P A C E A N A LY T IC A L LIF E S C IE N C E S

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SPreclinical Testing for the Medical Device Industry –

Material Properties, Leachables/Extractables, and Surface Cleanliness

Jonas Weissenrieder, Ph.D.

Pace Analytical Life Sciences

Oakdale, Minnesota

Life Sciences

Effects of Material and Chemical properties on the biological profile

Chemical and Material Analysis

Why do chemical characterization?

Equivalence studies?

Economy?

Leachables/Extractables

How to design an extraction study?

Surface cleanliness

What to look for?

Outline

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02

What is influencing the biocompatibility?

Materials directly influence biocompatibility

High or low leachables/extractables

Surface/interfacial properties

particulates chemical compounds

biomolecules

surface topography and chemistry (device)

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Why Chemical Characterization?

Stronger signals than in animal studies

Bisphenol A (BPA)

Validated LC/MS/MS method

Health Canada requires information of

devices made from or containing BPA

Polycarbonate and Epoxy

Once you know what is dangerous,

chemical characterization is to prefer.

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ISO 14971: Medical Device –Risk Management

The toxicological risk assessment should take into account the chemical nature of the material; therefore it is necessary to determine the chemical composition of processing additives, residues, potential extractables and leachables.

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05Why Chemical Characterization?

Why Chemical Characterization?

Safety and Regulatory requirements

Part of 10993-1, perform chemical

characterization prior to animal studies

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ISO 10993-1 Evaluation and Testing

Biological Evaluation

Biological Testing Testing Administrative

Material Characterization

Chemical Characterization / Toxicological Evaluation

ISO 10993-18Chemical characterization of materials

ISO 10993-9ID and Quant. of deg. products

ISO 10993-13Polymers

ISO 10993-14Ceramics

ISO 10993-13Metals and Alloys

ISO 10993-16Toxicokinetic degradation and leachables

ISO 10993-17Est. allowable limits for leachables

ISO 10993-7Ethylene Oxide

ISO 10993-19Phys. Chem. materials

ISO 10993-6local effects after implantation

ISO 10993-5vitro cytotoxicity

ISO 10993-4interactions with blood

ISO 10993-3Genotoxicity, carcinogenicity,

and reproductive toxicity



ISO 10993-10irritation and delayed-type

hypersensitivity

ISO 10993-11systemic toxicity

ISO 10993-20immunotoxicology

ISO 10993-12Sample Preparation


ISO 10993-12Sample Preparation

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ISO 10993-18

Identify chemical nature of materials

Composition (additives, residues, cleaning, processing etc.)

Predict biological response

Evaluating the potential of device to release substances or breakdown products due to manufacturing process

Changes in the material construction that are due to the manufacturing process or insufficient control of process

Potential reduction of animal testing

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ISO 10993-18

To demonstrate equivalence of a proposed material to a clinically established material

Screening for suitability of new materials

Judging equivalence of prototype to final device

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Decision Flow Chart from ISO 10993-18

STOP Extract Estimate clinical exposure

Composition

IdentifyMaterials, Components,

residue

Equivalent?

NoNo

Concerns?Yes

Yes

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Preliminary Evaluation

Supplier Data:• Technical data: known additives, residues, impurities, composition,

biological safety data, etc.

• Product literature: material specifications, MSDS

• Details of material composition and formulation

Device Manufacturer Data:• Internal specification and processing

• Material characterization data

• Biological safety data

• Clinical data

• Medical device reports

Other Pertinent data:• Literature Search: Journals, databases, etc.

• Known material interactions

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Composition


residue

Equivalent?

NoNo

Concerns?Yes

Yes

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Select the appropriate analytical method to provide the requiredinformation 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

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13Composition

Composition

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Evaluation using e.g.TOC, NVR and RoI

DI-GC-MS

ICP

FTIR

LC-MS

SHS-GCMS, DHS-GC-MS, SHS-FTIR

Polymer molecular weight

GPC or Viscosity

Surface AnalysisXPS, SEM-EDX, etc.

Material Equivalence

Perform an assessment of the data gathered:

• Is the proposed material equivalent to existing clinically established material including clinical exposure and processing?

• Does the proposed material meet an existing standard for intended use duration of contact and invasiveness?

• Is the proposed material already established in a more invasive exposure?

• Does the proposed material contain a chemical component or residue which has equal toxicological safety the component it replaces in a clinically established material (assuming similar exposure)?

• Is the only difference between the proposed material and clinically established material the elimination or reduction of an additive/contaminant/residue etc.?

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Composition


residue

Equivalent?

NoNo

Concerns?Yes

Yes

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Sources of Extractables/Leachables

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Additives – Stabilizers, Plasticizers, Modifiers, Catalysts

Process Impurities – Mould Release Agents, Anti-static and Anti-slip agents

Lubricants – Oils and Degreasing Agents

Monomers and Higher MW Oligomers from incomplete polymerization

Residual Solvents

Degradation Products

Exaggerated extraction

any extraction designed to get a greater extraction result than

simulated use

Simulated use extraction

extraction of sample with a medium and under conditions that

simulate product use, for the purpose of evaluating its potential

hazard to the patient during routine clinical use

exhaustive extraction

extraction until the amount of residues in a subsequent extraction is

less than 10% of that detected in the first extraction, or until there is

no significant increase in the cumulative residues detected.

Sample Preparation

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19ISO 10993-12 : Extraction ratios

Extract in both polar and non-polar medium

ISO 10993-12 : Extraction conditions

Extract under agitation

(121 ± 2)°C for (1 ± 0.1) h

(70 ± 1)°C for (24 ± 2) h

(50 ± 2)°C for (72 ± 2) h

(37 ± 1)°C for (72 ± 2) h

(37 ± 1)°C for (24 ± 2) h

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Accuracy and precision

Specificity

LOD and LOQ

Linearity and Range

Ruggedness

Robustness

Validation

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Chemical Equivalence Example

Exhaustive extraction in polar and non-polar liquid

Exaggerated (70°°°°C in Water and IPA)

SHS-GC-MS and DHS-GC-MS

Samples from Conditions

Before Change

Process change of a device with metal and polymers

Samples from Conditions After

Change

ICP, DI-GC-MS, TOC, and NVR

Compare ResultsLife Sciences

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SHS-GC-MS and DHS-GC-MS

Biological Evaluation Testing

If equivalence is demonstrated, it may be possible to reduce the degree of biocompatibility testing.

If equivalence cannot be demonstrated through

material characterization, it may be necessary to

perform the full battery of biocompatibility tests.

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Approximate Price comparison

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Chemical Characterization

$4,0005-10 days12 devices

Biological Evaluation

$20,000 60 days

28 devices

(less than 24 h, blood contact)

Tool to tighten up process control

Assist in in future generations and product families

Chemical Characterization

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Additional benefits:

Surface Cleanliness

Recovery, etc

Extraction → Analysis for Unknown and known contaminants

Complicated geometry -> swabbing, rinsing

Method Feasibility

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Method Validation

Surface Analysis

Direct evaluation,

particulates, etc.

Choose Analytical Techniques

Method Development

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Thank you for your attention!

Jonas Weissenrieder, Ph.D.Pace Analytical Life Sciences

Oakdale, [email protected]

www.pacelifesciences.com

Life Sciences

P A C E A N A LY T IC A L LIF E S C IE N C E S

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