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8/3/2019 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
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Mohan M.S| April 20082 |
Presented by :
Mohan M.SChief Scientific Officer
Strides Arcolab Limited
Bangalore
mohan.ms@stridesarco.com
Pharmaceutical Development withFocus on Paediatric Formulations
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Mohan M.S| April 20083 |
Presentation Outline
Introduction
Current Issues
Development Challenges
Drug Product Development
Clinical Evaluation
Regulatory Pathway
Summary
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Mohan M.S| April 20085 |
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
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Mohan M.S| April 20086 |
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
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Mohan M.S| April 20087 |
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
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Mohan M.S| April 20088 |
DefinePhase
ResearchPhase
DesignPhase
Development Phase
ImplementationPhase
IPM / Literature Pre formulation Bench Scale Scale Up Exhibit Batch
Drug Product Development- Process
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Mohan M.S| April 20089 |
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
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Mohan M.S| April 200810 |
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.
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Mohan M.S| April 200811 |
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
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Mohan M.S| April 200812 |
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
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Mohan M.S| April 200813 |
Drug Product Development- Factors
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
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Mohan M.S| April 200814 |
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 concentrationVs MCT
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Mohan M.S| April 200815 |
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
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Mohan M.S| April 200816 |
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 ……
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Mohan M.S| April 200817 |
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
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Mohan M.S| April 200818 |
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
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Mohan M.S| April 200819 |
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”
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Mohan M.S| April 200820 |
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
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Mohan M.S| April 200821 |
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
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Mohan M.S| April 200822 |
What additional innovative approaches to formulations should be considered ?
How can WHO encourage sponsors to develop pediatric formulations ?
Questions to Ponder
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Mohan M.S| April 200823 |
“ 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
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Mohan M.S| April 200824 |
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
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