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Fixed Dose Combinations- WHO Meet


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Practical problems of developing Fixed dose combinations and bilayer tablets

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Fixed Dose Combinations- WHO Meet

  1. 1. Pharmaceutical Development with Focus on Paediatric formulations <ul><li>WHO/FIP TRAINING WORKSHOP </li></ul><ul><li>Hyatt Regency Hotel </li></ul><ul><li>Sahar Airport Road, Andheri East, </li></ul><ul><li>Mumbai, India </li></ul><ul><li>28 April 2008 – 2 May 2008 </li></ul>
  2. 2. <ul><li>Practical problems in developing FDCs & Bilayer tablets </li></ul><ul><li>Presenter: Snehal Khedkar </li></ul><ul><li>Email: [email_address] </li></ul>Pharmaceutical Development with Focus on Paediatric formulations
  3. 3. What are Fixed Dose Combinations??? Practical problems in developing FDCs & Bilayer tablets…..
  4. 4. Fixed Dose combination (FDC) “ A combination of two or more actives in a fixed ratio of doses.” Source: WHO Technical report series, No. 929,, 2005 Examples of FDCs in WHO’s list of essential drugs Anti- Infective: Sulfamethoxazole + Trimethoprim Anti-Tuberculosis: Rifampicin + Isoniazid Antiviral: Stavidine + Lamivudine + Neviparine Antimalarial : Artesunate + Amodiaquine Practical problems in developing FDCs & Bilayer tablets…..
  5. 5. <ul><li>Patient Convenience </li></ul><ul><li>Patient Adherence </li></ul><ul><li>Monotherapy prevented </li></ul><ul><li>Least probability of developing drug resistance </li></ul><ul><li>Validated theory with other infectious diseases like TB, Leprosy, AIDS. </li></ul>Reduced Pill Burden Rationale….
  6. 6. <ul><li>Treat different ailments in the same patient (co-morbidity), at the same time and with one pill </li></ul><ul><li>Allows for synergistic combination </li></ul>Rationale…. Hypertension Heart Disease Diabetes Hyperlipidemia Obesity Co-morbid Conditions
  7. 7. POLY -PHARMACY Rationale…. Combination drugs that target the same indication Pain Ulcers AIDS Allergy/Asthma Malaria Hypertension Tuberculosis Diabetes
  8. 8. <ul><li>SIDE EFFECTS </li></ul><ul><li>Reduced by using one drug of the combination for this purpose </li></ul><ul><li>Amiloride may prevent hypokalemia caused by hydrochlorthiazide </li></ul>Rationale…. Stomach Irritation Weight Gain Nausea
  9. 9. <ul><li>“ Manufacturing challenges: </li></ul><ul><li> Product Formulation issues </li></ul><ul><li> Manufacturing issues </li></ul>Challenges in Development of FDCs
  10. 10. Product Formulation issues …… <ul><li>IR +SR (Use of OCRS) </li></ul><ul><li>Bilayer/ Trilayer </li></ul><ul><li>Different release kinetics </li></ul>e.g. Rabeprazole + Domperidone (20 + 30 mg) <ul><li>Solutions… </li></ul><ul><li>Dilution for low dose drug </li></ul><ul><li>Drug loading / Adsorption on excipients </li></ul>Problems… <ul><li>e.g. Metformin + Glibenclamide </li></ul><ul><li>(400 mg + 2.5 mg) </li></ul><ul><li>- Content uniformity </li></ul><ul><li>- Assay </li></ul><ul><li>Disproportionate doses </li></ul>
  11. 11. Solutions… <ul><li>Hygroscopicity </li></ul>Problems… e.g. Metformin + Glipizide Metformin - Poorly compressible Needs residual moisture Glipizide - Degrades in moisture <ul><li>Separate granulation </li></ul><ul><li>Coat the Glipizide particles </li></ul><ul><li>Altered solubility/ stability </li></ul>e.g. Atorvastatin + Ramipril + Aspirin Synergistic action Atorvastatin -is acid labile Aspirin- Undergoes alkaline hydrolysis <ul><li>Suitable excipients </li></ul>Product Formulation issues ……
  12. 12. Drug Delivery Systems for FDCs ….. <ul><li>Matrix system </li></ul><ul><li>Multilayered tablets (bi/tri) </li></ul><ul><li>Compression coated </li></ul><ul><li>Tab-in-tab </li></ul><ul><li>In-lay technology </li></ul>
  13. 13. Delivery systems to formulate FDCs….. <ul><li>Multiple unit system </li></ul><ul><ul><ul><ul><li>Beads / coating </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Particulate / Coating (MUPS) </li></ul></ul></ul></ul><ul><li>Multicompartment capsules </li></ul><ul><ul><ul><ul><li>Capsule within capsule </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Capsule – coated </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Mini-tab in capsules </li></ul></ul></ul></ul>
  14. 14. Dual Release Drug Absorption Systems <ul><li>Multi-layered tablets </li></ul><ul><li>Bilayer, Trilayer & Tab -in -Tab </li></ul><ul><li>One or more than one drug combination with different release patterns </li></ul><ul><li>Incompatibility, stability issue can be resolved </li></ul>
  15. 15. Multilayered Tablets….. Bilayer Tabletting + <ul><li>Release of both drugs starts immediately </li></ul><ul><li>Ease of manufacturing </li></ul><ul><li>Elegance to the product </li></ul>
  16. 16. Multilayered Tablets….. Trilayer tabletting + + Two incompatible drugs Inert layer <ul><li>Combination of incompatible drugs </li></ul><ul><li>Combination of different release profiles </li></ul><ul><li>Elegance to the product </li></ul>
  17. 17. Problems in layered tablets….. several days <ul><li>Lack of proper bonding of two layers </li></ul><ul><li>Stress due to high compression force </li></ul><ul><li>degrades certain actives e.g. ramipril </li></ul>100,000 tablets 200,000 layers
  18. 18. Crystal lattice ruptures Probable cause of increase in impurities
  19. 19. Tablet-in- Tablet Technology….. Tab-in-Tab <ul><li>Elegance to the product </li></ul><ul><li>Improved product stability </li></ul><ul><li>Minimal incompatibility </li></ul>
  20. 20. Inlay Technology….. <ul><li>A new platform technology for decreasing the mechanical shear on double compressed products which can lead to decrease in unknown/process related impurities. </li></ul><ul><li>Release of both drugs starts immediately </li></ul>
  21. 21. <ul><li>Dosing regimen based on weight to age data </li></ul><ul><li>Optimised dose ratio i.e. 1 : 3 </li></ul><ul><li>Rationale: To ensure that patients take both drugs together in the right dose, with a particular attention paid to paediatric needs (dose ratio, age-adapted strengths, optimized pharmaceutical formulation) </li></ul><ul><li>Ref : WHO Bulletin, Vol 84, No. 12 Dec. 2006, 921-1000 </li></ul>Case study……Artemisinin based FDCs Artesunate + Amodiaquine HCl
  23. 23. Bilayer technology A’sunate (Optionally coated) A’quine <ul><li>Limited contact </li></ul><ul><li>Degradation problem solved </li></ul>Technology Used ……
  24. 24. Critical Process Parameters …… <ul><li>Protect Artesunate from moisture </li></ul>ii. Storage i. Particle size distribution <ul><li>Wet mass (mixing time)= Improved wetability </li></ul>Granulation Point 2 <ul><li>Increase in effective surface area </li></ul>API 1 <ul><li>Layer separation </li></ul><ul><li>Decrease in Solubility/ Dissolution </li></ul>Hardness of Tablets Low High 4 <ul><li>Improvement in compaction properties </li></ul>Moisture Content Less than 1%w/w (Measured on IR moisture balance at 65ºC) 3 Remark Parameters Sr. No.
  25. 25. Evaluation studies …… Characterization of impurities Stability Indicating Assay Related Compounds Dissolution Profile Content Uniformity OVI / Residual Solvents Impurity profile study Drug : Excipients compatibility study
  26. 26. The starting formulation may be based on INTUITION but the ending formulation must be based on SCIENCE Science means: There will be no weak eye in the pharmaceutical development chain
  27. 27. Research & Development (Formulations)….. New Product Introduction Validation Tech. Transfer Regulatory Evaluation Development Identification Divisions Product Development Medical Marketing R&D Analytical Research Pharmacology Evaluation Regulatory Affairs R&D Production Validation team R&D Production Q.A.
  28. 28. Pre-formulation Establish Drug : Excipients compatibility Development lots Mini experimental trials to decide the formula / process Process optimization Fine tuning to avoid scale-up problem Process qualification To define critical processing steps (Scale-up batch) and test parameters usually mimics production conditions Pivotal batch Samples are used to perform the bio- equivalence study / clinical trials. Product development For PAI visit report & Submission Development Program Timelines….. 3 4 2 4 2 Stability Studies ~ 15 Months for Product Development, by Following ICH Guidelines Months Stages Activities
  29. 29. Technology Transfer….. R&D Development More effective as we move point of intersection to the left Manufacturing & Quality 0 100 Launch / Commercialization Early Development % Involved in Development <ul><li>Master Manufacturing Document </li></ul><ul><li>Development Report </li></ul><ul><li>Specifications </li></ul><ul><li>Validation Protocols/SOPs </li></ul><ul><li>Onsite training & technical Presentation </li></ul>
  30. 30. Product Quality Design….. Existing knowledge & new scientific data generated in the process Interaction of input variables & process parameters that provides Quality Product Includes Input material controls, Process controls & FPP control tests Design space Knowledge space Control strategy Development of ‘ ASSURED QUALITY PRODUCT’ DESIGN SPACE CONTROL STRATEGIES
  31. 31. <ul><li>BECAUSE </li></ul><ul><li>Knowledge space & resulting design space & process understanding </li></ul><ul><li>CONSTANTLY EVOLVES……!! </li></ul>