Case Study: Toxicology Assessment for a Pre-Filled Syringe. Stephen A. Barat, Ph.D. Director, Toxicology and Operations Forest Laboratories, Inc.

Transcription

1 Case Study: Toxicology Assessment for a Pre-Filled Syringe Stephen A. Barat, Ph.D. Director, Toxicology and Operations Forest Laboratories, Inc.

2 Toxicology Assessment The purpose of this portion of the presentation is to provide a working example of how to approach the safety assessment for a pre-filled syringe, consistent with the proposals set forth by the PQRi working group. Reference is made to example leachable data provided by the Chemistry sub-team. This approach integrates the presentations in a fashion so as to reflect the typical progression of efforts in an industrial setting. 2

3 Pre-Filled Syringe Components Main Point - Leachables can arise from various parts of the pre-filled syringe. Drug Product Very Complex Formulation Needle Stopper Siliconized Halobutyl Elastomer Barrel PP Piston PP 3

4 Case Study Evaluation of Leachable Profile Based on the results of a migration study, the substances identified as actual leachables will undergo toxicological evaluation. This evaluation will be based on an estimation of total daily dose of each leachable under the use conditions of the drug product. Total daily intakes for leachables will be assessed using the proposed thresholds. Based on this evaluation, conclusions and/or next steps are described. 4

5 Case Study Toxicological Evaluation Pertinent details of drug product: Pre-filled syringe (1 ml) Once daily dosing via intramuscular injection Dose volume is 0.5 ml (based on 50 kg individual) These variables, along with a qualitative and quantitative description of the leachable profile, are required for conducting the toxicological assessment. 5

6 Case Study Toxicological Evaluation The Leachable Profile, as provided by Chemistry, is evaluated based on individual leachables, concentration and estimated total daily dose, relative to the proposed thresholds for safety evaluation. Leachable Concentration Estimated Daily (µg/device)* Dose (µg)* 2,4-Bis(1,1-dimethyethyl)-phenol, 1,1,1 -phosphate ,4 Di t-butyl phenol Erucamide (3,5 -di-t-butyl-1 -hydroxy-4 -oxacyclohexa-2,5 -dienyl) propanoic acid Benzo(a)pyrene Octadecane Bromo-4-(1,1-dimethyl-propyl)-phenol Hexamethylcyclotrisiloxane Unknown A Unknown C Unknown E *µg/device = µg/ml, since device is 1 ml; **Based on 0.5 ml once daily injection. 6

7 Case Study - Toxicological Evaluation Review of Proposed Thresholds Class I Class II Class III Class IV Sensitizer Class IV Irritant Class V Genotoxicant Threshold Level (ug/day)

8 Case Study Toxicological Evaluation Based on the leachable profile, the substances in red represent those where the estimated total daily intake is less than the most stringent threshold level (< 0.15 µg/day). Therefore, no additional safety assessment is deemed necessary, as those leachables can be considered qualified by virtue of the very low levels. Leachable Concentration Estimated Daily (µg/device)* Dose (µg)* 2,4-Bis(1,1-dimethyethyl)-phenol, 1,1,1 -phosphate ,4 Di t-butyl phenol Erucamide (3,5 -di-t-butyl-1 -hydroxy-4 -oxacyclohexa-2,5 -dienyl) propanoic acid Benzo(a)pyrene Octadecane Bromo-4-(1,1-dimethyl-propyl)-phenol Hexamethylcyclotrisiloxane Unknown A Unknown C Unknown E *µg/device = µg/ml, since device is 1 ml; **Based on 0.5 ml once daily injection. 8

9 Case Study Toxicological Evaluation Three leachable substances remain for further evaluation. Each of them exceed the most stringent threshold of 0.15 µg/day. But are less than the proposed thresholds for substances structurally categorized as Class III or Class IV (sensitizers and irritants). Leachable Concentration Estimated Daily (µg/device)* Dose (µg)* 2,4 Di t-butyl phenol Erucamide Unknown A *µg/device = µg/ml, since device is 1 ml; **Based on 0.5 ml once daily injection. 9

10 Case Study Toxicological Assessment 2,4 Di T-butyl Phenol The estimated total daily intake of this is less than the thresholds proposed for Class III and Class IV compounds Therefore, this substance should be considered qualified for these endpoints, by virtue of the low estimated total daily dose. However, when evaluated in DEREK, an alert for genotoxicity (chromosomal damage) is raised. Actual experimental data for this compound is unavailable. The total daily intake of this leachable (0.65 µg) exceeds the threshold level for Class V compounds. Conclusion: The amount of this leachable needs to be reduced and controlled to appropriate levels (or eliminated) in the drug product, unless the genotoxic potential is evaluated experimentally and shown to be negative. 10

11 Case Study Toxicological Assessment Erucamide The estimated total daily intake of this substance is less than the thresholds proposed for Class III and Class IV compounds. Therefore, this substance should be considered qualified for these endpoints, by virtue of the low estimated total daily dose. However, the total daily intake of this leachable (0.75 µg) exceeds the threshold level for Class V compounds. The literature contains data from the Bacterial Mutagenicity study and the compound is negative for genotoxicity. Conclusion: Based on the available genetic toxicology data in the open literature, and by virtue of the low levels in the drug product, the levels of this leachable are considered to be qualified and no additional preclinical assessment is deemed necessary. 11

12 Case Study Toxicological Assessment Unknown A The estimated total daily intake of this is less than the threshold proposed for Class III and Class IV compounds. However, the total daily intake of this leachable (0.55 µg) exceeds the threshold level for Class V compounds. Irrespective of total daily intake relative to the thresholds, the problem here is that the compound is an unknown. Therefore, an adequate evaluation cannot be completed. Conclusion: While the compound can be compared relative to the thresholds based on quantitative data, given that it is an unknown, an adequate safety assessment cannot be conducted. Elucidation of the structure of the unknown should be requested to support subsequent evaluation. 12

13 Case Study Toxicological Assessment Putting it all together Overall Evaluation: Based on the results of the migration study, 11 substances were identified as actual leachables. Eight of these substances were present in the drug product at levels below the proposed threshold levels and are therefore considered qualified by virtue of the respective low estimated total daily intakes. Three substances required further evaluation, due to their respective estimated total daily intakes. These were 2,4 Di T-butyl phenol, erucamide, and unknown A. 2, 4 Di T-butyl phenol - Based on the presence of structurally-alerting features for genotoxicity, this leachable should be eliminated or reduced and controlled to an appropriate level. Erucamide Based on the estimated total daily intake and information in the literature, the levels of this leachable are considered qualified. Unknown A The structure of this substance should be elucidated and submitted to Toxicology for further evaluation. 13

14 Questions? 14