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Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
Development and Delivery of Pharmaceutical Products - MaRS Best Practices
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Development and Delivery of Pharmaceutical Products - MaRS Best Practices

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  • 1. Development and Delivery of Pharmaceutical Products Dr. Colin Minchom September 23, 20111
  • 2. Development  and  delivery  of   pharmaceu4cal  products     Chemistry  manufacturing  and  controls  (CM&C)     Colin  M.  Minchom  PhD  MRPharmS   MaRS  September  2011     colin.minchom@gmail.com  2
  • 3. Topics   •  Introduc4on   •  The  drug  development  process   •  “Drugability”   •  Oral  absorp4on   •  Biopharmaceu4cs  Classifica4on  System   •  Sterile  products  3
  • 4. Colin  M.  Minchom  PhD  MRPharmS   •  UK  trained  pharmacist   •  30  years  in  product  development   •  Patheon,  start-­‐up  pharma,  Eli  Lilly,  Squibb   •  13  products  launched  in  USA  and  EU   •  Chair  -­‐  AAPS  Annual  Mee4ng  Science  CommiTee   •  Member  -­‐  U.S.  Pharmacopoeia  CommiTee  of  Experts  4
  • 5. The  drug  development  process  5
  • 6. Discovery  to  launch  -­‐  The  drug  development  process   Discovery/Research   Development   Submission   Launch   Toxicology   Phase  I   Phase  II   Phase  III   Registra4on   Approval   Clinical         Proof  of   Large  safety  and   Safety   Post-­‐ efficacy   efficacy   marke4ng  6
  • 7. Discovery  to  launch  -­‐  The  drug  development  process   Discovery/Research   Development   Submission   Launch   Toxicology   Phase  I   Phase  II   Phase  III   Registra4on   Approval   Toxicology   Chronic  and  reproduc4ve  toxicology   Acute  tes4ng   Line   tes4ng   extensions  7
  • 8. Discovery  to  launch  -­‐  The  drug  development  process   Discovery/Research   Development   Submission   Launch   Toxicology   Phase  I   Phase  II   Phase  III   Registra4on   Approval   Organic  Chemistry   Route Scale up Scale up and optimisation identification8
  • 9. Discovery  to  launch  -­‐  The  drug  development  process   Discovery/Research   Development   Submission   Launch   Toxicology   Phase  I   Phase  II   Phase  III   Registra4on   Approval   Dose  Form  Development   Preformula4on  and   Market  image  formula4on,   Line   early  formula4on   scale  up  and  op4mise   extensions  9
  • 10. Discovery  to  launch  -­‐  The  drug  development  process   Discovery/Research   Development   Submission   Launch   Toxicology   Phase  I   Simple  solu4on/   Phase  II   suspension   Phase  III   Simple  capsule   Registra4on   or  solu4on  /suspension   Approval   Tablet   Market  image  tablet  10
  • 11. “Drugability”  11
  • 12. Drug  product  development   •  Facilitation of repeated safe delivery of the correct quantity of active substance at the correct rate to desired body compartment •  Guaranteed until the expiry date12
  • 13. How  product  development  facilitates…   Fred has a headache Stomach   Liver  13
  • 14. Preformula4on/formula4on   Molecular properties • Solubility • Hydrophilicity/Lipophilicity (log p) • pH • Surface active agents – Micelles • Stability – Chemical Particle properties • Morphology/Crystallinity • Surface area • Melting point • Solution rate • Stability – physical • Hygroscopicity - Adsorption isotherms • Particle Size • Hydration/Solvation state • Particle Shape • Material Properties elastic/plastic/brittle Powder properties • Odour • Bulk and Tap densities • Colour • Electrostatics • Flow Properties14
  • 15. Oral  Absorp4on  15
  • 16. Oral  delivery  of  drug  to  systema4c  circula4on  16
  • 17. Typical  oral  delivery  pharmacokine4c  profiles      Dose  Xtal  Form  Formn    High  A  A    Med  B  B    Low  C  C   Minimum  toxic   concentra4on   Minimum  effec4ve   concentra4on   Pharmacokinetics (PK): The study of blood levels of a substance over time after dosing/exposure17
  • 18. Crystal  form    -­‐  Carbamazepine   Form  III       Monoclinic     MP=  ~168  C   Stable  at  RT   Good  flow  and  tableeng  proper4es   Form  IV   Trigonal     MP=  ~190  C   Thermostable   Poor  flow  and  tableeng  proper4es  18
  • 19. The  biopharmaceu4cs   classifica4on  system  (BCS)  19
  • 20. Biopharmaceu4cs  classifica4on  system  (BCS)   High  Solubility   Low  Solubility   Permeability   Class  I   Class  II   High     High  Solubility   Low  Solubility   High  Permeability   High  Permeability   Permeability   Class  III   Class  IV   Low   High  Solubility   Low  Solubility   Low  Permeability   Low  Permeability       Source: Amidon et al. (Pharm.  Res.  1995,  12  (3):  413–20), adopted by the FDA (2000).20
  • 21. Trending  in  biopharmaceu4cs  classifica4on  system     New Chemical Entities Top 200 Marketed Drugs in the U.S.A. Source: Hauss, Oral Lipid-Based Formulations, 200721
  • 22. Bioavailability  enhancement   •  Mul4-­‐factorial  challenges   – No  one  solu4on  works  for  all  molecules   •  Time  consuming   •  Expensive  22
  • 23. Sterile  Products  23
  • 24. When  are  sterile  products  required?   •  When  the  route  of  administra4on  is:   –  Intravenous   –  Intra-­‐muscular   –  Sub-­‐cutaneous   –  Ophthalmic   –  Inhala4on   –  Wound  applica4on    24
  • 25. Sterility  and  sterility  tes4ng   –  A  product  is  either  sterile  or  non-­‐sterile   –  Test  is  destruc4ve   •  en4re  product  batch  cannot  be  tested   –  The  sterility  test  needs  to  be  developed  and   validated  for  each  formula4on   –  Sterility  Assurance   The  probability  that  a  package  will  test  posi4ve  on  sterility  tes4ng.   •  Assurance  of  asep@c  processes  is  1  in  1,000   •  Heat  steriliza@on  processes  1  in  10,000   •  Probability  of  sterility  failure  is  much  lower  when                                         validated  procedures  are  followed  25
  • 26. Endotoxins   –  Sterile  products  MUST  be  low  in  endotoxins   –  Endotoxins  (pyrogens)   •  Lipo-­‐polysaccharides  from  outer  shell                                                           of  gram  nega4ve  bacteria   •  May  cause  reac4ons  in  pa4ents   §  Minor-­‐Moderate:    Fever,  muscle  pain,  joint  pain   §  Life  threatening:  Thrombosis,  inflamma4on,  hypotension  26
  • 27. Steriliza4on   •  Methods   –  Autoclaving  the  product  in  its  final  container   –  Subjec4ng  the  product  to  sterilizing  gases.   §  E.g.  ethylene  oxide     –  Subjec4ng  the  product  to  ionizing  radia4on.   –  Asep4c  processing.   §  Drug  formula4on  –  sterilized  by  filtra4on     §  Vials,  stoppers,  all  contact  parts  are  sterilized  separately   §  Assembled  in  a  Class  A  (Class  100)  room.  27
  • 28. Heat  steriliza4on   •  If  a  product  can  withstand  heat  steriliza4on,  then  it   must  be  heat  sterilized  -­‐  regulatory  requirement   –  Heat  sterilized  products  are  sterile  filtered  using   0.2  micron  filters,  before  they  are  sterilized   §  Dead  bacteria,  especially  gram  nega4ve  bacteria,  can   cause  severe  problems  due  to  endotoxins  28
  • 29. Heat  steriliza4on   •  Before  a  product  is  heat  sterilized,  a  steriliza4on   cycle  must  be  developed  and  validated   –  Heat  sensi4vity  of  bacteria  is  a  func4on  of  the   formula4on   §  Typical  steriliza4on  cycle  –  steam  autoclave   §  120  Celsius   §  15  -­‐  30  minutes  29
  • 30. Ascep4c  processing   •  Sterile  filtra4on   –  Filtra4on  of  product   §  Filter  the  liquid  formula4on  through  0.22  micron  membrane   §  The  product  is  filtered  into  Class  A  room  containing  the  fillers  and   cappers   §  Different  filter  materials  are  used  depending  on  compa4bility   with  the  drug  formula4ons   §  Endotoxins  are  not  removed  by  sterile  filtra8on   –  Steriliza4on  /  de-­‐pyrogena4on  of  vials   §  Dry  heat  (  ~250  Celsius)   –  Stoppers   §  Oqen  siliconized  for  smooth  movement  in  filling  machines   §  Sterilized  in  steam  autoclaves  30
  • 31. Sterile  products   •  Sterile  products  can  be  classified  into…   –  Liquid   –  Lyophilized  (freeze  dried)   –  Powder  fills   –  Dispersed   §  Emulsions,  suspensions,  liposomes,  lipid  complexes  31
  • 32. Sterile  liquids   •  Drugs  are  formulated  as  ready  to  use  liquids:   –  If  the  ac4ve  drug  is…   •  sufficiently  water  soluble   •  stable  in  aqueous  solu4on  for  18-­‐24  months  at   expected  storage  condi4on     Preferred  storage  condi4on  is  room  temperature  ~25  Celsius   If  not  refrigera4on  at  2-­‐  8  Celsius  32
  • 33. Lyophiliza4on   –  Freeze  drying  removes  water,  preven4ng   hydroly4c  reac4ons  and  extending  shelf  life   –  Primary  Drying   •  Freeze  the  formula4on  in  vials,  apply  a  vacuum  then   slowly  raise  the  temperature  to  sublime  the  frozen   water   –  Secondary  drying   •  Bound  water  removed  by  raising  the  temperature   further     Lyophiliza4on  will  add  several  dollars  to  the  cost  of  processing  each  vial  33
  • 34. Sterile  powder  fills   –  Used  for  manufacturing  cephalosporins,  and   rarely  for  cytotoxic  drugs     –  The  last  stage  of  ac4ve  drug  synthesis  is  asep4c.   §  The  sterile  powder  of  ac4ve  drug  is  then  filled  in  vials   in  Class  A  rooms   §  Compared  to  freeze  drying,  powder  filling  is  rela4vely   inexpensive   §  Excipients  are  not  used  34
  • 35. Dispersed  sterile  dosage  forms   –  ~70%  of  all  ac4ve  drugs  are  insoluble  or  poorly   soluble   –  These  drugs  may  be  solubilized  using  surfactants       -­‐  possible  adverse  reac4ons   –  If  drug  is  oil  soluble,  then  an  emulsion  can  be   prepared   –  Alterna4ve  approach  is  to  prepare  liposomes  or   lipid  complexes.   Development  will  be  4me  consuming  (expensive)    35
  • 36. Review   •  The  drug  development  process   •  “Drugability”   •  Oral  absorp4on   •  Biopharmaceu4cs  Classifica4on  System   •  Sterile  products   Ques4ons?     colin.minchom@gmail.com  36

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