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.D Senior Applications Scientist Agilent Technologies Wood Dale, IL [email protected]
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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
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
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
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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
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
• 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
• 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.