Extractables and
Leachables for Medical
Devices
Tim Hulme and Keith Scott
Course Outline
• Introduction to Extractables and Leachables
• Regulatory
• Chemical characterisation
• Experimental
Experimental
How is the testing done?
Extractables Assessments
for Medical Devices
Purpose
Chemical characterisation can be used to:
• Support overall biological safety of a device
• Determine the amount of chemical substances that might be leached from a
medical device in clinical use, to support toxicological assessment
• Support equivalence:
• new medical device to a clinically established device
• modified medical device to original
• final version to prototype
• Screening potential new materials for use in a medical device
• Reduce the need for animal testing
5
Purpose
Extractions for a chemical charaterisation can be used to:
• Establish compositional aspects of a medical device’s
materials (digestion, dissolution or exhaustive extraction)
• Establish worst-case extractables profile of a medical device
or material (exaggerated or accelerated extraction)
• Establish extractables profile of a medical device or material
under its clinical conditions of use (simulated extraction)
6
Scope - Stepwise approach (ISO 10993-18)
Establish device’s hypothetical worst case
chemical release via compositional
profiling
Estimate device’s chemical release via its
extractables profile
Determine the device’s actual chemical
release via its leachables profile
7
Scope - Stepwise approach (ISO 10993-18)
Establish device’s hypothetical worst case
available data conclude device
chemical release via compositional
Does risk assessment of
profiling
has acceptable risk
Estimate device’s chemical release via its
extractables profile
Determine the device’s actual chemical
release via its leachables profile
8
Medical Device Extraction Conditions for Extractable
Profile
• Use exhaustive conditions
• Strong solvents of different polarities
• Aggressive extraction conditions
• Extraction time
• Monitor extractables level – < 10% increase
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Medical Device Extraction - Simulation Conditions
Use conditions appropriate to contact category
Contact Category Extraction Conditions
Limited contact devices Simlated use conditions
Prolonged contact devices Exhaustive conditions
Long-term contact devices Exhaustive conditions
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Medical Device Extraction Conditions
Solvent choice
Polar Water
Dimethyl sulphoxide, acetonitrile,
methanol, acetone, ethanol,
Exhaustive Semi-polar
tetrahydrofuran, n -propanol, i -propanol,
dichloromethane
Non-polar Toluene, cyclohexane, heptane, n -hexane
Contact with blood Ethanol/water mixture
Simulated use Contact with aqueous solution Saline (pH adjusted)
Solution with lipophilic properties Alcohol/water mixture
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Critical Dimensions of an Extraction Study
Generating the Extract Characterizing the Extract
12
Design Aspects of an Extraction
• The chemical nature of the extracting solvent
• The extraction time
• The extraction temperature
• The stoichiometry of the extraction (extracted surface
area per unit volume of extracting solution)
• The mechanism or process of extraction
13
Gentle versus Harsh Extractions
The Spectrum of Extraction “Intensity”
Gentle Harsh
Actual Use Accelerated Vigorous Exhaustive
Simulation Extractables
Studies profiling Aggressive
Dissolution/Digestion
14
Generalisations About Extraction Intensity
Speed Integrity
• Extraction conditions should allow completion in a reasonable time but
should not be so aggressive as to alter the nature of the resulting
extractables profile.
• The most aggressive extraction conditions are reserved for the
quantitative determination of chemical additive contents in components
and materials.
15
Extraction Time and Temperature
► Overview: The combination of extraction time and temperature establishes the magnitude of the
driving force and the degree to which equilibrium is actually achieved.
• Generalisations:
► In a simulating extraction study the purpose of elevated temperature is to increase the extraction
rate, so that a short experimental time may simulate longer leaching times.
► The relationship between the diffusion rate and temperature can be expressed empirically by the
Arrhenius equation.
► Extractables profiles obtained under exhaustive conditions, with a given extracting solvent and
extraction technique, should be monitored for equilibrium or the attainment of asymptotic levels of
extractables.
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Extraction to Asymptotic Levels
1400000
DCM
1200000
1000000
Hexane
800000
area
600000
400000 Methanol
200000
0
0 20 40 60 80 100 120 140
time (min)
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Factors Effecting Extraction Rate
• Solvent • Dynamic / static
• Material type • Concentration gradients
• Material thickness • pH • Time
• Material porosity • Ionic Strength • Temperature
• Surface area: volume
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Extraction Stoichiometry
►Overview: Extraction stoichiometry considers the physical mass of the test article
relative to the volume of the extracting solvent. Extraction stoichiometry can be
manipulated to facilitate the extraction study.
• Generalisations:
►The decision to size (e.g., cut, grind, etc.) a sample for testing must be carefully
considered.
►The proper extraction stoichiometry can be established based of accepted safety
thresholds.
►Extraction stoichiometry must consider the known capabilities of the extract analysis
methods.
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Extraction Technique
► Overview: Extraction can be accomplished in a variety of ways and it is necessary that the means
of performing the extraction match the objectives of the extractables assessment.
• Common Extraction Techniques:
► Maceration (solvent soaking)
► Filling Each of these extraction
► Reflux mechanisms/techniques
► Soxhlet has its own unique
► Sealed Vessel advantages and
► Instrumental Methods limitations.
► Sonication
► Dissolution/Digestion
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Common Extraction Techniques
Soxhlet Microwave
Reflux Accelerated Solvent Extraction
Sonication Agitation / shaking
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Solvents
• Solvents / oils can soften and swell the polymer
• Increased availability of migrating species within polymer
• Increased migration through the polymer
Solvent
Polymer
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Extractions that are not Solvent-mediated
Head-space extraction for
analysis of volatile organic
compounds
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Characterising the Extract
• Objective
• To discover, identify and quantify all extractables present at levels greater than an established
threshold.
• A Dose of Reality
• This objective cannot be realized in all cases, even when state-of-the-art analytical chemistry is
practiced with best available skill and diligence, as there is no analytical technique or combination
of analytical techniques that is capable of the discovery, identification and quantitation of any and
all extractable chemical entities known to science.
• Exercise “due diligence”
• Characterize extracts to a “reasonable degree of scientific certainty”
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Characterising the Extract
► Scouting: A measure of “total extractables”
► Total Organic Carbon
► UV spectroscopy
► Discovery: The detection of individual extractables to identify
► Identification:
► Structural Analysis
► Qualitative Analysis
► Levels of Identification
► Quantitation: “The dose makes the poison”
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Analytical Techniques for Identification
Non-volatiles
Elements
Volatiles Semi-volatiles
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Method Selection
Molecular
Weight SEC GFC
Pyrolysis HPLC CE
GC
IC
HS-GC
Derivatization Polarity
CE = Capillary electrophoresis
GFC = GEL Filtration Chromatography
SEC = Size exclusion chromatography
IC = Ion Chromatography
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Analysis of Extractables & Leachables
• GC-MS • GC-MS
• GC-HRMS • GC-HRMS
• Headspace • EI & CI
• EI & CI • Library
• Library
Semi-
Volatile
Volatile
Impurities
Impurities
Non-
Elemental
Volatile
Impurities
Impurities
• ESI & APCI
• LC-UV
• LC-MS/MS
• LC-HRMS • ICP-MS
• Library • ICP-OES
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Scope - Stepwise approach (ISO 10993-18)
Establish device’s hypothetical worst case
available data conclude device
chemical release via compositional
Does risk assessment of
profiling
has acceptable risk
Estimate device’s chemical release via its
extractables profile
Determine the device’s actual chemical
release via its leachables profile
29
Determine the device’s actual chemical release
• Simulation extraction conditions
• Will depend on the application of the medical device
• Will build on the Extractables Profile (previous step)
• Study should target substances of concern
• Selected from the extractables profile
• Input from a toxicological assessment of the extractables
profile is likely to inform this selection
• Quantify extractables/leachables in simulated extract.
Page 30 | © Smithers, 2021
Quantification for Simulated Extract
• The target extractables/leachables should be quantified against:
• Authentic reference standards where available
• Suitable surrogate where authentic references are not available
• Suitable thresholds should be used in designing methodology (probably
already established in extractables profiling)
• Simulation extraction tend to be in simple (not complex) solvent matrices
• So minimal method development required
• Methods will be based on those used in the extractables profiling
• Methods should be validated.
Page 31 | © Smithers, 2021
Method Validation
• Specific
• Linear
• Precise
• Repeatable
• Accurate
• Sensitive
• Suitable range
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Unknowns
• How should unknowns be handled?
• Confirm their presence in the simulated extract and semi-quantify.
• Submit for toxicological evaluation
• (yes it is possible for a toxicologist to make some preliminary evaluation based on TTC)
• Further analysis
• Submit extracts for analysis by:
• High resolution GC-MS
• High resolution LC-MS
• Allows molecular formula of the substance to be elucidated.
• Confirmation using authentic references (where available)
• Include confirmed substance in validated analysis of the extract.
Page 33 | © Smithers, 2021
A combination device - Inbrija Inhaler
Inbrija – FDA application response
[Link]
What is it like?
• DPI Device
• At most only transitory contact with the drug product
• Mucosal contact
• Air path way contact
• Drug in capsules in blister packs
• Long term (storage) contact with drug product
• Capsule – direct contact
• Blister foil – less direct contact, but more potential leachables
What is required for E&L? – Good question!
• PQRI
• USP <1664.1>
• OINDP require
• Leachables stability study
• Validated analytical methods
• Leachables assessment based on SCT
• Leachable-extractables correlation
What is required for E&L? – Good question!
• Drug product primary packaging
• Extractables using AET derived from:
• SCT (1.5 µg/day) and IT (0.15 µg/day)
• Dose regime
• Mass of packaging components
• Analytical methods
• Tox assessment
• Leachables – again based on AET
• Device
• Extractables based on AET (20 µg/g)
• Leachable - simulated
• Air quality (ISO 18562 parts 2 and 3) (requested by FDA for Inbrija device, but not mentioned in
PQRI or USP <1664.1>)
ISO 18562 – Biocompatibility evaluation of breathing
gas pathways in healthcare applications
• Part 1: Evaluation and testing within a risk management process
• Part 2: Tests for emissions of particulate matter
• Part 3: Tests for emissions of volatile organic compounds (VOCs)
• Part 4: Test for leachables in condensate
• Scope
• Tests for emissions of VOCs from the gas pathways of a medical device, its part or accessories,
which are intended to provide respiratory care or supply substances via the respiratory tract to
a patient
In summary!
Establish device’s hypothetical worst case
available data conclude device
chemical release via compositional
Does risk assessment of
profiling
has acceptable risk
Estimate device’s chemical release via its
extractables profile
Determine the device’s actual chemical
release via its leachables profile
39
Questions and discussion
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