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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
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
Industry Perspective on practical approaches and experiences in Development Pharmaceutics

Name: Ashish Gogia

E mail

ashishgogia@macleodspharma.com

factors influencing development of drug delivery systems7
Factors Influencing Development of Drug Delivery Systems

In vitro Dissolution

IVIVC

In vivo BA/BE

dosage form strategies paediatrics
Dosage Form Strategies - Paediatrics
  • Delivery Systems
    • Generics
    • New Drug Applications - 505(b)2
generics applicability anda 505 j
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)
nda 505 b 2 applicability
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
nda 505 b 2 applicability12
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
examples of 505 b 2 applications
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
new dosage forms paediatrics
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
new dosage forms paediatrics case study 1
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
new dosage forms paediatrics case study 2
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
what information can an applicant rely on
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
nda 505 b 2 type who filings paediatrics
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
pharmaceutical development al activities industry perspective
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.
pharmaceutical development al activities industry perspective20
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.
pharmaceutical development al activities industry perspective21
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
pharmaceutical development al activities industry perspective22
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
pharmaceutical development al activities industry perspective23
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)
pharmaceutical development al activities industry perspective24
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
pharmaceutical development al activities industry perspective25
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)
summary
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