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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