integration of risk assessment and chemical characterization (md&m minn. 2017)
TRANSCRIPT
Integration of Risk Assessment and Chemical CharacterizationRussell SlobodaSenior 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
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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)
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State of the Art Analytical InstrumentationLC/MS OrbitrapLC/MS Quad
GC/MS (autosampler injection)Headspace GC/MS & GC/FIDPurge and Trap GC/MSLC/UV, -FLD, -RI, -ELSD
ICP/MSICP-OES
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State of the Art Analytical Instrumentation
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State of the Art Analytical Instrumentation
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)
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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 manufacturing2. What classes of chemicals may leach3. Analytical methods that can identify all classes of
chemicals & detect threshold levels of concern4. Type of extraction best suited to generate representative
data for estimating patient exposure & toxicological risks
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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
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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
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Toxicological Risk Assessment: Regulatory Basis
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» 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:
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• 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?
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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
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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?
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RISK ASSESSMENT:
Understand the Device and Its Use
Understand Frequency and Magnitude of UseDetermine Data Needs
Basics of Extractables/Leachables (E&L)Chemical Characterization
EXTRACTABLES & LEACHABLES DEFINITIONS
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» 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
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Screening (Extraction) Refined (Leachability)Article: Media Ratio
3 or 6 cm2/mL, based on material thicknessOther options: irregular shape/porous materials (0.1 - 0.2 g/mL)
Extraction conditions
37, 50, 70°C24 or 72 hrs37°C for heat susceptible materials
real-world shelf life, temperatureOption to simulate accelerating aging
Extraction media
Polar: Saline, Purified water, Acidic or Alkaline pH waterNon-polar: HexaneMixed: An alcohol (20 - 50%)
Depends on drug product formulation and excipients incontact 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. TimeTake 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:
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02468
101214
0 50 100 150 200 250 300 350
Result
(mg/de
vice)
Hours Extraction
Leachable Mass From One Extraction
Exhaustive 24 Hrs
Gas Flow Pathway Analysis: Volatiles Released vs. TimeSimulated use, 48-hr. gas flow analysis by TD-GC/MS
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ISO 18562: test for SVOC/NVOC extractables, VOC gas flow analysisBreathing Circuit Analysis: Extraction, Headspace, Gas Flow
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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
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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
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Analytical Evaluation Threshold» 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
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» 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 HazardClass I, II, or III, as determined by chemical structure (Cramer, 1978)
» Thresholds for adverse noncancer effects depend on toxicokineticsand toxicodynamics (absorption, distribution, metabolism, excretion).
» Is 3 mg once every 3 days as potent as 1 mg daily doses for 3 days?
Analytical Evaluation Threshold
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Analytical Evaluation Threshold: Calculation
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TTCVDD UFAET
extcext
AET Analytical evaluation Threshold (in µg/mL or mg/L) – based on the most stringent of the SCTs for mutagenicity, sensitization, or general (noncancer) toxicityTTC 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 VextDc # 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
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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
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Extractable/Leachable Chemical Classes
Extractable/Leachable Chemical Classes
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Potential Inorganic Chemicals of Concern
Metals
If you don’t look for it, you won’t find it!
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Compounds that may elicit effects include:Potential Sources of Leachables» Polymer oligomers» Polymer degradation products» Polymer/Rubber Additives
AntioxidantsPhotostabilizersPlasticizersLubricantsAcid ScavengersPigments/ColorantsCarifying/Nucleating AgentsCross 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
CH3HO
H3CH3C CH3
OH
H3CO
H3C CH3
CH3
H3C CH3O
H3C OHO
H3CO
CH3 OO
O
OO
OO
O
O
O
O
O
CH3
CH2
H3C CH3CH3H3C
CH2
H3C CH3CH3H3C
Br
CH3
H3C CH3 CH3
CH2
H3CH3C CH3
CH3
Cl
O
O
O
O
O
O
O
O
CH3
CH3
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AntioxidantsFunction: 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 168Irganox 3114 Irganox 1076
OH
CH3 OO
OO
OH
OHO
OO
O
HO
HO
CH3
CH3
H3C
OH
OH
HOHOO
OCH3
OP OO
NN
NO
O
O
OH
OH
HO
H3CO O
O
OH
O CH3HO
OH
OH
Extractables and Leachables Sources
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PlasticizersFunction: Gives the plastic flexibility and durabilityPlasticizer requirements:o Low Water solubility (low extractibility)o Stability to heat and lighto Low Odor, taste and toxicity
OO
OO
CH3
CH3
CH3
CH3
OO
OO
CH3CH3
CH3
CH3
OOH3C
H3CDiethylhexylphthalate (DEHP)TOTM
O OO
O O
O
O
OO
O
O
O
ESBO
OHO
H3C
Stearic Acid
C4H9 O O C4H9C2H5
O
O
C2H5
Diethylhexylsebacate H3C O O CH3
O
OH3C
CH3
Diethylhexyladipate
Extractables and Leachables Sources
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PhotostabilizersFunction: Protects the Polymer from UV-Degradation (exposure to sunlight)
Tinuvin 328 Tinuvin 770
NN
N
CH3H3CHO
CH3H3C
CH3
CH3
OON
H3C CH3H
H3CH3C
OO N
H3C CH3H
CH3CH3
O
OO
NO
O
OO
N
O*
*
n
Tinuvin 622
Extractables and Leachables Sources
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Slip AgentsFunction: reduce the “friction” or “film adherence”, important when producing bags
from filmsErucamide Oleamide
CH3
NH2
O
CH3
NH2
O
Remark: because of their specific properties, Slip agents will be widely detected as Leachables!
Extractables and Leachables Sources
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Acid ScavengersFunction: 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 acidstrong acid weak acid
Extractables and Leachables Sources
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Pigments / ColorantsFunction: Gives the polymer/rubber the desired color (cosmetic)
Examples: Carbon Black (PAHs), TiO2 (white), Fe2O3 (red), Pigment Green 07
NNCl
Cl Cl
ClO
Solvent Red
N
OH
O
O
Solvent yellow 114O
O
N
N
H
H
H3C
H3C
Solvent Green 03
Extractables and Leachables Sources
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Clarifying Agents (Nucleating Agents)Function: by controlling the crystallization (nucleation) when cooling off polymer,
it becomes transparent.
NC-4 Millad 3988
OO
OO
C2H5
C2H5OHHO
OO
OO
CH3
H3C OHHO
H3CCH3
Extractables and Leachables Sources
Various residues from the production process:Solvents Monomers Catalysts
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H3C CH3
H
H
H3CO
CH3
CH3
H3COH
CH3
CH2
NO
H
CH3OH2CO
CH3
Styrene
Hexane
DHN
MIBK
IPA
CyclohexaneCaprolactam
Methyl methacrylate
H2C CH2CH3
Isoprene
TitaniumZirconiumCobaltAluminum...
Extractables and Leachables Sources
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OLIGOMERS: ExamplesPET PBT Nylon 6 Nylon 6.6 Butyl Rubber Polyester
N
N
O H
OH
NHHN
O O
N
NN
OO
OH
H
HHN
HN
O
ONH
NH
O
O
HN
HN
HN NH
NHNH
OO
O
O
O
O
O O O
OO OO
O
OO
O
OO
OO
O
O
O
O
O
CH3
CH2
H3C CH3CH3H3C
CH2
H3C CH3CH3H3C
Br
CH2
H3C CH3CH3H3C
Cl
CH3
H3C CH3 CH3
H3CCH2
H3CH3C CH3
CH3
CH3
H3C CH3 CH3
CH2
H3CH3C CH3
CH3
Cl
CH3
H3C CH3 CH3
CH2
H3CH3C CH3
CH3
Br
OO
O
O
O
O
O
O
OO
OO
OO
O
O
OO
O
O
O
OO
O
O
OHO
OO
OO
OH
O
OO
O
O
OHO
OH
O
O
O
O
OO
O
O
OO
O
O
OCH3
O
O
O
O
CH3
CH3
O
O
O
O
O
O
O
O
O O
O OO
OO
O
H3C CH3
H3C CH3
O
OO
O
O
OO
O
CH3
CH3
adhesive
Other typical oligomers from Silicone, PP, PE-adhesives ...
Extractables and Leachables Sources
Polymer degradation CompoundsOrigin: Oxidative degradation of the polymers
(when the polymer is not properly stabilized via antioxidants) Example of Polymer Degradation Compounds from Polypropylene
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H OHO
H3C OHO
CH3HO H3C OH
CH3
CH3H3C OH
H3CH3C CH3
OH
H3CO
H3C CH3
CH3
H3C CH3O
H3C OHO
H3CO
CH3
H CH3
O
CH3
CH3CH3
H3C
CH3H3C CH3CH3 CH3
H3C CH3
CH3 CH3CH3CH3H3C
H3CCH3H3C CH3
CH3
Acids Aldehydes Alcohols Ketones Polymer Fragments
Extractables and Leachables Sources
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OO
O
HOOH
O OH
OOH
O
HOO
OCH3
OOH
O
O
CH2O
O
Irganox 1010O
OO
OOH
OHO
OO
O
HO
HO
OO
OO
OH
OHO
OO
O
HO
HO
O
OO
OH
O
OO
O
HO
HO
OO
OO
O
OHO
OO
O
HO
HO
OH
OO
OO
O
OHO
OO
O
HO
HO
....
Example Degradation of Irganox 1010SMALL degradation Compounds LARGE degradation Compounds
Extractables and Leachables Sources
» EXAMPLE: Degradation of Irgafos 168(also other degradation compounds for Irgafos 168 are known)
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OP OO
OP OO O
+ ROOH + ROH
HO
Irgafos 168 Irgafos 168 Oxide
Extractables and Leachables Sources
Toxicological Risk AssessmentApplied 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
Toxicological Risk Assessment: Regulatory Basis
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» 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
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1. Identification of compounds that leach from the device
2. Quantify compounds detected3. Apply E&L data to estimate patient
exposure
Estimating Exposure to LeachablesExtrapolate 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
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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)
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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.
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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
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Optimizing Study Design for Risk Assessment
How to Optimize E&L Study Design for Risk Assessment
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» 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
How to Optimize E&L Study Design for Risk AssessmentWHAT 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 useSecondary 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
How to Optimize E&L Study Design for Risk AssessmentSELECTING APPROPRIATE E&L TESTING CONDITIONSExtraction 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 useExtraction 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
How to Optimize E&L Study Design for Risk AssessmentANALYTICAL METHODS- to maximize useful dataWhich 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. screeningVOC 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.
How to Optimize E&L Study Design for Risk AssessmentOptions 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)
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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
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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 01730Presenter:Russell Sloboda, Sr. Scientist and Risk Assessment [email protected] Doherty, Ph.D., Laboratory [email protected] Connor, Ph.D., DABT, TOX-SMART [email protected]