European Guidance on Modified Release Dosage Forms

Transcription

1 Safeguarding public health European Guidance on Modified Release Dosage Forms Terry Shepard, Pharmacokinetics Assessor Medicines and Healthcare products Regulatory Agency London PQRI Workshop on Application of IVIVC in Formulation Development September 5-6, 12 Bethesda, Maryland

2 Disclaimer The views expressed during this presentation are those of the speaker and do not necessarily represent the views of the MHRA or the EMA/CHMP. Slide 2

3 Outline European Regulatory System Status of European Guidance on MR Products MHRA Experience Key Messages and Opportunities Slide 3

4 European Regulatory System CHMP Assessors in National Agencies National MAs, National Scientific Advice EMA Working Parties e.g. Scientific Advice/Guidelines MA: marketing authorisation Slide 4

5 European Guidance on MR Products (currently in revision) Slide 5

6 European Guidance relating to IVIVC (currently in revision) IVIVC Topic Covered Quality Section Clinical Section Levels of IVIVC: definitions Levels of IVIVC: advantages, disadvantages of different levels Role of IVIVC establishing discriminatory power of in vitro dissolution test (Quality) clinical relevance of in vitro dissolution tests and associated dissolution specifications (PK and Clinical) Programme rationale: choice of formulations for IVIVC study X-ref Programme rationale: choice of reference formulation Programme rationale: extending IVIVC beyond IVIVC batches Slide 6

7 European Guidance relating to IVIVC (currently in revision) IVIVC Topic Covered Quality Section Clinical Section Study design: in vitro study design (dissolution media, sampling times) - Study design: in vivo study design (number of subjects, sampling times) - IVIVC data analysis: acceptable methodology for model development X-ref IVIVC validation: assessment of predictability X-ref IVIVC development and validation: reporting - Applications: specification setting - Applications: waiver of BE studies for product variations - Slide 7

8 Why do companies develop IVIVCs? in vitro dissolution = surrogate for BE study save time and money Why do regulators encourage IVIVCs? Approval Process Post-approval Benefit Risk Reassurance that positive benefit/risk balance is maintained throughout life of product Approval CHMP Opinion + Annexes (SmPC, Conditions) Refusal or Withdrawal Slide 8

9 Examples of MR Product Variations: Methods Search of Sentinel database granted licenses prolonged release formulations 385 licenses/69 companies Type II variations - pharmaceutical 63 licenses of interest Compiled all variations for 63 licenses 3 representative examples + additional points from 4-5 others Slide 9

10 MR Product Variations: Example 1 23 variations II 1b 1a 5 pharmaceutical variations MA: 1 1 Label/Leaflet : 2.5/year Pharmaceutical variations: Change chemical identification test Remove score line Increase pack size Change manufacturing site Change dissolution specification Slide 1

11 MR Product Variations: Example 2 58 variations II 1b 16 pharmaceutical variations MA: a Label/Leaflet : 4.5/year Pharmaceutical variations: Change manufacturing site x2 Change batch size, manufacturing process Change product specification (microbiological) Change storage site Change analytical methods Change frequency of IPC Change shelf life dissolution specification Slide 11

12 MR Product Variations: Example 3 54 variations 1b II MA: 4 1a Label/Leaflet pharmaceutical variations Pharmaceutical variations: 11: 9/year Manufacturer, batch release site x 3 Batch size In process control spec Add pack size Add storage and release site Extend shelf life Minor change to manufacturing process Add packaging site Change manufacturer of active Change dissolution method, specification Slide 12

13 MR Product Variations: Example 3 (cont d) Supporting evidence: Quality Overall Summary Batch data Stability data IVIVC (Level A) MA: Var 17: : 9/year Purpose of Variation: To update the dissolution test method in line with the USP monograph and to change the specification time points and limits. Slide 13

14 % Released in vitro % Released in vivo MR Product Variations: Example 3 (cont d) 1 1 Upper limit (UL) Proposed Low and High 8 upper limit 8 target Target (Pivotal Batch) Lower limit (LL) + lower limit 8 1 % Released in vitro IVIVC Predicted C(t) Relative Bioavailability PK Parameter UL/LL UL/Target LL/Target Cmax AUC Dissolution Profiles Slide 14

15 % Released in vitro % Released in vivo MR Product Variations: Example 3 (cont d) 1 1 Upper limit (UL) Proposed Low and High 8 upper limit 8 target Target (Pivotal Batch) Lower limit (LL) + lower limit 8 1 % Released in vitro IVIVC Predicted C(t) Relative Bioavailability PK Parameter UL/LL UL/Target LL/Target Cmax AUC Dissolution Profiles Slide 15

16 % Released in vitro % Released in vivo MR Product Variations: Example 3 (cont d) 1 1 Upper limit (UL) Proposed Low and High 8 upper limit 8 target Target (Pivotal Batch) Lower limit (LL) + lower limit 8 1 % Released in vitro IVIVC Predicted C(t) Relative Bioavailability PK Parameter UL/LL UL/Target LL/Target Cmax AUC Dissolution Profiles Slide 16

17 % Released in vitro % Released in vivo MR Product Variations: Example 3 (cont d) 1 1 Upper limit (UL) Proposed Low and High 8 upper limit 8 target Target (Pivotal Batch) Lower limit (LL) + lower limit 8 1 % Released in vitro IVIVC Predicted C(t) Dissolution Profiles Relative Bioavailability PK Parameter UL/LL UL/Target LL/Target Cmax AUC All batches within specification bioequivalent to each other 2. Proposed limits considered appropriately supported Slide 17

18 % Released in vitro % Released in vivo MR Product Variations: Example 3 (cont d) Upper limit (UL) Proposed Low and High 8 upper limit target Target (Pivotal Batch) Lower limit (LL) + lower limit 8 1 % Released in vitro IVIVC Predicted C(t) Dissolution Profiles Relative Bioavailability PK Parameter UL/LL UL/Target LL/Target Cmax AUC All batches within specification bioequivalent to each other 2. Proposed limits considered appropriately supported Conclusion: Proposed change will not have a detrimental effect on quality, safety or efficacy of the product. Slide 18

19 % Released in vitro % Released in vivo MR Product Variations: Example 3 (cont d) 1 8 Upper limit (UL) Proposed Low and High 1 1. Anchor 8to clinical batches. upper limit target Target (Pivotal Batch) Lower limit (LL) + 2. Relationship to BE limits. lower limit 8 1 % Released in vitro IVIVC 3 Predicted C(t) Dissolution Profiles Relative Bioavailability PK Parameter UL/LL UL/Target LL/Target Cmax AUC All batches within specification bioequivalent to each other 2. Proposed limits considered appropriately supported Slide 19

20 % Released in vitro Dissolution Limits in Product Specifications: Relationship to BE Limits 1 Upper limit (UL) Proposed Low and High IVIVC in vitro = surrogate for in vivo (BE) study 8 Target (Pivotal Batch) Lower limit (LL) Dissolution Profiles 8% 125% Test/Ref (%) Slide

21 % Released in vitro Dissolution Limits in Product Specifications: Relationship to BE Limits 1 8 Upper limit (UL) Proposed Low and High Target (Pivotal Batch) limits are based on a maximal difference of % in the predicted AUC and, if relevant C max. NfG CPMP/QWP/4/96 Lower limit (LL) All batches within dissolution specification limits should be bioequivalent to each other. 1? 8% 125% Test/Ref (%) Dissolution Profiles All batches should be bioequivalent to target (pivotal batch). 2 Slide 21

22 % Released in vitro Dissolution Limits in Product Specifications: Relationship to BE Limits 1 8 Upper limit (UL) Proposed Low and High Target (Pivotal Batch) Lower limit (LL) limits are based on a maximal difference of % in the predicted AUC and, if relevant C max. NfG CPMP/QWP/4/96 All batches within dissolution specification limits should be bioequivalent to each other. 1 1 UL/LL Dissolution Profiles 8% 125% Test/Ref (%) UL/target LL/target Slide 22

23 % Released in vitro Dissolution Limits in Product Specifications: Relationship to BE Limits 1 8 Upper limit (UL) Proposed Low and High Target (Pivotal Batch) Lower limit (LL) limits are based on a maximal difference of % in the predicted AUC and, if relevant C max. NfG CPMP/QWP/4/96 All batches should be bioequivalent to target (pivotal batch). 2 2 UL/LL 15% (off-scale) Dissolution Profiles 8% 125% Test/Ref (%) UL/target LL/target Slide 23

24 % Released in vitro Dissolution Limits in Product Specifications: Relationship to BE Limits 1 8 Upper limit (UL) Proposed Low and High Target (Pivotal Batch) limits are based on a maximal difference of % in the predicted AUC and, if relevant C max. NfG CPMP/QWP/4/96 Lower limit (LL) All batches within dissolution specification limits should be bioequivalent to each other. 1? 8% 125% Test/Ref (%) Dissolution Profiles All batches should be bioequivalent to target (pivotal batch). 2 Slide 24

25 % Released in vitro % Released in vitro Impact of IVIVC Validation Range on Justification of Dissolution Limits 1 IVIVC batches Dissolution limits Choice of formulations: widest possible range of dissolution behaviour, balancing need to keep release mechanism the same. consider extending IVIVC range. Slide 25

26 Information Question Stage Implications for MR Development Program Target Specification Prototype Selection Formulation Optimisation Scale-up Post-approval Changes What in vitro characteristics will achieve in vivo target? Which prototypes should be tested in vivo? How must we alter in vitro release to achieve in vivo target? What is a significant change in the in vitro profile? Drug PK In vitro dissolution Drug PK Many batches Conc-time data (+IVIVC) Conc-time data (+IVIVC) In vitro dissolution In vitro dissolution Drug PK Drug PK where extending range of IVIVC, showing applies to pivotal batches - need to consider in design of these studies and include a reference formulation requires prospective approach. Slide 26

27 European Guidance relating to IVIVC (currently in revision) IVIVC Topic Covered Programme rationale: choice of formulations for IVIVC study Programme rationale: extending IVIVC beyond IVIVC batches Applications: specification setting Key Points widest possible range of dissolution behaviour, balancing need to keep release mechanism the same sometimes need to extend range of IVIVC, sometimes need to show applies to pivotal batches; need to consider in design of these studies and include a reference formulation alignment to average BE criteria Slide 27

28 Key Messages and Opportunities Discriminatory Power of Dissolution Tests Anchor to Clinical Batches ICH Q8 Use IVIVC to interpolate within a validated range of dissolution Q1 Align dissolution specification to average BE limits Opportunities to contribute: Breakout session H Upon publication of draft guidance (ema.europa.eu) Slide 28