1. “The Third International Workshop: Drug Development and Registration” First Moscow State Medical University and Ministry of Healthcare in Russia October 28-29, Moscow, Russia Application of Dissolution Testing in Industrial Product Development

2. Contents Relevance of dissolution testing in pharmaceutical industry Case studies: Influence of stability testing on dissolution Special dosage form (ODT) Extended release formulation Copraecipitate formulation Fixe dose combination Conclusion page 2

3. page 3 Aims of method development A robust dissolution method, that provides rugged, reproducible and reliable data !  Appropriately discriminating, but not over discriminating !  „Quality indicating“ with regard to:  Stability effects  Failures during manufacturing process  Changes in composition  Capable of being transferred between laboratories !  Suitable to show changes affecting in-vivo performance ! Relevance of dissolution testing in pharmaceutical industry

4. page 4 Relevance of dissolution testing in pharmaceutical industry Dissolution testing is involved throughout the entire products life cycle  Formulation development and finding  important tool for formulation development in order to find the best candidate to fit the medical/kinetic requirements  Monitoring of clinical trials during phase 1, 2 and 3  release testing  Stability studies  to define shelf life  Challenge scale up und process validation  to ascertain conformity of lab- and production scale

5. page 5 Relevance of dissolution testing in pharmaceutical industry  Submission  Quality control of market products and during phase 4  release testing and as critical quality control tool for investigations on uniformity of product quality within the technical range of manufacturing processes  Post Approval Changes (SUPAC)  to prove similarity of pre - and postchange quality  Biowaiver, IVIVC (In-Vitro In-Vivo Correlation)  to avoid redundant clinical bioequivalence studies  Line Extensions  to support formulation development

6. Stability effects of a new tablet formulation within 1 month storage Conclusion:  water permeation though the PP blister occurs  clear influence of humidity on the tablet  can be avoided by using suitable packaging material ! Case study 1.1: Stability effects on the formulation 40°C/75 rh, PP blister 40°C/75 rh, alu/alu blister single value curves page 6

7. Stability effects of a new formulation within 3 month storage at accelerated test conditions: 40°C/75 rh OOS ! Conclusion: only dissolution is affected (assay and degradation in spec) clear influence of temperature and humidity in vivo relevance start 1 month 3 months HDPE bottle  water permeation non-protective packaging material mean value curves Case study 1.2: Stability effects on the formulation page 7

8. Stability effects of a new formulation within 3 month storage at accelerated test conditions: 40°C/75 rh OOS ! Conclusion: Dissolution profiles now the other way round  decreasing instead of increasing ! start 1 month 3 months mean value curves Case study 1.2: Stability effects on the formulation HDPE bottle with dessicant  non-protective packaging material page 8

9. Stability effects of a new formulation within 3 month storage at accelerated test conditions: 40°C/75 rh Conclusion: selecting a suitable packing material based on dissolution tests is possible material provides an appropriate protection of the product start 1 month 3 months mean value curves Case study 1.2: Stability effects on the formulation alu alu blisters  protective packaging material page 9

10. Stability effects of a new capsule formulation within 12 months storage Conclusion:  clear influence of temperature and humidity on the capsules requires a storage and transport advice for the product Case study 1.3: Stability effects on the formulation mean value curves start 3 month 6 months 12 months OOS ! cross-linking ! Q=75 %; t=45 min hart gelatine capsules 30°C/75 rh page 10

11. Case study 2: ODT as Line Extension ODT as a Line Extension of a standard IR tablet Orally Disintegrating Tablet (USA) / Orodispersible Tablet (EU):  a solid dosage form containing medical substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue. API is highly soluble in 0.1M HCl (pH 1), acetate-buffer pH 4.5 and dem. water (sink-conditions !) API is slightly soluble in phosphate-buffer pH 6,8  addition of 0.1% SDS required to reach sink-conditions “Official” method for IR tablet uses 0.1 M HCl as dissolution medium Aim: discriminating dissolution method for development purposes in order to find the fastest disintegrant ! page 11

12. Case study 2: ODT as Line Extension Starting point: dissolution profiles of IR tablets obtained in different media (pH 1, pH 4.5, dem. water, pH 6.8 + 0.1% SDS) at 50 rpm  rapidly dissolving at all pH-values page 12 pH 1 pH 4.5 dem. water pH 6.8 + 0.1% SDS

13. Case study 2: ODT as Line Extension Problem solving: evaluation of the characteristics of the API and the discriminatory power of the dissolution method  shorter sample drawing times under non sink-cond. (pH 6.8 without SDS) Submission: replacement of dissolution by disintegration acc. ICH QA6 page 13 clear differentiation of the formulations is feasible !

14. Case study 3: Development of a GIT System 1 - orifice GITS (Gastro Intestinal Therapeutic System) Modified release formulation based on an osmotic principle (OROS technology) SPM: semipermeable membrane  diffusion of water Drug layer: API homogeneously dispersed in a polymer matrix Push layer: diffusion of water  swelling  osmotic pressure  pushing out the API through the orifice page 14

15. Case study 3: Development of a GIT System Starting point: 1. formulation approach: 1 - orifice GITS  advantage: dissolution profiles are not affected by pH-changes and/or mechanical stress (rotation speed) Zero order kinetic  low batch intravariability  RSD < 2% page 15

16. Case study 3: Development of a GIT System Problem during release testing of clinical batch: OOS in dissolution ! All other release parameter comply to the specification  Reason ? page 16

17. Case study 3: Development of a GIT System page 17

18. Case study 3: Development of a GIT System Formulation optimization via a discriminating dissolution testing method ! Formulation after 24 hours of dissolution testing:  formulation bursts due to high osmotic pressure ! page 18

19. Case study 3: Development of a GIT System Problem solving: 2 - orifices reduce pressure in the formulation !  homogeneous profiles with low scatter and intra-batch variability page 19

20. Case study 4: Copraecipitate formulation Crystalline drug substance (two main modifications) is insoluble in aqueous media over the physiological pH range Addition of various surfactants do not provide sink conditions (40 mg dosage) Solubility data of crystalline substance at 37 °C: Problem solving: Drug product is formulated as a solid solution !  amorphous form increases solubility and therefore enhanced bioavailability dramatically ! no sink-conditions with SDS achievable page 20

21. Case study 4: Copraecipitate formulation Crystalline API: is lying on the aqueous surface due to high surface tension  no dissolution amorphization Copraecipitate: fast dissolution  high bioavailability page 21

22. Case study 4: Copraecipitate formulation Monitoring the amorphous state of the API in the drug product is absolutely mandatory  potential recristallisation directly influences bioavailability 1.Quantitative characterization by X-ray powder diffraction (XRPD) signals of different amounts of crystalline ‘mod I’, insoluble in aqueous media Problem: XRPD measurement time > 24 h method precision not acceptable: +/ - 10% 50 % mod I 20 % mod I 10 % mod I 5 % mod I page 22

23. Case study 4: Copraecipitate formulation crystalline amounts mean values of n=6 tablets solid solution Options for monitoring the amorphous state of the API in the drug product 2.Quantitative characterization by in vitro dissolution testing using fibre optic technique page 23

24. Conclusion: Quantitative characterization of crystalline amounts and monitoring of a potential re-crystallization of the API into the insoluble form is possible by in vitro dissolution testing via fibre optic Method precision +/- 3% Short measurement time of 60 minutes compared to 24 h Robust technique and automation with RoboDis1 is feasible, in particular for conducting a broad range of stability tests (e.g. packaging material tests) Case study 4: Copraecipitate formulation page 24

25. Case study 5: Innovative fixe dose combination Fixe dose combination with 2 different APIs: Modified release formulation combined with an IR formulation MR part: consists of a GIT system containing the first API, constant drug release over 24 hours IR part: coating of the MR part containing the 2 API, complete dissolution within 1 hour Optimal way: development of one automated dissolution procedure for routine analyses with regard to apparatus, dissolution medium, rotation speed and sampling time points including including one analytical method for the quantification of both API  both APIs can be analyzed in 1 tablet in parallel ! page 25

26. Case study : Innovative fixe dose combination Challenges with regard to dissolution method: page 26 IRMR Dissolution apparatusPaddle Dissolution mediumpH 6.8 + 1 % SDSpH 4.5 + 0.3% Brij Rotation speed100 rpm75 rpm Filtration25 µm0,45 µm Analytical methodOffline quantificationOnline quantification

27. Case study 5: Innovative fixe dose combination Result: Determination of both APIs in different dissolution tests  Prerequisite: batch to batch consistency ! 2 Dissolution systems  online measurement for the MR part using RoboDis 1 (fully automated)  fraction collection for the IR part selecting Sotax AT 70 smart (semi-automated)  two analytical methods (online and offline quantification) page 27

28. Case study 5: Innovative fixe dose combination page 28 IR part: dissolution profiles in buffer pH 4.5 containing 0.3% Brij

29. Case study 5: Innovative fixe dose combination page 29 Semi-automated dissolution system – Sotax AT70 smart ®

30. Case study 5: Innovative fixe dose combination page 30 MR part: dissolution profiles (n=6) in buffer pH 6.5 containing 0.5% SLS

31. Case study 5: Innovative fixe dose combination page 31 Fully automated dissolution system – RoboDis 1 ®

32. Conclusion In Industrial product development… … high flexibility is mandatory ! … willingness to unusual approaches ! … acceptance of increased effort ! Prerequisite: qualified personnel ! Courage for discussions with colleagues and authorities ! But always keep in mind: submission is priority 1 ! page 32

33. Thank you for your attention!