Extractables and Leachables in Early Phase Development

Transcription

1 Extractables and Leachables in Early Phase Development Wayland Rushing, Ph.D. Senior Scientific Advisor, ABC 11/23/2015 Product and Process Variants & Impurities 1

2 Regulatory Perspective Dr. Ingrid Markovic, FDA, CBER, ASTM E55 Workshop, May 21, 2014 Approaches for E&L Assessment Under Discussion at CBER (NOT a Guidance) Agency supports a risk based approach to assess impacts from E&L to product quality and patient safety For IND s E&L and other impurities are considered to be controlled in the IND phase because the clinical outcomes are closely monitored; therefore, E&L studies are generally not required, unless so deemed warranted However, from a manufacturing perspective, it is advisable to be cognizant of E&L during component and packaging selection in early development in order to avoid possible problems in late development 11/23/2015 2

3 Timing Survey At which phase do you initiate E&L studies? 45% 10% 45% Phase 1 Phase 2 Phase 3 11/23/2015 3

4 Early Phase Regulatory Questions First request: ~24 months ago Unique product, non-aqueous formulation To date about a dozen programs Monitor product for leachables Provide an E&L assessment Evaluate compatibility of the container closure in terms of leachables 3 programs placed on clinical hold Provide a safety assessment in relation to leachables 11/23/2015 4

5 Regulatory Questions? Have you received a request for E&L data during early phase development? 25% 75% Yes No 11/23/2015 5

6 What Products are Getting Questions? Have only been on parenterals (to date) Non-aqueous formulations Unique syringe configuration Not used in any approved product Implantable devices Bio-polymers Injection Cartridges Auto-injectors Infusion sets IND didn t include any assessment for E&L 11/23/2015 6

7 E&L Timelines Prep 1-2 months CES 3-6 months Simulation Study 3-4 months Dev/Val Methods 3-6 months Stability 3-36 months 11/23/2015 7

8 Simplified Design for Clinical Hold CES Leachables Leachable ID 11/23/2015 8

9 Fingerprinting (RT and MS) 11/23/2015 9

10 Case Study 1 Infusion Pump/Set Drug infused by pump <24 hours Infusion set contained multiple components and materials of construction No E&L data presented in IND None available besides materials met USP Placed on Clinical Hold Required to provide an E&L evaluation Extractables/Leachables data was rate limiting 11/23/

11 Case Study 1 Infusion sets Study Design Extractables performed on individual components of infusion set Leachables under actual conditions of use Dynamically generated over 24 and 48 hours Two infusion rates 37 o C Results >100 extractables observed 18 leachables were observed at the 48 time point (2x intended use) All identified/confirmed by MS Risk Assessment showed no safety issues ~8 weeks Removed from hold 11/23/

12 Designing an early phase program Challenges Container/Closure system may not be finalized Formulation may not be finalized Cost-effective Can we use the accepted phase-appropriate approach for CMC methods as a model? 11/23/

13 Phase Appropriate E&L CES study Use 1 solvent minimally, 3 recommended 1 solvent mimics the placebo/dp formulation Similar to normal CES Use standard screening methods Methods may be optimized but not fully developed Methods are phase appropriately validated Using surrogate standards Leachables monitored on stability Observed leachables are identified if they grow greater than the AET 11/23/

14 Case Study 2 Glass Vial/Rubber Stopper configuration Likely not the final C/C Cottonseed oil based formulation Sponsor was required to monitor for leachables Clinical study scheduled for 3 months Product stored under refrigerated conditions 11/23/

15 Case Study 2 Design Study Design Extractables performed on stopper Standards used for expected extractables Methods optimized for formulation Methods phase appropriately developed/validated Leachables Stability 5 o C and 25 o C samples for 6 months Stability started 3 months prior to initiation of clinical study (in conjunction with normal stability) 11/23/

16 Case Study 2 Results Results >20 extractables observed 2 leachables were observed at 5 o C and 4 leachables were observed at 25 o C 1 was an unknown Unknown was identified based by MS Risk Assessment showed no safety issues Satisfied regulatory request Significantly less effort and cost than full E&L program 11/23/

17 Summary Questions on early phase programs continue A phase-appropriate approach can be applied Most questions focused around non-standard configurations Highest concern seems to be based around infusion products 11/23/

18 Thank You Questions? Ask ABC 11/23/