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

[email protected]

Overview

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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

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Silent Spring Institute, Environ. Sci. Technol. Lett

Durable Weather Clothing

Move in Europe to develop PFC Free

Clothing and Consumer Products

Bisphenol A

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Baby Bottles

Water Bottles

Expoxy BPA containing Resin Cans

Extractable/Leachable Analysis:Pharma/BioPharma, Medical Devices, Food Contact

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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

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Don’t Forget Packaging and Migration of Inks and Adhesives

Additives are Everywhere!

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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

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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

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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

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Biotechnol. Prog. 2016, 32(6) 1547-1558

Glass vs Plastics: New High Recovery Glass Vials

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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

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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

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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


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.

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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

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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

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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


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

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ICPMS Case Study


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 !


Extraction conditions vs. number of found elements

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Agilent Publications about USP <232>/<233>

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pub 5990-9382EN, 2014 pub 5990-9365EN, 2015


ICP-OES App Note following USP <661.1> protocols

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GC/MS Workflow Examples


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.


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5977B

SQ

7000D,

7010B

TQ

7200

QTOF



High Efficiency Ion Source

JetClean


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5977B

SQ

7000D,

7010B

TQ

7200

QTOF



High Efficiency Ion Source

JetClean

Intuvo GC


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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

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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

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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

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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

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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

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& 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

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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

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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


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."

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MassHunter PCDL Manager Software

Library

- Normalized MS/MS spectra

- Positive and negative polarity

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multiple confirmation points, and other energies if needed

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Database

- Names, formulas, monoisotopic

masses, structures, common identifiers

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Mass Hunter Software suite

- Additional compounds can be added

- Class tags allow easy generation of

personalized/subset PCDLs


What is “Curation”?: PCDL Curating compound information is very time-consuming – we can save you that time…

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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

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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.

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What is “Curation”: PCDL Library Spectra Example

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• Each precursor and product ion peak are corrected to

theoretical accurate mass

• Spectra acquired at 10, 20, and 40 V collision energies

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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

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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


MassHunter Profiler

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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

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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

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differential analysis software

programs

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negative results

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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


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Non-Target Screening: Unknown Discovery

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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


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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.


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)

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Maria VanDamme

Smriti Khera

Kai Chen

Sarah Xu

Shi-Fen Xu

With slides and significant input from…

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http://1.bp.blogspot.com/_jASDEQTiBx8/SOeGcf6-FrI/AAAAAAAAASE/Eaazn5tVzms/s400/thank-you.jpg

Appendix

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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


• 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


http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/stim_article_661_final.pdf



http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003448.pdf

http://www.bpsalliance.org/wp-content/uploads/2014/06/BPSA-Extractables-101-BPI-Suppl-May-2008.pdf

http://www.bioprocessintl.com/wp-content/uploads/bpi-content/BPI_A_080601AR06_O_76422a.pdf

http://www.europeanpharmaceuticalreview.com/wp-content/uploads/EPR-Manufacturing-Packaging-Supplement-2013.pdf

http://www.americanpharmaceuticalreview.com/Featured-Articles/116570-Metal-Leachables-in-Therapeutic-Biologic-Products-Origin-Impact-and-Detection/

https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Focus_Groups/PABCFGnewsMay2011.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134644/pdf/12249_2011_Article_9617.pdf

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


http://pqri.org/wp-content/uploads/2015/11/Markovic.pdf

https://www.usp.org/sites/default/files/usp_pdf/EN/meetings/09_markovich_presentation.pdf

http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf

http://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Focus_Groups/Protein_Aggregation_and_Biological_Consequences/PABCFGWrkshp20114_Singh.pdf

http://www.ncbi.nlm.nih.gov/pubmed/26429108

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


http://steriletechportal.pda.org/?q=content/pdajpst/67/5/413.full.pdf

http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM301045.pdf

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

SLAS Labware Leachables Special Interest Group SLAS2017 Presentation

Government & Nonprofit

Transcript of SLAS Labware Leachables Special Interest Group SLAS2017 Presentation