Chemical Characterization

Chemical Characterization

Introduction to Chemical Characterization Testing for Medical Devices

1. Basic Concepts

Chemical characterization: As defined in ISO 10993-18, the process of identifying the materials of a medical device and the chemicals that may be released under clinical use conditions, and analyzing them qualitatively and quantitatively.

Core purposes:

  • Identify chemicals that may be released from the medical device into the body

  • Provide chemical information as input to the biological evaluation

  • Reduce animal testing (replacing some biological tests through chemical equivalence arguments)

  • Assess the impact of material and process changes on product safety

Why it matters: Chemical characterization is a core element of modern biological evaluation of medical devices. Biocompatibility assessments under the FDA and EU MDR increasingly rely on chemical characterization data rather than on animal testing alone.

2. Key Regulations and Standards

Standard/guidance Content
ISO 10993-1:2018 Framework for biological evaluation within a risk management process
ISO 10993-17:2023 Toxicological risk assessment of medical device constituents (new edition, replacing the old one)
ISO 10993-18:2020 + A1:2022 Chemical characterization of medical device materials (core standard)
ISO/TS 21726:2019 Application of the threshold of toxicological concern (TTC) in biological evaluation
FDA Guidance (2020) Use of International Standard ISO 10993-1 for biological evaluation of medical devices
FDA Draft Guidance (2021) Chemical analysis for biocompatibility assessment / chemical characterization
GB/T 16886.18 Chinese equivalent standard (identical adoption of ISO 10993-18)
USP <661>/<665> Assessment of materials for pharmaceutical packaging/manufacturing systems
ICH Q3D Guideline for elemental impurities (for reference)

3. Key Terms

Term Meaning
Leachables Chemicals released from the device under actual conditions of use
Extractables Chemicals extracted from the device under exaggerated conditions (> actual release)
Target leachables Specific known substances of concern
Unknown leachables Substances discovered through non-targeted analysis
AET (Analytical Evaluation Threshold) Analytical Evaluation Threshold – substances below this value can be disregarded
TTC (Threshold of Toxicological Concern) Threshold of Toxicological Concern – a generic safety threshold
TI (Tolerable Intake) Tolerable Intake – the daily tolerable intake of a substance
MoS (Margin of Safety) Margin of Safety = TI / actual exposure
PDE (Permitted Daily Exposure) Permitted Daily Exposure

4. Chemical Characterization Process (ISO 10993-18)

1. Information gathering (formulation, process, contact conditions)
 ↓
2. Risk assessment and determination of need
 ↓
3. Chemical characterization plan
 ↓
4. Sample preparation (simulating actual use)
 ↓
5. Extraction study
 ↓
6. Chemical analysis (qualitative + quantitative)
 ↓
7. Data evaluation and AET calculation
 ↓
8. Toxicological risk assessment (TRA, ISO 10993-17)
 ↓
9. Decide whether additional biological testing is needed

5. Levels of Chemical Characterization (ISO 10993-18)

Step 1: Information gathering

  • Material composition (formulation, additives, catalysts)

  • Manufacturing processes (sterilization, cleaning, processing aids)

  • Nature of body contact (site, duration, area)

  • Existing chemical/toxicological data

Step 2: Chemical equivalence assessment

If the materials are equivalent to those of a marketed product, some testing can be waived.

Step 3: Actual chemical characterization

Selected according to risk level:

  • Targeted analysis: for known substances of concern

  • Non-targeted analysis: screening for unknown substances

  • Semi-quantitative/quantitative analysis

6. Extraction Study

Three elements of extraction conditions

Element Options
Polarity Polar (water), semi-polar (isopropanol/ethanol), non-polar (hexane)
Temperature 37 °C (simulated), 50 °C, 70 °C, 121 °C (exaggerated)
Time 24 h, 72 h, repeated extraction until exhaustion

Extraction modes

Mode Description
Simulated extraction Simulates actual conditions of use
Exaggerated extraction Harsher than actual conditions
Exhaustive extraction Until no more substances are released (each extraction <10% of the previous one)

Common extraction solvent combinations

  • Polar: purified water, saline

  • Semi-polar: 50% ethanol, isopropanol

  • Non-polar: hexane, dichloromethane, corn oil

Typical plan: three solvents of different polarity × exaggerated conditions × appropriate temperature and time

7. Analytical Techniques and Their Scope

Main instrumental techniques

Technique Full name Applicable to
GC-MS Gas chromatography–mass spectrometry Volatile/semi-volatile organic compounds (VOC/SVOC)
HS-GC-MS Headspace GC-MS Highly volatile organic compounds
LC-MS/HRMS Liquid chromatography–(high-resolution) mass spectrometry Non-volatile organic compounds (NVOC)
ICP-MS Inductively coupled plasma mass spectrometry Metals and inorganic elements
ICP-OES Inductively coupled plasma optical emission spectrometry Metals
IC Ion chromatography Anions, cations, organic acids
FTIR Fourier-transform infrared spectroscopy Material identification, functional groups
NMR Nuclear magnetic resonance Structure confirmation
TOC Total organic carbon analysis Total organic content
UV-Vis UV-Vis spectrophotometry Specific light-absorbing substances

Typical analytical combination

Different types of substances require a combination of methods – no single method can cover all leachables:

Organic analysis:
 Volatile → HS-GC-MS
 Semi-volatile → GC-MS
 Non-volatile → LC-MS (positive/negative ion mode), HRMS

Inorganic analysis:
 Metals → ICP-MS / ICP-OES
 Anions → IC

Supporting:
 TOC (overview), FTIR (material identification)

8. AET (Analytical Evaluation Threshold) Calculation

The AET is the “threshold” for deciding whether a chemical needs further evaluation.

Basic formula

$$AET = frac{DBT times A}{B times UF}$$

Where:

  • DBT (dose-based threshold): a daily dose based on the TTC, usually 1.5 μg/day (sensitizers) or 120 μg/day (non-sensitizers)

  • A: total volume of the extract

  • B: mass or number of devices contacted per day

  • UF: uncertainty factor (usually 1.5–2)

Application rules

  • Substances below the AET → can be disregarded

  • Substances above the AET → require identification + toxicological assessment

Contact duration determines the threshold (ISO/TS 21726)

Contact duration Base TTC value
≤24 hours 120 μg/day
>24 h to 30 days 20 μg/day
>30 days to 10 years 1.5 μg/day
Lifetime (>10 years) 1.5 μg/day

Substances of special concern (cohort of concern carcinogens): no safe threshold; case-by-case assessment required.

9. Toxicological Risk Assessment (TRA) – ISO 10993-17

After chemical characterization, the identified substances must undergo toxicological assessment:

Assessment steps

1. Substance identification (CAS number, structure)
 ↓
2. Retrieve toxicological data (authoritative databases)
 ↓
3. Determine the TI (tolerable intake)/PDE
 ↓
4. Calculate actual exposure (EDI)
 ↓
5. Calculate the margin of safety MoS = TI / EDI
 ↓
6. Decision:
 MoS ≥ 1 → acceptable
 MoS < 1 → further evaluation or risk control

Common toxicological databases

  • ECHA (European Chemicals Agency)

  • PubChem (US National Institutes of Health)

  • TOXNET

  • IARC (carcinogen classification)

  • NIOSH/REACH/GRAS lists

  • Cosmetic Ingredient Review(CIR)

10. Relationship Between Chemical Characterization and Biological Testing

The new ISO 10993-1 emphasizes a chemistry-first evaluation approach:

Risk identification
 ↓
Chemical characterization + toxicological assessment
 ↓
 ┌────┴────┐
 ↓ ↓
Risk controlled Risk unclear
 ↓ ↓
Corresponding Additional biological testing
biological tests waived (cytotoxicity, sensitization, irritation, etc.)

Biological tests that can be replaced/reduced by chemical characterization:

  • Systemic toxicity (subacute, subchronic, chronic)

  • Genotoxicity

  • Carcinogenicity

  • Reproductive and developmental toxicity

Biological tests still required directly:

  • Cytotoxicity (often used as a basic screen)

  • Sensitization and irritation (local reactions that chemical characterization can hardly predict)

  • Implantation tests (local tissue reactions)

11. Focus Areas for Different Devices

Device type Key substances of concern
PVC infusion sets DEHP/DINP plasticizers
Implants (metal) Release of nickel, cobalt, chromium, titanium
Bone cement (PMMA) Residual MMA monomer
EO-sterilized products EO/ECH residues
Radiation-sterilized polymers Radiation degradation products
Silicone/rubber D4/D5/D6 siloxane oligomers
Adhesives/inks Bisphenol A, photoinitiators
Coated catheters Coating degradation products, initiators

12. Common Misconceptions in Chemical Characterization

  1. TOC alone cannot replace chemical characterization: TOC only gives overall information and cannot identify specific substances

  2. Extraction conditions too mild: potential risk substances are missed; exaggerated conditions are recommended

  3. Incorrect AET calculation: ignoring differences in contact duration and contact area

  4. Unknowns not identified: reporting only “unknown X” without attempting structural identification

  5. Ignoring semi-quantitative data: even without precise quantification, semi-quantitative data are valuable

  6. Confusing extractables and leachables: extractables ≠ leachables; they must be distinguished

  7. Insufficient method validation: LOD/LOQ, recovery and repeatability must be validated

13. Regulatory Trends

FDA

  • The 2020 guidance emphasizes chemical characterization as the core of biological evaluation

  • Encourages replacing animal tests such as chronic toxicity and carcinogenicity with chemical characterization

  • Requires detailed method validation and quality control data

EU MDR

  • Emphasis on a complete toxicological risk assessment

  • Stricter chemical data requirements for high-risk implants

China NMPA

  • GB/T 16886.18 is an identical adoption of ISO 10993-18

  • Increasing acceptance of chemical characterization data, though traditional biological testing remains the norm

  • New guidelines are gradually converging with international trends

14. Key Contents of a Chemical Characterization Report

  1. Sample information: formulation, lot number, sterilization method, manufacturing process

  2. Clinical use information: contact site, duration, body contact area/mass

  3. Extraction plan: solvents, temperature, time, sample-to-solvent ratio, rationale

  4. Analytical methods: instrument conditions, standards, method validation data

  5. AET calculation

  6. List of detected substances: CAS numbers, concentrations, uncertainty

  7. Toxicological assessment: source of TI/PDE, MoS calculation

  8. Conclusion: whether the risk is acceptable and whether additional testing is needed

15. Typical Project Timelines and Costs

  • Full chemical characterization + TRA: 8–16 weeks

  • Simplified projects: 4–8 weeks

  • Cost: from tens of thousands to hundreds of thousands of RMB (depending on complexity and device category)

  • Influencing factors: number of materials, contact duration, presence of metals, depth of unknown identification

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