surface has strong influence upon the inter-
action between the medical device and the contacting tissues or body fluids, depending on the in-
tended application of the device. Valuable information concerning the qualitative and semi-quantitative

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composition of a material surface is obtained when using SEM-EDX (scanning electron microscopy in
combination with energy dispersive x-ray).

Thermal Analysis

Thermal analyses, which can be performed using a differential scanning calorimeter (DSC), indicate
critical thermal properties of the respective material, e.g. polymer melting point and glass-transition
temperature. Furthermore, it is possible to obtain information regarding the thermal history and purity
of the polymer.

2. Physicochemical Analyses of Polymeric Materials

2.1. Physicochemical Tests - Plastics

Water Extraction

Procedure according to USP, <661>

-

Preparation of a sample extract with purified water

-

Test of nonvolatile residues

-

Test of residues on ignition

-

Test of heavy metals

-

Test of buffering capacity

Isopropanol Extraction

Procedure according to Pharmacopeial Forum, Nov-Dec 1992

-

Preparation of a sample extract with isopropanol

-

Test of nonvolatile residues

-

Test of residues on ignition

-

Test of turbidity

-

Test of UV absorption

2.2. Extractable Organic Substances in Polymeric Materials (‘GC/MS Fingerprint’)

Procedure using gas chromatography with mass selective detector

-

Extraction with 3 aqueous and/or organic solvents in accordance with EN ISO 10993-
12

-

Optional: gas extraction at elevated temperatures

-

System standardization with external reference compound

-

Identification of typical extracted substances using a mass selective detector

Note:

The test may be applied as a routine quality control measure to compare different
material batches or stability samples. Identification of extracted substances further al-
lows preparation of a toxicological profile.

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2.3. Determination of Methyl Methacrylate (MMA) in Polymethyl Methacrylate (PMMA)

Procedure according to mdt-SOP PM 01-016 or PM 01-031

- Gas

chromatography

-

System calibration with MMA, 5 concentrations

-

2 independent determinations

2.4. Residual Monomers of Complex Polymeric Materials

Procedure using gas chromatography with mass selective detector

-

Gas or liquid injection

-

System calibration with the respective monomers, 5 concentrations

-

2 independent determinations

Note:

Materials-related validation work is necessary in most cases

2.5. Molecular Mass Distribution of Polymers (e.g., PMMA, PC, Poly-L-Lactid, etc.)

Procedure according to mdt-SOP PM 01-015

-

Gel permeation chromatography (GPC)

-

System calibration with 6 reference substances

-

2 independent determinations

2.6. Determination of Degradation Products in Polymeric Materials

Procedure according to EN ISO 10993-13

-

Testing of hydrolytic and/or oxidative degradation

-

Determination of mass reduction and molar mass distribution or density after acceler-
ated ageing (70

± 1 °C, exposure time depending of the intended application period

between 2 and 60 days)

-

Depending on the determined changes of the investigational material: identification
and quantification of the compounds available in the degradation medium or the
treated polymer

-

If necessary: repetition of the experiment with test items after real-time ageing (37

± 1

°C, exposure for 1, 3, 6 and 12 months)

Note:

The applicable analytical methods strongly depend on the test material and will be
selected individually. Analytical validation work may also be required.

2.7. Tests of Denture Based Polymers According to EN ISO 1567

'mdt' offers several physicochemical and mechanical tests for denture based polymers, as listed in EN
ISO 1567:

- Color
- Color

stability

-

Bending strength and bending modulus

-

Bonding to synthetic polymer teeth

-

Residual monomer content

-

Water absorption and solubility

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3. Metal and Ceramic Analyses

3.1. Quantitative Determination of Extractable Metallic Ions

Procedure using ICP analysis (inductively coupled plasma)

-

Extraction with 3 different aqueous solvents in accordance with EN ISO 10993-12 and
EN ISO 10993-14

-

Screening for identification of the extracted metallic ions

-

System calibration for each identified metallic ion

-

Quantification of the metallic ions

-

Non-exposed extraction medium as negative control

Note:

In the course of a cytotoxicity tests it may be beneficial to determine metallic ions in
the extraction medium in order to find potential reasons for an observed toxic reac-
tions of the investigated material.

3.2. Corrosion Test

Procedure according to EN ISO 10271 as a static corrosion test

-

Cleansing with ethanol

-

Corrosion medium: lactic acid and NaCl in water

-

Exposure to corrosive medium for 7 days at 37 °C

-

Calibration of each element with 4 concentrations

3.3. Mechanical Tests of Metals and Ceramics

-

Tensile strength / elasticity modulus

-

Strain at failure

-

Flexural strength

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4. Residue Analyses

4.1. Residues after Sterilization with Ethylene Oxide

According to EN ISO 10993-7, medical devices are classified into three categories: Devices with lim-
ited exposure (≤ 24 h), prolonged exposure (24 h until 30 days) and permanent contact (> 30 days).
Depending on the device category exhaustive extractions and/or in-use simulations have to be per-
formed in order to minimize the toxicological risk of sterilization residues. Materials containing chlorine
have to be tested for both ethylene oxide (EO) and ethylene chlorohydrin (ECH). The determination of
ethylene glycol (EG) in aqueous systems is possible, however, not compulsively requested in EN ISO
10993-7.
For the validation of a degassing process both, positive and negative product controls, have to be
investigated. The positive product control proves that EO has been applied, the negative product con-
trol (no EO contact) proves that no other substances elute with the same retention time as EO, re-
spectively ECH. Typically, 3 sterilization batches are investigated and products from various places of
the degassing chamber are tested. For routine controls of EO, respectively ECH residues, testing of
positive and negative controls is not compulsory.
Products consisting of various components and materials have to be tested in a way that all materials
are tested individually, because EO/ECH adhesion to polymeric materials may differ significantly.

Medical Devices with Limited Exposure (≤ 24 h)

-

In-use simulation (aqueous extraction for 24 h at 37 °C)

-

Determination of residual EO; if applicable, determination of ECH and EG

-

System calibration with 5 different concentrations

-

Negative control: test items not exposed to ethylene oxide

-

Positive control: EO treated but not subjected to degassing

Acceptance limits: 20 mg EO and 12 mg ECH

Medical Devices with Prolonged Exposure (between 24 h and 30 days)

-

Exhaustive extraction (extraction using suitable solvent)

-

In-use simulation (aqueous extraction if limits for 24 h are exceeded)

-

Further procedure as for medical devices with limited exposure.

Acceptance limits:First 24 h: 20 mg EO and 12 mg ECH

Total amount after 30 days: 60 mg EO and 60 mg ECH

Medical Devices with Permanent Exposure (> 30 days)

-

Procedure as for medical devices with prolonged exposure

Acceptance limits:First 24 h: 20 mg EO and 12 mg ECH

Total amount after 30 days: 60 mg EO and 60 mg ECH
Total amount for a lifetime: 2.5 g EO and 50 g ECH
Special limits for intraocular lenses, blood oxygenators and dialyser membranes

4.2. Surface Analyses for Identification of Possible Residues

Procedure using X-ray photoelectron spectroscopy (XPS) or Auger-electron spectroscopy (AES)

-

Determination of the surface composition of the test item

-

Penetration depth of 3 nm

-

Presentation of the surface composition in atomic percentages