Pham Dev Paed

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Mohan M.S| April 20081 |

Pharmaceutical Development withFocus on Paediatric Formulations

WHO / FIP Training Workshop Hyatt Regency Hotel

Sahara Airport RoadAndheri East,Mumbai, India

28 April 2008 – 2 May 2008




Presented by :

Mohan M.SChief Scientific Officer

Strides Arcolab Limited

Bangalore

[email protected]

Pharmaceutical Development withFocus on Paediatric Formulations

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Presentation Outline

Introduction

Current Issues

Development Challenges

Drug Product Development

Clinical Evaluation

Regulatory Pathway

Summary




Current Issues

Many adult dosage forms not suitable for infants / children – ONESIZE DOES NOT FIT ALL

Non compliance rates in 50-70% , worse in chronic cases

Limited drugs currently labeled for pediatric use. Pediatric drugdevelopment internationally is an issue.

Lack of appropriate formulations- denied access ,

extemporaneous preparation risk ,

non reproducibility,adverse events ,overdose or under treatment




Development ChallengesScientifically challenging – measurable dose based on body weight , taste masking

Availability of limited ingredients for pediatric design – functional , taste

Drug taste an issue – Adults have a better tolerance to bad taste

Taste / Sweetness preference – differ significantly

Alcohol not desirable, Toxicity of excipients vary across age groupsCompliance – Taste , smell, texture , shape , mouth feel etc etc …Acceptablepalatability

Convenience for administration

Clinical evaluation difficult – new sampling methods, new analytical techniques, limitedpatient population

Achievement of PK parameter associated with efficacy in adults




Drug Product Development- AimPediatric Product should be designed to meet –

Patient Need (Clinical Benefit , accurate dosing , compliance )

&

Intended Product Performance ( product quality , stability , drug release )

Aim is to design a Quality Product and Ensure its manufacture to consistently deliver the Intended Product Performance

Must address general Drug Development Processes and PK profile for population ageand side effect profile

Cover the evolution of the formulation design from initial concept to final design




DefinePhase

ResearchPhase

DesignPhase

Development Phase

ImplementationPhase

IPM / Literature Pre formulation Bench Scale Scale Up Exhibit Batch

Drug Product Development- Process




IPM / Literature

Research

Pre –

FormulationsBench Scale Lab Scale PE Batch

Exhibit

Batch

Stability /

BioStudies

Define Research Design Develop Implement

Stage Specific Tasks During Product Development

Define

• Product identified

• Bulk supplieridentified & committed

• Literature / IPMresearch

• IPM strategy & submission strategyfirmed up

•

Packagingdevelopmentinitiated

Research

• Development strategyfirmed up

• Tentative methoddevelopment started

Design

• Prototype developedand put on stability

•

AR&D Methodsdeveloped• Formulation / process

finalized

Develop

• Prototype scaled up toLab scale

• AR&D methods firmedup and validated

• Exhibit batch replicaexecuted

• Pilot bio studiesconducted on PE Batch

Implement

• Exhibit batch

•

Stability test• Pivotal bio studies

• ANDA compilation/DCGILicense

• ANDA filing/Productlaunch




Drug Product Development- ElementsElements of Drug Development Process

Target Product Profile Definition :

Forms the basis of design pharmaceutics

Summary of product characteristics that would be achieved to ensure Quality

( hence Safety and Efficacy is Assured )

Includes details on : Dosage Form, Strength, Release Rate, PK, Product Specifications

reflecting quality

Critical Quality Attribute Definition :

Product attributes impacting Quality – Studied and Controlled

Physical, Chemical, Microbiological attributed that would be within specified limit toensure Quality

C Q A s associated with API , Excipients, Intermediates, Drug Product and Pack Components

Drug product CQA can guide product/process development.




Drug Product Development- ElementsElements of Drug Development Process

● Manufacturing Process Selection :

Type

Design Space of the Unit Operation

State of Control on the Process – Validation

● Control Strategy Identification : Designed to consistently ensure product quality

Inputs and In-process controls impacting final product quality

Variability of sources leading to product failures – identified , understood ,managed/controlled

Shifting controls upstream to minimize end product testing




Drug Product Development- Factors

Drug Substance : Physicochemical & Biological Characteristics :

Performance ( dissolution , stability , BA )Manufacturability

Compatibility :

With excipients

Between drugs● Excipients :

Type , Concentration, Characteristics Performance ( dissolution , stability , )

ManufacturabilityCompatibility

Within excipients / Between Excipients

Functionability - taste maskers, disintegrant





Manufacturing Process :

Type of ProcessRobustness ,Critical process attributes

Drug Product Characteristics : Active Stability

Preservative system effectivenessPalatability considerations ,pH , Viscosity etc

Container Closure System:Intended Use ,

Suitability for Storage/Transportation ,CCS Integrity ,Non Interaction ,Adequate Protection ,Safety of construction material





Microbiological Attributes :

May / May not be require – Dosage Form specific

Type / Concentration – Product

Concentration – Efficacy & Safety ,

Shelf-life ,MCT ,Chemical content ,Least concentrationVs MCT




Drug Product Development - OptionsReady To Use (Oral ) :

Solution,Syrup,Suspension,Tablet,Scored Tablet,

Chewable Tablet,Orally Disintegrating Tablet,Sublingual Strip,Flavored Medicated Lozenges,Lolli-pop formats ,

Wafers ,Sublingual ,Easy to Swallow Dosages etc .

Compliance – Palatability

Taste , Flavor , Colour




Drug Product Development - OptionsModification Before Use ( Oral ) :

Sachets,Powder for Constitution to Suspension/Solution ,Tablet for Constitution to Suspension / Solution,Drops for Reconstitution to Suspension/Solution,Concentrated Solution for Dilution ,Sachets,Effervescent Tablet,Sprinkles for Dispersion in drink/food.

Alternate Delivery Route :

Suppository dosages ,Painless injections ,

Transdermal ……




Clinical Evaluation

Unfortunately few drugs have been studies for bio-availability ortherapeutic equivalence

Such products would often differ from the drug product used in adults

Difference in BA may be accentuated in this population subgroup due toage related changes in GI absorption, volume of distribution changes,changes in rates of metabolism and excretion

Lack of data precludes blanket approval of generic prescription forinfants /children

Pediatric patients move from one age category to another – study designand statistical plan should factor this




New Drugs :

PK Evaluation –

Determine how to achieve target exposure that is safe and effective

Should include all pediatric age groups

take into consideration developmental challenges in absorption,metabolism, excretion

Monitor Safety and Tolerability

Conclude on efficacy in pediatric age groups

Clinical Evaluation




Clinica Clinical Evaluation

“… adequate data to establish pediatric safety andeffectiveness may not require controlled clinical trials…”

“… where disease course for both population is similar ,effectiveness data on the adult with additional data on

dosing , PK ,and safety in pediatric population wouldconvince regulations for approval”




Generic Drugs : Demonstrate Bioequivalence –

Single Product : Compare Generic with Reference Drug

FDC : Compare Generic FDC to Individual reference drug taken

together

Study Design : Randomized , single dose , 2 way cross over

Monitor Safety and Tolerability

Conclude on efficacy based on PK equivalence

Clinical Evaluation




Regulatory Pathway

Regulatory Strategy would be inline with the NDA / ANDA guidelinesdepending on the product.

Desired Development Pharmaceutics details covered in the Module 3 of

the Common Technical Document ( CTD ) for Registration of

Pharmaceuticals

Pediatric Exclusivity – Additional 6M market for exclusivity for approved

drugs for studies in pediatric population




What additional innovative approaches to formulations should be considered ?

How can WHO encourage sponsors to develop pediatric formulations ?

Questions to Ponder




“ Pediatric Drug Development ”

It is like turning over rocks and discovering how much you did

not know about what was under the rock. The next problem is

how to communicate what is under the rock and how to answer

questions that arise from looking.”

Reflection




SummaryDevelopment of paediatric drug product is challenging and very complex.

Product Quality w.r.t stability, safety , efficacy, acceptability , compliance are verycritical

Spurt in paediatric drug development inspired by increased regulatory initiative

Patient compliance can be radically improved by creative dosage delivery

While their is business lucritiveness in form of paediatric exclusivity yet Big Pharmashave diffused focus on this space

Conducting the necessary bridging studies in early development stages isinexpensive compared to rerunning the studies after approval

Shared responsibility – Pharma Companies, Regulatory Agencies, HealthProfessionals and Society



Mohan M.S| April 200825 | 25

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Pham Dev Paed

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