Teaching Old Drugs New Tricks: Applications of ASAP in OTC Product Development. The Procter and Gamble Company SoS 9/26/16

Transcription

1 Teaching Old Drugs New Tricks: Applications of ASAP in OTC Product Development The Procter and Gamble Company SoS 9/26/16

2 Overview of OTC Development Monograph Stability Design Strategy with ASAP MSR (Multi-Symptom Relief) Development Case Study Conclusions

3 Overview: Over the Counter (OTC) Drugs

4 Overview: OTC Development Monograph Products New Filing (IND) Products New Product Forms Differentiation through consumer understanding and novel product experience (new excipients) Extended/Delayed Release New API Combinations

5 Overview: Challenges in OTC OTC Monograph Modernization: ICH Q3B(R2)

6 Overview: Challenges in OTC Multi-Active Formulations API mg/dose API 1 20 mg/dose API 2 5 mg/dose

7 Overview: Challenges in OTC API 1 API 2 API 3????????

8 Overview: OTC Degradation What s possible? What s likely? What s real?

9 Overview of OTC Development Monograph Stability Design Strategy with ASAP MSR (Multi-Symptom Relief) Development Case Study Conclusions

10 Holistic Stability Design Strategy Commercial Concepts Market Product 6-12 months

11 Holistic Stability Design Strategy Commercial Concepts ASAP Performance Testing Packaging Sensory GMP Stability

12 Stability Strategy Case Study: Monograph Flavor upgrade for Phenylephrine containing liquid product + =

13 Stability Strategy Case Study: Monograph Power and speed of ASAP ASAP 2 weeks Color 4 weeks Performance 6 weeks

14 Overview of OTC Development Monograph Stability Design Strategy with ASAP MSR (Multi-Symptom Relief) Development Case Study Conclusions

15 Case Study: MSR New Drug Product (IND/NDA filing) mixture of Naproxen (NAP), Dextromethorphan (DEX) and Pseudoephedrine (PSE) in 12 hour, extended release, bilayer tablet During process scale up for prototypes and preparation for a clinical study, PSE was observed to be off-target high by 5-15% An extraneous peak ~5% of parent DEX was also observed Fig. 1: Overlay of high and on-target granulations and UV Spectra of API peak. Peak purity match of 993.

16 Case Study: MSR New Drug Product Dry blending Wet granulation Fluid Bed Drying Tableting

17 Case Study: MSR New Drug Product Original Conditions Alternate Selectivity for ID Optimized HPLC Conditions Restek Raptor C18 SPP Column, 0.1% TFA/MeCN Agilent SB Phenyl Column, 0.1% TFA/MeCN Waters T3 Column, 0.5% Ammonium Acetate/MeCN

18 Case Study: MSR New Drug Product Peaks were isolated via 1 st dimension separation and fractionation 2 nd Dimension of HPLC was performed prior to analysis on a Thermo Exactive Mass Spectrometer The HCD fragment spectrum confirmed a structural match with the proposed chemicals: DEA Schedule 1 Controlled Substance

19 Case Study: MSR New Drug Product Fig. 3: Presence of Metals in Formula Excipients (weighted by formula amounts)

20 Case Study: MSR New Drug Product Are peroxides/metals observed in any raw materials? Do the materials deliquesce? What are the ph of API/excipient mixtures? Raw materials not a major source of peroxides as received Raw materials contribute reactive metals (i.e. Fe) at potential catalytic levels Supplier specifications contain levels that can contribute to oxidation Deliquescence occurs at lower RH for DEX/PSE mixture than for pure drug substance (55% vs 70%) ph of API/HPMC mixtures range from 6-7.5

21 Case Study: MSR New Drug Product Are the API stable alone and in combination? Actives are stable individually and in combination No degradation of either API observed at high temperature and high humidity No inherent incompatibility between PSE and DEX No degradation observed, even in samples undergoing deliquescence

22 Case Study: MSR New Drug Product Do we need a formula change? No inherent incompatibility between PSE/DEX and HPMC in the presence of high environmental moisture or spiked water at elevated temperatures Can t break the molecules with ASAP

23 Case Study: MSR New Drug Product Fluid Bed Drying

24 Case Study: MSR New Drug Product Fluid Bed Dryer Simulator: conceptualization and execution

25 Case Study: MSR New Drug Product Degradation also observed in convection ovens, but much less in static ovens

26 Case Study: MSR New Drug Product

27 Conclusion ASAP is valuable upstream and downstream at P&G Oxidation and solid state chemistry is complicated HPLC matters, stability indication needs to be bulletproof (Peak Purity can be wrong)

28 Allyn Kaufmann, P&G Samantha Donald, P&G Kylen Whitaker, P&G Jennifer Lewis, FreeThink

29 Thank you! Questions?