Case Study Toxicological Impact

Transcription

1 William P. Beierschmitt, PhD, DABT February 22, 2011

2 There are currently no universally accepted regulatory guidelines in place for assessing the risk of extractables and leachables A qualitative/quantitative methodology has been developed to assess extractable safety data for internal use Comprehensive quantitative assessments are reserved for leachables as part of a drug s registration package The qualitative/quantitative methodology to risk assess extractables is best performed on packaging components that are as close to, if not the exact ones intended for the market 2

3 Extractable data are generated before the leachable profile Typically, the leachables are a subset of the extractables Toxicologist may run in silico (e.g. DEREK) analyses on extractables, and perform a cursory qualitative/quantitative high level look at relevant safety data for each extractable This gives the toxicologist a heads - up regarding potential issues that may arise when leachable data are subsequently generated Allows early identification of a potentially problematic chemical when it is easier to make changes to the container closure system, or time to work with supplier to mitigate the problem The extractable assessment assumes, however unlikely, that the patient will receive the entire dose of the extractable (based on analytical results) 3

4 When performing the qualitative/quantitative extractable risk assessment, the toxicologists considers various critical issues related to the specific product Dose (based on worst case extractable analytical data) Route of administration Duration of treatment Indication Patient population Special populations (ie, pediatrics or women of child bearing potential) 4

5 For Extractable Risk Assessment - Consider the Big Five Genetic Toxicology, Carcinogenicity, Reproductive Toxicology, Sensitization, & Irritation Qualitative Assessment (Pass/Fail/No Data) If Needed, Perform Quantitative Assessment Assuming Same Amount Will Occur in Leachable Study (Pass/Fail) If Quantitative Assessment Fails, How Similar Are Extractable And Actual Formulation (i.e. leachable) Test Conditions? Final Assessment Pass/Data Gaps May Require Some Testing/Fail 5

6 Stopper Extractable Data Partial List RT (min) Conc, ug/g ID Formula CAS# Status NA NA NA Unknown NA NA NA NA NA NA Unknown NA NA NA Unknown BHT C 15 H 24 O Allyldimethyl (prop-1-ynyl)silane Or 2H-Tetrazole, 5-(thiophen-2- yl)methyl- C 8 H 14 Si Or C 6 H 6 N 4 S Or Confirmed Unknown NA NA NA Unknown Pentadecanoic acid, 14-methyl-, methyl C 17 H 34 O Confident ester n-hexadecanoic acid C 16 H 32 O Confident Isopropyl Palmitate C 19 H 38 O Confident NA NA NA Unknown NA NA NA Unknown Octadecanoic acid, methyl ester C 19 H 38 O Confident NA NA NA Unknown NA NA NA Unknown Octadecanoic acid (Stearic Acid) C 18 H 36 O Confident 6

7 Extractable Qualitative/Quantitative Risk Assessment Example Stearic Acid (CAS Number ) O HO MW Total Daily Dose (TDI) Based on Extraction Data 100 µg/day, or 2 µg/kg/day for a 50 kg individual 7

8 Stearic Acid at a TDI of 100 µg/day (2 µg/kg/day) Genetic Toxicology No DEREK structural alerts for this endpoint Negative in the Ames test in six strains (TA98; TA100; TA1535; TA1537; TA1538; E. Coli WP2 UVRA) both with and without metabolic activation Result Passes safety review for this endpoint 8

9 Stearic Acid at a TDI of 100 µg/day (2 µg/kg/day) Carcinogenicity No DEREK structural alerts for this endpoint Not mutagenic In a feeding study in mice, stearic acid was noncarcinogenic up to the highest dose tested of 50 g/kg/day (25 million-fold TDI) Not listed as an animal or human carcinogen (IARC, NTP, or ACGIH) Accepted in the United States as a direct and indirect food additive Result Passes safety review for this endpoint 9

10 Stearic Acid at a TDI of 100 µg/day (2 µg/kg/day) Reproductive Toxicology No DEREK structural alerts for this endpoint No evidence of reproductive toxicology effects were found No direct data on the reproductive and developmental toxicity of stearic acid were found. However, when female rats were fed diets with 6.25% butyl stearate for 10 weeks and subsequently mated, no adverse effects on fertility, litter size, or survival of offspring were noted occurred Result Passes safety review for this endpoint 10

11 Irritation Stearic Acid at a TDI of 100 µg/day (2 µg/kg/day) No DEREK structural alerts for this endpoint 500 mg administered to rabbit skin (24 hours) caused moderate effect (5000-fold TDI) 75 mg administered to human skin (over 3 days) caused a mild effect (750-fold TDI) Result Passes safety review for this endpoint 11

12 Sensitization Stearic Acid at a TDI of 100 µg/day (2 µg/kg/day) No DEREK structural alerts for this endpoint Several formulations containing 0.13% to 2.66% stearic acid were tested for sensitization potential in human subjects, and the results were negative Result Passes safety review for this endpoint 12

13 PQRi Toxicology Team Approach to Thresholds The team envisions the final recommendations, based on the described approach, to be categorized and captured in a table such as the following: Threshold Level (ug/day) Class I Class II Class III Class IV Sensitizer Class IV Irritant Class V Genotoxicant The PQRi toxicology sub-team recognizes that the subject of thresholds for potentially genotoxic substances continues to be a matter for international discussion and debate. As such, while our proposals are consistent with the most current thinking related to that subject, any changes in perspective will be closely monitored by the PQRi team and the proposals cited may require revision, accordingly

14 Stearic Acid at a TDI of 100 µg/day (2 µg/kg/day) The DEREK/Cramer sort for stearic acid led to a Class 1 assignment (threshold level 150 µg/day) Sorting consistent with the qualitative/quantitative risk assessment performed for this chemical If stearic acid were even to go on to be identified as a leachable, it would occur at much lower levels/doses that that risk assessed in this paradigm This could lead to the conclusion that this extractable need not be an analyte in subsequent leachable studies 14

15 Acknowledgements Edward J. Smith Desmond Hunt Frank Holcombe Ingrid Markovic Diane M. Paskiet Douglas J. Ball All research work supported under the direction of PQRI 15