Qualification of Drug Product Contact Materials used in Small Volume Parenterals (SVP): Chemistry Considerations Edward J. Smith, Ph.D.

Transcription

1 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

2 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

3 Packaging Components Included in the PQRI PODP Study COC Vial Bromobutyl rubber closure Label/Adhesive (to be included in future study) 3

4 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

5 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

6 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

7 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

8 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

9 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 NP 3 Br NP 3 Fe 0.24 NP 3 NP 3 Mg NP 3 Mn 0.02 NP 3 NP 3 Al 0.07 NP 3 NP 3 Zn Ti NP 3 NP 3 V NP 3 NP 3 Cr NP 3 NP 3 B NP 3 NP 3 Ni 0.01 NP 3 NP 3 As NP 3 Sr 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

10 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 Mg Na ME 1 ME 1 Zn NP 3 Ca NP 3 Al Fe NP 3 Ti 0.29 NP 3 NP 3 NP 3 Ni NP Cr 0.01 NP NP 3 Mn 0.01 NP 3 NP 3 NP 3 Sr NP V 0.01 NP K ME 1 ME 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

11 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

12 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 ,4-Dioxane C 10 H Confident H H Cis-decahydronaphthalene

13 BB Rubber Volatiles Identified by Headspace GC Formula Structure/Fragmentation RT, min Conc, μg/g ID C 6 H 12 CAS# Status Confident Cyclopentane, methyl- C 6 H Confident Cyclohexane C 4 H 8 O Internal Standard O O ,4-Dioxane

14 COC Semi-Volatile and Non- Volatile Organics (Reported to date) One of the most fruitful methods was Sealed Vessel Extraction IPA/Water Mixture 3 55 o C GC/MS 14

15 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 Glycerol Phthalic Anhydride Dodecamethyl cyclohexasiloxane Tetradecamethyl cycloheptasiloxane tert-butylcatechol, dimethyl ether Hexadecamethyl, Cyclooctasiloxane ,4-benzene dicarboxylic acid Azelaic acid Sebacic acid Hexadecanoic acid, methyl ester Hexadecanoic acid Octadecanoic acid, methyl ester Octadecanoic acid Cis-6-octadecanoic acid Di(2-ethylhexyl) phthalate

16 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 Methyl dodecanoate Dodecanoic acid Diethyl phthalate Silicon containing compound [TMS] ,2-Benzenecarboxylic acid, monoethylester Methyl Tetradecanoate Tetradecanoic acid [TMS] Tri-tert. Butyl-di-hydroxy benzene Methyl Hexadecanoate Hexadecanoic acid Hexadecanoic acid, 1-methyl ester Methyl Octadecanoate Heptadecanoic acid Octadecanoic acid [TMS] Octadecanoic acid, Isopropyl ester Oxo Octadecanoic acid, methyl ester Nonadecanoic acid [TMS] Eicosanoic acid [TMS] Hexadecanoic acid-2,3-dihydroxypropyl ester [2TMS] n-nonanoyl morpholine Consistent with C18 fatty acid [TMS] n-decanoyl Morpholine Nonadecanoic acid-2,3-dihydroxypropyl ester

17 Non-Volatile Organic Extractables of BB Rubber LC Analysis 17

18 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

19 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

20 Daily Dose Volumes for General Classes of Pharmaceutical Products Ref: D. Jenke, LVP Presentation Daily Dose (ml) MDI Eye drops Syringe SVP LVP Dialysis 20

21 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 µg/ml 0.5 µg/ml µg/ml 0.02 µg/ml 21

22 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 µg/ml 0.5 µg/ml µg/ml 0.02 µg/ml 22

23 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