Integration of Risk Assessment and Chemical Characterization (MD&M Minn. 2017)

Integration of Risk Assessment and
Chemical Characterization
Russell Sloboda
Senior Scientist and Risk Assessment Specialist

» Nearly 40 yrs of experience in Medical
Device, Pharma, & Biotech Industry
• Material Qualification
• Biocompatibilty
• Microbiology
• Efficacy/ Surgical Research
• Toxicology Testing
• Extractables & Leachables
• Risk Assessment
• Consulting Services
» FDA Registered
» ISO 17025 Accredited
» GLP & GMP Compliant testing
» Global Organization
1
Toxikon Company Profile

Chemistry and Risk Assessment Capabilities Overview
CONFIDENTIAL2
» Chemistry Staff (Stephen Doherty, Ph.D., Laboratory Director):
8 study directors (12 - 37 years experience);
16 research assistants and senior chemists;
3 Quality Assurance, protocol, and document control specialists
» Toxicology Staff (Kevin Connor, Ph.D., DABT, TOX-SMART Director):
4 Toxicologists (each with 20+ years experience); 3 PhDs

Quality Credentials and Certifications
CONFIDENTIAL3
» ISO/IEC 17025: 2005 Accredited
» AAALAC Accredited
» FDA Registered
» USDA Registered
» OLAW Assurance
» MSPCA Permit
» Nuclear Regulatory Commission (Radiolabel)

4 CONFIDENTIAL
State of the Art Analytical Instrumentation
LC/MS Orbitrap
LC/MS Quad
GC/MS (autosampler injection)
Headspace GC/MS & GC/FID
Purge and Trap GC/MS
LC/UV, -FLD, -RI, -ELSD
ICP/MS
ICP-OES

5 CONFIDENTIAL

6 CONFIDENTIAL
In addition to instrumentation, Toxikon has
extensive laboratory equipment for virtually
any technique utilized in test article extraction

ANALYTICAL SCREENING TO IDENTIFY FULL RANGE OF UNKNOWNS
» Mass Spectral (MS) Advanced Identification Methods:
» TOXIKON chemists: Decades of experience in device characterization
by HS-GC/MS, GC/MS and UPLC-HRAM (accurate mass LC/MS)
» Custom libraries focus on compounds seen in elastomers/polymers
» NIST, mzCloud, and proprietary in-house mass spectral libraries
» Target compound databases - both spectrum & retention time match
» Robust identification using LC-HRAM is more powerful, but more
resource intensive
Reliable & Comprehensive Identification of Organic Substances

INTRODUCTION
» Purpose of chemical characterization & risk assessment
» Evaluate safety of biomedical products using chemical analysis
 Extractable chemical analysis data (medical devices)
 Leachables data (drug product container closure systems)
» Typical information used in a toxicological risk assessment
 Clinical indications for use, patient age, dosage, & duration
 Test article size & composition
 Detected concentrations & analytical method details
 Chemical structure analysis using QSAR software
 Literature studies of toxicity (animal or human data)
 Bioavailability (absorption, distribution, metabolism, and excretion)
 Risk-benefit factors (treatment efficacy)
8

Chemical Characterization:
What ISO 10993 Part 18 and Part 12 CAN offer?
» A framework to ensure use of appropriate chemical
characterization methods to evaluate device safety
» Requires knowledge of:
1. What was introduced during manufacturing
2. What classes of chemicals may leach
3. Analytical methods that can identify all classes of
chemicals & detect threshold levels of concern
4. Type of extraction best suited to generate representative
data for estimating patient exposure & toxicological risks
9

Chemical Characterization:
What ISO 10993 Part 18 and Part 12 CANNOT offer?
» Does NOT provide a blanket assessment to
eliminate biocompatibility testing
» Study design not specified; details are key to ensure:
1. Thoroughness of analytical techniques to detect broad range
of substance classes
2. Extraction conditions that allow data to be extrapolated to
assess exposures during clinical use
3. Material properties can affect extraction success & must be
taken into account in study design
10

Toxicological Risk Assessment: Regulatory Basis
» Regulatory Basis:
• ISO 10993-17 (2002) – Toxicological Risk Assessment. Establishment of Allowable
Limits for Leachable Substances
• Calculation of toxicological effects of chemical leachables & impurities
• Calculation of thresholds to ensure adequate testing for evaluating safety
• FDA/ICH ‘M7’ Guidance. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. 2015
• FDA Final Guidance (June 17, 2016). Use of ISO 10993-1, Biological Evaluation of
Medical Devices – Part 1: Evaluation and testing within a risk management process
» Other Guidance on the Risk Management Process:
• ISO 14971 (2007) – Application of Risk Management to Medical Devices
• ISO 15499 (2012) – Guidance on the conduct of biological evaluation within a risk
management process
11

12
» FDA Final Guidance (June 17, 2016). Use of ISO 10993-1,
Biological Evaluation of Medical Devices – Part 1: Evaluation
and testing within a risk management process.
» Increasing role for Risk Assessment (and Chemical
Characterization) – possibly even a prerequisite to
biocompatibility testing?
Use Risk Assessment in the design of a biocompatibility
testing program
 No mutagens or carcinogens identified
 No toxic leachables identified
 Omit long-term tox and cancer studies?
 Minimize genotoxicity testing?

Toxicological Risk Assessment - Objectives
» For Medical Devices, the Risk Assessment is:
13
• A complementary approach to biocompatibility testing
program
• Based upon a chemical-specific toxicity evaluation
• Relies on extractables/leachables data
» What are the questions it hopes to answer?
• What are residues, extractables, impurities of concern?
• What are permissible levels for these analytes?
• Could there be an unacceptable risk to the patient?
essential component?
--------------------------------
^

Correctly Categorize the Body Contact of a Device
» Surface Device
• Does it contact intact skin?
• Does it contact intact mucosal membranes?
• Does it contact breached or compromised surfaces?
» External Communicating Device (conduit)
• Does it have indirect blood contact?
• Does it contact tissue/bone/dentin?
• Does it have contact with circulating blood?
» Implant Device
• Does it have contact with tissue/bone?
• Does it have contact with blood?
14

Correctly Categorizing the Contact Duration of a Device
» Limited Exposure
• Less than 24 hours
» Prolonged Exposure
• 24 hours to 30 days
» Permanent Exposure
• Greater than 30 days
15
Longer exposure period can require
more rigorous exhaustive extraction

The Ties that Bind: Chemistry and Risk Assessment
CHEMISTRY:
Extractions:
» Conditions?
» Extraction media?
» Which components to
include?
Analysis:
» AETs
Data Reduction:
» How to present data?
16
RISK ASSESSMENT:
Understand the Device
and Its Use
Understand Frequency
and Magnitude of Use
Determine Data Needs

Basics of Extractables/Leachables (E&L)
Chemical Characterization

EXTRACTABLES & LEACHABLES DEFINITIONS
18
» Extractables:
Extractables are compounds that migrate from the contact surface
under more aggressive conditions such as elevated temperature,
extended contact time, or aggressive solvent system. Any component
that is added to or pulled from the device or the materials used to
make the device, including degradants and residuals.
What CAN come out.
» Leachables:
Leachables are compounds that migrate from the contact surface
under normal conditions of exposure. Leachables are usually subset
of extractables.
What DOES come out.

Extractable and Leachable (E&L) Analysis
» What are the targets?
• Chemical constituents of the device and its packaging
• Impurities/Contaminants in the materials
• Degradants of the material constituents
» How are they measured?
• Incubation of the representative device in a relevant medium
• Using appropriate extraction media
• Relevant, but rigorous conditions, e.g., 50ºC for 72 hrs
• Inclusion of components making patient contact
Chemical analysis should be – to the greatest extent possible
– conducted on final, finished (sterilized and packaged)
product.
19

Typical Extraction Conditions for E&L Analysis
20
Screening (Extraction) Refined (Leachability)
Article: Media
Ratio
3 or 6 cm2/mL, based on material thickness
Other options: irregular shape/porous materials (0.1 - 0.2 g/mL)
Extraction
conditions
37, 50, 70°C
24 or 72 hrs
37°C for heat susceptible
materials
real-world shelf life, temperature
Option to simulate accelerating
aging
Extraction
media
Polar: Saline, Purified water,
Acidic or Alkaline pH water
Non-polar: Hexane
Mixed: An alcohol (20 - 50%)
Depends on drug product
formulation and excipients in
contact with device: (aqueous,
acidic, alkaline, nonpolar)
Selection of
components
Components that make direct patient contact or which directly
contact drug formulations/solutions administered to the patient

Extraction Methodology: Leachables Released vs. Time
Take into account the duration of use, type of use
• Single extraction vs. consecutive, exhaustive extractions
• If a risk assessment uses the former to estimate recurrent
daily exposures it most likely will yield an over-estimate:
21
0
2
4
6
8
10
12
14
0 50 100 150 200 250 300 350
Result(mg/device)
Hours Extraction
Leachable Mass From One Extraction
Exhaustive 24 Hrs

Gas Flow Pathway Analysis: Volatiles Released vs. Time
Simulated use, 48-hr. gas flow analysis by TD-GC/MS
22

ISO 18562: test for SVOC/NVOC extractables, VOC gas flow analysis
Breathing Circuit Analysis: Extraction, Headspace, Gas Flow
23

What Can Affect Migration?
Factors that affect leaching (rate/amount & final product)
» Polymer type: Tg
» Polymer crystalinity: > amorphous, ↑ migra on
» Additive size: ↑ MW, ↓ rate of diﬀusion
» Polarity: Like dissolves alike
» Processes: Aging, Sterilization, Solvating steps
» Temperature: ↑ temp, ↑ diﬀusion
» Contact Solution/Environment
» Environment of Concern: aqueous (polar), organic, apolar...
» Solvatation
24
Diffusion

Analytical Evaluation Threshold
» Analytical Evaluation Threshold = AET.
» Translates the leachables threshold required for further
toxicological evaluation into a concentration for analytical
methods
» Ensures the laboratory defines a minimum detection level
to ensure adequate detectability for the assessment of
material safety
» The AET is a “cut-off” concentration level for analytical
techniques
25

» AET concept is not new, but has undergone refinement
over last two decades
» AET requires an anchor in an appropriate Safety Concern
Threshold (SCT)
» SCTs are derived for different routes of exposure to
toxicants (oral, inhalation, and parenteral/systemic)
» SCTs are based on Toxicological Thresholds of Concern
(TTCs) and are distinct for genotoxicity (mutagenic
carcinogens), chemicals that are sensitizers, & general
(noncancer) toxicity
26

» SCT for genotoxicity (ICH M7): ranges from 1.5 to 120 µg/day.
SCT is lowest for longer duration exposures (Haber’s rule)
» SCT for sensitization (PQRI, 2013): 5 µg/day. SCT does not
necessarily scale to a higher value for shorter duration exposures
» SCTs for noncancer effects (general toxicity) depend on Hazard
Class I, II, or III, as determined by chemical structure (Cramer, 1978)
» Thresholds for adverse noncancer effects depend on toxicokinetics
and toxicodynamics (absorption, distribution, metabolism, excretion).
» Is 3 mg once every 3 days as potent as 1 mg daily doses for 3 days?
27

Analytical Evaluation Threshold: Calculation
28
TTC
VD
D
UFAET
extc
ext








AET Analytical evaluation Threshold (in µg/mL or mg/L) – based on the most
stringent of the SCTs for mutagenicity, sensitization, or general (noncancer)
toxicity
TTC Threshold for further Toxicological Evaluation, as applicable for the Device
exposure type (µg/day)
UF Uncertainty Factor (a default value of 0.5 should be considered when utilizing
semi-quantitative methods)
Dext # of Devices present in the extraction volume of Vext
Dc # of Devices clinically utilized in a day (Dc ≥ 1 unless study conditions provide
adequate resolution in release kinetics of a prolonged or permanent
exposure device and kinetics demonstrate linear release)
Vext Extraction Volume (in mL)
Note: Both Vext & Dext must be resolved accordingly to account for any extract
modifications such as concentrations and/or dilutions prior to analysis

AET – Instrument Detection Threshold Illustrated
29
Requirement to detect levels > AET
Note: Actual AET is often based on peak area, not height

Analytical Evaluation Threshold: Improvements
What if method(s) is not sensitive enough to achieve AET?
» Adjust extraction methodology (e.g., extraction ratio)
» Increase the extract solvent concentration factor
» Adjust Analytical Methods:
• SIM – Selected Ion Monitoring – Can enable detection at levels
10-100X lower than standard screen
• Method becomes targeted rather than screening
30

Extractable/Leachable Chemical Classes

Extractable/Leachable Chemical Classes
32
Potential
Inorganic
Chemicals
of Concern
Metals
If you don’t look for it, you won’t find it!

33
Compounds that may elicit effects include:
Potential Sources of Leachables
» Polymer oligomers
» Polymer degradation products
» Polymer/Rubber Additives
Antioxidants
Photostabilizers
Plasticizers
Lubricants
Acid Scavengers
Pigments/Colorants
Carifying/Nucleating Agents
Cross Linking Agents (Rubbers)
Initiators (Rubbers)
Accelerators (Rubbers)
» Polymer additive degradation products
» Impurities in polymer additives
» Catalysts
» Polymer residues (e.g. monomers)
» Adhesives
» Manufacturing impurities/residuals
Extractables and Leachables Sources
CH3H
O
H3C
H3C CH3
OH
H3C
O
H3C
CH3
CH3
H3C
CH3
O
H3C
OH
O
H3C
O
CH3
OO
O
OO
O
O
O
O
O
O
O
CH3
CH2
H3C CH3
CH3H3C
CH2
H3C CH3
CH3H3C
Br
CH3
H3C CH3
CH3
CH2
H3C
H3C CH3
CH3
Cl
O
O
O
O
O
O
O
O
CH3
CH3

34
Antioxidants
Function: assuring protection against thermal and oxidative degradation during
processing and during shelf life of polymer
(Sterically Hindered Phenols & Organic Phosphites/Phosphonates are mostly used)
European Pharmacopoeia lists a.o. the following Antioxidants:
BHT Hostanox 03
Irganox 1010
Irganox 1330
Irgafos 168
Irganox 3114 Irganox 1076
OH
CH3 O
O
O
O
OH
OH
O
O
O
O
HO
HO
CH3
CH3
H3C
OH
OH
HO
HO
O
O
CH3
O
P
OO
N
N
N
O
O
O
OH
OH
HO
H3C
O
O
O
OH
O
CH3
HO
OH
OH

35
Plasticizers
Function: Gives the plastic flexibility and durability
Plasticizer requirements:
o Low Water solubility (low extractibility)
o Stability to heat and light
o Low Odor, taste and toxicity
O
O
O
O
CH3
CH3
CH3
CH3
O
O
O
O
CH3
CH3
CH3
CH3
O
OH3C
H3CDiethylhexylphthalate (DEHP)
TOTM
O
O
O
O O
O
O
O
O
O
O
O
ESBO
OH
O
H3C
Stearic Acid
C4H9
O
O
C4H9
C2H5
O
O
C2H5
Diethylhexylsebacate
H3C O
O CH3
O
O
H3C
CH3
Diethylhexyladipate

36
Photostabilizers
Function: Protects the Polymer from UV-Degradation (exposure to sunlight)
Tinuvin 328 Tinuvin 770
N
N
N
CH3
H3C
HO
CH3
H3C
CH3
CH3
O
ON
H3C CH3
H
H3C
H3C
O
O N
H3C CH3
H
CH3
CH3
O
O
O
N
O
O
O
O
N
O
*
*
n
Tinuvin 622

37
Slip Agents
Function: reduce the “friction” or “film adherence”, important when producing bags
from films
Erucamide Oleamide
CH3
NH2
O
CH3
NH2
O
Remark:
because of their specific properties, Slip agents will be widely
detected as Leachables!

38
Acid Scavengers
Function: Protects the polymer from “acid attacks” through conversion of strong
acids (high degradation impact) to weak acids (low degradation impact)
Examples: Ca(Stearate)2 + 2HCl  CaCl2 + Stearic acid
strong acid weak acid

39
Pigments / Colorants
Function: Gives the polymer/rubber the desired color (cosmetic)
Examples: Carbon Black (PAHs), TiO2 (white), Fe2O3 (red), Pigment Green 07
N
N
Cl
Cl
Cl
Cl
O
Solvent Red
N
OH
O
O
Solvent yellow 114
O
O
N
N
H
H
H3C
H3C
Solvent Green 03

40
Clarifying Agents (Nucleating Agents)
Function: by controlling the crystallization (nucleation) when cooling off polymer,
it becomes transparent.
NC-4 Millad 3988
O
O
O
O
C2H5
C2H5
OH
HO
O
O
O
O
CH3
H3C
OH
HO
H3C
CH3

Various residues from the production process:
Solvents Monomers Catalysts
41
H3C
CH3
H
H
H3C
O
CH3
CH3
H3C
OH
CH3
CH2
N
O
H
CH3
O
H2C
O
CH3
Styrene
Hexane
DHN
MIBK
IPA
Cyclohexane
Caprolactam
Methyl methacrylate
H2C
CH2
CH3
Isoprene
Titanium
Zirconium
Cobalt
Aluminum
...

42
OLIGOMERS: Examples
PET PBT Nylon 6 Nylon 6.6 Butyl Rubber Polyester
N
N
O H
OH
NHHN
O O
N
N
N
O
O
O
H
H
H
HN
HN
O
O
NH
NH
O
O
HN
H
N
H
N
N
H
N
H
NH
O
O
O
O
O
O
O
O O
O
O
O
O
O
OO
O
OO
O
O
O
O
O
O
O
CH3
CH2
H3C CH3
CH3H3C
CH2
H3C CH3
CH3H3C
Br
CH2
H3C CH3
CH3H3C
Cl
CH3
H3C CH3
CH3
H3C
CH2
H3C
H3C CH3
CH3
CH3
H3C CH3
CH3
CH2
H3C
H3C CH3
CH3
Cl
CH3
H3C CH3
CH3
CH2
H3C
H3C CH3
CH3
Br
OO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
OH
O
O
O
O
O
O
HO
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
CH3
O
O
O
O
CH3
CH3
O
O
O
O
O
O
O
O
O O
O O
O
O
O
O
H3C CH3
H3C CH3
O
O
O
O
O
O
O
O
CH3
CH3
adhesive
Other typical oligomers from Silicone, PP, PE-adhesives ...

Polymer degradation Compounds
Origin: Oxidative degradation of the polymers
(when the polymer is not properly stabilized via antioxidants)
Example of Polymer Degradation Compounds from Polypropylene
43
H OH
O
H3C OH
O
CH3H
O
H3C OH
CH3
CH3
H3C OH
H3C
H3C CH3
OH
H3C
O
H3C
CH3
CH3
H3C
CH3
O
H3C
OH
O
H3C
O
CH3
H CH3
O
CH3
CH3CH3
H3C
CH3H3C CH3CH3
CH3
H3C CH3
CH3 CH3CH3CH3H3C
H3C
CH3H3C CH3
CH3
Acids Aldehydes Alcohols Ketones Polymer
Fragments

44
O
O
O
HO
OH
O OH
O
OH
O
HO
O
O
CH3
O
OH
O
O
CH2
O
O
Irganox 1010
O
O
O
O
OH
OH
O
O
O
O
HO
HO
O
O
O
O
OH
OH
O
O
O
O
HO
HO
O
O
O
OH
O
O
O
O
HO
HO
O
O
O
O
O
OH
O
O
O
O
HO
HO
OH
O
O
O
O
O
OH
O
O
O
O
HO
HO
....
Example Degradation of Irganox 1010
SMALL degradation Compounds LARGE degradation Compounds

» EXAMPLE: Degradation of Irgafos 168
(also other degradation compounds for Irgafos 168 are known)
45
O
P
OO
O
P
OO
O
+ ROOH + ROH
HO
Irgafos 168 Irgafos 168 Oxide

Toxicological Risk Assessment
Applied to Chemical Characterization Data

Risk Assessment of Medical Devices
Two complimentary, but not overlapping,
areas that the FDA expects the Sponsor to
evaluate via risk assessment:
BIOLOGICAL ASSESSMENT (ISO 10993-1)
Evaluation and testing within a risk management process
TOXICOLOGICAL ASSESSMENT (ISO 10993-17)
Establishment of Allowable Limits for Leachable Substances
47 CONFIDENTIAL

48
» FDA Final Guidance (June 17, 2016). Use of ISO 10993-1,
Biological Evaluation of Medical Devices – Part 1: Evaluation
and testing within a risk management process.
» Increasing role for Risk Assessment (and Chemical
Characterization) – possibly even a prerequisite to
biocompatibility testing?
Use Risk Assessment in the design of a biocompatibility
testing program
 No mutagens or carcinogens identified
 No toxic leachables identified
 Omit long-term tox and cancer studies?
 Minimize genotoxicity testing?

Toxicological Risk Assessment
First Step - Understand what is Delivered to Patient
49
1. Identification of compounds that
leach from the device
2. Quantify compounds detected
3. Apply E&L data to estimate patient
exposure

Estimating Exposure to Leachables
Extrapolate E&L data to estimate patient exposure
» Consider exposure type: contact route affects toxicity studies to
select as relevant and need for oral bioavailability adjustment
 Parenteral or systemic exposure (IV, subcutaneous, or implants)
 Inhalation exposure (breathing gas ventilation or nebulized aerosols)
 Oral exposure (oral medications or dental devices)
 Dermal absorption (transdermal patches, wound dressings, gels)
» Frequency of use (daily or intermittent)
» Duration of use (short term, prolonged, or permanent)
» Extrapolate release from test article size extracted to clinical
device size
» Convert analytical data units from µg/mL to µg/device
50

Establishing Chemical-Specific Toxicity Thresholds
» Derive toxicity-based thresholds: Tolerable Intake (TI, µg/kg-day)
and Tolerable Exposure level (TE, µg/day).
 TI represents a maximal dose at which adverse effects are not expected (with a
margin of safety)
 Based on a toxicological “point of departure”, identified from a literature search of
available toxicology studies. Expressed as a No Observed Adverse Effect Level
(NOAEL) or Lowest Observed Adverse Effect Level (LOAEL).
 Modifying Factor (MF) is applied with several Uncertainty Factors (UFs)
 TI = (NOAEL or LOAEL) / Modifying Factor (MF)
 Where, MF = (UF1 × UF2 × UF3)
51

Establishing Chemical-Specific Toxicity Thresholds
» Tolerable Exposure level (TE, in µg/day) represents an adjusted
tolerated exposure level of a chemical within a population subset, and
incorporates a Utilization Factor (UTF).
 TE = TI × mB × UTF
 Where:
 mB = Body Weight
 UTF = Concomitant Exposure Factor (CEF) × Proportional Exposure Factor (PEF)
 UTF account for variables potentially impacting clinical exposure, including
frequency of exposure and potential exposure to similar extractables from other
sources.
» Note: FDA does not accept general use of the PEF as defined in ISO
10993-17.
52

Are Estimated Exposure Levels Safe?
» TE is compared to the estimated daily exposure (in µg/day)
» Comparison is expressed as a ratio, or Margin of Safety (MOS):
 MOS = (TE) / (Daily Exposure)
 A MOS greater than 1.0 indicates the estimated exposure is below the TE and
unlikely to present any adverse effects
» Hypothetical risk estimates typically will not represent actual risks of
adverse effects in a patient population
» Overestimation of risk is due to conservative aspects of risk analysis:
 rigorous extraction conditions employed
 conservative assumptions in exposure assessment
53

Optimizing Study Design for Risk Assessment

How to Optimize E&L Study Design for Risk Assessment
55
» Relevance of E&L test results depends on good study design
» TOXIKON risk assessors provide input to study design to
ensure useful data generated
• Explore range of most appropriate extraction media
• Optimize conditions and duration of extraction for device category
» Where E/L analysis can go astray...
• Objectives are not aligned to risk assessment goals
• Incorrectly attempting to simulate aging/degradation of product
• Inclusion of non-patient contacting surfaces

WHAT DEVICE COMPONENTS SHOULD BE TESTED?
Analyze Components Separately or as Combined System? (affects exposure estimate)
 Separate chemical characterization analysis for components w/ different contact duration
 Understand potential toxicity of new materials in modified components. If a new material is
contemplated, can test it separately to demonstrate safety and suitability for an existing device
 Combining multiple components into one extract for analysis might dilute the amount of
individual components being extracted.
 Relative proportion of extract that originates from each component should match clinical use
Secondary packaging (e.g., ink label or pouch) - Likelihood of migration and relevance
for testing with appropriate type(s) of analysis
 Migration from secondary packaging into device (such as drug vial) more likely for VOCs
 Secondary migration less likely if primary container highly impervious (e.g., glass vial), or if
materials are not in close contact

SELECTING APPROPRIATE E&L TESTING CONDITIONS
Extraction solvent should contact surfaces that will directly contact the body or
solutions introduced into the body
 Fluid path extraction if inner vs. outer surfaces are different materials
 One-sided extraction (example: leachables from a transdermal patch)
 Traditional cut and cover extraction used for homogenous materials.
Multiple Extraction Solvents: several solutions capture a larger range of leachables
 ISO/FDA: Use nonpolar and polar solvents (more than one pH if clinically relevant)
 Alcoholic mixtures mimic solution properties for clinical contact with blood or contact with
a drug formulation of like polarity
 A drug excipient solution can mimic solution contact during clinical use
Extraction Temperatures/Duration:
 Permanent implants – need exhaustive extraction duration to estimate total release
 Aggressive conditions should not cause component material degradation
 Leachables tests of drug stored in container system under shelf life conditions or accelerated
 Flow-through simulation using realistic conditions: if drug merely flows through device

ANALYTICAL METHODS- to maximize useful data
Which Analytical Tests?
 Many types of VOCs, SVOCs, NVOCs found in elastomers/polymers
 Metallic substances - leachables in glass, metal, or polymer materials (less often high-risk)
 Non-volatile residue (NVR) - surrogate endpoint to measure exhaustive extraction
 FTIR indicates polymer type (not chemical-specific data for risk estimation)
Mass Spectrometry Method Options:
 High Resolution Accurate Mass (HRAM) – better able to ID unknowns vs. Low-Resolution MS
 Mass spectral libraries: Fewer compounds for LC/HRAM (~2K to 5K) than for GC/MS (>200K).
 Best accuracy using target compound analysis (requires calibration standards) vs. screening
VOC options:
 VOCs in extracts can be analyzed by GC/MS by (1) purging VOCs from extract then GC/MS, or
(2) direct injection of headspace from extract vial (P&T better detection limits & accuracy)
 Component material heated in sealed vial w/ injection of headspace can release greater total
mass of VOCs than solvent extraction
 ISO 18562 addresses devices that deliver gas into patient airways. Requires three methods:
solvent extraction, gas flow sampling, & particulate testing. FDA hasn’t approved 18562.

Options to enhance sensitivity:
 Lower detection limits achievable by extract evaporation/concentration (to meet AET)
 Selected Ion Monitoring (SIM) can achieve 10X to 100X improvement (to meet AET)
 Chemical classes with low sensitivity: Nitrosamines, carboxylic acids, diols, and alcohols
are derivatized with trimethyl silane for better detection. Not critical for compounds with low
toxicity (fatty acids & simple alcohols) or degradants of rarely used additives (nitrosamines)
Metals analysis – Specify target metals list up-front
 Comprehensive target analyte list (USP List) often needed for testing drug container systems
 ICP/MS has lower detection limits than ICP/OES. However, ICP/MS interferences
can occur with high excipient levels, and in isolated cases causes bias (e.g., Si)

60
 Understanding a device’s intended use:
 Facilitates proper study design for extractables/leachables testing
 Provides key input used in the toxicological risk assessment
 Coordination between chemists and toxicologists ensures that:
 Analytical detection limits are adequate for a comprehensive risk assessment
 The conditions of extraction are appropriate for estimating patient exposure
 The scope of the analysis includes all compound classes of potential interest
 Conducting a proper risk assessment for regulatory approval requires:
 Consideration of intended use of the device (type of body contact, duration, etc.)
 Knowledge of the potential patient population (age, body weight, etc.)
 Research into available toxicity literature (chronic toxicity, mutagenicity, bioavail.)
 Professional judgment to select appropriate NOAELs, uncertainty factors, etc.
 Ability to weigh the relevance of different types of analytical data (solvents, etc.)
 Consideration of risks vs. benefits in formulating a conclusion as to overall safety
TOXIKON chemists and toxicologists work closely together in order to
optimize E&L study design and ensure regulatory approval
Conclusions – Key Elements in the Integration of
Risk Assessment and Chemical Characterization

Questions and Comments
61
If you have any questions on the full range of chemistry and
biocompatibility testing services offered by TOXIKON Corporation,
*** Please stop by booth # 1929 ***
Thanks for attending !
15 Wiggins Ave, Bedford, MA 01730
Presenter:
Russell Sloboda, Sr. Scientist and Risk Assessment Specialist
Russell.Sloboda@Toxikon.com
Stephen Doherty, Ph.D., Laboratory Director
Stephen.Doherty@Toxikon.com
Kevin Connor, Ph.D., DABT, TOX-SMART Director
Kevin.Connor@Toxikon.com

Integration of Risk Assessment and Chemical Characterization (MD&M Minn. 2017)

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