Designing an Extractables and Leachables Study

Transcription

1 Designing an Extractables and Leachables Study 1

2 2 Overview

3 Background InformaAon Materials of Construction What addiaves are used? MulAlayer films? PrinAng Inks? Finished Packaging Which surfaces does the product contact? Are there interacaons between components? Is there opportunity for non- product contact components to migrate? Are there any processing aids used? 3

4 Use CondiAons How will it be used? How should it be extracted? Extractables challenge the use condi/on Temperature Solvent Strength Time Leachables mimic the most stringent use condi/on 4

5 ExtracAon Strategies Cut and Cover MulAlayer Films Cap Liners Printed Packaging Containers based on Homo-polymers Irregularly shaped Large Simple containers systems Extraction Irregularly shaped ArAcles requiring two- sided extracaon Cut and Cover Very large containers ExtracAon 5

6 ExtracAon Strategies MulAlayer Films Cap Liners Printed Packaging MulAlayer Films Printed Packaging Bags Small containers Tubing Non-permeable Printed containers Full Fill Extraction 6

7 ExtracAon Strategies MulAlayer Films Cap Liners Printed Packaging MulAlayer Films Printed Packaging MulA- layer Printed materials Coated materials Product contacts one side One- Sided Extraction 7

8 ExtracAon Strategies Tubing MulAlayer Films Cap Liners Printed Packaging MulAlayer Films Printed Packaging Complex systems In- Line filters Connectors Flow Through Extraction 8

9 ExtracAon Strategies MulAlayer Films Cap Liners Printed Packaging MulAlayer Films Printed Packaging Direct analysis of the enare aracle Very high sensiavity No risk of volaales loss Large Volume Dynamic Headspace 9

10 ExtracAon Solvent From the background informaaon provided for a container closure system the probable extractables were: Expected Extractable Type Log P Boiling point Erucamide Hydrophobic C Linear Alkanes Hydrophobic C Dibutylphthalate Hydrophobic C Dimethoxyethane VolaAle C Irganox 1010 Non- volaale 23 N/A Irgafos 168 Non- volaale 15.5 N/A Tinuvin 770 Basic 6.3 N/A Stearic acid Acidic C Sodium benzenesulfonate Anionic N/A N/A 10

11 Effect of Solvent Polarity Agilent 1290 Infinity UHPLC; Agilent 6520 QTOF- MS Column: Agilent Zorbax Eclipse Plus C8; 1.8 µm, mm Electrospray IonizaAon (ESI); Polarity: posiave 11

12 Extract PreparaAon Example: 250 ml per bag Worst case 3 bags per day Product contact surface area 310 cm 2 Safety concern threshold (SCT) = 0.15µg/ day AET( µμg/bag )= 0.15 µμg day /3 bags day =0.05 µμg/bag Extract Vol. (ml)= 310 cm 2 /6 cm 2 ml =52 ml LOD= 0.05 µμg bag /52 ml bag 1 ng ml 12

13 13 QualitaAve Analysis

14 ConcentraAon of Extracts Extractables & Leachables can be lost during concentration Loss depends on VolaAlity of the analyte(s) Extract handling Best PracAces Mild condiaons Method validaaon Headspace analysis 14

15 QualitaAve Analysis No universal analyhcal technique exists for E&L analysis QTOF- GCMS HGCMS QTOF- LCMS Headspace GCMS VolaAles QTOF- GCMS VolaAles Semi- volaales Non- polar analytes QTOF- LCMS Polar/ionizable ICP- MS Metals 15

16 ExtracAon CondiAons - - Ethanol Extract- - Expected Extractables Type Log P Boiling point Erucamide Hydrophobic C Linear Alkanes Hydrophobic C Dibutylphthalate Hydrophobic C Dimethoxyethane VolaAle C Irganox 1010 Non- volaale 23 N/A Irgafos 168 Non- volaale 15.5 N/A Tinuvin 770 Basic 6.3 N/A Stearic acid Acidic C Sodium benzenesulfonate Anionic N/A N/A 16

17 QualitaAve Analysis Agilent 1290 Infinity UHPLC; Agilent 6520 QTOF- MS Column: Agilent Zorbax Eclipse Plus C8; 1.8 µm, mm Electrospray IonizaAon (ESI) 17

18 QualitaAve Analysis Agilent 7890B GC; Agilent 7200 QTOF- MS Column: DB- 5MS UI; 0.25 mm 30 m, 0.25 µm Electron Impact IonizaAon 18

19 QualitaAve Analysis Agilent 6890 GC; Agilent 5973 inert MSD Electron Impact IonizaAon 19

20 QualitaAve Analysis Technique Analyte Boiling Point ( C) HGCMS QTOF- GCMS QTOF- LCMS Dimethoxyethane 85 C Hexadecane 286 C Linear Alkanes C Dibutylphthalate 340 C Tinuvin 770 >350 C Irgafos 168 N.A. Stearic Acid 361 C Erucylamide 474 C Irganox 1010 Non- VolaAle 20

21 IdenAficaAon of Unknowns Database Searches Commercial Databases (NIST, Wiley) Jordi Proprietary AddiAve and Oligomer Databases QTOF- GC / QTOF- LC Molecular Formula GeneraAon (MFG) MS/MS for QTOF - LCMS CI for QTOF- GCMS 21

22 IdenAficaAon of Unknowns Score Diff. m/z Best Match Species Mass DBE (MFG) (ppm) C 16 H 35 N O 2 [M+H]

23 IdenAficaAon of Unknowns Fragment Ion Best Match Score Possible Structure [C 16 H 34 N O] [C 14 H 32 N O] [C 4 H 12 N O 2 ] [C 4 H 10 N O]

24 QuanAtaAve Strategies Relative Quantitation QuanAficaAon of compounds observed is performed against surrogate standards Accuracy depends on the surrogate standard used Estimated Analyte Conc.= Observed Analyte Peak Area/Surrogate Peak Area Surrogate Conc. 24

25 25 QuanAtaAve Strategies

26 QuanAtaAve Strategies Formal Quantitation Confirmed compounds are quanafied against an analyacal standard at a series of concentraaons Methodologies: External StandardizaAon Standard AddiAon Requires high purity analyacal standards 26

27 27 QuanAtaAve Strategies

28 QuanAtaAve Method Development QuanAtaAve Methods Dynamic Headspace GCMS UHPLC- UV UHPLC- CAD QTOF- GCMS In formal quanataaon limit of quanataaon (LOQ) can be improved using: Targeted MS/MS Large Volume InjecAon 28

29 QuanAtaAve Method Development Agilent 1290 Infinity UHPLC Column: Zorbax SB- C18, 1.8 µm, mm Mobile Phase: H 2 O ACN Grad. DetecAon: 230 nm (DAD) 29

30 2D UHPLC Quaternary Pump Column 1 VWD Loop Valve Waste FLD DAD Column 2 VWD Variable Wavelength Detector DAD Diode Array Detector FLD Fluorescence Detector Binary Pump 30

31 QuanAtaAve Method Development Column: Zorbax SB- C18; 1.8 µm, mm Mobile Phase: H 2 O ACN Gradient DetecAon: 230 nm (VWD) CollecAon Mode: Heart- curng; minutes (40 µl) 31

32 QuanAtaAve Method Development Column: Eclipse Plus Phenyl- Hexyl; 1.8 µm, mm Mobile Phase: H 2 O ACN IsocraAc DetecAon: 230 nm (DAD) 32

33 QuanAtaAve Method Development Column: Eclipse Plus Phenyl- Hexyl; 1.8 µm, mm Mobile Phase: H 2 O ACN IsocraAc DetecAon: Fluorescence; 225 nm excitaaon, 310 nm emission 33

34 A SUCCESSFUL STUDY HAS: 1. Appropriate ExtracAon CondiAons 2. Careful ConcentraAon of Extracts 3. DefiniAve IdenAficaAons 4. Accurate QuanAficaAon 34