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Pharmaceutical Development with Focus on Paediatric formulations

Pharmaceutical Development with Focus on Paediatric formulations. WHO/FIP TRAINING WORKSHOP Hyatt Regency Hotel Sahar Airport Road, Andheri East, Mumbai, India 28 April 2008 – 2 May 2008. Greetings from . Ipca. Ipca Laboratories Limited. Partnering Healthcare Globally.

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Pharmaceutical Development with Focus on Paediatric formulations

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  1. Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP TRAINING WORKSHOP Hyatt Regency Hotel Sahar Airport Road, Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

  2. Greetings from Ipca Ipca Laboratories Limited Partnering Healthcare Globally

  3. Pharmaceutical Development with Focus on Paediatric formulations Practical problems in developing FDCs & Bilayer tablets Presenter: Snehal Khedkar Email:snehalkhedkar@ipca.co.in

  4. What are Fixed Dose Combinations??? Practical problems in developing FDCs & Bilayer tablets

  5. Practical problems in developing FDCs & Bilayer tablets Fixed Dose combination (FDC) “ A combination of two or more actives in a fixed ratio of doses.” Source: WHO Technical report series, No. 929, p.no-107, 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

  6. Patient Convenience Patient Adherence Monotherapy prevented Least probability of developing drug resistance Validated theory with other infectious diseases like TB, Leprosy, AIDS. Rationale…. Reduced Pill Burden

  7. Co-morbidConditions Hypertension Heart Disease Obesity Diabetes Hyperlipidemia Rationale…. • Treat different ailments in the same patient (co-morbidity), at the same time and with one pill • Allows for synergistic combination

  8. Rationale…. POLY -PHARMACY Combination drugs that target the same indication

  9. Stomach Irritation WeightGain Nausea Rationale…. • SIDE EFFECTS • Reduced by using one drug of the combination for this purpose • Amiloride may prevent hypokalemia caused by hydrochlorthiazide

  10. Challenges in Development of FDCs “Manufacturing challenges: ProductFormulationissues Manufacturing issues

  11. Problems… Solutions… • Dilution for low dose drug • Drug loading / Adsorption on excipients • Disproportionate doses e.g. Metformin + Glibenclamide (400 mg + 2.5 mg) - Content uniformity - Assay • Different release kinetics e.g. Rabeprazole + Domperidone (20 + 30 mg) • IR +SR (Use of OCRS) • Bilayer/ Trilayer ProductFormulationissues……

  12. ProductFormulationissues…… Problems… Solutions… • Hygroscopicity e.g. Metformin + Glipizide Metformin-Poorly compressible Needs residual moisture Glipizide - Degrades in moisture • Separate granulation • Coat the Glipizide particles • Altered solubility/ stability e.g.Atorvastatin + Ramipril + Aspirin Synergistic action Atorvastatin -is acid labile Aspirin- Undergoes alkaline hydrolysis • Suitable excipients

  13. Drug Delivery Systems for FDCs….. Matrix system • Multilayered tablets (bi/tri) • Compression coated • Tab-in-tab • In-lay technology

  14. Delivery systems to formulate FDCs….. • Multiple unit system • Beads / coating • Particulate / Coating (MUPS) • Multicompartment capsules • Capsule within capsule • Capsule – coated • Mini-tab in capsules

  15. Dual Release Drug Absorption Systems • Multi-layered tablets • Bilayer, Trilayer & Tab -in -Tab • One or more than one drug combination with different release patterns • Incompatibility, stability issue can be resolved

  16. Multilayered Tablets….. Bilayer Tabletting + • Release of both drugs starts immediately • Ease of manufacturing • Elegance to the product

  17. Multilayered Tablets….. Trilayer tabletting Inert layer + + Two incompatible drugs • Combination of incompatible drugs • Combination of different release profiles • Elegance to the product

  18. Problems in layered tablets….. 200,000 layers 100,000 tablets • Lack of proper bonding of two layers several days • Stress due to high compression force degrades certain actives e.g. ramipril

  19. Probable cause of increase in impurities Crystal lattice ruptures

  20. Tablet-in- Tablet Technology….. Tab-in-Tab • Elegance to the product • Improved product stability • Minimal incompatibility

  21. Inlay Technology….. • A new platform technology for decreasing the mechanical shear on double compressed products which can lead to decrease in unknown/process related impurities. • Release of both drugs starts immediately

  22. Artesunate + Amodiaquine HCl Case study……Artemisinin based FDCs • Dosing regimen based on weight to age data • Optimised dose ratio i.e. 1 : 3 • 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) Ref: WHO Bulletin, Vol 84, No. 12 Dec. 2006, 921-1000

  23. Chemical incompatibility….. ACID –DEGRADED ARTESUNATE AMODIAQUINE. HCl ARTESUNATE

  24. Technology Used…… A’sunate (Optionally coated) A’quine Bilayer technology • Limited contact • Degradation problem solved

  25. Critical Process Parameters……

  26. Stability Indicating Assay Related Compounds Dissolution Profile Content Uniformity OVI / Residual Solvents Impurity profile study Characterization of impurities Drug : Excipients compatibility study Evaluation studies ……

  27. Some of IPCA’s Unique Products*….. *For Indian Market

  28. Science means: There will be no weak eye in the pharmaceutical development chain The starting formulation may be based on INTUITION but the ending formulation must be based on SCIENCE

  29. Pharmacology Evaluation Regulatory Affairs R&D Analytical Research R&D Production Q.A. Divisions Medical Marketing R&D Production Validation team Product Development Validation Identification Development Tech. Transfer Regulatory Evaluation Research & Development (Formulations)….. New Product Introduction

  30. Development Program Timelines….. Activities Stages Months 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 4 3 2 Stability Studies 4 2 ~ 15 Months for Product Development, by Following ICH Guidelines

  31. Technology Transfer….. 100 R&D Development More effective as we move point of intersection to the left % Involved in Development Manufacturing & Quality 0 Early Development Launch / Commercialization • Master Manufacturing Document • Development Report • Specifications • Validation Protocols/SOPs • Onsite training & technical Presentation

  32. DESIGN SPACE CONTROL STRATEGIES Product Quality Design….. Knowledge space Existing knowledge & new scientific data generated in the process Design space Interaction of input variables & process parameters that provides Quality Product Control strategy Includes Input material controls, Process controls & FPP control tests Development of ‘ASSURED QUALITY PRODUCT’

  33. BECAUSE Knowledge space & resulting design space & process understanding CONSTANTLY EVOLVES……!!

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