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SLAS Labware Leachables Special Interest Group SLAS2017 Presentation

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David A. Weil, Ph.D, senior applications scientist with Agilent Technologies, presented "Identification of Potential Bioactive Leachables and Extractables from Plastic Lab Ware by using GC and LC Separation Methods linked with MS Detection."

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SLAS Labware Leachables Special Interest Group SLAS2017 Presentation

  1. 1. 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 David_Weil@agilent.com
  2. 2. 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.
  3. 3. 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
  4. 4. Bisphenol A SLAS 2017 Meeting Baby Bottles Water Bottles Expoxy BPA containing Resin Cans
  5. 5. 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
  6. 6. No Guidelines or Regulations for Plastic Lab Ware SLAS 2017 Meeting Don’t Forget Packaging and Migration of Inks and Adhesives
  7. 7. Additives are Everywhere! SLAS 2017 Meeting
  8. 8. 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
  9. 9. 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
  10. 10. Process-Relevant Concentrations of the Leachable bDtBPP Impact Negatively on CHO Cell Production Characteristics SLAS 2017 Meeting Biotechnol. Prog. 2016, 32(6) 1547-1558
  11. 11. Glass vs Plastics: New High Recovery Glass Vials SLAS 2017 Meeting
  12. 12. SLAS 2017 Meeting bis-(3,4-dimethylbenzylidene sorbitol diacetal, Irgafos 168, glycerol stearate and palmitate (SA)
  13. 13. 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.
  14. 14. 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
  15. 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.
  16. 16. Phthalate Additives are Everywhere SLAS 2017 Meeting 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
  17. 17. Solvent Effects SLAS 2017 Meeting 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
  18. 18. 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 SLAS 2017 Meeting
  19. 19. SLAS 2017 Meeting Ref: White Paper No 26, Sept 2015 by Eppendorf Leachables from Plastic Consumables
  20. 20. 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.
  21. 21. Key Separation Methods Analytical 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) Orthogonal Chromatography (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 MolecularWeight HPLC GC SEC CE GFC IC SLAS 2017 Meeting For Research Use Only. Not for use in diagnostic procedures.
  22. 22. Relative Applicability of LC/MS Techniques MolecularWeight Analyte Polarity API/Electrospray APPI APCI 1000 100,000 10,000 nonpolar very polar
  23. 23. 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 collateral Supporting Info • Who? Their E&L Strategy? How to win against them?Competition SLAS 2017 Meeting
  24. 24. Analytical Technologies Required SLAS 2017 Meeting 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 MassHunterDataAnalysis SampleSeparation 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.
  25. 25. QQQ 6400 series TOF 6200 series 7010 GC/QQQ Q-TOF 6500 series 7200 GC/QTOF 7900 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.
  26. 26. SLAS 2017 Meeting ICPMS Case Study For Research Use Only. Not for use in diagnostic procedures.
  27. 27. Elemental E&Ls in Eye Drops SLAS 2017 Meeting Aqueous Extract PH 2.5 Aqueous Extract PH 9.5 IPA/Water 50/50 Sealed Vessel 121°C Sealed Vessel 121°C Sonication Sonication Reflux 3 hours Sealed Vessel 55°C / 3d Elemental Analysis by ICP-MS and ICP-OES Extraction Extraction 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.
  28. 28. Extraction conditions vs. number of found elements SLAS 2017 Meeting For Research Use Only. Not for use in diagnostic procedures.
  29. 29. 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.
  30. 30. ICP-OES App Note following USP <661.1> protocols SLAS 2017 Meeting
  31. 31. SLAS 2017 Meeting GC/MS Workflow Examples For Research Use Only. Not for use in diagnostic procedures.
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. For Research Use Only. Not for use in diagnostic procedures. SLAS 2017 Meeting
  37. 37. SLAS 2017 Meeting
  38. 38. 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 collateral Supporting Info • Who? Their E&L Strategy? How to win against them?Competition SLAS 2017 Meeting
  39. 39. Extractable/Leachable LC-QTOF Workflow MassHunterData Analysis SampleSeparation Semi-Volatile and Non-volatile Residues Extractions Samples -Standards -Extracts Drug Containers -Extracts Drug Product Chromatography Columns: C18/C8/C3 Organic Mobile Phase: ACN, MeOH, ACN/IPA, MeOH/IPA Varied Buffers: None, 0.1% Formic Acid, 2mM & 4mM NH4Acetate Ionization Sources Jet Stream (ESI), APCI, Multimode MS-Instrument 6530 / 6545 / 6550 SLAS 2017 Meeting
  40. 40. Comparing C3, C8, C18 Separations Using Same Buffers Base Peak Chromatograms C3 C8 C18 Results: C3 Column Optimum for Higher Mass Extractables Create orthogonality by using multiple chemistries SLAS 2017 Meeting
  41. 41. 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
  42. 42. 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 Range Five 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
  43. 43. Irganox 1093 Irganox 1076 Irganox 1330 Irgacure 369 C38H78SO7 C26H29PO4 Irganox 1035 Ionization Modes: APCI vs Jet Stream ESI Examples: Irganox and Irgacure Mixture Red = APCI Blue = Jet Stream SLAS 2017 Meeting
  44. 44. Mass Profiler: Stem DCM Extract Jet Stream vs APCI SLAS 2017 Meeting Polyol surfactant
  45. 45. SLAS 2017 Meeting
  46. 46. 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
  47. 47. 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.
  48. 48. Database Content and Curation Agilent Custom Database ELSIE 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
  49. 49. 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.
  50. 50. 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 commonality Accurate 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
  51. 51. 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
  52. 52. Entitlement to 3-year Free Update When 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
  53. 53. 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
  54. 54. 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
  55. 55. 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
  56. 56. 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
  57. 57. 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
  58. 58. Differential Analysis for E&L Studies Mass 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
  59. 59. 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
  60. 60. 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.
  61. 61. 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.
  62. 62. Non-Target Screening: Unknown Discovery Mass 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
  63. 63. 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…
  64. 64. SLAS 2017 Meeting For Research Use Only. Not for use in diagnostic procedures.
  65. 65. Appendix SLAS 2017 Meeting For Research Use Only. Not for use in diagnostic procedures.
  66. 66. 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.
  67. 67. 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.
  68. 68. 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.
  69. 69. REF: Porex Corporation SLAS 2017 Meeting
  70. 70. 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

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