1. ICH Q11 – Definisjon av startmaterialer – Fleksibilitet og dokumentasjonskrav Andreas Sundgren LMI 17. april 2012

2. Definition of Starting Materials Non-scientific approach: Justification based on complexity/non-complexity of starting materials. Justification based on commercial availability Focus on number of steps, less focus on the manufacturing process as a whole.

3. Definition of Starting Materials Q11 – A scientific approach: A starting material should be a substance of defined chemical properties and structure. Steps that impact the impurity profile of the drug substance should normally be included in the manufacturing process Changes in material attributes or operating conditions that occur near the beginning of the manufacturing process have lower potential to impact the quality.

4. Starting Material Active Substance No GMP requirements No detailed description MA holder might have limited access to documentation Limited change control GMP requirements Detailed documentation MA holder has access to relevant documentation Full change control

5. Definition of Starting Materials Starting Material Manufacturer Starting material Active substance Starting Material Supplier Starting Material Manufacturer Intermediate Starting Material Manufacturer Errors in communication Not same defined SM Different quality control standards Considers their processes confidential

6. Definition of Starting Materials Formation of stereochemical center All significant impurities from Step 4-6 A or D as Starting Material?

7. Definition of Starting Materials D acceptable as Starting Material provided that: D can be fully identified from tests in the Starting Material specifications. Full control of all potential stereoisomers.

8. Definition of Starting Materials Indicates that A should be defined as Starting Material Stereochemistry controlled by the manufacturing process A or D as Starting Material? E, F etc Identity not fully controlled by Specifications

9. Definition of Starting Materials Second example: Proposed SM Concerns regarding (genotoxic) impurities in Step 4 Indicates that the proposed SM (E) should be redefined to D

10. Definition of Starting Materials Proposed SM Impurities from the manufacture of D should be insignificant. All significant impurities from Step 4-6 Information on the manufacturing process for D important?

11. Definition of Starting Materials Commercial availability: Commodity in a pre-existing, non-pharmaceutical market Chemicals produced by custom synthesis are not considered to be commercially available If a justification is needed, it is most likely not commercially available

12. Definition of Starting Materials Commercial availability: A compound that, based on the manufacturing process, is more expensive to produce by an in-house manufacturing process than to buy from a manufacturer using a “specialised” manufacturing process. Typically manufactured by well established processes

13. Definition of Starting Materials Examples: Purification Starting MaterialActive Substance ”?” One step Insufficient control of impurities Stereochemistry based on SM man. process

14. Definition of Starting Materials Examples: Typical daily dose is 3  g SM Latanoprost Necessity to include a large part of the manufacturing process within GMP?

15. Definition of Starting Materials Examples: BenzydamineSM

16. Definition of Starting Materials Examples: N-nitrosoamine genotoxic? Benzydamine SM Indicates that the N-nitrosoamine and control of related impurities should be included in the manufacturing process. N-nitrosoamine

17. Design Space & Documentation Requirements Chapter 6, 7 & 8 in ICH Q11 Should be read in conjuction with Q8, Q9 & Q10 Guidelines discusses approach, not requirements. Presentation by the ICH Quality Implementation Working Group: http://www.ich.org/uploads/media/Q-IWG_Web_Key_Messages.pdf

18. Design Space & Documentation Requirements What is a design space? ”…the multidimensional combination and interaction of input varables and process parameters that have been demonstrated to provide assurance of quality.””…the multidimensional combination and interaction of input varables and process parameters that have been demonstrated to provide assurance of quality.” Working within a design space is not considered as a change. The Guidelines applicable also to one or two dimensions, e.g. flexibility for one parameter?

19. Design Space & Documentation Requirements What is a design space? Enhanced approach - Operational ranges for one or more process parameters (forms a Design Space.) Traditional approach – Set values for process parameters.

20. Design Space & Documentation Requirements Traditional vs. Enhanced? …4 kg of NH 4 Cl is added to the reaction mixture… …4-5 kg of NH 4 Cl is added to the reaction mixture… …NH 4 Cl is added to the reaction mixture until a pH of 5-6 is obtained… …1-8 kg of NH 4 Cl is added to the reaction mixture… …NH 4 Cl (8 kg MAX) is added to the reaction mixture… …NH 4 Cl is added to the reaction mixture… NH 4 Cl Traditional? Enhanced?

21. Design Space & Documentation Requirements The manufacturer / developer possesses much more knowledge and expertise on their own manufacturing processes than any external reviewer. The intention with the documentation is to convince any external reviewer that the quality control is sufficient. The process description should be still be reproducible.

22. Design Space & Documentation Requirements ICH Quality Implementation Working Group: Design Space need to be clearly presented and justified in regulatory submission Design Space need to be described in sufficient details in regulatory filing Description should include critical and non critical parameters to assure complete understanding Designation of criticality need to be justified in regulatory submission based on QRM and/or experimental results

23. Design Space & Documentation Requirements ICH Quality Implementation Working Group: Critical parameter ranges/model are considered a regulatory commitment and non-critical parameter ranges support the review of the filing Critical parameter changes within design space are handled by the Quality System and changes outside the design space need appropriate regulatory notification Non-critical parameters would be managed by Quality System

24. Design Space & Documentation Requirements Identify Quality Attributes Critical Quality Attributes? Identify potentially Critical Process Parameters Experimental data and/or scientific discussion Critical Process Parameters?

25. Design Space & Documentation Requirements R-enantiomer Quality Attributes: S-enantiomer Potentially Critical Process parameters: Solvent ratio Temperature Critical?- Yes Acceptable limit 0.3%

26. Design Space & Documentation Requirements Process ParameterCritical Attribute Solvent ratioTemperatureS-enantiomer 1:320°C0.13% 3:120°C0.41% 1:360°C0.11% 3:160°C0.43% Design of Experiments at laboratoty scale (10g):

27. Design Space & Documentation Requirements ParametersAttribute Solvent ratioS-enantiomer 1:30.13% 1:20.18% 1:10.25% 2:10.38% Design of Experiments at laboratoty scale (10g):

28. Design Space & Documentation Requirements Design of Experiments at laboratoty scale (10g): Impurity Content (%) Solvent ratio

29. Design Space & Documentation Requirements Parameter Operational Range TargetCriticality Solvent ratio1:3 to 1:11:1Critical Process Parameter Temperature20-60°C25°C Non-Critical Process Parameter Should also be included in S.2.2 Description of Manufacturing Process

30. Design Space & Documentation Requirements Temperature Solvent ratio pH Second example: Design of Experiments for three process parameters S-enantiomer above 0.3% S-enantiomer below 0.3%

31. Design Space & Documentation Requirements Temperature Solvent ratio Second example: Design of Experiments for three process parameters Below 0.3% Above 0.3% Operational boundaries should be included in section S.2.2 and could be presented as a; figure function or range

32. Design Space & Documentation Requirements Full Design of Experiments on laboratory scale (10 g?) Verification on larger scale comparable to commercial scale (100 kg?) –Suitable set of experiments –Equipment comparable to that used at commercial scale –Not necessary to challange the edge of failure

33. Design Space & Documentation Requirements Summary of expectations from the documentation: S.2.6 Manufacturing Process Development Critical & non Critical Quality Attributes Critical & non Critical Process Parameters Based on experimental data unless justified on a rigid scientific discussion Verification on commercial scale S.2.2 Description of Manufacturing Process Criteria for process parameters clearly depicted Specified scale and expected yields

34. Design Space & Documentation Requirements Scope: In order to enhance the manufacturing process... Present: 10 kg of intermediate is dissolved in 100 L of water and 5 kg of reagent is added. The reaction is stirred at 50ºC for 30 minutes. The reaction mixure is extracted with 3 40 L of ethyl acetate… Proposed: The intermediate from last step is dissolved in water followed by addition of reagent (Max. 10 kg). The reaction is stirred until completion. The reaction mixure is extracted with ethyl acetate… Type IB change in the manufacturing process Wrong category Most likely not acceptable

35. Design Space & Documentation Requirements

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