Analysis of Extractables from a Pressurized Metered Dose Inhaler

Analysis of Extractable Compounds from a Pressurized Metered-Dose Inhaler (pMDI) Using GC/MSD Systems

Application Note

Pharmaceuticals

Authors Abstract

Diana M. Wong and Roger L. Firor A pressurized metered-dose inhaler (pMDI) is an inhalation device developed for the Agilent Technologies, Inc. direct delivery of active pharmaceutical ingredient (API) to the respiratory tract for Wilmington, DE, USA the treatment of respiratory conditions. Rubber and plastic components in the pMDI are potential sources of extractables by the API/propellant. Therefore, volatile and David Weil semivolatile extractable compounds were investigated in these components using Agilent Technologies, Inc. two 5977 GC/MSD systems. This application note focuses on identifying extracta - Schaumburg, IL, USA bles in the pMDI using the complementation of headspace GC/MS and MMI GC/MS. Introduction Industry guidelines and working groups provide the basis for the analysis of extractables/leachables testing in drug A regulatory expectation for drug manufacturers is to perform delivery and medical devices. The Product Quality Research a safety risk assessment for the presence of potential leach - Institute (PQRI) is a leading working group established to able and extractable compounds in medical devices that may develop regulatory guidance for extractables/leachables occur during the manufacturing process. Extractables are analysis. PQRI is recognized by the FDA and has released a chemical compounds that can be extracted from a pharma - recommendation document that includes safety thresholds for ceutical packaging component using high temperatures to orally inhaled and nasal drug products (OINDP). Several other obtain a leachable profile at the worst case scenario or sol - guidelines and assessments on extractable and leachable vent extraction to mimic similar properties of the drug prod - testing exist, including chapters from USP<661>, USP<1663>, uct. Leachables are chemical compounds from the packaging USP<1664>, USP<1665>, and regulations from international material that have leached into the drug product. Leachables organizations EP 3.2.2.1 and EP 3.2.8. The intent of this appli - are often a subset of extractables and new compounds may cation note is not to provide safety impact or toxicological form due to the packaging-drug interaction. Compound information. Recent articles by Dennis Jenke [3], PQRI work - migration involves correlating extractables to leachables. ing group [4,5], and the Extractable Leachable Safety Extractables determine potential compound migration, while Information Exchange (ELSIE) group address these issues [6]. leachables determine actual compound migration. If leach - ables are identified, it is necessary to consult with the United A pressurized metered-dose inhaler (pMDI) is a pharmaceuti - States Food and Drug Administration (FDA) and toxicological cal construct in the high risk category (Table 1). Inhalation safety guidelines for the acceptable amount. Sources of aerosols/solutions have the highest degree of concern based leachable/extractable compounds include plastic and elas - on the route of administration [7]. The pMDI administers a tomeric components, inks and adhesives from labeling, resid - precise amount of medication directly to the lungs in the form ual impurities from manufacturing, and degradation products of a short burst of aerosolized drug suspension self-adminis - from processing, storage, and sterilization [1,2]. tered through inhalation for treating asthma and respiratory diseases [8].

Table 1. Risk Associated with Various Pack Types Degree of concern associated with route Likelihood of interaction between packaging component and dosage form of administration High Medium Low

Highest Inhalation aerosols and solution Sterile powders Injections and injectable suspensions Injection powders Inhalation powders High Ophthalmic solutions and suspensions Transdermal ointments and patches Nasal aerosols and sprays Low Topical solutions and suspensions Topical powders Oral tablets Topical and lingual aerosols Oral powders Oral hard capsules Oral solutions and suspensions Oral soft gelatin capsules Adapted from Guidance for Industry; Container Closure Systems for Packaging Human Drug and Biologics , US Department of Health and Human Services, Food and Drug Administration, Rockville, MD, May 1999.

2 Elastomeric, plastic, and metal components of the pMDI are A Canister (metal) capable of leaching compounds into the API formulation due to the close contact. Components that have the highest likeli - Drug/propellant hood of interaction with the API/propellant include: canister liquid mixture (metal), retaining cup (plastic), two gaskets (rubber), metering Actuator Retaining cup (plastic) valve (plastic), o-ring (rubber), valve stem (plastic), spring Gaskets (rubber) (metal), and actuator nozzle (plastic) (Figure 1A). The API Metering chamber formulation is stored in the canister where the retaining cup Metering valve (plastic) O-ring (rubber) fills with the precise dosage under gravity. When the canister Stem (plastic) High velocity spray is pressed, the metering valve delivers an accurate dose of Actuator nozzle (plastic) medication through the stem to the actuator nozzle. The rubber components (gaskets and o-ring) are placed snugly Mouthpiece around the stem to prevent leakage of API formulation when the valve is in the closed position. The mouthpiece directs the B API formulation (Figure 1B). When canister is pressed, channel Elastomeric components in the pMDI are considered the opens between major source of extractables. Rubber seals can swell because metering chamber of solubility with the propellant. Heptafluoroalkane (HFA) pro - and atmosphere Droplets form at nozzle: 2-phase gas-liquid air-blast pellants have been identified as suitable alternatives to the tra - Propellants boils ditional chlorofluorocarbon (CFC) propellants that have been in expansion implicated in stratospheric ozone depletion. HPA propellant is chamber not soluble with surfactants that are necessary to create an Ligament API formulation. Thus, surfactant and ethanol (cosolvent) are produced from shearing commonly used in conjunction to increase solubility. However, force Evaporation and cooling ethanol causes swelling of elastomers, increases extractives Figure 1. Design of a pressurized metered dosed inhaler (A) and operation of gasket material, and affects the amount of lubrication of the metering valve (B). between the stem and gaskets. Efforts are in progress to reformulate HFA propellant and to create valves that exhibit low levels of extractables/leachables. Experimental Methods This application note focuses on identifying volatile and semivolatile extractable compounds in an expired pMDI Materials and instrumentation device using two GC/MS systems. Two types of analysis were The pMDI used in the investigation was expired for used: headspace sampling and large volume liquid injection. six months and was manufactured by a leading pharmaceuti - Plastic and rubber components were investigated using cal company. The canister contained fluticasone propionate in aggressive extraction conditions, which were intended for HFA-134a propellant. Extractables analysis of pMDI compo - quantitative determination of chemical additives rather than nents were investigated at high temperatures using the simulation of a drug product leachable profile. Compounds in Agilent 7697A Headspace Sampler and an Agilent 7890 Series pMDI components were extracted using different solvents GC coupled with an Agilent 5977A MSD (Headspace GC/MS). and using high-temperatures. Dichloromethane (DCM) (650463), hexane (34859), and ethanol (459844) were solvents used for extraction and were purchased from Sigma-Aldrich. Solvent extracts were analyzed using the Agilent 7693A Automatic Liquid Sampler (ALS) and a 7890 Series GC coupled with a 5977A MSD. The ALS was equipped with a multimode inlet (MMI) operated in solvent vent mode for large volume liquid injection (MMI GC/MS).

3 Sample preparation Table 2. GC and MSD Instrument Parameters for Analysis of DCM Extract Using MMI GC/MS Extractables analysis using MMI GC/MS Gas chromatograph Agilent 7890 Series GC Rubber and plastic pMDI components (1-cm 2 pieces) were Injection port Multimode Inlet (MMI), CO cooling placed in separate vials for analysis. Components were rinsed 2 with water to minimize any residue from the API formulation. Mode Solvent vent Ethanol, DCM, and hexane were solvents used to extract Inlet program* –5 °C (0.7 minutes) to 325 °C (5 minutes) at 600 °C/min elastomeric components. DCM and hexane were solvents used to extract plastic components. Elastomeric seals Liner 2-mm id, dimpled, ultra inert (p/n 5190-2297) (80–90 mg) were extracted with 3.0 mL of solvent. The stem Inlet vent 100 mL/min (5 psi) until 0.7 minutes (100–120 mg) was extracted with 2 mL of solvent. The retain - Carrier gas Helium ing cup (230–270 mg) was extracted with 3 mL of solvent. The Purge flow to split vent 60 mL/min at 3.15 minutes metering valve (270–280 mg) was extracted with 5 mL of sol - Oven program 50 °C (3 minutes) to 350 °C (5 minutes) at 6 °C/min vent. The actuator nozzle (140–170 mg) was extracted with Columns Agilent J&W-5msUI, 30 m × 250 µm, 0.25 µm 5 mL of solvent. Components were extracted with solvent in a (p/n 19091S-433UI) 12-mL amber glass vial, sonicated for 5 hours, and allowed to MSD Agilent 5977A MSD sit at room temperature for 1–2 days. The organic layer was Transfer line 280 °C transferred to a glass insert placed inside an amber autosam - MS source 300 °C pler vial for GC/MS analysis. Ten microliters of extract were injected using the MMI operated in solvent vent mode. The MS Quad 175 °C solvent elimination wizard was used to develop parameters Tune atune.u specific to the analysis of DCM, hexane, and ethanol extracts. Scan 29 to 700 amu, 2.2 scans/sec Similar GC and MSD parameters were used for all extract Threshold 150 analyses (Table 2). Gain factor 1.0 Software Agilent MassHunter B.07.00 Extractables analysis using headspace GC/MS Components (1-cm 2 pieces) of pMDI were analyzed in sepa - *Initial temperature and initial hold time differs depending on solvent extract. rate 10-mL headspace vials. The components consisted of seals (90 mg), retaining cup (440 mg), valve stem (230 mg), metering valve (410 mg), and actuator nozzle (320 mg). Headspace vials were purged with nitrogen, sealed with a high-performance PTFE crimp cap, and investigated at head - space equilibration temperature of 250 °C. Table 3 lists the system parameters.

4 Table 3. Instrument Parameters Using Headspace GC/MS Compound identification Headspace Agilent 7697A Headspace Sampler Chemical compounds were characterized using MSD Vial pressurization gas Helium Chemstation Data Analysis F.01.01, AMDIS 2.72, and Loop size 1.0 mL Agilent MassHunter Unknowns Analysis B.07.00. Mass spec - tra of all compounds were matched with the NIST14 Library Vial standby flow 50 mL/min 2.2. Compounds with a match score ¡80 were considered Transfer line 0.53 mm id, deactivated fused silica and the top match was selected for investigation. HS oven temperature 250 °C HS loop temperature 250 °C Results and Discussion HS transfer line temperature 270 °C Vial equilibration time 25 minutes, level 2 shake Elastomeric (rubber) seals GC run time 80 minutes Volatiles and semivolatiles investigation of rubber seals using Vials 10 mL, PTFE/silicone septum headspace GC/MS showed peaks attributed to (Figure 2A): Vial fill mode Flow to pressure • Softening agent (1,3-dioxolane) Vial fill pressure 15 psi • Antioxidant in lubricant (1-naphthalenol) Loop fill mode Custom • Releasing agents (palmitic acid) Loop ramp rate 20 psi/min • Rubber composition (octadecanamide, octadecanenitrile) Loop final pressure 1.5 psi • Molding material (cyclohexasiloxane, dodecamethyl-) Loop equilibration time 0.05 minutes Semivolatiles testing of solvent extracts of rubber seals using Carrier control mode GC carrier control MMI GC/MS showed an extractable profile consisting of Extraction mode Single (Figure 2B): Vent after extraction ON Ethanol extract Post injection purge 100 mL/min for 1 minutes • Curing agents in silicone rubber system (Dynasil A) Gas chromatograph Agilent 7890 Series GC • Residual solvents (acetophenone) Injection port Split/Splitless • Surface active agents (myristic acid) Liner 0.75-mm ultra-inert, straight, tapered • Ingredients in rubber products (oleic acid) (p/n 5190-4048) • Lubricants (stearic acid) Inlet temperature 280 °C • Slip agents (oleimide) Inlet flow Constant flow, 1.3 mL/min • Sealants (13 -docosenamide) Split ratio 30:1 • Stabilizers ( tris (2,4 -di -tert -butylphenyl)phosphate) Carrier gas Helium DCM extract • Thermodegradation products (nonanal) Oven program 35 °C (2 minutes) to 320 °C (3 minutes) at 8 °C/min • Antioxidants (2,4-di- tert -butylphenol) • Monomers (dodecyl acrylate) Columns Agilent J&W-5ms UI, 30 m × 0.25 mm, 0.5 µm (p/n 19091S-133UI) Hexane extract MSD Agilent 5977A MSD • Wax from the vulcanization of rubber (docosane) Transfer line 280 °C • Antioxidant (Irganox 1076) MS Source 280 °C MS Quad 180 °C Tune atune.u Scan 15 to 700 amu, 2.5 scans/sec Threshold 0 Gain Factor 1.0 Software Agilent MassHunter B.07.01

5 6 ×10 Peak ID 16. 2-Pentene, 2,4,4-trimethyl- A 3.6 1. 2-Propanol, 2-methyl- 17. 2-Ethyl-1-hexanol, trifluoroacetate 25 3.4 TIC of rubber seal (250 °C) 2. Acetic acid 18. Disulfide, bis (1,1,3,3-tetramethylbutyl) 3.2 Background 3. 1,3-Dioxolane 19. Cyclohexasiloxane, dodecamethyl- Rubber seal 4. Benzene 20. 2,4-Di- tert -butylphenol 3.0 5. Propanoic acid 21. 1-Naphthalenol 2.8 6. 1-Pentene, 2,4,4-trimethyl- 29 22. Phthalate, cyclobutyl propyl 2.6 7. Pyrrole 23. Myristic acid 2.4 8. 2-Pentanone, 4,4-dimethyl- 24. Pentadecanenitrile 9. Propanenitrile, 2-hydroxy- 25. Palmitic acid 2.2 10. 1,3,5-Trioxepane 26. Octadecanenitrile 2.0 11. 2-Cyclopenten-1-one 27. trans -13-Octadecenoic acid 1.8 15 12. 4-Pentenenitrile, 2-methylene- 28. cis -Vaccenic acid C

o 1.6 13. Benzonitrile 29. Stearic acid u

n 14. Heptane, 2,2,6,6-tetramethyl- 30. Octadecanamide t

s1.4 4-methylene- 31. Tetracosamethyl-cyclododecasiloxane 1.2 18 15. 3-Heptene, 2,2,4,6,6-pentamethyl- 32. Cyclodecasiloxane, eicosamethyl- 1.0 1 28 0.8 27 0.6 14 17 24 26 0.4 6 9 3 16 20 0.2 2 5 8 10 12 23 31 32 4 7 11 13 19 21 22 30 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 Acquisition time (min) ×10 7 1.9 B Peak ID 1.8 1. Hexanal, 2,2-dimethyl- 28 17. 1-Octadecanol TIC of rubber seal (ethanol extract) 1.7 2. 2,5-Hexanedione 18. cis -13-Octadecenoic acid 1.6 Background 3. Dynasil A 19. Oleic acid 20. Stearic acid 1.5 Rubber seal 4. Cyclohexanone, 3,3,5-trimethyl- 21. Octadecanoic acid, ethyl ester 1.4 5. 2,5-Hexanediol, 2,5-dimethyl- 6. Acetophenone 22. 1,8-Diazacyclotetradecane-2,7-dione 1.3 7. Ethyl benzoate 23. Behenic alcohol 1.2 24. Oleimide 20 8. 1-Dodecanol 1.1 9. 2,4-Di- tert -butylphenol 25. Antioxidant BKF 1.0 10. Ethyl 4-ethoxybenzoate 26. Di(oct-3-yl) phthalate 27. 13-Docosenamide, (Z)- C 0.9 11. Diethyl phthalate o 28. tris (2,4-di- tert -butylphenyl) u 16 12. 1-Tetradecanol n 0.8

t phosphate s0.7 13. Phenol, 4-(1,1,3,3-tetramethylbutyl)- 14. Myristic acid 29. Fluticasone propionate 0.6 19 15 15. Dodecyl acrylate 0.5 16. Palmitic acid 0.4 18 21 29 0.3 5 14 22 24 0.2 2 6 3 13 23 25 27 0.1 1 4 7 8 9 11 12 17 26 10 0 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 Acquisition time (min) Figure 2. Extractables analysis of a rubber seal using headspace equilibrium temperature of 250 °C (A) and ethanol extraction by MMI GC/MS (B).

6 Retaining cup Semivolatiles testing of solvent extracts of retaining cup using Volatiles and semivolatiles investigation of retaining cup MMI GC/MS showed an extractable profile consisting of using headspace GC/MS showed peaks attributed to (Figure 3B): (Figure 3A): DCM extract • Flavor/fragrance (2,3-butanedione) • Antioxidant (2,4-di- tert -butylphenol) • Softening agent (1,3 -dioxolane) • Plasticizers (Kodaflex TXIB) • Thermoplastic composition • Lubricants (1-hexadecanol) (eicosamethyl cyclodecasiloxane) • Stabilizer (Metilox) Hexane extract • Catalyst (ethyl 4-ethoxybenzoate) • Phthalate plasticizers (diethyl phthalate) • Monomer (dodecyl acrylate) ×10 6 TIC of retaining cup (250 °C) 6.0 A Background 5.6 Retaining cup 5.2 7 Peak ID 4.8 1. Methylal 4.4 2. 2,3-Butanedione 3. 1,3-Dioxolane 4.0 4. 1,3-Dioxolane, 2-methyl- 3.6 5. 1,3,5-Trioxane

s 6. Ethanol, 2-(vinyloxy)- t

n 3.2

u 7. 1,2-Ethanediol, monoformate o

C 2.8 8. 1,3,5-Trioxepane 1 9. 1,2-Ethanediol, diformate 2.4 10. 1,3,5-Trioxane 2.0 11. 3-Heptene, 2,2,4,6,6-pentamethyl- 2 12. 5-Methyl-2,4-diisopropylphenol 1.6 4 13. Octane, 1,1'-oxy bis - 3 1.2 8 14. Cyclodecasiloxane, eicosamethyl- 5 0.8 6 10 9 0.4 12 11 13 14 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 Acquisition time (min)

×10 6 B 5.2 8 TIC of retaining cup (DCM extract) Peak ID 4.8 Background 1. 2,4-Di- tert -butylphenol 2. Kodaflex TXIB Retaining cup 4.4 3. 1-Hexadecanol 4. Phenol, 4-(1,1,3,3-tetramethylbutyl)- 4.0 5. 1,2-Benzenediol, o-(4-methoxybenzoyl)- o' -(2,2,3,3,4,4,4-heptafluorobutyryl)- 3.6 6. Dodecyl acrylate 7. 7,9-Di- tert -butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione 3.2 8. Metilox s

t 2.8 n u o

C 2.4 7

2.0

1.6 6 1.2

0.8

0.4 1 4 5 2 3 0 18.8 19.2 19.6 20.0 20.4 20.8 21.2 21.6 22.0 22.4 22.8 23.2 23.6 24.0 24.4 24.8 25.2 25.6 26.0 26.4 26.8 27.2 27.6 28.0 28.4 28.8 Acquisition time (min) Figure 3. Extractables analysis of a retaining cup using headspace equilibrium temperature of 250 °C (A) and DCM extraction by MMI GC/MS (B).

7 Metering valve Semivolatiles testing of solvent extracts of the plastic Volatiles and semivolatiles investigation of plastic metering metering valve using MMI GC/MS showed an extractable valve using headspace GC/MS showed peaks attributed to profile consisting of (Figure 4B): the compounds listed below (Figure 4A). Octadecanitrile was Hexane extract also observed in headspace GC/MS analysis of elastomeric • Plasticizer (Kodaflex TXIB) seal at a similar retention time (Figure 2A), indicating • Thermoplastic decomposition (eicosamethyl cyclodecasiloxane) potential compound migration. • Antioxidants (Antioxidant BKF) • Solvents (pyridine) • Stabilizers ( tris (2,4-di- tert -butylphenyl)phosphate) • Processing aids (butyrolactone) DCM extract • Catalysts (propylbenzene) • Plasticizers (Kodaflex TXIB) • Monomers (succinimide) • Catalyst (ethyl 4-ethoxybenzoate) • Odor agents (2-pentylcyclopentanone) • Polymer byproducts (styrene-acrylonitrile trimer) • Antioxidant for lubricants (1-naphthalenol) • Lubricant (13-docosenamide) • Releasing agents (palmitic acid) • Lubricants (stearic acid) • Plasticizers (diisooctyl phthalate) • Rubber component (octadecanenitrile)

×10 6 A TIC of metering valve (250 °C) Peak ID 17. 2H-Pyran-2-one, tetrahydro- 2.6 Background 1. Butanal 18. Succinimide Metering valve 2. 2-Pentenal, (E)- 19. 2-Piperidinone 9 2.4 3. 1-Butanol 20. 2-Pentylcyclopentanone 2.2 4. 2H-Pyran, 3,4-dihydro- 21. Caprolactam 5. Pentanal 22. Benzenebutanal 2.0 6. Propanoic acid 23. [1,1'-Bicyclopentyl]-2-one 1.8 5 7. Pyridine 24. Benzenebutanol 1.6 8. Pentanenitrile 25. Cyclopropylphenylmethane s t

n 9. Cyclopentanone 26. 1-Naphthalenol

u 1.4 o 10. Cyclopentanone, 2-methyl- 27. 3-Octadecene, (E)- C 1.2 11. Pentanoic acid 28. Palmitic acid 23 1.0 12. 2-Butenal, 2-ethenyl- 29. Octadecanenitrile 13. Butyrolactone 30. Methyl stearate 0.8 31 32 14. Benzene, propyl- 31. Stearic acid 0.6 15. Benzaldehyde 32. 1,8-Diazacyclotetradecane-2,7-dione 28 1 22 16. Pentanamide 33. Diisooctyl phthalate 0.4 7 12 21 2 6 11 14 20 30 0.2 34 8 16 24 27 33 10 13 15 17 18 19 25 26 29 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 Acquisition time (min)

×10 6 B Peak ID 1.1 TIC of metering valve (hexane extract) 1. Kodaflex TXIB Background 7 2. Hexadecane 1.0 Metering valve 3. 1-Tetradecanol 0.9 4. Cyclononasiloxane, octadecamethyl- 5. Octadecane 0.8 6. Isobutyl 4-octyl phthalate 7. Dodecyl acrylate 0.7 8. Phenanthrene, 1-methyl- s t 9. Cyclodecasiloxane, eicosamethyl- n 0.6 u

o 10. Butyl 4-methylpent-2-yl phthalate C 0.5 11. Phenanthrene, 2,5-dimethyl- 12. Cyclodecasiloxane, eicosamethyl- 0.4 13. Tetracosamethyl-cyclododecasiloxane 16 0.3 14. bis (2-ethylhexyl) fumarate 15. Antioxidant BKF 0.2 16. tris (2,4-di- tert -butylphenyl) phosphate 4 910 0.1 3 12 13 5 6 8 11 14 12 15 0 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Acquisition time (min) Figure 4. Extractables analysis of a metering valve using headspace equilibrium temperature of 250 °C (A) and hexane extraction by MMI GC/MS (B).

8 Valve stem DCM extract • Odor agents (nonanal) Volatiles and semivolatiles testing of valve stem using • Resins (dimethyl adipate) headspace GC/MS showed an extractable profile consisting • Adhesives (2,4,7,9-Tetramethyl-5-decyn-4,7-diol) of (Figure 5A): • Lubricants (1-dodecanol) • Preservatives (formic acid) • Antioxidants (2,4-di- tert -butylphenol) • Softening polymer (1,3-dioxolane) • Plasticizers (Kodaflex TXIB) • The manufacture of polyols (hydroxyacetone) • Photoinitiators (Irgacure 184) • Catalysts (ethyl 4-ethoxybenzoate) • Comonomer/intermediate (dodecyl acrylate) • Thermoplastic compositions (eicosamethyl cyclodecasiloxane) • Antioxidant in polypropylene • Resins (hexadecamethyl cyclooctasiloxane) (7,9-di- tert -butyl-1oxaspiro(4,5)deca-6,9-diene-2,8-dione) • Plasticizer (Irganox 1076) Semivolatiles investigation of solvent extracts in valve stem using MMI GC/MS showed peaks attributed to (Figure 5B): Hexane extract • Odor agents (nonanal) • Molding material (dodecamethyl cyclohexasiloxane) • Phthalate plasticizer (hept-4-yl isobutyl phthalate)

×10 6 6.8 1 3 A 6.4 TIC of stem (250 °C) 6.0 Background 5.6 Stem 5.2 Peak ID 4.8 6 1. Formic acid 4.4 2. 1,3-Dioxolane 3. 1,3-Dioxolane, 2-methyl- 4.0 4. Hydroxyacetone s t 3.6

n 5. 1,3,5-Trioxane u

o 3.2 6. 1,2-Ethanediol, monoformate C 2.8 7. 1,3,5-Trioxepane 2.4 8. 1,2-Ethanediol, diformate 9. 1,3-Propanediol 2.0 2 10. 1,3,5-Trioxane 1.6 11. 5-Methyl-2,4-diisopropylphenol 5 10 1.2 8 12. Ethyl 4-ethoxybenzoate 0.8 9 13. Cyclooctasiloxane, hexadecamethyl- 4 7 13 14. Cyclodecasiloxane, eicosamethyl- 0.4 11 12 14 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 Acquisition time (min) ×10 6 B 5.6 TIC of stem (DCM extract) 17 Peak ID 1. Nonanal 5.2 Background Stem 2. Dimethyl glutarate 4.8 3. Dimethyl adipate 4. Nonanoic acid 4.4 5. Glycerol 1,2-diacetate 4.0 6. 2,4,7,9-Tetramethyl-5-decyn-4,7-diol 7. p-Diacetylbenzene 3.6 8. 2,6-Di- tert -butyl- p-benzoquinone s t

n 3.2 9. 1-Dodecanol u 16 o 10. 2,4-Di- tert -butylphenol C 2.8 11. Ethyl 4-ethoxybenzoate 2.4 12. Kodaflex TXIB 2.0 13. Irgacure 184 14. 3,5-di- tert -Butyl-4-hydroxybenzaldehyde 1.6 8 15. Dodecyl acrylate 1.2 15 16. 7,9-Di- tert -butyl-1-oxaspiro(4,5)deca-6,9-di - 11 ene-2,8-dione 0.8 17. Irganox 1076 5 7 10 0.4 9 12 13 1 2 3 4 6 14 0 11 12 13 14 15 16 17 18 19 20 21 23 24 25 26 27 28 29 30 Acquisition time (min) Figure 5. Extractables analysis of the valve stem using headspace equilibrium temperature of 250 °C (A) and DCM extraction by MMI GC/MS (B).

9 Actuator nozzle Semivolatiles testing of solvent extract in plastic nozzle using Volatiles and semivolatiles analysis of plastic nozzle using MMI GC/MS showed peaks attributed to (Figure 6B): headspace GC/MS showed peaks attributed to the DCM extract compounds listed below (Figure 6A). Dye additive could be • Odor agents (2,7-dimethyl-1-octanol) attributed to the colorant in the actuator. • Antioxidants (butylated hydroxytoluene, Irgafos 168, 4,4'-ethyl - ene bis (2,6-di- tert -butylphenol)) • Monomers (acetic acid) • Catalysts (ethyl 4-ethoxybenzoate) • Manufacture of dyes (hydroxyacetone) • Releasing agents (palmitic acid) • Paint/coating (2-pentanone) • Stabilizers ( tris (2,4-di- tert -butylphenyl) phosphate) • Solvents for polymers (methyl isobutyl ketone) • Fragrances (4-methyl-4-penten-2-one) Hexane extract • UV stabilizer (2,4-di- tert -butylphenol) • Lubricants (phytane) • Catalysts (ethyl 4-ethoxybenzoate) • Antioxidants (butylated hydroxytoluene) • Releasing agents (palmitic acid) • Catalysts (ethyl 4-ethoxybenzoate) • Lubricants (stearic acid) • Monomers (dodecyl acrylate) • Antioxidants (Irgafos 168) • Thermal conversion of plastics (heneicosane) • Stabilizers ( tris (2,4-di- tert -butylphenyl) phosphate) • Wax (hentriacontane) • Antioxidants (Irgafos 168) • Stabilizers ( tris (2,4-di- tert -butylphenyl) phosphate)

×10 7 A TIC of actuator nozzle (250 °C) 1.0 Peak ID Background 17. Dodecane Nozzle 1. 1-Pentene, 2-methyl- 0.9 2. Acetic acid 18. Octane, 3,5-dimethyl- 11 3. Hydroxyacetone 19. Undecane 0.8 4. 2-Pentanone 20. Dodecane, 2,6,11-trimethyl- 5. 2,4-Dimethylfuran 21. Decane, 3,6-dimethyl- 0.7 6. Methyl isobutyl ketone 22. Heptadecane, 2,6,10,15-tetramethyl- 7. 4-Penten-2-one, 4-methyl- 23. 2,4-Di- tert -butylphenol 8. Heptane, 4-methyl- 24. Ethyl 4-ethoxybenzoate 0.6 17

s 9. Acetylacetone 25. Heptadecane t

n 10. 3-Penten-2-one, 4-methyl- 26. Hexadecane, 2,6,11,15-tetramethyl- u 0.5 12 o 11. Heptane, 2,4-dimethyl- 27. Eicosane, 2-methyl- C 15 20 12. 2,4-Dimethyl-1-heptene 28. Palmitic acid 0.4 18 4 13 13. Octane, 4-methyl- 29. Stearic acid 23 14. 2,5-Hexanedione 30. Irgafos 168 21 0.3 1 22 24 15. 2-Heptanone, 4-methyl- 31. tris (2,4-Di- tert -butylphenyl) phosphate 19 3 6 16 16. 2-Heptanone, 4,6-dimethyl- 0.2 9 25 2 5 8 10 14 26 27 28 0.1 7 31 29 30 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 Acquisition time (min) ×10 7 2.6 B TIC of actuator nozzle (DCM extract) 17 Peak ID 1. Heptane, 2,4-dimethyl- 2.4 Background Nozzle 2. Dodecane 2.2 3. 1-Octanol, 2,7-dimethyl- 2.0 4. Octane, 2,3,6,7-tetramethyl- 5. Undecane, 4-methyl- 1.8 6. 2-Bromo dodecane 7. Dodecane, 2,6,11-trimethyl- 1.6 8. Pentadecane

s 9. Butylated hydroxytoluene t 1.4 n 10. Ethyl 4-ethoxybenzoate u o 1.2 11. Pentadecane, 2-methyl- C 18 12. Tremetone 1.0 13. Hexadecane, 2,6,11,15-tetramethyl- 13 14 0.8 7 10 14. Pentacosane 8 15. Palmitic acid 0.6 15 16. 4,4'-Ethylene bis (2,6-di- tert -butylphenol) 2 4 17. Irgafos 168 0.4 1 9 11 16 18. tris (2,4-Di- tert -butylphenyl) phosphate 12 0.2 3 5 6 0 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 Acquisition time (min) Figure 6. Extractables analysis of an actuator nozzle using headspace equilibrium temperature of 250 °C (A) and DCM extraction by MMI GC/MS (B).

10 Volatile and semivolatile extractable compounds identified in Most extractables were identified only by solvent extraction pMDI components included monomers, polymers, adhesives, or only by high-temperature headspace sampling. For lubricants, surfactants, odor agents, paint additives, coating instance, oleimide is a slip agent/lubricant that was identified additives, plasticizers, resins, intermediates, antioxidants, by ethanol extraction. Irganox 1076 is an antioxidant that was UV -stabilizers, stabilizers, flavor and fragrance byproducts, characterized using hexane extraction. 3-chlorophenyloctyl colorants, regulators, processing aids, thermoplastic composi - terephthalate is used in the production of polyester that was tions, adhesives, wax from vulcanization of rubber, identified by DCM extraction. 2-pentanone is a painting/coat - preservatives, photoinitiators, rubber ingredients, curing ing additive that was characterized using high -temperature agents, finishing agents, dyes, and residual solvents. Table 4 headspace sampling. Table 3 lists the extraction technique contains a list of all extractables identified in pMDI. and pMDI component used to identify the particular extractable.

Table 4. Extractables identified in pMDI device Extraction Compound a (component) b Origin c [1,1'-Bicyclopentyl]-2-one HS(V) 1,2-Benzenediol, o-(4-methoxybenzoyl)- o' -(2,2,3,3,4,4,4-heptafluorobutyryl)- D(C) 1,2-Ethanediol, diformate HS(C);HS(S) 1,2-Ethanediol, monoformate HS(C);HS(S) 1,3,5-Trioxane HS(C);HS(S) 1,3,5-Trioxepane HS(R);HS(C);HS(S) 1,3-Dioxolane HS(R);HS(C);HS(S) Softening polymer (PA and PVC) 1,3-Dioxolane, 2-methyl- HS(C);HS(S) 1,3-Propanediol HS(S) Polyester polymer 1,8-Diazacyclotetradecane-2,7-dione E(R); D,HS(V) Ingredient in polymer 13-Docosenamide, (Z)- E(R),D(V) Adhesives, sealant, lubricants 1-Butanol HS(V) Manufacture of polymers, pyroxylin, plastics 1-Dodecanol D(S), E(R) Surfactants, lubrication, polymers 1-Hexadecanol D(C), H(R) Lubrication, odor agent, paint and coating additive, plasticizer 1-Naphthalenol HS(R,V) Intermediate for antioxidants in lubricants 1- n-Hexyladamantane H(R) 1-Octadecanol E(R) Lubricants, resins 1-Octanol, 2,7-dimethyl- D(N) Odor agent 1-Pentene, 2,4,4-trimethyl- HS(R) 1-Pentene, 2-methyl- HS(N) 1-Phenoxypropan-2-ol H(S) 1-Tetradecanol E(R),H(C);H(V);H(S) 2,2,4-Trimethyl-1,3-pentanediol diisobutyrate D(C);D,H(V);D(S) Plasticizer 2,3-Butanedione HS(C) Flavor 2,4,7,9-Tetramethyl-5-decyn-4,7-diol D(S) Adhesives, surfactants 2,4-Dimethyl-1-heptene HS(N) 2,4-Dimethylfuran HS(N) 2,4-Di- tert -butylphenol D(C,S); HS(N); E,H,D,HS(R) UV stabilizer, potential migrant 2,5-Cyclohexadiene-1,4-dione, 2,6- bis (1,1-dimethylethyl)-; D(S) 2,6-di- tert -butyl-p-benzoquinone

11 Extraction Compound a (component) b Origin c

2,5-Hexanediol, 2,5-dimethyl- E,D(R) Intermediate 2,5-Hexanedione E(R);HS(N) Deodorizing agent 2-[1-(4-Cyano-1,2,3,4-tetrahydronaphthyl)]propanenitrile; D(V) Byproduct in acrylonitrile styrene plastics styrene-acrylonitrile trimer 2-Bromo dodecane D(N) 2-Butenal, 2-ethenyl- HS(V) 2-Butenedioic acid (E)-, bis (2-ethylhexyl) ester; bis (2-ethylhexyl)fumarate H(V) 2-Cyclopenten-1-one HS(R) 2-Ethyl-1-hexanol, trifluoroacetate HS(R) 2-Heptanone, 4,6-dimethyl- HS(N) 2-Heptanone, 4-methyl- HS(N) 2H-Pyran, 3,4-dihydro- HS(V) 2H-Pyran-2-one, tetrahydro-; d-valerolactone HS(V) Intermediate (copolymer) in polyester 2-Pentanone HS(N) Paint and coating additives 2-Pentanone, 4,4-dimethyl- HS(R) 2-Pentenal, (E)- HS(V) Flavor and fragrance agent 2-Pentene, 2,4,4-trimethyl- HS(R) 2-Pentylcyclopentanone HS(V) Odor agent 2-Piperidinone HS(V) Intermediate (copolymer) 2-Propanol, 2-methyl- HS(R) 2-Propanone, 1-hydroxy-; hydroxyacetone HS(S);HS(N) Manufacture of polyols, acrolein, dyes 3,5-di- tert -Butyl-4-hydroxybenzaldehyde D(C,S) 3-[1-(4-Cyano-1,2,3,4-tetrahydronaphthyl)]propanenitrile D(V) 3-Heptene, 2,2,4,6,6-pentamethyl- HS(C); H,D,HS(R) 3-Octadecene, (E)- HS(V) 3-Penten-2-one, 4-methyl- HS(N) Flavor and fragrance 4,4'-Ethylenebis(2,6-di- tert -butylphenol) D(N) Stabilizer and antioxidant for polyolefins 4-Penten-2-one, 4-methyl- HS(N) Flavor and fragrance 4-Pentenenitrile, 2-methylene- HS(R) 5-Methyl-2,4-diisopropylphenol HS(C,S) 7,9-Di- tert -butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione D(C,S) Antioxidant in polypropylene 9-Octadecenamide, (Z)-; oleimide E(R) Slip agent, lubricant, corrosion inhibitor; potential to leach Acetic acid HS(R,N) Production of vinyl acetate monomer Acetophenone E(R) Solvent for plastic and resins Acetylacetone HS(N) Behenic alcohol E,H(R) Lubricant Benzaldehyde HS(V) Precursor to plastic additives Benzene HS(R) Benzene, propyl- HS(V) Catalyst for olefin polymerization Benzenebutanal HS(V) Benzenebutanol HS(V) Benzenepropanoic acid, 3,5- bis (1,1-dimethylethyl)-4-hydroxy-, methyl ester; D(C);D(S); H(R) Polymer stabilizer Irganox 1076

12 Extraction Compound a (component) b Origin c

Benzoic acid, 4-ethoxy-, ethyl ester; ethyl 4-ethoxybenzoate E(R);H(C);D(V);D,HS(S); Catalyst for olefin polymerization D,H,HS(N) Benzoic acid, ethyl ester; ethyl benzoate E(R) Fragrance Benzonitrile HS(R) Butanal HS(V) Intermediate Butylated hydroxytoluene (BHT) D,H(N) Antioxidant Butyrolactone HS(V) Colorant; intermediates, process regulators, processing aid, solvents Caprolactam HS(V) Precursor to nylon 6, a widely used synthetic polymer cis -13-Octadecenoic acid E,H,D(R) Lubrication in plastics and coatings cis -Vaccenic acid HS(R) Cyclodecasiloxane, eicosamethyl- HS(R);HS(C);H(V);HS(S) Thermoplastic Cycloheptasiloxane, tetradecamethyl- H(S) Resin Cyclohexanone, 3,3,5-trimethyl- E(R) Monomer for polycarbonate; polymerization initiator, coating, paint, gloss and surface finish Cyclohexasiloxane, dodecamethyl- HS(R);H(S) Intermediate, solvent, molding material Cyclononasiloxane, octadecamethyl- H(C);H(V);H(S) Polymer synthesis Cyclooctane, 1,4-dimethyl-, trans - H(N) Cyclooctasiloxane, hexadecamethyl- H,HS(S) Thermoplastic, resin Cyclopentanone HS(V) Fragrance Cyclopentanone, 2-cyclopentylidene- D(V) Cyclopentanone, 2-methyl- HS(V) Cyclopropylphenylmethane HS(V) Decane, 3,6-dimethyl- HS(N) Dibutyl phthalate H(C) Potentially toxic plasticizer Diethyl phthalate E,H(R);H(C) Potentially toxic plasticizer Diisooctyl phthalate HS(V) Potentially toxic plasticizer Disulfide, bis (1,1,3,3-tetramethylbutyl) HS(R) Docosane H(R) Wax in vulcanization of rubber Dodecane D,H,HS(N) Dodecane, 2,6,11-trimethyl- D,H,HS(N) Dodecyl acrylate E,D(R);D,H(C);H(V);D,H(S); Intermediate, comonomer H(N) Eicosane, 2-methyl- HS(N) Ethanol, 2-(vinyloxy)- HS(C) Ethanone, 1,1'-(1,4-phenylene) bis -; p-diacetylbenzene D(S) Fluticasone propionate E(R);D(V) Corticosteroid used to treat asthma Formic acid HS(S) Preservative and antibacterial agent Glycerol 1,2-diacetate D(S) Thermal conversion of plastics Heneicosane H(N) Hentriacontane H(N) Wax Heptadecane HS(N) Heptadecane, 2,6,10,15-tetramethyl- HS(N) Heptane, 2,2,6,6-tetramethyl-4-methylene- HS(R) Heptane, 2,4-dimethyl- D,H,HS(N)

13 Extraction Compound a (component) b Origin c

Heptane, 4-methyl- HS(N) Hexadecane H(V) Pyrolysis of plastic Hexadecane, 2,6,10,14-tetramethyl-; phytane H(N) Plasticizers, lubricant Hexadecane, 2,6,11,15-tetramethyl- D,HS(N) Hexadecanoic acid; palmitic acid E,H,D,HS(R);HS(V); Releasing agent, plasticizer D,HS(N) Hexanal, 2,2-dimethyl- E(R) Hexanedioic acid, dimethyl ester; dimethyl adipate D(S) Hexestrol D(R) Isophthalic acid, 3,5-difluorophenyl octyl ester; D(R) 3,5-difluorophenyl isophthalate Isophthalic acid, ethyl tridec-2-ynyl ester; ethyl tridec-2-ynyl isophthalate D(R) Methanone, (1-hydroxycyclohexyl)phenyl-; Irgacure 184 D(S) Photoinitiator Methyl isobutyl ketone HS(N) Solvent for lacquers, polymers and resin Methyl stearate HS(V) Lubricant and surfactants Methylal HS(C) Blowing agent in PU foam system Nonanal D(R);D,H(S) Causes off-taste/odor due to thermo degradation of polyolefins containers, antioxidants are usually added to counter Nonanoic acid D(S) Plasticizers; lubricants, paints and coating, plastic and rubber products Octadecanamide HS(R) Additives in rubber Octadecane H(V) Plasticizer in PVC Octadecanenitrile HS(R);HS(V) Rubber composition Octadecanoic acid, 2-propenyl ester; allyl stearate H(R) Lubricant Octadecanoic acid, ethyl ester; ethyl stearate E(R) Fragrance, plasticizer, lubricant Octadecanoic acid; stearic acid E,H,D,HS(R);HS(V);HS(N) Lubricant, softening, and release agents; soften PVC; potential to migrate Octane, 1,1'-oxy bis - HS(C) Octane, 2,3,6,7-tetramethyl- D(N) Octane, 3,5-dimethyl- HS(N) Octane, 4-methyl- H,HS(N) Oleic acid E(R) Plasticizer; ingredient in rubber Pentacosane D,H(N) Plasticizer Pentadecane D(N) Aliphatic hydrocarbon plasticizer with potential to migrate Pentadecane, 2-methyl- D(N) Pentadecanenitrile HS(R) Pentanal HS(V) Odor agent Pentanamide HS(V) PA-6 additives (potential migration) Pentanedioic acid, (2,4-di-t-butylphenyl) mono-ester H(C) Pentanedioic acid, dimethyl ester; dimethyl glutarate D(S) Resin, viscosity Pentanenitrile HS(V) Pentanoic acid; valeric acid HS(V) Lubricant Phenanthrene, 1-methyl- H(V) Phenanthrene, 2,5-dimethyl- H(V)

14 Extraction Compound a (component) b Origin c

Phenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-methyl-; Antioxidant BKF E,D(R);H(V) Antioxidant in rubber and plastic Phenol, 2,4- bis (1,1-dimethylethyl)-, phosphite (3:1); Irgafos 168 D,H,HS(N) Antioxidant, potential migration Phenol, 4-(1,1,3,3-tetramethylbutyl)- E,H,D(R);D(C) Phthalic acid, butyl 4-methylpent-2-yl ester; butyl 4-methylpent-2-yl phthalate H(V) Phthalate plasticizer; potentially toxic Phthalic acid, di(oct-3-yl) ester; di(oct-3-yl) phthalate E(R) Phthalate plasticizer; potentially toxic Phthalic acid, hept-4-yl isobutyl ester; hept-4-yl isobutyl phthalate H(S) Phthalate plasticizer; potentially toxic Phthalic acid, isobutyl 4-octyl ester; isobutyl 4-octyl phthalate H(V) Phthalate plasticizer; potentially toxic Propanenitrile, 2-hydroxy- HS(R) Propanoic acid HS(R);HS(V) Antimicrobial packaging material Propanoic acid, 2-methyl-, 3-hydroxy-2,2,4-trimethylpentyl ester; D(V) Plasticizer 2,4,4-trimethyl-1,3-pentanediol monoisobutyrate (Kodaflex TXIB) Pyridine HS(V) Solvent and reagent Pyrrole HS(R) Monomer Silane, diethylheptyloxyoctadecyloxy- D(N) Succinimide HS(V) Monomer Terephthalic acid, 3-chlorophenyl octyl ester; D(R) Monomer 3-chlorophenyl octyl terephthalate Tetracosamethyl-cyclododecasiloxane HS(R);H(C);H(V);H(S) Tetracosane H(R) Plastic decomposition; diffusion out of rubber Tetradecanoic acid; myristic acid E,D,HS(R) Adhesives, sealant, finishing agent, lubrication, surface active agents Tetraethyl silicate; Dynasil A E(R) Curing agent; crosslinker in silicone rubber system trans -13-Octadecenoic acid HS(R) Tremetone D,H(N) Toxic compound tris (2,4-Di- tert -butylphenyl) phosphate E,H(R);H(V);D,H,HS(N) Stabilizer for polymers Undecane HS(N) Lubricant Undecane, 4-methyl- D(N) a Compounds are alphabetized based on name listed in NIST14 library. Common names are indicated in blue. b Solvent extraction: ethanol (E), dichloromethane (D), and hexane (H). High-temperature headspace sampling (HS). pMDI components: rubber seal (R), retaining cup (C), valve stem (S), metering valve (V), and actuator nozzle (N) c Origin of compounds are based on literature reference [3].

15 Conclusion 4. D. L. Norwood, et al . Best practices for extractables and leachables in orally inhaled and nasal drug products: an The complementation of headspace GC/MS and MMI GC/MS overview of the PQRI recommendations. Pharm. Res. 25 , provided a broad extractables profile of compounds that can 727-739 ( 2008 ). be extracted from a pMDI. Most of the compounds identified 5. L. Dick. Best Practices of Routine Extractables Testing were specific to high-temperature headspace sampling or [Webinar]. IPAC-RS Materials Webinar ( 2012 , Sept 13). solvent extraction techniques. The MMI in solvent vent mode Retrieved from http://solutions.3m.com/ allows for the detection of low-level leachable/extractable 3MContentRetrievalAPI/BlobServlet?lmd=1352355247000 compounds by making large volume injection. Headspace &locale=en_WW&assetType=MMM_Image&assetId=131 sampling simplifies sample preparation as the pMDI compo - 9241566419&blobAttribute=ImageFile nent can be placed directly into the headspace vial for analysis. MMI GC/MS and headspace GC/MS provide a 6. L. M. Nagao, et al . The ELSIE Extractables and Leachables nontargeted approach to determine an extractables/leach - Database. Pharmaceutical Outsources, Journal of ables profile. GC/Q-TOF and GC/MSMS would be the next Pharmaceutical & Biopharmaceutical Contract Services step for targeted compound analysis. This application note is (2011 , Nov 01). Retrieved from http://www.pharmout - not intended to do quantitation on the extractable and leach - sourcing.com able components. Literature contains references on using 7. Guidance for Industry; Container Closure Systems for GC/MS and GC/MSMS to quantify the presence of potential Packaging Human Drug and Biologics, US Department of endrocrine disruptors, such as phthalates, extracting from Health and Human Services, Food and Drug pMDI devices [9,10]. Administration, Rockville, MD, May 1999 . 8. J. H. Wildhaber, et al . “Inhalation therapy in asthma: References Nebulizer or pressurized metered-dose inhaler with holding chamber? In vivo comparison of lung deposition in 1. D. J. Ball, et al . Safety Evaluation, Qualification, and Best children” J. Pediatr . 135 , 28–33 ( 1999 ). Practices Applied to Inhalation Drug Products. In Leachables and Extractables Handbook , John Wiley & 9. J. Chan, F. Shuang. Rapid, Sensitive, and Robust Detection Sons ( 2012 ). of Phthalates in Food Using GC/MS or LC/MS. Agilent Technologies Application Note , publication number 2. A. Feilden. Update on Undertaking Extractable and 5990-9510EN ( 2012 ). Leachable Testing 1st ed. Smithers-Rapra ( 2011 ). 10. X. Ye, et al . “Analysis of 21 phthalate leachables in 3. D. Jenke, T. Carlson. “A Compilation of Safety Impact metered dose inhalers by gas chromatography tandem Information for Extractables Associated with Materials mass spectrometry” Anal. Methods , 6, Used in Pharmaceutical Packaging, Delivery, 4083-4089 ( 2014 ). Administration, and Manufacturing Systems” PDA J. Pharm. Sci. Technol. 68 , 407-455 ( 2014 ). For More Information

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