Development and Delivery of Pharmaceutical Products - MaRS Best Practices

1. Development and Delivery of Pharmaceutical Products Dr. Colin Minchom September 23, 2011 1

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 identification 8

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 date 12

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 Properties 14

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/exposure 17

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, 2007 21

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

Development and Delivery of Pharmaceutical Products - MaRS Best Practices

Development and Delivery of Pharmaceutical Products - MaRS Best Practices

Recommended

More Related Content

Viewers also liked

Viewers also liked(20)

More from MaRS Discovery District

More from MaRS Discovery District(18)

Recently uploaded

Recently uploaded(20)

Development and Delivery of Pharmaceutical Products - MaRS Best Practices