SLAS Labware Leachables Special Interest Group SLAS2017 Presentation
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Transcript of SLAS Labware Leachables Special Interest Group SLAS2017 Presentation
Identification of Potential Bioactive Leachables and Extractables from Plastic Lab Ware by using GC and LC Separation Methods linked with MS Detection.
David A. Weil, Ph.DSenior Applications ScientistAgilent TechnologiesWood Dale, IL
Overview
SLAS 2017 Meeting
Introduction: Bioactive Compounds
Lab Ware: Plastic or Glass
Leachables and Sample Loss
Challenges of E/L Analysis:
Commonly Found Impurities:
Agilent E and L Solutions Inorganic Analysis using ICP/MS
GC/MS Workflow
Accurate Mass E/L Database
LC/MS Workflows
Questions:
For Research Use Only. Not for use in diagnostic procedures.
PFC’s: From Popcorn to French Fries to Clothing
SLAS 2017 Meeting
Silent Spring Institute, Environ. Sci. Technol. Lett
Durable Weather Clothing
Move in Europe to develop PFC Free
Clothing and Consumer Products
Bisphenol A
SLAS 2017 Meeting
Baby Bottles
Water Bottles
Expoxy BPA containing Resin Cans
Extractable/Leachable Analysis:Pharma/BioPharma, Medical Devices, Food Contact
SLAS 2017 Meeting
Drug Delivery, Container Closure System (CCS), Single-Use-Systems (SUS)
Focus on Identifying E/L Compounds based on RISK
No Guidelines or Regulations for Plastic Lab Ware
SLAS 2017 Meeting
Don’t Forget Packaging and Migration of Inks and Adhesives
Additives are Everywhere!
SLAS 2017 Meeting
Lab Ware Focus Identify Potential Bioactive Contaminants
Glossman et. al. Proc. Natl. Acad. Sci.1993: Tinuvin 770 from Polypropylene plastic tubes was a potential L-type Ca+2-channel blocker
Holt et al, Science 2008: Erucamide, Stearamide (SA), and di(2-hydroxyethyl) methyldodecylammnoium (DiHEMDA) biocide leachable from disposable tubes. Inhibiting monoamine oxidase-B.
Jeffrey McDonald; Anal. Chem. 2008, Identified sorbitol based nuclear clarifying agents extracts from microcentrifuge tubes, various size pipette tips and conical tubes.
J. Biomolecular Screening 2009, With DMSO both Erucamide and Oleoylethanolamide (OEA) extract from pipette tips and are active in a functional bioassay of a G-protein-coupled fatty acid receptor.
J. Biomolecular Screening, 2014, Dilauryl thiodipropionate (DLTDP) AO and break down products leached microplate active in monoamine oxidase-B (MAO-B) inhibition assay.
Clinical Chemistry 2009, Blue Pipette Tips extracted Nonylphenol Ethoxylate that inhibited mitochondrial enzymatic activities
SLAS 2017 Meeting
Identification of Leachable Compounds Detrimental to Cell Growth in Single-Use-Bioprocess Containers
Polyethylene Storage
Breakdown Products from
Irgafos 168
Irganox 1010
Irganox 1076
• bDtBPP from Irgafos 168
• 2,4-di-tert-butylphenol
• DtBP
SLAS 2017 Meeting
J Pharm Sci and Tech, 2013, 67, 123-134
Biotechnol. Prog. 2016, 32(6) 1547-1558
Process-Relevant Concentrations of the Leachable bDtBPP Impact Negatively on CHO Cell Production Characteristics
SLAS 2017 Meeting
Biotechnol. Prog. 2016, 32(6) 1547-1558
Glass vs Plastics: New High Recovery Glass Vials
SLAS 2017 Meeting
SLAS 2017 Meeting
bis-(3,4-dimethylbenzylidene
sorbitol diacetal, Irgafos 168,
glycerol stearate and palmitate (SA)
What are Extractable/Leachable Compounds?Extractables
• Chemical compounds that can be extracted out of
a packaging, single-use-system, or drug delivery
system at
• High-temperatures: to obtain the worst
case leachable profile
• Solvent extraction: polar and non-polar
solvent to mimic similar properties as drug
product
Leachables
• Chemical compounds from the components that
leach into the final drug product system
• Normal use conditions
• Accelerated storage conditions
Compound migration
• Chemical Compounds that crossed the primary
packaging material barrier from secondary and
tertiary packaging, accumulating in the drug
product
Determining Potential
Compound Migration
Determining Actual
Compound Migration
Leachables
(Drug)
Extractables
(Packaging)
Extractables
Leachables are generally
a subset of extractables
Leachables Leachables
Extractables
New Leachables may be
identified from drug-
packaging interaction
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
Plastic Materials: Source of Contamination
Sources of extractables are plastic and elastomeric components
(monomers, polymeric initiators, plasticizers, etc.) ink and adhesives
(label) and degradation products (processing, storage, sterilization)
Cindy Zweiben, Pfizer, Inc., Characterization of Extractables and Leachable in Parenteral Drug Products
February 8, 2017
Extractable Leachable ASTS 2016
15
SLAS 2017 Meeting
Vulcanizing Agents
Antioxidants
Azo Dyes
Phthalates
Lubricants, Slip
Agents, Fatty Acids and EstersNitrosamines
Silicone
Oils
Toxic
Elements (Hg,
Cd, Pb, As, Cr,
W, Tl, Os, Ba)
PAHs
Monomers,
Dimers,
Oligomers
Compounds Frequently Identified as Contaminants
Wide variety of Chemical Classes, Polarity, Molecular Weights, Properties
For Research Use Only. Not for use in diagnostic procedures.
Phthalate Additives are Everywhere
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Antoinette M. Reid et. el. (2007) An investigation into possible sources of phthalate contamination in the
environmental analytical laboratory, International Journal of Environmental Analytical Chemistry, 87:2, 125-133
Solvent Effects
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Antoinette M. Reid et. el. (2007) An investigation into possible sources of phthalate contamination in the
environmental analytical laboratory, International Journal of Environmental Analytical Chemistry, 87:2, 125-133
Common Compounds Leached from Lab-ware
• PAH’s from Elastomers
• Anti-static Agents from Packaging
• Mold Release Agents: Fatty Acids and Fatty acid amide
• Surfactants!
• Stabilizers, Antioxidants, UV inhibitors, Antioxidants
• Break Down Products from Adhesives and Dyes
• Biocides
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Ref: White Paper No 26, Sept 2015 by Eppendorf
Leachables from Plastic Consumables
Challenges of Extractable and Leachable Analyses
Extracts contain compounds with wide range of MW, polarity, hydrophobicity,
concentrations, and from commercial sources with wide range of purities
and breakdown/degradation products produced during manufacturing and
sterilization.
• No standardized LC separation method exists.
• Which ionization method(s): ESI, APCI or APPI?
• Acid/Base properties of mobile phase greatly effects ionization efficiency.
• Does higher sensitivity of MS eliminates concentration step.
• Identification: is accurate mass MS and MS/MS enough?
• Databases: open source vs commercial.
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
Key Separation MethodsAnalytical Technology
Analyte Type
Headspace
GC/MS
Volatiles/high migration potential
species(e.g. inks, adhesives, glue, residual solvents)
GC/MS Semi-volatiles(e.g. residual monomers, antioxidants,
plasticizers, hydrocarbon, preservatives, PAHs)
HPLC/UV/MS Non-volatiles(e.g. plasticizer, antioxidants, mold releases,
accelerators, slip agents, lubricants, solubilizing
agents, silicones and low MW polymers)
ICP/OES or ICP/MS
Elemental (e.g.. Leachable Metals, residual catalyst)
Ion Mobility Mass Spectrometry (IMMS)
Oligomers and polymers (e.g. pegylated materials, plasticizers,
surfactants, siloxane0 resin)
OrthogonalChromatography (SFC, 2D LC)
Non-volatile or semi-volatile additives challenging to detect by traditional methods due
to issues of matrix effects, ion suppression,
selectivity and sensitivity
FT-IR Non-volatile organic molecules
CE: Capillary electrophoresis
GFC: Gel-filtration chromatography
SEC: Size-exclusion chromatography
IC: Ion chromatography
Polarity
Mo
lecu
lar
We
ight
HPLC
GC
SEC
CE
GFC
IC
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
Relative Applicability of LC/MS TechniquesM
ole
cu
lar
Weig
ht
Analyte Polarity
API/Electrospray
APPI
APCI
1000
100,000
10,000
nonpolar very polar
Extractable and Leachable (E&L) Analysis
• What? Why? How?Overview
• Comprehensive E and L SolutionAgilent Portfolio
• LC/MS Data Analysis Workflow
• GC/MS Data Analysis WorkflowTraining Focus
• Commercialization
• Available collateralSupporting Info
• Who? Their E&L Strategy? How to win against them?Competition
SLAS 2017 Meeting
Analytical Technologies Required
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Objective: To detect a wide class of known and unknown organic/inorganic compounds that
maybe present in container closure systems at levels links to risk assessment threshold levels
Mass H
unte
r Data
Analy
sis
Sa
mple
Se
pa
ratio
n
Toxic elements/ Heavy metals
Non-volatile residues
Volatile Residues
Agilent delivers the most comprehensive analytical solutions portfolio
For Research Use Only. Not for use in diagnostic procedures.
QQQ
6400 series
TOF
6200 series
7010
GC/QQQ
Q-TOF
6500 series
7200
GC/QTOF7900 ICP-MS
Cary 610
FTIR Microscopes
7697A Headspace GC
5100 ICP-OES
Infinity II
LC Systems
SQ
6100 series
Agilent’s Comprehensive Portfolio for E&L Analysis
MassHunter Control
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
ICPMS Case Study
For Research Use Only. Not for use in diagnostic procedures.
Elemental E&Ls in Eye Drops
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Aqueous Extract
PH 2.5
Aqueous Extract
PH 9.5IPA/Water 50/50
Sealed Vessel
121°C
Sealed Vessel
121°CSonication Sonication Reflux
3 hoursSealed Vessel
55°C / 3d
Elemental Analysis
by ICP-MS and ICP-OES
ExtractionExtraction Techniques:
• Sonication (2 hrs, T=10°C)
• Sealed Vessel (55 °C / 3 d)
• Sealed Vessel (140 °C / 1 hr)
Purchased from
the DollarTree
in Berkeley, CA
Agilent 7900 ICP-MS
Agilent App Note in Progress !
For Research Use Only. Not for use in diagnostic procedures.
Extraction conditions vs. number of found elements
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
Agilent Publications about USP <232>/<233>
SLAS 2017 Meeting
pub 5990-9382EN, 2014 pub 5990-9365EN, 2015
For Research Use Only. Not for use in diagnostic procedures.
ICP-OES App Note following USP <661.1> protocols
SLAS 2017 Meeting
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GC/MS Workflow Examples
For Research Use Only. Not for use in diagnostic procedures.
Agilent’s GC/MS Portfolio
5977B
SQ
7000D,
7010B
TQ
7200
QTOF
Plus various sample introduction devices:
Headspace sampler, Thermal Desorber, Purge and trap, Twister, etc.
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
Agilent’s GC/MS Portfolio
5977B
SQ
7000D,
7010B
TQ
7200
QTOF
Plus various sample introduction devices:
Headspace sampler, Thermal Desorber, Purge and trap, Twister, etc.
High Efficiency Ion Source
JetClean
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
Agilent’s GC/MS Portfolio
5977B
SQ
7000D,
7010B
TQ
7200
QTOF
Plus various sample introduction devices:
Headspace sampler, Thermal Desorber, Purge and trap, Twister, etc.
High Efficiency Ion Source
JetClean
Intuvo GC
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
Agilent’s GC/MS Portfolio
5977B
SQ
7000D,
7010B
TQ
7200
QTOF
Plus various sample introduction devices:
Headspace sampler, Thermal Desorber, Purge and trap, Twister, etc.
High Efficiency Ion Source
JetClean
Intuvo GC
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
SLAS 2017 Meeting
Extractable and Leachable (E&L)
• What? Why? How?Overview
• Positioning and Value Proposition
• Differential Analysis Software Overview and Positioning
Agilent Portfolio
• LC/MS Qualitative Data Analysis WorkflowWorkflow Focus
• Commercialization
• Available collateralSupporting Info
• Who? Their E&L Strategy? How to win against them?Competition
SLAS 2017 Meeting
Extractable/Leachable LC-QTOF WorkflowM
ass H
unte
r Data
Analy
sis
Sam
ple
Separa
tion
Semi-Volatile and
Non-volatile Residues
Extra
ctio
ns
Samples -Standards
-Extracts Drug Containers
-Extracts Drug Product
ChromatographyColumns: C18/C8/C3
Organic Mobile Phase:
ACN, MeOH, ACN/IPA,
MeOH/IPA
Varied Buffers: None,
0.1% Formic Acid, 2mM &
4mM NH4Acetate
Ionization SourcesJet Stream (ESI),
APCI, Multimode
MS-Instrument 6530 / 6545 / 6550
SLAS 2017 Meeting
Comparing C3, C8, C18 Separations Using Same BuffersBase Peak Chromatograms
C3
C8
C18
Results: C3 Column Optimum for Higher Mass Extractables
Create orthogonality by using multiple chemistriesSLAS 2017 Meeting
Agilent 6545 QTOF Performance 50K Resolution and <1ppm Accuracy on 6545 QTOF
Mass
(m/z)
Resolution
(FWHM)
Accuracy
(ppm)
118.0862 19599 0.01
322.0481 32295 -0.05
622.0290 41212 0.05
922.0098 45590 0.01
1221.9906 49020 -0.04
1521.9716 51019 0.06
2121.9332 53292 0.04
2421.9140 52961 0.05
2721.8947 53277 -0.03
53,277 mass resolution for
2,722 m/z ion
SLAS 2017 Meeting
6x10
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
2.8 455.290321
(M+H)+
441.274704
471.284287
487.279822
(M+H)+
Counts vs. Mass-to-Charge (m/z)435 440 445 450 455 460 465 470 475 480 485 490 495 500 505
Wide In-spectrum Dynamic RangeFive decades of response in a single scan
2.68 million
counts
25 counts
verapamil dihydroxy metabolite of verapamil
desmethyl
metabolite
monohydroxy
metabolite
400
counts
verapamil
SLAS 2017 Meeting
Irganox 1093
Irganox 1076
Irganox 1330
Irgacure 369
C38H78SO7
C26H29PO4
Irganox 1035
Ionization Modes: APCI vs Jet Stream ESIExamples: Irganox and Irgacure Mixture
Red = APCI
Blue = Jet Stream
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Mass Profiler: Stem DCM Extract Jet Stream vs APCI
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Polyol surfactant
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Extractable and Leachable Accurate Mass LC/MS PCDL
• Comprehensive database with > 1000 compounds
• Library with accurate MS/MS mass spectra from > 350
compounds for seamless integration into the All Ions workflow
• Retention times for > 129 compounds
• Database/library are designed and curated for highest quality
& reliability
• Easy development of screening LC/MS methods
• Use with 1260/1290 Infinity LC, and high resolution 6200
Series TOF & 6500 Series Q-TOF LC/MS Systems
• Literature references for first pass risk assessment (e.g.
ELSIE cross-references)
• Continuous refresh with new spectra -3 years of free PCDL
updates
1290 Infinity II UHPLC
6550 iFunnel LC/Q-TOF
Quickly and Confidently Identify Known E & L Compounds
For Research Use Only. Not for use in diagnostic procedures.SLAS 2017 Meeting
Increasing Your Confidence in Compound Identification
Accurate Mass (AM)
AM +
Isotope Pattern
(IP)
AM
+
Retention
Time (RT)
+
IP
MS/MS Library
AM
+
RT
+
MS/MS
Library
Confident
compound
identification
is crucial
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
Database Content and Curation
Agilent
Custom
DatabaseELSIE
Compounds
Agilent
Database
E&L
Database
Entries
SWISS
Lists
Jenke &
Carlson 1
Compounds
SciFinder
Chemspider
Pubchem
Curation of
Compound
Data and
Spectra
Agilent
E&L PCDL
For Research Use Only. Not for use in diagnostic procedures.
Ref 1: PDA JPST, Jenke and Carlson: PDA J Pharm Sci Technol 2014 Sep-Oct;68(5):407-55. "A compilation of safety impact
information for extractables associated with materials used in pharmaceutical packaging, delivery, administration, and manufacturing
systems."
SLAS 2017 Meeting
MassHunter PCDL Manager Software
Library
- Normalized MS/MS spectra
- Positive and negative polarity
- Multiple adduct ion species
- Multiple collision energies
- Additional spectra can be added
- Spectra acquired at 10, 20, and 40 V collision energies for
multiple confirmation points, and other energies if needed
SLAS 2017 Meeting
Database
- Names, formulas, monoisotopic
masses, structures, common identifiers
- Retention times from experimental data
- Fully searchable and integrated into
Mass Hunter Software suite
- Additional compounds can be added
- Class tags allow easy generation of
personalized/subset PCDLs
For Research Use Only. Not for use in diagnostic procedures.
What is “Curation”?: PCDL Curating compound information is very time-consuming – we can save you that time…
SLAS 2017 Meeting
Essential Chemical list
• Carefully selected and
prioritized by experts.
• Reviewed for relevance in
application area in question (e.g.
E&L)
Common
name: Verified
from multiple
different
sources for
commonalityAccurate and up-to-date
compound information: IUPAC
name, accurate mass of neutral
molecule, molecular formula,
molecular structure, Chemspider,
CAS etc.
Notes Area:
• Compound class
tags
• Regulation tags
and references
• Chinese,
Japanese and
English synonyms
• Toxicology
research
references
• Outdated and
alternative CAS
identifiers
• Compound
descriptions
Retention Time for Increased Confidence
SLAS 2017 Meeting
Factors causing your retention times to differ include different instrument
delay volumes, dead volumes or configuration changes.
Retention time information added to 129 compounds, thus adding in
retention time to the identification score and increasing identification
confidence. Our RTs can be used as reference
• Retention times are included for 129 compounds in the E_n_L_AMRT_PCDL.
• Retention times can be specified as optional or required in your MassHunter
Qualitative Analysis workflow
• System Configuration document describing necessary chromatographic setup
allows you to replicate retention times
Entitlement to 3-year Free UpdateWhen you buy the standalone tMRM DB/PCDL, you will be entitled to a 3-year free update via
SubscribeNet.
Snapshot of SubscribeNet
When you order standalone database/library, you will
o Receive an activation code.
o Go to SubscribeNet and create a profile.
o Enter the activation code, see a line item with a link to the software they purchased
with a visible Expiration Date.
o Receive an email when a new update of database/library is released.
o Go to the website and download it If your product has not expired. The Expiration Date
is 3 years after the day you register on SubscribeNet with the activation code.
SLAS 2017 Meeting
What is “Curation”: PCDL Library Spectra Example
SLAS 2017 Meeting
• Each precursor and product ion peak are corrected to
theoretical accurate mass
• Spectra acquired at 10, 20, and 40 V collision energies
• Spectra acquired with more collision energies if
necessary in separate data file
• Spectra measured in positive and/or negative ion
mode where applicable
• Spectra measured for multiple ion species
• Spectra are filtered for signal intensity and curated for:
• Spectrum noise
• Chemical impurities
• Incorrectly set instrumentation parameters
10V
40V
20V
SLAS 2017 Meeting
Add YOUR curated accurate MS/MS spectra to new or existing compound entries
PCDL Library Spectra
FBF = Find by Formula
Open data in
MH Qual
Open method
(LibrarySearching-
Default.m)
FBF wt extract
MS/MS spectra
Check annotation
SEND to PCDL
Export curated spectra to
customized PCDL
Curate spectra by
filtering on:
• Calculated m/z (MS/MS
annotated peaks)
• Minimum base peak
abundance
• Spectral noise
Annotated MS/MS Spectra for
Benzothiazole
CE: 20 eV
CE: 10 eV
CE: 40 eV
CE: 20 eV
CE: 10 eV
CE: 40 eV
Untargeted QTOF data can be retrospectively reviewed
with addition of new compounds
MassHunter Profinder Mass Profiler Professional
Agilent LC/MS
Process/ID Profilingdetect
High Level Data Analysis Workflow for LC/MS Data
For Research Use Only. Not for use in diagnostic procedures.
MassHunter Profiler
SLAS 2017 Meeting
What Does Molecular Feature Extractor Do?
Raw data Background noise
removed
Individual m/z peaks
grouped into isotope
clusters
Isotope
clusters
grouped into
molecular
features
Identification, Quantification, Differential Analysis are performed on chemically qualified
compound data
SLAS 2017 Meeting
Profinder Software Automated Data Mining
• Batch Processing Feature Extraction
for Differential Analysis
• Supports Data from:
GC/MSD and GC/QTOF
LC/TOF and LC/QTOF
• Wizard Driven Software
• Targeted or Untargetd Analysis
• Supports Differential and All Ions
• Seamlessly integrated with
differential analysis software
programs
• Minimizes false positive and
negative results
SLAS 2017 Meeting
Differential Analysis for E&L StudiesMass Profiler and Mass Profiler Professional
Mass Profiler (MP) Mass Profiler Professional (MPP)
LC/MS Untargeted Feature Finding (With Profinder)
LC/MS Targeted Feature Finding (With Profinder) (With Profinder)
Normalization
Abundance Filter
Fold Change Filter
Frequency Filter
PCA Plots
Database search
2 Sample Set Analysis
Multiple Sample Set Analysis
Advanced Data Visualization
Advanced Statistical Analysis
GC/MS EI data
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
Non-Target Screening: Unknown Discovery
SLAS 2017 Meeting
Mass Profiler Professional: Multivariate Analysis
Study looks at characterising extractables from 4 different gaskets using 3
different solvents.
Gaskets:
E3609-70
FF350-75
HF355-65
S1138-70
Solvents:
Isopropyl Alcohol (IPA)
Dichloromethane (DCM)
Heptane
Using multivariate analysis of all permutations allows the dissection of
common and unique extractables across the study.
Samples were kindly provided by Andrew Feilden, Smithers Rapra, UK
Non-Target Screening: Unknown Discovery
SLAS 2017 Meeting
Mass Profiler Professional : Multivariate Analysis
• Four different gaskets were extracted with DCM, IPA and Heptane.
• Molecular Feature Extraction was used to reveal compounds, while Multivariate analysis allows us to examine the differential
presence of the compounds in each gasket.
Non-Target Screening: Unknown Discovery
SLAS 2017 Meeting
Mass Profiler Professional :
Multivariate Analysis
• Four different gaskets
were extracted with
DCM.
• Molecular Feature
Extraction was used to
reveal compounds.
• Multivariate analysis
allows us to examine the
differential presence of the
compounds in each
gasket.
Non-Target Screening: Unknown DiscoveryMass Profiler Professional : Multivariate Analysis
SLAS 2017 Meeting
Four different gaskets were extracted with DCM. Using Molecular Feature Extraction to reveal compounds and
multivariate analysis to examine their differential presence, the extractables in each gasket can be investigated.
This shows that no compounds were
extracted from all gaskets and each
gasket has compounds extracted
exclusively from them.
E3609-70 -112
FF350-75 – 1
S1138-70 – 121
HF335-65 -19
Acknowledgements
Robert Williams
Syed Lateef
Emma Rennie
Mahsan Miladi
Dorothy Yang
Thomas Glauner
Andrew Feilden (SR)
SLAS 2017 Meeting
Maria VanDamme
Smriti Khera
Kai Chen
Sarah Xu
Shi-Fen Xu
With slides and significant input from…
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
Appendix
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
References
SLAS 2017 Meeting
• USP Plastic Packaging General Chapters: An Overview, D. Jenke, D. Norwood, Packaging, Storage, and Distribution Expert Committee, USP,
http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/stim_article_661_final.pdf
• USP <1663> ASSESSMENT OF EXTRACTABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS
http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/m7126.pdf
• USP <1664> ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS
http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/m7127.pdf
• Guidelines on Plastic Immediate Packaging Materials, EMEA, European Medicines Agencies Inspections, 2005,
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003448.pdf
• Recommendations for Extractables and Leachables Testing, Introduction, Regulatory Issues and Risk Assessment,
BioProcess International 5(11):pp36-49 (December 2007),
http://www.bpsalliance.org/wp-content/uploads/2014/06/BPSA-Extractables-101-BPI-Suppl-May-2008.pdf
• Recommendations for Extractables and Leachables Testing, Executing a Program,
BioProcess International 6(1):pp44-53 (January 2008) ,
http://www.bioprocessintl.com/wp-content/uploads/bpi-content/BPI_A_080601AR06_O_76422a.pdf
• The chemical safety assessment process for extractables and leachables associated with packaged pharmaceutical products,
D. Jenke, European Pharmaceutical Review, Volume 18, Issue 1, 2013,
http://www.europeanpharmaceuticalreview.com/wp-content/uploads/EPR-Manufacturing-Packaging-Supplement-2013.pdf
• Metal Leachables in Therapeutic Biologic Products: Origin, Impact and Detection, Shuxia Zhou et al, Americal Pharmaceutical Review, May 01, 2010, http://www.americanpharmaceuticalreview.com/Featured-Articles/116570-Metal-Leachables-in-Therapeutic-Biologic-Products-Origin-Impact-and-Detection/
• Newsletter of the AAPS Aggregation and Biological Relevance Focus Group, May 2011, volumn2, Issue
https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Focus_Groups/PABCFGnewsMay2011.pdf
• Development of Biotechnology Products in Prefilled Syringes: Technical Considerations and Approaches, Advait Badkar et al.,
AAPS PharmSciTech, Vol. 12, No. 2, June 2011: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134644/pdf/12249_2011_Article_9617.pdf
For Research Use Only. Not for use in diagnostic procedures.
References• HPLC and LC/MS Analysis of Pharmaceutical Container Closure System Leachables and Extracatbles, D. Norwood et al.,
Journal of Liquid Chromatography & Related Technologies, 32: 1768-1827, 2009
• Application of the threshold of toxicological concern ( TTC) concept to the safety assessment of chemically complex food matrices,
M.A.J. Rennen et al., Food and Chemical Toxicology 49.(2011) 933-940
• Leachables and Extractables Handbook, Safety Evaluation, Qualification and Best Practices Applied to Inhalation Drug Products; First Edition, D.
Ball, D. Norwood, C Stults, L. Nagao, John Wiley& Sons, Inc, Published 2012
• Development of Safety Qualification Thresholds and Their Use in Orally Inhaled and Nasal Drug Product Evaluation,
Douglas Ball et al., Toxicological Sciences 97 (2), 226 – 236 (2007)
• Regulatory Perspective on Safety Qualification of Extractables and Leachables, Ingrid Markovic ,PQRI Workshop, Bethesda (MD), Feb 22, 2011
http://pqri.org/wp-content/uploads/2015/11/Markovic.pdf
• Regulatory Perspective on E&L in Biologics: Quality Considerations, Ingrid Markovic, UPS/PQORI E&L Workshop, April 28, 2014, Rockville ( MD)
https://www.usp.org/sites/default/files/usp_pdf/EN/meetings/09_markovich_presentation.pdf
• SAFETY THRESHOLDS AND BEST PRACTICES FOR 6 EXTRACTABLES AND LEACHABLES IN ORALLY INHALED 7 AND NASAL DRUG
PRODUCTS, PQRI, 2006, http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf
• Current FDA Perspective on Leachable Impurities in Parenteral and Opthalmic Drug Products, AAPS Workshop on Pharmaceutical Stability, 2011,
D. Lewis, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf
• Subvisible Particulate Matter, Development in Regulations and Low Volume Methods, Satish K. Sing, AAPS Workshop 2014,
http://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Focus_Groups/Protein_Aggregation_and_Biological_Consequences/PABCFG
Wrkshp20114_Singh.pdf
• Creating a holistic extractable & leachables (E&L) program for biotechnology products, Kim Li, Gary Rogers, Yasser Nashed-Samuel, et al., PDA J
Pharm Sci and Tech 2015, 69, 590-619, http://www.ncbi.nlm.nih.gov/pubmed/26429108
• Creating a Holistic Extractables and Leachables (E&L) Program for Biotechnology Products; Kim Li et al., PDA J Pharm Sci and Tech 2015, 69
590-619
SLAS 2017 Meeting
For Research Use Only. Not for use in diagnostic procedures.
SLAS 2017 Meeting
• Perspectives on the PQRI Extractables and Leachables “ safety thresholds and best practices” recommendations for inhalation drug products,
D. Norwood, L. Nagao, C. Stults, PDA J Pharm Sci and Tech 2013, 67, 413 – 429
http://steriletechportal.pda.org/?q=content/pdajpst/67/5/413.full.pdf
• SAFETY THRESHOLDS AND BEST PRACTICES FOR 6 EXTRACTABLES AND LEACHABLES IN ORALLY INHALED 7 AND NASAL DRUG PRODUCTS,
PQRI, 2006, http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf
• Current FDA Perspective on Leachable Impurities in Parenteral and Opthalmic Drug Products, AAPS Workshop on Pharmaceutical Stability, 2011,
D. Lewis, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf
• Determination of elemental impurities in leachate solutions from syringes using sector field ICP-mass spectrometry,
K. Van Hoecke, C. Catry, F. Vanhaecke, Journal of Pharmaceutical and Biomedical Analysis, 77 (2013), 139-144
• Identification and analysis of polymer additives using packed-column supercritical fluid chromatography with APCI mass spectrometric detection,
M. Carrot, D. Jones, G. Davidson, Analyst, 1998, 123, 1827-1833
• Utilization of Internal Standard Response Factors to Estimate the Concentration of Organic Compounds Leached from Pharmaceutical Packaging Systems
and Applications of Such Estimated Concentrations to Safety Assessment, D.Jenke and A.Odufu,
Journal of Chromatographic Science, 2012; 50:206-212
• Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing, Weibin Ding et al., Pharmaceutical Engineering,
November/December, Vol 34, No 6, 2014
• Minimizing immonogenicity of biopharmaceuticals by controlling critical quality attributes of proteins, Miranda van Beers; Muriel Bardor
Biotechnol. J. 2012, 7
• A Method Utilizing Ultra-High Performance Liquid Chromatography and Mass Spectrometric Detection for the Analysis of Material Extracts Produced
During a Controlled Extraction Study; Steven A. Zrdavkovic et.al; PDA J Pharm Sci and Tech 2014, 68 504-526
• Controlled Extraction studies Applied to Polyvinyl Chloride and Polyethylene Materials: Conclusions from the ELSIE Controlled Extraction Pilot Study,
Andrew Teasdale et al.; AAPS PharmSciTech, Vol 16, No 3, June 2015
• Risk-Based Scientific Approach for Determination of Extractables/Leachables from Biomanufacturing on Antibody-Drug Conjugates (ADCs); Weibing Ding;
From Antibody Drug Conjuagtes, Methods in Molecular Biology, Springer Verlag, vol. 1045, pp 303 – 311
• Single-use in biopharmaceutical industry: A review of current technology impact, challenges and limitation,
Adriana G. Lopes, Food and Bioproducts Processing 93 (2015) 98-114
• A Compilation of Safety Impact Information fo Extractables Associated with Material Used In Pharmaceutical Packaging, Delivery, Administration,
and Manufacturing Systems, D. Jenke and T. Carlson, PDA J Pharm Sci and Tech 2014, Vol. 68, 407-455
• Safety Risk Categorization of Organic Extractables Associated with Polymers used in Packaging , Dennis Jenke, Pharm Res (2015) 32:1105-1127
References
For Research Use Only. Not for use in diagnostic procedures.
REF: Porex Corporation
SLAS 2017 Meeting
FluidX GC/MS Analysis of PP Sample Storage
SLAS 2017 Meeting
Extraction with Ethanol at 20oC for 24 hours
Ref: Poster from FluidX, Robin Grimwood, Brooks Life Science Systems, Stockport, UK