Download Guidelines

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
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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]
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Mohan M.S | April 2008
Presentation Outline
Introduction
Current Issues
Development Challenges
Drug Product Development
Clinical Evaluation
Regulatory Pathway
Summary
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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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Mohan M.S | April 2008
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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Mohan M.S | April 2008
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
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Mohan M.S | April 2008
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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Mohan M.S | April 2008
Drug Product Development- Process
Define
Phase
IPM / Literature
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Research
Phase
Pre formulation
Mohan M.S | April 2008
Design
Phase
Bench Scale
Development
Phase
Scale Up
Implementation
Phase
Exhibit Batch
Define
Research
Design
IPM / Literature
Research
Pre –
Formulations
Bench Scale
Develop
Lab Scale
PE Batch
Implement
Exhibit
Batch
Stability /
BioStudies
Stage Specific Tasks During Product Development
Define
• Product identified
• Bulk supplier
identified &
committed
Research
• Development strategy
firmed up
• Tentative method
development started
• Literature / IPM
research
• IPM strategy &
submission strategy
firmed up
• Packaging
development
initiated
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Mohan M.S | April 2008
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
 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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Mohan M.S | April 2008
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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Mohan M.S | April 2008
Drug Product Development- Factors
 Drug Substance :

Physicochemical & Biological Characteristics :



Performance ( dissolution , stability , BA )
Manufacturability
Compatibility :


With excipients
Between drugs
● Excipients :

Type , Concentration, Characteristics





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Performance ( dissolution , stability , )
Manufacturability
Compatibility
Within excipients / Between Excipients
Functionability 
taste maskers, disintegrant
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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Mohan M.S | April 2008
Drug Product Development- Factors
 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
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Mohan M.S | April 2008
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 .
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Mohan M.S | April 2008
Compliance – Palatability
Taste , Flavor , Colour
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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Mohan M.S | April 2008
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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Mohan M.S | April 2008
Clinical Evaluation
 New Drugs :
 PK Evaluation –
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
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
Mohan M.S | April 2008
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”
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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
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
Monitor Safety and Tolerability

Conclude on efficacy based on PK equivalence
Mohan M.S | April 2008
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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Mohan M.S | April 2008
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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Mohan M.S | April 2008
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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Mohan M.S | April 2008
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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Mohan M.S | April 2008
Thank You
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Mohan M.S | April 2008
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