PQRI Workshop Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products (PODP) Qualification of Drug Product Contact Materials used in Small Volume Parenterals (SVP): Chemistry Considerations Edward J. Smith, Ph.D. February 22, 2011 Bethesda, MD 1
SVP Scenario DP = Vaccine SVP = 3mL volume Packaging components to consider for an E&L study COC Vial (direct contact) Bromobutyl rubber closure (direct contact) Label/Adhesive (indirect contact; possible migration of chemical components through COC vial into DP) 2
Packaging Components Included in the PQRI PODP Study COC Vial Bromobutyl rubber closure Label/Adhesive (to be included in future study) 3
Extraction Solvents for COC & BB Rubber Material Versus Extraction Solvent Map Aqueous Mixed Organic Thermal* ph 2.5 ph 9.5 IPA/Water IPA Hexane COC/BB X X X X X X * Headspace Analysis In our vaccine scenario The above 5 solvents would be used in a Controlled Extraction Study for the purpose of Material Characterization or to identify list of Tentative or Possible Leachables Another Simulated Extraction Study would be done with a solvent that mimics the vaccine DP to identify a list Probable or Confident Leachables This would followed by a Target Leachables Study to identify Confirmed or Actual Leachables. 4
Extraction Methods for COC & BB Rubber Extraction Method Versus Extraction Solvent Map (1) Aqueous Mixed Organic ph 2.5 ph 9.5 IPA/Water IPA Hexane Soxhlet --- --- --- X X Reflux --- --- --- X X Sonication X X --- X --- Sealed Vessel X (2) X (2) X (3) --- -- Notes: (1) An X denotes a method/solvent couple that was performed, an --- denotes a couple that was not performed. (2) Under autoclave conditions (121 o C for 1 hr). (3) Storage at 55 C for 3 days. 5
Analytical Methods GC/FID and GC/MS volatile and semivolatile extractables HPLC/DAD and LC/MS polar and nonvolatile extractables ICP/MS metals The necessity of using multiple techniques for the detection, identification, and quantitation of the leachables in this study indicates that no single method is sufficient and suggests that multiple, orthogonal techniques be routinely employed. * EPREX Study, DePaolis, A., et al, American Pharmaceutical Review, July/Aug 2006, pp. 54-59. 6
Qualitative or Quantitative Analyses? Controlled Extraction Study Purpose is Qualitative Analysis but some methods will provide semi-quantitative information (e.g. ICP and GC with internal standards) Simulated Extraction Study Quantitative Analysis will be executed in order to apply SCT/AET tools to evaluate the safety risk of the probable leachables identified. 7
Review of Selected Analytical Data Metals by ICP/MS Volatiles by Headspace GC Semi-Volatile and Non-Volatile Organics by Sealed Vessel Extraction & GC/MS Non-Volatile Organic Extractables of BB Rubber LC Analysis 8
COC Metals by ICP/MS Quantitative Data Trace Elements and Metals Results, COC. Element Extracted Amount, μg/g ph 2.5 Extracts ph 9.5 Extracts Sonication Sealed Vessel 4 Sonication Sealed Vessel Na 0.96 ME 1 ME 1 Ca 0.81 1.7 NP 3 Br 0.54 0.02 NP 3 Fe 0.24 NP 3 NP 3 Mg 0.16 0.15 NP 3 Mn 0.02 NP 3 NP 3 Al 0.07 NP 3 NP 3 Zn 0.07 0.03 0.01 2 Ti 0.06 2 NP 3 NP 3 V 0.01 2 NP 3 NP 3 Cr 0.01 2 NP 3 NP 3 B 0.01 2 NP 3 NP 3 Ni 0.01 NP 3 NP 3 As 0.01 0.01 2 NP 3 Sr 0.01 0.01 2 NP 3 Pt 0.01 NP 3 NP 3 1 ME = this element a component of the extracting solution used and thus was not measurable as an extractable. 2 Detected in only one of the two replicate extracts. 3 NP = not present in this extract in measurable quantities. 4 This data is currently under review. 9
BB Rubber Metals by ICP/MS Quantitative Data Element Trace Elements and Metals Results, RE. ph 2.5 Extracts Extracted Amount, μg/g ph 9.5 Extracts Sonication Sealed Vessel Sonication Sealed Vessel Br 17.5 0.29 9.40 20.5 Mg 3.50 0.06 2.83 2.90 Na 3.05 0.96 ME 1 ME 1 Zn 2.89 0.04 0.49 NP 3 Ca 2.60 4.07 2.07 2 NP 3 Al 0.66 0.03 2.19 3.56 Fe 0.33 0.07 0.08 2 NP 3 Ti 0.29 NP 3 NP 3 NP 3 Ni 0.011 NP 3 0.01 0.01 2 Cr 0.01 NP 3 0.01 2 NP 3 Mn 0.01 NP 3 NP 3 NP 3 Sr 0.01 0.01 NP 3 0.01 V 0.01 NP 3 0.01 0.02 K ME 1 ME 1 6.84 NP 3 Notes: 1 ME = this element a component of the extracting solution used and thus was not measurable as an extractable. 2 Detected in only one of the two replicate extracts. 3 NP = not present in this extract in measurable quantities. 10
Metals COC vs. BB Rubber Higher levels of metals from BB Rubber Br from polymer Al from filler Ti from pigment Mg, Zn, and Ca from activators From COC Na, Ca, Br, Fe, Mg (all at ~ 1ppm) From BB Rubber Br (18 ppm), Mg (~3), Na (~3), Zn (~3), Ca (~3), Al (~1) For a Vaccine DP Evaluate sensitivity of DP to extractable metals; get information from suppliers before doing extractable studies 11
COC Volatiles Identified by Headspace GC Headspace GC Results for COC, Volatile Extractables RT, min Conc, μg/g ID Formula C 4 H 8 O 2 Structure/Fragmentation CAS# Status Internal Standard O O 33.23 21.65 1,4-Dioxane C 10 H 18 123-91-1 Confident H H 37.00 0.03 Cis-decahydronaphthalene 493-01-6 12
BB Rubber Volatiles Identified by Headspace GC Formula Structure/Fragmentation RT, min Conc, μg/g ID C 6 H 12 CAS# Status Confident 5.68 1.19 Cyclopentane, methyl- C 6 H 12 96-37-7 Confident 6.75 0.48 Cyclohexane C 4 H 8 O 2 110-82-7 Internal Standard O O 33.22 20.8 1,4-Dioxane 123-91-1 13
COC Semi-Volatile and Non- Volatile Organics (Reported to date) One of the most fruitful methods was Sealed Vessel Extraction IPA/Water Mixture 3 days @ 55 o C GC/MS 14
COC Semi-Volatile and Non- Volatile Organics Identified Organic Extractables from the COC Material; Sealed Vessel Extraction. Tentative CAS RN Maximum Conc, mg/l 2 Identification 1 IPA/W Octanoic Acid 124-07-2 0.01 Glycerol 56-81-5 0.01 Phthalic Anhydride 85-94-9 0.04 Dodecamethyl cyclohexasiloxane 540-97-6 0.01 Tetradecamethyl cycloheptasiloxane 107-50-6 0.01 4-tert-butylcatechol, dimethyl ether 3527962 5 0.06 Hexadecamethyl, Cyclooctasiloxane 556-68-3 0.01 1,4-benzene dicarboxylic acid 100-21-0 0.01 Azelaic acid 123-99-9 0.06 Sebacic acid 111-20-6 0.02 Hexadecanoic acid, methyl ester 112-39-0 0.06 Hexadecanoic acid 57-10-3 0.12 Octadecanoic acid, methyl ester 112-61-8 0.09 Octadecanoic acid 57-11-4 0.03 Cis-6-octadecanoic acid 593-39-5 0.03 Di(2-ethylhexyl) phthalate 117-81-7 0.09 15
BB Rubber Semi-Volatile and Non-Volatile Organics Identified Information Related to the GC Peaks Associated with Organic Extractables from BB Rubber Material; Sealed Vessel Extraction. Tentative CAS RN Maximum Conc, mg/l 2 Identification 1 ph 2.5 ph 9.5 IPA/W 2,6-di-tert-butyl-4-methyl phenol 128-37-0 --- --- 0.22 Methyl dodecanoate 111-82-0 --- --- 0.11 Dodecanoic acid 143-07-7 --- 0.29 0.35 Diethyl phthalate 84-66-2 0.62 0.02 0.24 Silicon containing compound [TMS] --- --- --- 0.05 1,2-Benzenecarboxylic acid, monoethylester 2306-33-4 --- 0.08 --- Methyl Tetradecanoate 124-10-7 --- --- 0.12 Tetradecanoic acid [TMS] 544-63-8 --- 0.28 0.24 Tri-tert. Butyl-di-hydroxy benzene 24851-96-5 --- --- 0.38 Methyl Hexadecanoate 112-39-0 --- 0.05 3.19 Hexadecanoic acid 57-10-3 --- 1.84 8.67 Hexadecanoic acid, 1-methyl ester 142-91-6 --- --- 0.16 Methyl Octadecanoate 112-61-8 --- 0.02 3.86 Heptadecanoic acid 506-12-7 --- --- 0.15 Octadecanoic acid [TMS] 57-11-4 --- 0.66 9.68 Octadecanoic acid, Isopropyl ester 3654-92-2 --- --- 0.21 9-Oxo Octadecanoic acid, methyl ester 1842-70-2 --- --- 0.40 Nonadecanoic acid [TMS] 646-30-0 --- 0.49 0.29 Eicosanoic acid [TMS] 506-30-9 --- --- 0.08 Hexadecanoic acid-2,3-dihydroxypropyl ester [2TMS] 542-44-9 --- 0.09 0.20 n-nonanoyl morpholine 5299-64-9 --- --- 0.20 Consistent with C18 fatty acid [TMS] --- --- 0.07 --- n-decanoyl Morpholine 5299-65-0 --- --- 0.36 Nonadecanoic acid-2,3-dihydroxypropyl ester 62927-07-5 --- --- 0.07 16
Non-Volatile Organic Extractables of BB Rubber LC Analysis 17
Issues Related to the SVP Scenario Three new materials & new suppliers? COC Vials from supplier in Asia BB Rubber Stoppers from supplier in Asia Vial Labels (? from supplier in Asia) 18
Issues Related to the SVP Issues Scenario continued Sampling of rubber stoppers & COC vials for extractables testing Representative Samples Lots/batches of rubber produced; number of lots of RMs used Change controls & quality issues Audits; Inspections; Supplier Contracts Migration of label & adhesive components through COC vial in drug Possible O 2 & water vapor transmission through vial 19
Daily Dose Volumes for General Classes of Pharmaceutical Products Ref: D. Jenke, LVP Presentation 5000 4500 4000 3500 3000 2500 Daily Dose (ml) 2000 1500 1000 500 0 MDI Eye drops Syringe SVP LVP Dialysis 20
Est. AET Range for SVPs Est. AET from SCT of 0.15 µg/day Est. AET from QT of 5.0 µg/day 0.2 ml dose; 2 ml multi-dose vial; 1 dose/day 3 ml dose; 3 ml single-dose vial; 1 dose/day 10 ml dose; 10 ml single-dose vial; 1 dose/day 50 ml dose; 50 ml single-dose bag; 5 doses/day 0.75 µg/ml 25 µg/ml 0.05 µg/ml 1.7 µg/ml 0.015 µg/ml 0.5 µg/ml 0.0006 µg/ml 0.02 µg/ml 21
Assuming an analytical quantitation limit of 0.2 µg/ml; a challenging scenario is reached very quickly with SVPs. Est. AET from SCT of 0.15 µg/day Est. AET from QT of 5.0 µg/day 0.2 ml dose; 2 ml multi-dose vial; 1 dose/day 3 ml dose; 3 ml single-dose vial; 1 dose/day 10 ml dose; 10 ml single-dose vial; 1 dose/day 50 ml dose; 50 ml single-dose bag; 5 doses/day 0.75 µg/ml 25 µg/ml 0.05 µg/ml 1.7 µg/ml 0.015 µg/ml 0.5 µg/ml 0.0006 µg/ml 0.02 µg/ml 22
Acknowledgements Members of the SVP Scenario Team William P. Beierschmitt, Pfizer Frank Holcombe, FDA Desmond Hunt, USP Ingrid Markovic, FDA Diane Paskiet, West Pharmaceutical Services Dennis Jenke, Baxter All research work supported under the direction of PQRI. 23