Ashish Gogia 30 th April 2008 1 | Industry Perspective on practical approaches and experiences in...

Ashish Gogia 30th April 20081 |

Industry Perspective on practical approaches and experiences in Development Pharmaceutics

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





Name: Ashish Gogia

E mail

[email protected]



The Long Road to a New Medicine

Discovery

Exploratory Development

Full Development

Registration

Large Amounts ofCandidate Medicine

Synthesized

Project Teamand Plans

Synthesisof Compounds

EarlySafety

Studies

Candidate

FormulationsDeveloped

ExtensiveSafety

Studies

Screening

Studies in HealthyVolunteers Phase I

Candidate Medicine Tested in3-10,000 Patients (Phase III)

Studies in 100-300Patients (Phase II)

Clinical DataAnalysis



Drug Development - OpportunitiesDrug Development - Opportunities



Drug Discovery and DevelopmentDrug Discovery and Development

Class III

Permeability

Macro M olecules

B IOTECH

Solubility Permeability

A ll C lasses

Small M olecules

CC/HTS

NCE

Class I C lass III

C lass II C lass IV

BCS

GENERIC

DRUG



Factors Influencing Development of Drug Delivery Systems


First pass metabolism

Quality/Quantityto be delivered

Drug stability

Drug size

Drug polarity

PH AR M AC EU TIC AL

Pharmacokinetics

Pharmacodynamics

Onset/duration

Therapeutic index

PH AR M AC O LO G Y

Patient acceptability

Preferred route

Acute/chronictreatment

PATH O LO G Y

Regula tory hurdles

T ime to market

Cost o f goods

EC O N O M IC S





F irst pass metabolism

Quality/Quantityto be delivered

Drug stability

Drug size

Drug polarity

PH AR M AC EU TIC AL

In vitro Dissolution

In vivo BA/BE

IVIVC



Drug Dissolution and AbsorptionDrug Dissolution and Absorption



Dosage Form Strategies - PaediatricsDosage 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 (non exclusive uses)



NDA 505(b)(2) ApplicabilityNDA 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) ApplicabilityNDA 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 Products Excluded Products Product covered by 505(J) Only difference is lower extent than RLD Only difference is unintended lower rate than RLD Only

difference is unintended lower rate than RLD



Examples of 505(b)(2) applicationsExamples 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 - PaediatricsNew 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 – 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





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 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), ([email protected]

) etc.





API Sourcing & Evaluation International suppliers, supplier evaluation

DMF availability and Patent non-infringement

Compliance with USP, BP, Ph. Eur and other international pharmacopoeias

Impurity profile, stability data, polymorphic forms

Analytical testing of API

Physical characterization – polymorphism, BET, PSD and bulk density

Chemical characterization - Assay, Stress analysis, degradants, enantiomeric purity and residual solvents testing.





Innovators Product Selection/ testing Various pack types, evaluation of physical parameters (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





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





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)





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





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-vitro dissolution (3 pH media)



SummarySummary

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 (in line with Q –8 addendum) Strength identification Organoleptic acceptability

Ashish Gogia 30 th April 2008 1 | Industry Perspective on practical approaches and experiences in...

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