Each & every molecule is different, there is no standard ANDA checklist which can help achieve BE by standard dissolution methods, critical and design thinking is required by all Scientists- Generics is application science gained by diversity of experiences

1. GAP 2019
Conference for Regulatory &
Science
29th -30th Aug,Shanghai
Formulation & BE Study
Design for Highly variable
drugs
Jaya Abraham, Ph.D. in Drug Delivery
President R&D, Auckland
We bring innovative R&D solutions…

2. Highly Variable
Drugs
•BIO-international '92 [2001] "Drugs which exhibit
intra "Drugs which exhibit intra-subject variabilities
>30 % (CV from ANOVA) are to be classified as highly
variable …“
•Challenging molecules- Kinase inhibitors, Delayed
release proton pump inhibitors, anti-fungals, immuno-
suppressants ,statins etc
We bring innovative R&D solutions…

3. Why Highly
Variable Drugs
exist
• Complex Target & SAR
• Does not follow Lipinsky’s Rule of 5
• Complex Physico-chemical properties as well as
Stability
• Significant interactions with physiological factors-
food/gender/gastric ph/ gastric retention
time/precipitation in gastric fluids
We bring innovative R&D solutions…

4. Multiple Factors
• Drug substance -Variable absorption rate or Low
extent of absorption
• Extensive pre-systemic metabolism
• Drug product formulated with functional excipients
• Manufacturing Scale effects
• Bioanalytical assay sensitivity
• Suboptimal PK sampling
• Impractical to identify root cause and attribute
mechanism in each case
We bring innovative R&D solutions…

5. Challenges
• Strong IP protection
• Often hard to get IVIVR/ IVIVC model using standard
dissolution methods
•Pi
• Misleading Pilot BE results- requires in-depth
analysis and inferences
• Lack of understanding of equipment from R&D to
Commercial Scale effects
• Bioanalytical method development with appropriate
sensitivity & wider range of linearity ,ruling out matrix
effect
• Extensive PK sampling points considering range of
tmax variation
We bring innovative R&D solutions…

6. Complex R&D
We bring innovative R&D solutions…

7. Solutions
We bring innovative R&D solutions…
Appropriate DOE design selection to
understand interaction effects between
Formulation & Process and inference of data
sets

8. Critical
We bring innovative R&D solutions…
Pilot Study Design

9. Pilot Study Design
Critical Decisions
• Study design
• Sample size & Sampling points
• Inclusion /Exclusion criterion
• Choice of BAN method including metabolite
profiling
• Formulations to be tested and scale of
manufacturing
• Reference Lot Selection
• Dissolution profiles of Test Formulations
selectedWe bring innovative R&D solutions…

10. Pilot Study
Inference
Simulations of in-vivo – in-vitro
We bring innovative R&D solutions…
Cause –Effect Analysis

11. Pilot Study
Inference
Effect of Formulation and
Processing Factors
We bring innovative R&D solutions…
Cause –Effect Analysis

12. Validation Batches &
Pivotal BE study
We bring innovative R&D solutions…
Wayforward
Critical steps
• Strategic Road Map for Batch Execution and
Pivotal Study Design
• Structured Risk Assesment & Mitigation Plan
• Engagement of cross-functional SME
Keep your fingers crossed till
the end …
OR

13. We bring innovative R&D solutions… to all your complex problems
Reach us out
jaya@korulifescience.com