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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. Industry Perspective on practical approaches and experiences in Development Pharmaceutics.

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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. Industry Perspective on practical approaches and experiences in Development Pharmaceutics Name: Ashish Gogia E mail ashishgogia@macleodspharma.com

  3. Drug Development - Opportunities

  4. Drug Discovery and Development

  5. Factors Influencing Development of Drug Delivery Systems

  6. Factors Influencing Development of Drug Delivery Systems In vitro Dissolution IVIVC In vivo BA/BE

  7. Drug Dissolution and Absorption

  8. Dosage Form Strategies - Paediatrics • Delivery Systems • Generics • New Drug Applications - 505(b)2

  9. Generics Applicability - ANDA 505(j) 21 CFR 314.92 Abbreviated applications may be submitted for: • Drug products that are the same as a listed drug • Identical in active ingredient (s) • Identical in form • Identical in strength • Identical in route of administration • Identical in conditions of use (nonexclusive uses)

  10. NDA 505(b)(2) Applicability 21 CFR 314.54 • Contains Reports of Safety and Effectiveness wherein • some investigations are not conducted by applicant and for which the applicant has no right of reference • Types of products 21 CFR 314.54 • New Chemical or New Molecular Entity • Info from studies not conducted by applicant • Info where applicant lacks the right of reference • Changes to Previously Approved Drugs (RLD) • New Dosage Form, Strength, Route of Administration • Substitution of an Active Ingredient in Combo Product • Formulation changes outside 505(j) limits

  11. NDA 505(b)(2) Applicability • – Changes to Previously Approved Drugs (RLD) …..contd • Dosage Regimen • API change - salt, ester, complex, chelate, racemate, enantiomer • New Indication • Rx/OTC switch • May or may not be bioequivalent to existing RLD but n • Excluded ProductsExcluded Products • Product covered by 505(J) • Only difference is lower extent than RLD • Only difference is unintended lower rate than RLDOnly difference is unintended lower rate than RLD

  12. Examples of 505(b)(2) applications • Dosage form • Strength • Route of administration • Substituted active ingredient in combo. • Formulation • Dosing regimen • Active ingredient • Intentional bio-inequivalence • Combo. of individually approved products • Indication • Rx/OTC Switch • OTC monograph • Naturally derived or recombinant active ingredient • NME

  13. New Dosage forms - Paediatrics • Existing adult dosage forms • No benchmarking Paediatric Reference Product • BA/BE against existing adult dosage form • Creation of Paediatric Reference Product

  14. New Dosage forms – PaediatricsCase Study 1 • Metformin Liquid Formulation (Riomet) • Reference Product – Glucophage Tablet • Approval of Citizen petition for liquid formulation • Grant of US Patent • Creation of new Paediatric Reference Product • Relative BA Comparable to Reference !! • Marketing of Branded Paediatric Product in US

  15. New Dosage forms – PaediatricsCase Study 2 • Cefalexin Tabs for Oral Suspension (Panixine) • Reference Product – Powder for Oral Suspension • Approval of Citizen petition for ODT • Grant of US Patent • Grant of USP monograph (Tablets for oral suspension) • Creation of new convenient Paediatric Reference Product • Bio equivalent to RLD • Marketing of Branded Paediatric Product in US

  16. What information can an applicant rely on? • Published literature specific to the approval sought in the NDA • FDA’s finding of safety and effectiveness for an RLD

  17. NDA 505(b)(2) type WHO filings - Paediatrics • Paediatric Formulations proposals for • Anti HIV – New Dosage Forms for FDC/Single ingredient • Liquid syrup – e.g LA/LZ/LZA • Aqueous ready made Liquid Suspensions - e.g Efavirenz • Dispersible Tablets - e.g LA/LZ/LZA

  18. Pharmaceutical Developmental Activities – Industry Perspective • Literature Search • Pharmacopoeial • Electronic databases,FDA documents (www.fda.gov/cder/guidance) • WHO medicines program (http://www.who.int/medicines/en/) • ICH website (http://www.ich.org ) • European guidelines for human medicines (http://www.emea.europa.eu/htms/human/humanguidelines/background.htm) • International Pharmaceutical federation: Pharmaceutical sciences section (http://www.fip.org/www2/sceinces/index.php) • Dissolution methods for drug products (http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm) • Patent & exclusivity evaluation(www.wipo.int), (www.uspto.org), (www.esp@cenet.in) etc.

  19. Pharmaceutical Developmental Activities – Industry Perspective • API Sourcing & Evaluation • International suppliers, supplier evaluation • DMF availability and Patent non-infringement • Compliance with USP, BP, Ph. Eur and other internationalpharmacopoeias • Impurity profile, stability data, polymorphic forms • Analytical testing of API • Physical characterization –polymorphism, BET, PSD and bulk density • Chemical characterization - Assay, Stress analysis, degradants, enantiomericpurity and residual solvents testing.

  20. Pharmaceutical Developmental Activities – Industry Perspective • Innovators Product Selection/ testing • Various pack types, evaluation of physicalparameters (weight, thickness, hardness, LOD, disintegration and friability) • Evaluation of innovator formula ingredients and microscopic testing • Evaluation of biostudy parameters • Dissolution profile • Excipients • Suitable excipients selection– compatibility and Stability and tolerance in paediatric population

  21. Pharmaceutical Developmental Activities – Industry Perspective • Container Closure System • Material composition, thermoplastic resin, liner and seals, cotton, desiccants • DMF availability and access letters • Analytical method validation • API – Impurity Profile, Assay, Residual Solvents, PSD • Formulation - Impurity Profile, Assay, Dissolution

  22. Pharmaceutical Developmental Activities – Industry Perspective • Manufacturing Process • Solid dosage forms • Direct compression - Granulation - wet or dry - aqueous or non aqueous, high shear mixing/low shear mixing, order of mixing, premixing, fluid addition, granulation time, torque end point value, drying parameters and LOD limits • Granulate flow properties, density, PSD and compressibility, • Compression –weight, thickness, hardness, friability and disintegration • Assessment of final formulation and stability profile (1-3 months)

  23. Pharmaceutical Developmental Activities – Industry Perspective • Liquid Dosage Forms • Solutions • Solubility of API and dependence on pH • Choice of Co solvents for poorly soluble drug, selection of excipients(Sweetening agents, Viscosity control,Coloring Agent etc) • Suspensions • Solubility of API,Particle Size, Propensity for crystal growth • Viscosity of vehicle, Rate of sedimentation or settling, Chemical stability • Emulsions • Stability w.r.t pH, Freeze Thaw Cycles, Creaming • Flocculation, Coalescence or breaking

  24. Pharmaceutical Developmental Activities – Industry Perspective • Process Optimization/Evaluation • Granulation, drying, blending and compression parameters • Process Qualification/Pilot Scale/Submission/Exhibit Batch • Simulation of production/Laboratory Facilities • Manufacturing under cGMP conditions • Minimum 100, 000 units • API and Excipients sourcing from qualified suppliers • Master Formula and manufacturing instructions • Packaging order and packaging instructions • Different pack types on stability • Bioequivalence Study • Usually Higher strength - Fasting/Fed as applicable • Other strengths – In-vitrodissolution (3 pH media)

  25. Summary • Create new convenient paediatric dosage formulation • Rely on published literature for safety & efficacy • No additional Clinical Trials • BA/BE vs adult formulations !! • Usual pharmaceutical development curriculum (inline with Q –8 addendum) • Strength identification • Organoleptic acceptability

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