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Stability Of Drug Eluting Stents

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Podium Presentation made at the CBI Stability Conference, June 13, 2008.

Podium Presentation made at the CBI Stability Conference, June 13, 2008.


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  • 1. Stability of Drug- Eluting Stents Mark A. Schreiber, Ph.D. Director, Analytical Development Conor Medsystems CBI Stability Conference June 13, 2008
  • 2. Outline Overview 1. Drug-Eluting Stents 2. Conor’s Reservoir Technology 3. Tests (chemical) applicable to stents 4. Stability protocol design 5. Summary/Conclusion 6.
  • 3. Why Drug-Eluting Stents? First Bare Metal Stent was implanted 1987  Set the stage for stents to be regulated by  CDRH (with review of CMC by CDER) First DES approved in US (Cypher™) in 2003  Drug/polymer matrix is applied to a scaffold  that props the artery open. Drug slowly elutes further reducing restenosis  In some cases, the remaining metal is  endothelialized in the arterial wall
  • 4. Stent Reservoir Technology Drug is formulated with bio-resorbable polymer  Solution is deposited in wells in the stent struts as a  solution Solvent is evaporated, leaving drug/polymer matrix  Isolates the matrix from the stresses of insertion and  expansion. Drug is slowly released as the polymer decomposes  (hydrolysis of ester linkages) and is absorbed Directionality as well as the rate of drug release can  be controlled
  • 5. Tests for DES’s Appearance Assay (Total Drug Load) Impurities Release Kinetics (Elution) Residual Solvent Polymer MW / Content Particulates (USP) LAL Mechanical tests (not addressed here)
  • 6. Sirolimus Chemical Structure
  • 7. Assay  HPLC method – composite of 5 stents  Content on stent is <<1 mg (sum of Isomers B&C)  Sample volume is low to keep concentration at acceptable level  Sample directly injected without further dilution
  • 8. Impurities/Degradation Products Thousands of isomers possible  HPLC – Size Exclusion Chromatography  (SEC) Same sample solution as for assay  Impurity “monomers” are indistiguishable from  parent drug Based on response of reference standard and  assay value, monomers are determined by difference (average RRF) Oligomers are separated and are quantitated  by normal area response calibration (RRF)
  • 9. In Vitro Release Desirable traits:  Predicts the release of the drug in vivo would be optimal and highly desirable  Selected test should be simple, reliable, and reproducible in order to be used for QC purposes  USP apparatus/special equipment
  • 10. In Vitro Release (continued) Define robustness of the method:  Release media composition  pH  Dips/flow rate  Temperature  Physical factors, e.g. stent orientation, stent diameter/  length Demonstrate discrimination – determine lots that  should be rejected As least 3 specification-sampling times covering  initial, middle, and terminal elution Develop IVIVC, if possible 
  • 11. Conor Elution Method USP 4 Apparatus, closed-loop recirculating  system Media: Buffered Tween 20 / ACN, 50 mL/stent  7-hour release method  Method development performed to have in vitro  curve resemble in vivo release Complete profile being determined in  development, with 3 specified timepoints chosen: early (burst), middle, >80% release
  • 12. In Vitro Release Curve Cummulative Sirolimus Released (% ) 100.00% 90.00% 80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 0 2 4 6 8 Time (hr)
  • 13. Residual Solvent  Solvent extraction  GC with FID  Solvent is difficult to remove below ~10% (w/w) relative to drug content  Solvent can potentially affect release kinetics  Tested on release and stability
  • 14. Polymer MW/Content GPC Method with polystyrene stds / UV detection  Raw material controlled by Lactide/Glycolide ratio  and Inherent Viscosity (IV) of PLGA polymer MW testing on raw material being performed to  develop correlation to IV Product sterilization performed by e-beam, which  reduces MW by ~30% Limited stability testing of MW on finished product  Polymer content controlled by drug/polymer ratio in  formulation.
  • 15. Particulates Sources: Formulation, stent platform, stent delivery  system, packaging, and environment. Simulated use conditions should be employed in  testing From Draft DES Guidance: “It is highly  recommended that particulate matter generation over time be evaluated at each time point in the stability protocol (instead of only at t=0 and t=proposed expiration date). In the event that the particle counts continually increase with aging or fail to meet the acceptance criteria at the proposed expiration date, additional data will be available to support a shorter expiration date for the DES. “ Particle characterization and other considerations,  see draft guidance.
  • 16. Stability Protocol For establishment of shelf-life/expiration dating and  to support product stability for the duration of clinical studies Protocol can include appropriate bracketing and  matrixing designs as detailed in Guidance Document Q1D. The protocol design should include the extremes (in terms of both stent dimensions and total drug load) as well as an intermediate size, bracketing different stent designs. “We recommend that stability testing include  samples from a minimum of three finished product batches for each size tested.”
  • 17. Stability Protocol (continued)
  • 18. Stability Protocol (continued) ICH recommended conditions including accelerated  are recommended. Depending on the polymer being used, accelerated  may not be appropriate (Tg). The following tests are recommended:   Appearance  Assay/drug content  Impurities/degradation products  In vitro drug release  Particulate matter  Sterility/package integrity at release, annually, & expiration
  • 19. Long Term (25 °C/60%RH) Stability Testing Protocol Time Points (months) Tests Acceptance 0 3 6 9 12 Criteria* Appearance X X X X X Assay (drug X X X X X content) Impurities X X X X X Individual Total Drug Release X X X X X Particulate X X X X X Matter Endotoxins X X Time Points (months) *Same as regulatory specifications
  • 20. Accelerated (40 °C/75%RH) Stability Testing Protocol Time Points (months) Tests Acceptance 0 1 3 6 Criteria* Appearance X X X X Assay (drug content) X X X X Impurities X X X X Individual Total Drug Release X X X X Time Points (months) *Same as regulatory specifications
  • 21. Stability Protocol (continued) Real time, RT data should be used to establish a DES  shelf life. Depending on the quality of the data, reasonable extrapolation of accelerated data may be considered to assign shelf life.
  • 22. Summary/Conclusion Some testing is specific to the dosage form:  polymer characterization (MW, Tg), particulate matter, residual solvents, elution Review the draft guidance. You may have  specific circumstances in which a scientific justification can be made for doing something different, minimizing samples & studies. Release and stability testing of Drug-Eluting  Stents similar to that of drugs with a different controlled-release mechanism