First to file (FTF) regulatory challenge to QbD adoption

1. First to file (FTF) regulatory challenge to QbD adoption Kishor K Chakraborty, Ph.D Head – R&D kishorc@riyadhpharma.com

2. Dilemma for Generics Right balancing between speed, efficiency and Excellence FTF QbD Source: IFPAC 2015 Teva, Inna Ben

3. First to file race slowing QbD adoption in generics “If you are not first to file you may as well be last”. Hard-fact Coming second can mean a $100m opportunity withers to just a few million dollars: Nick Taylor, Teva

4. Branded Strategy: Gaming of patent FTC V. CEPHALON, INC • Average time keeping generics out increased from • 9 to 11.5 years Source: www.slideshare.net/naveenniper/hatch-waxman-act

5. Average market exclusivity period Source: IMS Health data

6. Paragraph IV challenges Source: IMS Health data

7. QbD challenges and way forward Step 0 -1 Investment (Process Understanding) Step 1 -2 Regulatory challenge Step 2 -3 Regulatory flexibility. Investment Regulatory challenge Regulatory flexibility

8. Sources of Product Variability

9. Industry Impediments to QbD Adoption QbD doesn't address key business issues such as COGS, sustainability and scaleability from the earliest conceptual stages “Could this approach help companies address, from the earliest stages, the reasons why so many drugs fail during clinical trials, regulatory review, or commercial stages” ? Source: www.in-pharmatechnologist.com/

10. What option is left to Generics

11. What is Generic Strategy ? “To develop a mix of equipment and manufacturing strategies that maximize quality, scalability, and sustainability, with an eye toward cost-effectiveness and commercial viability” Thinking Beyond QbD Rapid Process Understanding “Getting Off the Critical Path and Onto the Right Path”

12. Generic opportunity –Development stageSingle-cycle development - Eliminate scale upA new QbD paradigm. Using R&D equipment for commercial production Using the same equipment from R&D to scale up for commercial productions will cut costs, time & improve efficiency. Running clinical batches at a commercial facility allows comparability and validation runs to be performed at same time, reducing the number of engineering runs required and the timing between those runs and the validation campaign. In simple terms, rather than making 1000kg at once, with this process you make 1 kg 1000 times.

13. Generic opportunity –Process design stageSingle-use Approaches (Clinical Fill & Finish Mfg.: Tank-to-needle concept ) CLINICAL VALIDATION OUT, MORE API IN Source: www.drug-dev.com (April 2014

14. Generic opportunity –Process design stageSingle-use Approaches (Clinical Fill & Finish Mfg.: Tank-to-needle concept ) QUICKER TO GET, MORE EXPENSIVE TO BUY Source: www.drug-dev.com (April 2014

15. Generic opportunity –Process design stageContinuous ProcessingThe end game for PAT (and of course, QbD)- A changing processing Paradigm Traditional (step-by-step development) tablet manufacturing Continuous manufacture of tablets Source: Rapti D. Madurawe, FDA

16. Generic opportunity – Process design stageRTRT The end game for PAT (and of course, QbD)- A changing testing Paradigm OFF line testing ON line testing

17. Generic opportunity –Process design stageDesigning Process Optimization(Hybrid Approach) Traditional Approach : Quality ensured by end-product testing( OFAT). QbD Approach : Full design of experiments (MFAT). Hybrid Approach : Combining elements of approaches (OFAT) and (MFAT). i.e. 60-kg blend could be divided into 3-kg sub lots, allowing up to 20 experiments to be run. Breaking the manufacturing process into defined sections : Initial blending step - Approach 1 Dry granulation - Approach 2 Tablet compression - Approach 2 Source: Pharmaceutical Tech ‐ Sep 10 ‐ Process Opt & Scale‐Up

18. Generic opportunity –Stability stageImplementing an Accelerated Stability Assessment Program (ASAP)Humidity Correction Arrhenius Equation: An isoconversion paradigm

19. ASAP - Case study Typical Proposed ASAP Screening Protocol target utilized in the ASAP study design.

20. Generic opportunity –Process design stageAnalytical PlatformingMore rapid, sensitive and accurate analytical methods development Fusion QbD software Plateform Revolutionary • Rapid Chemistry Screening. • Robust Method Development and Optimization. • Pharma Customer Benchmarking. • Statistical Data Modeling- Robustness Simulation, Data Visualization, Optimization. Source: www.smatrix.com/fusion_pro

21. Source: CAD Outsourcing Services Generic opportunity –Process design stageOutsourcingLeveraging prior and public knowledge Considerations For Strategic Partnering With CRO / CMOs : Incorporating QbD Early in Product Development Is Key To Success.

22. Generic opportunity –Process design stageInformatics platform strategy Leverage Big Data Handling to Speed up innovation Silos Data capture & management (ERP,LIMS,MES) Seamless Data capture & management (ELN) Speed to value is 1 -3 months vs 6+ months Source: Maven wave

23. Generic opportunity –Process design. stageImplementing Supplier Risk Monitoring Programs Narrow focused, Subjective & Reactive processes Complete visibility of Suppliers http://www.iqs.com/

24. Generic opportunity –Process design stageDeveloping Early Indicators of Product Quality( From Sample to Decision) Compendial method (Human’s error-prone) Rapid Microbial method (Automated digital imaging detection & counting by auto-flurescence)

25. Generic opportunity –Process design stageDevelop better biomarkers(New platforms for pharmacodynamic end-point or for safety testing)

26. Generic opportunity –Process design stageImplementing Process-improvement methodologies (e.g., Lean six sigma and operational excellence) Traditional Improvement (Focuses 10% value add activity) Continuous Improvement (Focuses 90% non-value add activities)

27. Generic opportunity – Process design stageDeveloping Quality Metrics Risk and Escalation Quality Metrics (Qualitative & subjective) Mfg. quality metrics ( More Quantitative & objective) FDA release : 28July 2015 Peter Drucker said “you can’t manage what you can’t measure,” Source: www. nvp.ca/quality-assurance-metrics

28. Generic opportunity – Process design stage SELF-AUDITING “An extra step falling between the documentation of compliance and the investigation of that documentation by the FDA”. Area of indirect cost saving: Reduced time to approval and eventual Market improved regulatory reputation. Probable FDA conformance satisfaction level: Very high. Source: http://qbdworks.com/quality-metrics-qbd

29. Generic opportunity – Submission stageUnderstanding the FDA’s Expedited PathwaysProposed Priority Review Program First-to-file review Priority review (MAPP 5240.3 Rev. 1) in August 2014

30. Generic opportunity – Submission stage Single-cycle regulatory review Number of cyclesto ANDA approval Source: FDA.GOV Source: FDA.GOV

31. Generic opportunity – Submission stage Single-cycle regulatory reviewOriginal ANDA Review Time OGD’s formal Communication (Multi-cycle review) Real time Communication (Single cycle review)

32. Concluding thoughts ……. QbD paradigm to be expanded so that some of the factors critical to market success are also considered from the earliest conceptual stages, such as: ·     Cost of goods ·      Sustainability of the process ·      Scalability ·       Way forward : The ability to address predictable and identified risks throughout the development cycle reduces the likelihood of costly delays and failures. Regulatory compliance costs (e.g., the potential savings from examining comparability requirements to optimize timing for process changes,  or by using new technologies, for instance,  installing new IT system for batch records that would enable “release by exception” and reduce validation and documentation requirements). Robert Preti, NeoStem (CDMO) division, Pharmatech.com

33. QUERIES PLEASE!!!!!!!! ?