1. Mohan M.S | April 2008 1 |1 | 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

2. Mohan M.S | April 2008 2 |2 | Presented by : Mohan M.S Chief Scientific Officer Strides Arcolab Limited Bangalore mohan.ms@stridesarco.com Pharmaceutical Development with Focus on Paediatric Formulations

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

4. Mohan M.S | April 2008 4 |4 | 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.

5. Mohan M.S | April 2008 5 |5 | 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

6. Mohan M.S | April 2008 6 |6 | 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

7. Mohan M.S | April 2008 7 |7 | 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

8. Mohan M.S | April 2008 8 |8 | Define Phase Research Phase Design Phase Development Phase Implementation Phase IPM / Literature Pre formulation Bench Scale Scale Up Exhibit Batch Drug Product Development- Process

9. Mohan M.S | April 2008 9 |9 | IPM / Literature Research Pre – Formulations Bench ScaleLab ScalePE Batch Exhibit 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

10. Mohan M.S | April 2008 10 | 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.

11. Mohan M.S | April 2008 11 | 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

12. Mohan M.S | April 2008 12 | 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

13. Mohan M.S | April 2008 13 | 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

14. Mohan M.S | April 2008 14 | 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

15. Mohan M.S | April 2008 15 | 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

16. Mohan M.S | April 2008 16 | 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 ……

17. Mohan M.S | April 2008 17 | 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

18. Mohan M.S | April 2008 18 | 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

19. Mohan M.S | April 2008 19 | 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”

20. Mohan M.S | April 2008 20 | 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

21. Mohan M.S | April 2008 21 | 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

22. Mohan M.S | April 2008 22 | What additional innovative approaches to formulations should be considered ? How can WHO encourage sponsors to develop pediatric formulations ? Questions to Ponder

23. Mohan M.S | April 2008 23 | “ 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

24. Mohan M.S | April 2008 24 | 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

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