mohan m.s | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations who /...

Mohan M.S | April 20081 |

Pharmaceutical Development with Focus on Paediatric FormulationsPharmaceutical Development with Focus on Paediatric Formulations

WHO / FIP Training Workshop Hyatt Regency Hotel

Sahara Airport Road

Andheri East,

Mumbai, India

28 April 2008 – 2 May 2008


Presented by :

Mohan M.SChief Scientific Officer

Strides Arcolab Limited

Bangalore

[email protected]

Pharmaceutical Development with Focus on Paediatric Formulations


Presentation Outline Presentation Outline

IntroductionIntroduction

Current IssuesCurrent Issues

Development ChallengesDevelopment Challenges

Drug Product DevelopmentDrug Product Development

Clinical EvaluationClinical Evaluation

Regulatory PathwayRegulatory Pathway

SummarySummary


Introduction Introduction

Pediatrics is the fastest growing prescription segment

Pediatric patients should be given medicines properly evaluated in appropriate subjects

Pediatric Drugs are new formulations – not tweaking existing formulations

Significant risk due to lack of adequate pediatric use information – almost ¾ medications lack pediatric use data

Need for the establishment of Bioavailability data in Pediatric population needs to be amplified.


Current Issues Current Issues

Many adult dosage forms not suitable for infants / children – ONE

SIZE DOES NOT FIT ALL

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

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

Lack of appropriate formulations- denied access , extemporaneous preparation risk , non reproducibility, adverse events , overdose or under treatment


Development Challenges Development Challenges Scientifically 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 groups

Compliance – Taste , smell, texture , shape , mouth feel etc etc …Acceptable palatability

Convenience for administration

Clinical evaluation difficult – new sampling methods, new analytical techniques, limited patient population

Achievement of PK parameter associated with efficacy in adults


Drug Product Development- Aim Drug Product Development- Aim Pediatric 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 age and side effect profile

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


Define Phase

Research Phase

Design Phase

Development Phase

Implementation Phase

IPM / LiteratureIPM / Literature Pre formulationPre formulation Bench ScaleBench Scale Scale UpScale Up Exhibit BatchExhibit Batch

Drug Product Development- Process Drug Product Development- Process


IPM / Literature Research

Pre – Formulations

Bench ScaleLab ScalePE BatchExhibit Batch

Stability / BioStudies

DefineResearchDesignDevelopImplement

Stage Specific Tasks During Product Development

Define

• Product identified

• Bulk supplier identified & committed

• Literature / IPM research

• IPM strategy & submission strategy firmed up

• Packaging development initiated

Research

• Development strategy firmed up

• Tentative method development started

Design

• Prototype developed and put on stability

• AR&D Methods developed

• Formulation / process finalized

Develop

• Prototype scaled up to Lab scale

• AR&D methods firmed up and validated

• Exhibit batch replica executed

• Pilot bio studies conducted on PE Batch

Implement

• Exhibit batch

• Stability test

• Pivotal bio studies

• ANDA compilation/DCGI License

• ANDA filing/Product launch


Drug Product Development- Elements Elements of Drug Development Process Drug Product Development- Elements Elements 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 to ensure 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- Elements Elements of Drug Development Process Drug Product Development- Elements Elements 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 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 , ) Manufacturability Compatibility Within excipients / Between Excipients

Functionability - taste maskers, disintegrant



Manufacturing Process : Type of Process Robustness , Critical process attributes

Drug Product Characteristics :

Active Stability Preservative system effectiveness Palatability 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 concentration Vs MCT


Drug Product Development - Options Drug Product Development - Options Ready 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 - Options Drug Product Development - Options Modification 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 Clinical Evaluation

Unfortunately few drugs have been studies for bio-availability or therapeutic equivalence

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

Difference in BA may be accentuated in this population subgroup due to

age 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 for infants /children

Pediatric patients move from one age category to another – study design and 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



Clinica Clinical EvaluationClinica Clinical Evaluation

“… adequate data to establish pediatric safety and

effectiveness 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 would

convince 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



Regulatory Pathway Regulatory Pathway

Regulatory Strategy would be inline with the NDA / ANDA guidelines

depending 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 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 Reflection


SummarySummary

Development of paediatric drug product is challenging and very complex.

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

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 Pharmas have diffused focus on this space

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

Shared responsibility – Pharma Companies, Regulatory Agencies, Health Professionals and Society

Mohan M.S | April 200825 | 25

Thank You

mohan m.s | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations who /...

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pediatric drug development

pharmaceutical development

taste drug

quality product

pediatric population

pediatric design functional

final design slide