ISO 10993-18 in the MDR - Nelson Labs · 2020. 3. 10. · MDR: 10.4.2. Justification R A T isk...

Understanding the restrictions and risk assessment for substances which are

Carcinogenic, Mutagenic, toxic to Reproduction (CMR) or have Endocrine-

Disrupting (ED) properties (section 10.4, Annex I MDR)

Annelies Vertommen, PhD

4 MARCH 2020

ISO 10993-18 in the MDR :

Introduction

2020: The Year Of Change for the Medical Device Industry

Introduction

ssessment

Outline

• MDR: section 10.4, Annex I, Chapter II

• ISO 10993-18:

o a screening vs a targeted analytical approach

o three levels of quantification

• ISO 10993-18 in the MDR

• Conclusion: proposed workflow

Section 10.4 in the MDR

MDR Annex I (GSPR)

Design and manufacture of devices to reduce risks posed by substances or particles that may be released from the device

MDR Annex I, Chapter II, Section 10.4.

Risk justification and labelling for substances

• 10.4.1: when? Design and manufacture of devices

• 10.4.2: how justification?

o Section 10.4.3: guideline on phthalates

o Section 10.4.4: guideline on other CMR & ED substances

• 10.4.5: how labelling?

Section 10.4 in the MDR

10.4.1 When?

1. What type of test items?

Device, part or material

• Invasive & direct contact with human body

• (Re)administering medicines or other substances to/from body

• Transport or storing medicines or other substances

MDR: 10.4.1 Design and manufacture of devices

10.4.1 When?

2. Cannot contain CMR 1A, CMR 1B or ED substance > 0.1 % weight/weight unless justification & labelling o CMR: Carcinogenic, mutagenic, or reprotoxic

CMR 1A: Known human CMR

CMR 1B: Presumed human CMR

CMR 1A/1B: As per Annex VI CLP Regulation

o ED substance: Endocrine disruptor (human health) Article 59, EC 1907/2006 (REACH)

Article 5(3) EC 528/2012 (biocidal)

MDR: 10.4.1 Design and manufacture of devices

• Analysis of (patient & user) exposure

MDR: 10.4.2. Justification

ssessment

ISO 10993-18

= risk assessment : ISO 10993-18

• Analysis of alternative substances, materials, designs

• Benefit-risk assessment

Terephthalate No endocrine-disruptor

Isophthalate Endocrine-disruptor

DEHP DEHT

• 10.4.3: Guideline on phthalates (Scheer, 2019)

• 10.4.4: Guideline on other CMR and endocrine-disrupting substances

Where?

• on the device itself and/or

• on the packaging for each unit or,

• on the sales packaging

MDR: 10.4.5: labelling

The missing link?

MDR: missing link

> 0.1 % weight/weight: HOW?

ISO 10993-18?

MDR: missing link

Test my device for all substances?? 0.1 % w/w = a lot !

MDR: missing link

Test my device for all substances??

MDR: missing link

Test for all substances??

Supplier: intentionally added

Polycarbonate – Bisphenol A (BPA)

PVC - Phthtalates

Only those substances that can be present > 0.1% w/w

MDR: missing link

PVC - Phthtalates

MDR: missing link

ISO 10993-18: - Answer for > 0.1 % w/w?

- Tool for risk assessment/justification

ISO 10993-18

ISO 10993-18: - Answer for > 0.1 % w/w?

- Tool for risk assessment/justification

ISO 10993-18

a screening versus a targeted approach

• No predefined target: screen for all • General techniques:

• HS-GC/MS: volatile organic compounds (VOC) • GC/MS: semi-volatile organic compounds (SVOC) • LC/MS: non-volatile organic compounds (NVOC)

• No LOD, LOQ for each compound

Screening

ISO 10993-18: screening vs targeted

• A limited number of known targets • Selective technique:

• ICP/OES: elements • IC: anions • Validated method: specific organic compound, e.g. Bisphenol A: GC/MS method

• LOD, LOQ for each compound

Targeted

ISO 10993-18: screening vs targeted

• A screening versus a targeted analytical approach :

three levels of quantification in ISO 10993-18

ISO 10993-18: three levels of quantification

• A screening versus a targeted analytical approach :

three levels of quantification in ISO 10993-18:

1. Estimated quantification

2. Semi-quantification

3. Full quantification Targeted approach

Screening approach

I.S. [I.S.]known = 10 mg/L AreaIS = 100

Area[EXT] = 100 [EXT]Estimated = 10 mg/L

Assuming RFIS = RF [EXT]

I.S. Bisphenol A

ESTIMATED QUANTITATIVE ANALYSIS

Bisphenol A

Internal Standard (IS) Bisphenol A

a. Semi-quantitative analysis via surrogate compound b. Semi-quantitative analysis via individual RRF correction

a. SEMI-QUANTITATIVE ANALYSIS VIA SURROGATE RRF CORRECTION

[SUR] = 10 mg/L Area [SUR] = 50 [I.S.] = 10 mg/L Area [I.S.] = 100

RRFSUR = 0.5

Bisphenol A

SURROGATE

Surrogate compound: compound similar to target compound BUT: many variation, e.g. Bisphenol A_d16, Naphthalene_d4

Area EXT = 100 [EXT] = 20 mg/L

Surrogate compound

Bisphenol A

Surrogate compound

[SUR] = 10 mg/L Area [SUR] = 50 [I.S.] = 10 mg/L Area [I.S.] = 100

RRFSUR = 0.5

Bisphenol A

SURROGATE

Area EXT = 100 [EXT] = 20 mg/L

b. SEMI-QUANTITATIVE ANALYSIS VIA INDIVIDUAL RRF CORRECTION

Bisphenol A

>>>>>>

Bisphenol A

0 2 4 6 8 10 12

Relative concentration

RRF, Bisphenol A

Bisphenol A Bisphenol A

Bisphenol A

0 5 10 15 20 25

concentration

Multiple point calibration curve, Bisphenol A

1. Estimated 2.1 Semi-quantitative through surrogate

2.2 Semi-quantitative through RRF

3. Fully quantitative

[EXT]Estimated = 10 mg/L

Assuming RFSur = RF [EXT]

[EXT]semi-quant = 20 mg/L

RF [EXT]

AT 1 CONC LEVEL

[EXT]quant = 35 mg/L

RF [EXT] AT MULTIPLE CONC LEVELS

[EXT]Estimated = 10 mg/L

Assuming RFSur = RF [EXT]

RF [EXT]

AT 1 CONC LEVEL

[EXT]quant = 35 mg/L

RF [EXT] AT MULTIPLE CONC LEVELS

High uncertainty Low uncertainty

Screening

Screening Targeted

ISO 10993-18: - Answer for 0.1 % w/w?

- Tool for risk assessment

a screening versus a targeted approach: three levels of quantification

PVC - Phthtalates

ISO 10993-18 in the MDR

> 0.1 % weight/weight: HOW?

ISO 10993-18?

• Target the substance that is expected : BPA

• Target the substance that is expected : BPA • Knowledge on total amount BPA needed

• Extract the total amount BPA: “digest the material”: Use solvent that best solubilizes the target substance

• Extract the total amount BPA: “digest the material”: Use solvent that best solubilizes the target substance • Use 1 analytical technique (GC/MS)

• Extract the total amount BPA: “digest the material”: Use solvent that best solubilizes the target substance • Use 1 analytical technique (GC/MS) • Include calibration curve: quantitative result

ISO 10993-18: Answer for 0.1 % w/w (= Material characterization)

Screen for all possible target substances

Keep device/material/part intact during extraction: • Extraction conditions: ISO 10993-18

• CMR/ED substance: different sizes, different nature Different extraction solvents, different analytical techniques • CMR/ED not known: no calibration curve of target substance

Screening: estimated/semi-quantitative concentration

525 95

CMR/ED substance detected?

Lists in MDR (> 2000 compounds)

Reduced lists (MedTech Europe, proprietary, < 200)

525 95

CMR/ED substance detected?

DEHP: CMR 1B (toxic for reproduction), ED properties

Ziram: potential ED (under evaluation)

525 95

No calibration curve! ESTIMATED (semi-quantitative) concentration close to 0.1 w/w %? (1000 µg/g)

525 95

• No calibration curve! • ESTIMATED (semi-quantitative) concentration • close to 0.1 w/w %? (1000 µg/g)

Include second step

• No calibration curve! • ESTIMATED (semi-quantitative) concentration • close to 0.1 w/w %? (1000 µg/g)

Include second step

• Run same extract with calibration curve for detected CMR/ED (DEHP, Ziram) Quantitative result!!!

• calibration curve • QUANTITATIVE concentration • close to 0.1 w/w %? (1000 µg/g)

• Extract the total amount: “digest the material”: Use solvent that best solubilizes the target substance

• Use 1 analytical technique • Include calibration curve:

quantitative result

ISO 10993-17

Using chemical characterization for CMR/ED substances in lack of information? - Information on all substances that can be released from the device: Estimate overall risk to the patient (not only CMR/ED) Evaluation results: ISO 10993-17 - Justification in case conc CMR/ED substances > 0.1 % (w/w)

Conclusion: proposed workflow

Information on concentration present (e.g. conc. CMR/ED = 0.5% w/w)?

STEP 1: ASK INFORMATION FROM SUPPLIERS Information on nature of CMR/ED present (e.g. contains BPA)

YES NO

CMR/ED > 0.1 % w/w ? Full digestion of material Targeted analysis Fully quantitative

YES NO

CMR/ED > 0.1 % w/w ? Full digestion Targeted analysis Fully quantitative

YES NO

JUSTIFICATION LABEL

YES NO

JUSTIFICATION LABEL

YES NO

NO LABEL

YES NO

NO LABEL JUSTIFICATION LABEL

Chemical characterization ISO 10993-18: Screen for all Semi-quantitative

Set-up chemical characterization for safety risk assessment

1. Make extract 72h -50°C, shaking incubation polar & non-polar solvent

2. Analytical techniques:

VOC: HS-GC/MS screening SVOC: GC/MS screening NVOC: LC/MS screening Elements: ICP/OES

Estimated/ Semi-quantitative results

Fully quantitative results

STEP 1. Gather all results

1. Make extract 72h -50°C, shaking incubation polar & non-polar solvent

2. Analytical techniques:

VOC: HS-GC/MS screening SVOC: GC/MS screening NVOC: LC/MS screening Elements: ICP/OES

Compare with published CMR/ED substances lists

STEP 2. CALIBRATION CURVE: more QUANTITATIVE results for CMR/ED

Compare with published CMR/ED substances lists

Information on concentration present ?

YES NO

Chemical characterization: ISO 10993-18 RISK TO PATIENT SCREEN for all, SEMI-QUANT Compare with CMR/ED lists CMR/ED IN LIST (2-step): QUANT

RESULTS: ISO 10993-17

CONC close to 0.1 % (w/w)

YES NO

Full digestion Targeted analysis Fully quantitative

CMR/ED > 0.1 % w/w ?

JUSTIFICATION LABEL

YES NO

CMR/ED > 0.1 % w/w ?

JUSTIFICATION LABEL

YES NO

CMR/ED > 0.1 % w/w ?

eception

our of lab

ISO 10993-18 in the MDR - Nelson Labs · 2020. 3. 10. · MDR: 10.4.2. Justification R A T isk...

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