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www.Eurofins.com/medical-device
Understanding Extractables and
Leachables Testing for ENDS
products
Charles Ducker, Ph. D.Principal Chemist/Group Leader
Extractables & Leachables Testing
Overview
❖ Background – What are Extractables and
Leachables
❖ Regulatory guidance
❖ Designing E&L experiments
❖ Toxicological assessment
❖ Conclusions
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Key Definitions
Extractables
Chemical compounds that are extracted from a product contact material
when exposed to an appropriate solvent under exaggerated conditions of
time and temperature
Leachables
Chemical compounds that migrate into a e-liquid formulation, or into the
vapor, from any product contact material as a result of direct contact under
typical use and/or storage conditions
• Likely to be found in the bulk e-liquid and finished e-liquid product
• Arise from interaction of material or system during intended use - vapor
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Extractables and Leachables
Extractables
Leachables
Additives
Impurities
Polymer Components
Degradation Products
Known Extractables
Extractable e-liquid Formulation/vapor Interactions
Extractables Modified by Conditions of Use
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Extractables
What Leads to Extractables?
❖ Many extractables are
additives
• Antioxidants
• Plasticizers
• Lubricants
• Heat & UV Light Stabilizers
• Colorants
• Coating Agents
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❖ Other sources of extractables• Monomers & Oligomers
• Elastomeric Degradation Products
• Surface Residues
• Inks, and Adhesives from Labels
❖Container Closure Systems
• Storage Bags, Bottles & Caps, Ampoules
❖Delivery Devices
• Nebulizers, Inhalers & ENDS
❖Secondary Packaging
• Foil Pouches & Boxes
• Container Labels
❖Manufacturing Equipment
• Storage & Mixing
• Tubing, Gaskets, Valves, & Connectors
Leaching can occur at
multiple steps of the
manufacturing process• Up stream
• Down stream
• Intermediate Storage
• Packaging
Possible Sources of Leachables
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Risk from Leachables
Leachable compounds may:❖ Increase the impurity level of your product to an unacceptable level
❖ React with one or more of the product components
❖ Cause inactivation of ingredients, precipitation, absorption, pH
shift, and/or discoloration
❖ Increase toxicity of your product
Potential to become a leachable increases as the product comes
closer to final formulation and packaging steps
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Regulatory Expectations
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Guidance Document – FDA
Premarket Tobacco Product Applications for Electronic
Nicotine Delivery Systems
• “A description of product container closure system…”
• “Storage and stability information for the new tobacco product…”
• “Extractable leachable information from the aerosolizing
apparatus”
• “A conclusion as to whether there is a toxicological concern with
respect to the ingredients, constituents, flavors, humectants…”
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Guidance from USP
❖ USP <660> Glass
❖ USP <661.1> Plastic Materials of Construction
❖ USP <661.2> Plastic Packaging Systems for Pharmaceutical Use
❖ USP <1663> Assessment of Extractables Associated with
Pharmaceutical Packaging/Delivery Systems
❖ USP <1664> Assessment of Drug Product Leachables
Associated with Pharmaceutical Packaging Delivery Systems
❖ USP <1664.1> Orally Inhaled and Nasal Drug Products
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Guidance Document – ISO 10993
❖ ISO 10993 Biological Evaluation of Medical Devices
(2012)
• Document is a guidance and is not prescriptive
• 20 parts – one part for each type of analysis
• Not all parts are required for every type of medical device
“This guidance document was developed to assist industry in preparing Premarket Applications
(PMAs), Humanitarian Device Exceptions (HDEs), Investigational Device Applications (IDEs),
Premarket Notifications (510(k)s), and de novo requests for medical devices that come into direct
contact or indirect contact with the human body in order to determine the potential for an
unacceptable adverse biological response resulting from contact of the component materials of the
device with the body.” - ISO 10993-1
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Guidance - Regulatory Agencies
❖ EMEA/205/04: Guideline on Plastic Immediate Packaging
Materials (2005)
❖ CFR Title 21 Part 211.94 and 211.65 Containers, closures and equipment should not be “reactive, additive, or absorptive
so as to alter safety, identity, strength, quality, or purity of the drug product”
❖ FDA CDER/CBER Guidance for Industry: Container
Closure Systems for Packaging Human Drugs and
Biologics (1999)
These documents are not prescriptive as to how to design the study or
perform the testing.
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Designing Extractables and
Leachables Studies
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Staging an E&L Study
Controlled Extraction Study
Generate extractable profileIncrease knowledge of materialUtilize worst case extraction conditions
Simulation Study
Evaluate potential leachablesUtilize conditions close to real usePerform safety/risk assessment
Leachable StudyDevelop and validate specific analytical methodsPlace product on stability storageMonitor targeted leachable compounds
Profile should represent compounds
that could potentially leach into the
sample matrix.
The simulation study sub-list of
extractables compounds are the probable
leachables, which are then evaluated to
determine impact to the product.
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Considerations
❖ What to test
❖ Container closure system
❖ Final packaging
❖ Manufacturing components
❖ What solvents should be used?
❖ How do we extract – time/temperature?
❖ What techniques to use to analyse the extracts?
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Initial Extractables Evaluation
❖ Compile a list of all materials utilized in the process
❖ Does the material come into direct contact with in-
process material or product?
• If no – no action required
• If yes – Collect all available information on composition of
material and potential extractable compounds from the
supplier
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Perform Material Risk Evaluation
❖ Location of Material in Process
• Closer to final container closure – higher risk
❖ Contact Temperature and Time
• Longer time and higher temp – higher risk
❖ Surface Area of Material
• Larger area of contact – higher risk
❖ Pretreatment Steps Performed
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Risk Assessment - Dosage Form
Dosage Form and Route of Administration
Degree of Concern
Associated with Route of
Administration
Likelihood of Packaging Component-Dosage Interaction
High Medium Low
Highest Inhalation Aerosols and Sprays Injections and Injectable
Suspensions: Inhalation Solutions
Sterile Powders and Powders for
Injection: Inhalation Powders
High Transdermal Ointments and Patches Ophthalmic Solutions and
Suspensions; Nasal Aerosols and
Sprays____
Low Topical Solutions and Suspensions;
Topical and Lingual Aerosols; Oral
Solutions and Suspensions____
Oral Tablets and Oral (Hard and Soft
Gelatin) Capsules; Topical Powders;
Oral Powders
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Sample Preparation
❖ Selection of Representative Portion
• Each component type should be extracted separately
• One representative for each material type
• Representative portion of joint and/or seal
• Composite material as finished material
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Sample Preparation
❖Extraction Solvents:• Aqueous Solvents: water, HCl/KCl Buffer (pH 3), Phosphate
Buffer (pH 10)
• Non-Polar Organic Solvents: Hexanes
• Polar Organic Solvents: Ethanol, Isopropanol, Methanol
❖Extraction Time/Temperature• Reflux – 30 minutes.
• Exaggerate normal process/storage conditions, but do not
be overly extreme
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Mode of Extraction
❖ Common techniques: reflux, sonication, incubation,
soxhlet, ASE
• Avoid decomposition or breakdown products
❖ Mode of extraction will be dependent on use of
component
• Materials with long contact time (CCSs) → reflux or sonication
• Materials with short contact time (Device) → incubation/puffer
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Other Considerations
❖ Surface area to volume ratio (cm2/mL)
• 6:1, 3:1 or greater – depending on the guidance
− ISO 10993, USP
❖ Pretreatment of Component
• Material should be in same condition/state as actual use
❖ Agitation or Recirculation
• Draft USP <665> recommends agitation
• Filters, tubing, etc. may require recirculation
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Analyzing the Extracts
❖ Analytical techniques must be able to detect and
monitor a wide range of chemicals
❖ Techniques must be able to achieve required level of
sensitivity
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Analyzing the Extracts
❖ Common Techniques:
• HPLC-UPLC/MS with PDA (non-volatile organics)
– Utilize both Electrospray and APCI in positive and negative mode
• GC/MS Direct Injection Sample Introduction (semi-volatile organics)
• GC/MS Headspace Sample Introduction (volatile organics)
– May be performed on aqueous extracts and also on dry component
• ICP (inorganics and metals)
– Either ICP/MS or ICP-OES dependent on required sensitivity – performed on extracts or
digests of solid components
• IC or Indirect UV (anions)
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Determining Sensitivity Requirements
❖Evaluate use of product – determine doses per day, doses per
device, and weight of the device
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Example (valve)• 60 actuations per device
• 4 actuations per day
• 0.25 g valve (1 Valve per device)
0.15 ug/day x 60 actuations/device = 2.25 ug/device
4 actuations/day
2.25 ug/device X 1 valve/device / 0.25 g/valve = 9 ug/g
Build in an uncertainty factor of 50% = 4.5 ug/g
Simulation Studies
❖ Performed using final product, placebo, or similar
model solvent
❖ Extraction conditions should mimic
• Use or accelerated aging conditions
❖ Data evaluated for compounds observed during
the controlled extraction testing
❖ Compounds identified from simulation studies are
then assessed for their impact on product safety
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❖ Study performed on finish product in the
final container closure
❖ Study duration based on shelf life of
product
❖ Testing can be performed with validated
methods – Specific compounds
❖ Testing can also be performed with
general screening methods
Monitoring For Leachables
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❖ Study performed on Vapor:
• Aerosol mass - vapor
• VOC-screening - vapor
• Aldehydes - vapor
• Heavy metals - vapor
• Diacetyl in e-liquids and - vapor
• Phtalates in - vapor (17 Phtalates)
• PAHs in - vapor (16 types of PAHs)
Monitoring For Leachables
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Knowledge Space
Design Space
Control Space
AB
C
D
E
F G
HI
JK
LMNP
Extractables
C
E
L
Leachables
A
C
E
H JK
L
MLeachables
stabilityevaluation
Each step of the study lets you
target in on the compounds that
must be controlled in your product
Figure courtesy of ELSIE and Eli Lilly
QbD and E&L Control Space
Controlled Extraction Study
Simulation Study
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Toxicology Assessment
Perform a toxicological risk assessment of the data from the controlled
extraction and simulation studies to determine what compounds should
be monitored during a leachables stability study
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Toxicity
“Everything is poison, there is poison in everything. Only the
dose makes a thing not a poison” (Paracelsus)
Lethal Doses of Common Substances
Substance Grams/150 lb Human
Nicotine 3.6
Caffeine 13
Tylenol 23
Aspirin 84
Advil 85
Table Salt 272
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Tolerable Intake (TI)The TI is an estimate of the amount of a substance, expressed on a body
weight basis that can be taken without appreciable health risk
Select NOAEL (no observed adverse
effect level) from toxicology studies
Derive Uncertainty Factors (based on
interindividual, interspecies,
data quality variables, etc.)
TI = NOAEL / UFs
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Example of TI Derivation
NOAEL = 30 mg/kg/day (from Tox Data)
UF1 (interindividual) = 10 (default)
UF2 (interspecies) = 10 (default)
UF3 (data quality) = 10
MF = UF1 * UF2 * UF3 = 1000
TI = NOAEL / MF = 0.03 mg/kg/day
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Can be up to 6
uncertainty factors
Summary
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New regulatory guidelines require extractables and
leachables testing
❖ Difference between an extractable and a leachable
❖ Available guidance documents – No specifics
❖ How we design an extractable and leachable experiment
❖ How do we use the data
Thank You All! – Questions?
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