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					      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



mohan.ms@stridesarco.com




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.


4|   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

5|   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


  6|   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



  7|   Mohan M.S | April 2008
    Drug Product Development- Process


  Define                 Research           Design     Development    Implementation
  Phase                   Phase             Phase         Phase          Phase


IPM / Literature       Pre formulation   Bench Scale   Scale Up      Exhibit Batch




   8|   Mohan M.S | April 2008
      Define               Research                 Design                     Develop                        Implement




IPM / Literature            Pre –                                                                        Exhibit       Stability /
                                                  Bench Scale          Lab Scale        PE Batch
   Research              Formulations                                                                    Batch         BioStudies

                          Stage Specific Tasks During Product Development

        Define                 Research                     Design                    Develop                  Implement

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




   9|     Mohan M.S | April 2008
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.


 10 |   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




  11 |       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
                       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

 13 |   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




 14 |   Mohan M.S | April 2008
Drug Product Development - Options
 Ready To Use (Oral ) :               Compliance – Palatability
      Solution,                        Taste , Flavor , Colour
      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 .


  15 |   Mohan M.S | April 2008
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 ……

  16 |   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




17 |   Mohan M.S | April 2008
                    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



18 |   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”




 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




20 |   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



21 |    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 ?




 22 |   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.”




23 |    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



 24 |   Mohan M.S | April 2008
                                Thank You
25 |   Mohan M.S | April 2008
                                            25

				
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