Pharmaceutical 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

1 | Mohan M.S | April 2008

Pharmaceutical Development with Focus on Paediatric Formulations

Presented by

:

Mohan M.S

Chief Scientific Officer Strides Arcolab Limited Bangalore

[email protected]

2 | Mohan M.S | April 2008

Presentation Outline

Introduction Current Issues Development Challenges Drug Product Development Clinical Evaluation Regulatory Pathway Summary 3 | Mohan M.S | April 2008

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.

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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

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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 – palatability Taste , smell, texture , shape , mouth feel etc etc …Acceptable  Convenience for administration  Clinical evaluation difficult – patient population new sampling methods, new analytical techniques, limited  Achievement of PK parameter associated with efficacy in adults

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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

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Drug Product Development- Process

Define Phase Research Phase Design Phase IPM / Literature Pre formulation Bench Scale Development Phase Implementation Phase Scale Up Exhibit Batch

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Define Research Design Develop Implement

IPM / Literature Research

Define

• Product identified • Bulk supplier identified & committed • Literature / IPM research • IPM strategy & submission strategy firmed up • Packaging development initiated Pre – Formulations Bench Scale Lab Scale PE Batch Exhibit Batch

Stage Specific Tasks During Product Development

Research Design Develop

Stability / BioStudies

Implement

• Development strategy firmed up • Tentative method development started • Prototype developed and put on stability • AR&D Methods developed • Formulation / process finalized • Prototype scaled up to Lab scale • AR&D methods firmed up and validated • Exhibit batch replica executed • Pilot bio studies conducted on PE Batch • Exhibit batch • Stability test • Pivotal bio studies • ANDA compilation/DCGI License • ANDA filing/Product launch

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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.

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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

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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 12 | Mohan M.S | April 2008

Drug Product Development- Factors

  

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

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Drug Product Development- Factors



Microbiological Attributes :

  

May / May not be require – Type / Concentration – Dosage Form specific Product

    

Concentration –

Efficacy & Safety , Shelf-life , MCT , Chemical content , Least concentration Vs MCT

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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

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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 ……

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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

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Clinical Evaluation



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

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Clinica 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 ” 19 | Mohan M.S | April 2008

Clinical Evaluation

 

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

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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

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Questions to Ponder



What additional innovative approaches to formulations should be considered ?



How can WHO encourage sponsors to develop pediatric formulations ?

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Reflection

“ 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.

”

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Summary

 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

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25 | Mohan M.S | April 2008

Thank You 25