Accelerated Stability Assessment Program (ASAP) Using Science to Set Shelf Life

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1 Accelerated Stability Assessment Program (ASAP) Using Science to Set Shelf Life Ken Waterman, Ph.D. Research Fellow Pfizer Global R&D, Groton, CT USA

2 Outline Background and Scope Heterogeneous Kinetics and Isoconversion Moisture Sensitivity ASAP Experimental Design Packaging Regulatory Considerations Conclusions 2

3 Accelerated Stability Assessment Program (ASAP) Modeling tool that improves product understanding Credible predictions for product expiration dating Reduces uncertainty Has the potential to change the way industry meets its stability commitments Clinical investigations Registration Annual review Post-Approval Changes Scope Solid drug products Solid API s Small molecules 3

4 Heterogeneous Kinetics for Solids API Overall product excipient API/excipient interface Inside crystal molecules 4

5 Excipient/API Interactions lo og k Power Law relation for API + excipients: more surface interactions---more reactivity log (100/%API) Aspirin tablets at 40ºC/75%RH 5

6 Stability at Different Temperatures %Degra adant Low Temperature High Temperature Relative Time Same curvature independent of T 6

7 Stability at Different Temperatures: Historical Approach 60 Days at low or high T Low T High T k<<k to specification limit k k to specification limit 60 Historical approach: Time axis fixed independent of actual % degradant or T 7

8 Stability at Different Temperatures: ASAP (Isoconversion) Approach Low T High T ASAP approach: % degradant fixed at specification limit, time adjusted as needed 8

9 80 C Arrhenius Plot: Two Approaches 70 C 60 C 50 C 30 C isoconversion CP-456,773/60%RH Historical method: high T deviations give nonlinear behavior Real time data Predicted Shelf Life (historical method) Predicted Shelf Life (ASAP/isoconversion) Experimental Shelf Life 0.5 yrs 1.2 yrs 1.2 yrs 9

10 Humidity Corrected Arrhenius Equation collision frequency humidity sensitivity factor cal/deg ln k = ln A - E a /(RT) + B(ERH) 1/(isoconversion time) equilibrium relative humidity activation energy 10

11 Aspirin Tablet Degradation 70 C 50 C 40 C 30 C 20 C 75% RH 10%RH Parallel Arrhenius curves seen at each RH 11

12 Typical E a and B values (n=60) RH sensitivity does not indicate hydrolysis! 12

13 Effect of B Values on Shelf Life (Constant T) B 0.00 low moisture sensitivity 0.04 average moisture sensitivity 0.09 high moisture sensitivity 60%RH in PVC Blister 65%RH in PVC Blister 75%RH in PVC Blister 60%RH in Bottle + Desiccant 5.0 yrs 5.0 yrs 5.0 yrs 5.0 yrs 5.0 yrs 3.8 yrs 2.6 yrs 7.1 yrs 5.0 yrs 3.0 yrs 1.2 yrs 8.8 yrs 13

14 Effect of Activation Energies on Shelf Life (Constant RH) Shelf-Life (years) E a (kcal/mol) 25 C 30 C 40 C 12 Low activation energy Average activation energy High activation energy

15 ASAP Screening-Protocol: Set to Generate Specification Levels Generically Protocol T ( C) %RH Days Drug Product Stability Screen Actual protocol is product-specific! 15

16 ASAP Design Space (DOE) ln k = ln A - E a /R(1/T) + B(%RH) ln k %RH 70/75 80/40 60/40 50/75 40/75 30/75 Ln A 70/ 5 30/65 25/60 B E a /R 1/T 16

17 Error Bars for Predicted Shelf-Life ln k Shelf-life error bars depend on: Extrapolation distance Errors in k s Design/degrees of freedom 70/75 %RH 80/40 60/40 50/75 Ln A 70/ 5 25ºC/60%RH B 1/T E a /R 17

18 Error Bars for Predicted Shelf-Life Example: Confidence Interval For 2 year shelf life (25ºC/60%RH) = 95% For 3 year shelf life (25ºC/60%RH) = 75% ln k 70/75 %RH 80/40 60/40 50/75 Ln A 70/ 5 25ºC/60%RH B 1/T E a /R Calculated using Monte-Carlo simulation process 18

19 Error Bars for Predicted Shelf-Life ln k Example: Confidence Interval For 2 year shelf life (25ºC/60%RH) = 99% For 3 year shelf life (25ºC/60%RH) = 95% 70/75 %RH 80/40 60/40 50/75 40/75 Ln A 70/ 5 25ºC/60%RH B 1/T E a /R 19

20 Likely Causes for Poor Fit/Prediction Form/Phase change caused by T/RH: melts, glass transitions, anhydrate/hydrate formation ln k 80/40 70/75 %RH 60/40 50/75 40/75 30/75 Ln A 30/65 25/60 70/5 B E a /R 1/T 20

21 Protocol Example Final protocol may require several iterations! T ( C) %RH Days % Degradant ± ± ± ± ±0.06 Specification Limit = 0.2% 25 C/60%RH shelf-life (PVC blister) 25 C/60%RH shelf-life (HDPE bottle) 30 C/65%RH shelf-life (HDPE bottle) 30 C/65%RH shelf-life (HDPE bottle, desiccant) yrs yrs yrs yrs 21

22 Protocol Example Final protocol may require several iterations! T ( C) %RH Days (screening protocol) %Degradant using screening (generic) protocol Days: Product specific protocol Not tested Not tested Not tested Not tested

23 Protocol Example Final protocol may require several iterations! T ( C) %RH Days: Protocol 2 (product specific) %Degradant using product specific protocol ± ± ± ± ± C/60%RH shelf-life (PVC blister) 25 C/60%RH shelf-life (HDPE bottle) 30 C/65%RH shelf-life (HDPE bottle) 30 C/65%RH shelf-life (HDPE bottle, desiccant) yrs yrs yrs yrs 23

24 ASAP Protocol Validation Over 50 drugs have now been studied at Pfizer! 24

25 Packaged-Product Stability H 2 O H 2 O H 2 O H 2 O Moisture transfer depends on MVTR + RH Moisture inside packaging equilibrates between headspace (RH), tablets, desiccant (vapor sorption isotherms) 25

26 Moisture Sorption Isotherm Microcrystalline Cellulose % H 2O %RH 26

27 Moisture Sorption Isotherm Desiccants %H 2 O %RH Silica Gel Molecular Sieves Clay Mineral 27

28 Moisture Equilibration in Bottle 35 Tablets introduced %RH mg tablets (2) 1:1 spray-dried lactose:mcc (RH 32%) in N 2 - purged120-cc bottle Time (min) 28

29 Moisture Vapor Transmission Rate permeability moisture transferring into a package at a fixed difference in RH; fixed T P = MVTR/ RH difference in RH inside and outside package m = P RH t mass of water entering/leaving container unit of time 29

30 MVTR Values Vary with T in Arrhenius manner Proportional to surface area Bottles 60-cc HDPE (75%RH) 20 C C C cc HDPE (75%RH) 30 C Blisters (30 C;75%RH) Aclar PVDC

31 Empty Bottle/Blister Equilibration %RH Aclar Blister 60-cc bottle Days 25ºC/60%RH Oven 31

32 Bottle/Blister Equilibration with Tablets %RH years 25ºC/60%RH Oven mg tablets 2:1 MCC:lactose 60-cc bottle + 60 tablets Aclar blister + 1 tablet 32

33 Predicted (Lines) vs. Measured RH empty bottle 2 tablets %R RH tablets 15 tablets + desiccant Days 500 mg tablets of CP cc HDPE Bottles (40 C/75%RH) 33

34 Example 1: Very Unstable (When Unprotected) Drug Product (B = 0.068) 4 %D Degradant PVC blister (open bottle) 2 tablets/60-cc bottle 15 tablets/60-cc 15 tablets + bottle desiccant/60-cc bottle Days Lines: predicted (ASAP + calculated RH) Diamonds: experimental CP-481,715 in 60-cc HDPE Bottles (40 C/75%RH) 34

35 Example 2: More Stable Drug Product (B = 0.015) Real time ASAP Varenicline tablets ( mg in 180-cc bottle); 30 C/65%RH 35

36 ASAP vs. Real Time Example 3 (25 C/60%RH in Bottles with Desiccant) B = ASAP Prediction Real Time 36

37 Bridging Science and Regulations Early Clinical Trials Use ASAP to support Clinical Use Period assignments During Development Use ASAP to predict stability for changes in: Formulations/processes o ocesses Synthetic routes Packaging At Registration Use ASAP as supportive data or as an alternative to traditional stability to minimize stability commitments Post-Approval Use ASAP to justify changes that will not affect stability Replace annual commitment with ASAP commitment 37

38 Conclusions ASAP provides a scientific basis for setting shelf-lives Dramatically shorter time Better understanding Lower risk Allows package selection without screening lowers risk + saves time 38

39 Acknowledgments Pfizer scientists Groton and Sandwich Paul Gerst Bruce MacDonald Mike Roy Anthony Carella Garry Scrivens 39

40 Related Publications Waterman, K.C.; MacDonald, B.C. Package selection for moisture protection for solid, oral drug products, J. Pharm. Sci. 99 (2010) ; (on line) DOI /jps (2010) Waterman, K.C. Accelerated stability assessment program (ASAP): using science to set shelf life, accepted in American Pharm. Rev. Waterman, K.C. Understanding and predicting pharmaceutical product shelf-life. In Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, Huynhba, K., Ed. Springer Science and Media Publishing, Chapter 6 (2008) Waterman, K.C.; Colgan, S.T. A science-based approach to setting expiry dating for solid drug products. Regulatory Rapporteur 5 (2008) Waterman, K.C.; Carella, A.J.; Gumkowski, M.J.; Lukulay, P.; MacDonald, B.C.; Roy, M.C.; Shamblin, S.L. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharmaceutical Research 24 (2007) Waterman, K.C.; Adami, R.C. Accelerated aging: prediction of chemical stability of pharmaceuticals. Intern. J. Pharm. 293 (2005) Waterman, K.C.; Adami, R.C., Hong, J. Impurities in drug products. In Handbook of Isolation and Characterization of Impurities in Pharmaceuticals. S. Ajira and K.M. Alsante, Eds. 2003, pp Waterman, K.C.; Adami, R.C.; Alsante, K.M.; Antipas, A.S.; Arenson, D.R.; Carrier, R.; Hong, J.; Landis, M.S.; Lombardo, F.; Shah, J.C.; Shalaev, E.Y.; Smith, S.W.; Wang, H. Hydrolysis in pharmaceutical formulations. Pharm. Dev. Tech. 7 (2002) Waterman, K.C.; Adami, R.C.; Alsante, K.M.; Hong, J.; Landis, M.S.; Lombardo, F.; Roberts, C.J. Stabilization of pharmaceuticals to oxidative degradation. Pharm. Dev. Tech. 7 (2002)

Implementing an Accelerated Stability Assessment Program: Case Study

Implementing an Accelerated Stability Assessment Program: Case Study Cherokee Hoaglund Hyzer With Special Thanks to Jeff Hofer, Timothy Kramer, Chad Wolfe, Seungyil Yoon, Steve Baertschi and Ken Waterman