DNA Vaccines 2011 - Talk by Rick Hancock

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DNA Vaccines 2011 - Talk by Rick Hancock

  1. 1. Commercializing DNA Vaccines DNA Vaccines 2011 Rick Hancock, President [email_address]
  2. 2. Challenges Along the Pathway to Commercialization <ul><li>You know about molecular biology, vector design, expression systems and immunology; lets talk about: </li></ul><ul><ul><li>Formulation </li></ul></ul><ul><ul><li>Stability </li></ul></ul><ul><ul><li>Final Container Selection </li></ul></ul><ul><ul><li>Cold Chain Management </li></ul></ul>
  3. 3. Early Process Development Considerations <ul><li>Scalable process with no unit operation bottle-necks </li></ul><ul><li>No mutagenic agents or animal derived materials </li></ul><ul><li>Minimize the use of flammables and caustic solutions </li></ul><ul><li>Avoid (or at least fully understand) Intellectual Property issues </li></ul>
  4. 4. Manufacturing Considerations by Phase <ul><li>Phase I </li></ul><ul><li>Initial formulation to meet short term stability requirements </li></ul><ul><li>“ Off the Shelf” container / closure system </li></ul><ul><li>Very limited distribution </li></ul><ul><li>Minimal process and assay qualification </li></ul>
  5. 5. Manufacturing Considerations by Phase <ul><li>Phase II </li></ul><ul><li>Establish robust formulation </li></ul><ul><li>Perform accelerated stability studies </li></ul><ul><li>Optimize and qualify upstream and downstream manufacturing processes </li></ul><ul><li>Qualify analytical methods and establish robust SOPs </li></ul><ul><li>Thorough evaluation of container / closure systems </li></ul><ul><li>Evaluate supply chain distribution issues </li></ul>
  6. 6. Manufacturing Considerations by Phase <ul><li>Phase III </li></ul><ul><li>Last chance for formulation optimization </li></ul><ul><li>Identify a commercial manufacturer </li></ul><ul><li>Final container selection and validation </li></ul><ul><li>Validation of manufacturing process and all analytical methods </li></ul><ul><li>Qualification / Validation of supply chain distribution </li></ul>
  7. 7. Formulation Challenges <ul><li>The goal is “Room Temperature” stability </li></ul><ul><li>Minimize degradation of DNA as evaluated by loss of supercoiled form </li></ul><ul><li>Minimize visible and sub-visible particles </li></ul><ul><li>Best evaluated through accelerated stability studies </li></ul><ul><li>Must be compatible with delivery systems </li></ul><ul><li>Minimize pain and injection site reactions </li></ul>
  8. 8. <ul><li>Water for Injection (WFI) </li></ul><ul><ul><li>Pros: Plain and simple, introduces no impurities or contaminants </li></ul></ul><ul><ul><li>Cons: Not buffered and not isotonic </li></ul></ul><ul><li>0.9% Saline for Injection </li></ul><ul><ul><li>Pros: Isotonic </li></ul></ul><ul><ul><li>Cons: Not buffered, wide pH swings </li></ul></ul>Commonly Used Formulation Buffers
  9. 9. Commonly Used Formulation Buffers <ul><li>Phosphate Buffered Saline (PBS) </li></ul><ul><ul><li>Pros: Buffered and isotonic </li></ul></ul><ul><ul><li>Cons: Which one to use? Wide variety of formulations, some formulations enhance aggregate formation and precipitation, sub-optimal for plasmid stability </li></ul></ul><ul><li>Detergents, Surfactants, Liposomes </li></ul><ul><ul><li>Pros: Enhanced solubility, stability </li></ul></ul><ul><ul><li>Cons: IP issues </li></ul></ul>
  10. 10. <ul><li>Tris- EDTA (TE) </li></ul><ul><ul><li>Pros: Buffered and isotonic, metal ion chelation minimizes precipitation, stability further enhanced through addition of ethanol </li></ul></ul><ul><ul><li>Cons: Limited buffering capacity (temperature dependent) </li></ul></ul>Commonly Used Formulation Buffers
  11. 11. Plasmid Stability vs. Formulation Buffer
  12. 12. Evaluation of degradation pathways for plasmid DNA in pharmaceutical formulations via accelerated stability studies <ul><li>Evans RK, Xu Z, Bohannon KE, Wang B, Bruner MW, Vokin DB </li></ul><ul><li>J Pharm Sci , January 2000 </li></ul><ul><li>Key Points: </li></ul><ul><ul><li>Plasmid DNA stability was monitored during accelerated stability studies (50°C) </li></ul></ul><ul><ul><li>Results indicate free radical oxidation may be major degraditive process for plasmid DNA </li></ul></ul><ul><ul><li>Free radical scavengers, specific metal ion chelators, or both can control oxidation </li></ul></ul><ul><ul><li>Combination of EDTA and ethanol had a synergistic enhancing effect on DNA stability </li></ul></ul>
  13. 13. Final Container Considerations <ul><li>DNA’s affinity for glass </li></ul><ul><li>Leaching of metal ions from glass </li></ul><ul><li>Extractables and leachables from primary container and stopper </li></ul><ul><li>Solution: Fill Phase I clinical materials in “off the shelf” container for clinical trial and 3-4 other container systems for accelerated stability studies; vials, syringes, glass, plastic </li></ul>
  14. 14. Cold Chain Management Challenges <ul><li>For the developing world and remote locations cold (2-8°C) chain management is a challenge </li></ul><ul><li>Frozen chain management, almost impossible </li></ul><ul><li>Lyophilization or liquid ambient temperature distribution is clearly the objective and is achievable </li></ul>
  15. 15. Thank you and Good Luck!

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