1. First to file (FTF) regulatory challenge to QbD adoption 1

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

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 Hard-fact Coming second can mean a $100m opportunity withers to just a few million dollars : Nick Taylor, Teva

4. 4 Average time keeping generics out increased from 9 to 11.5 years FTC V. CEPHALON, INC 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. Step 0 -1 Investment (Process Understanding) (Process Understanding) Step 1 -2 Regulatory challenge challenge Step 2 -3 Regulatory flexibility. flexibility. QbD challenges and way forward Investment Regulatory challenge Regulatory flexibility 7

8. Sources of Product Variability 8

9. to QbD Adoption 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 “ Could this approach help companies address, from the earliest stages, the reasons earliest stages, the reasons why so many drugs fail during, during clinical trials,, or regulatory review, or ” ? commercial stages” ? Source: www.in-pharmatechnologist.com/ 9

10. What option is left to Generics 10

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. Single-cycle development - A new QbD paradigm. Using R&D equipment for commercial production Generic opportunity –Development stage Single-cycle development - Eliminate scale up A 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. Single-use Approaches (Clinical Fill & Finish Mfg.: Tank-to-needle concept ) Generic opportunity –Process design stage Single-use Approaches (Clinical Fill & Finish Mfg.: Tank-to-needle concept ) CLINICAL VALIDATION OUT, MORE API IN Source: www.drug-dev.com (April 2014

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

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

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

17. Generic opportunity –Process design stage Designing 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. Humidity Correction Arrhenius Equation: An isoconversion paradigm Generic opportunity –Stability stage Implementing an Accelerated Stability Assessment Program (ASAP) Humidity Correction Arrhenius Equation: An isoconversion paradigm

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

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

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

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

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

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

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

26. Generic opportunity –Process design stage Implementing 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) 26

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

28. SELF-AUDITING 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. First-to-file review Priority review Generic opportunity – Submission stage Understanding the FDA’s Expedited Pathways Proposed Priority Review Program 29 (MAPP 5240.3 Rev. 1) in August 2014MAPP 5240.3 Rev. 1

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

31. Single-cycle regulatory review Generic opportunity – Submission stage Single-cycle regulatory review Original 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 32

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