ICH Q11 – Definisjon av startmaterialer – Fleksibilitet og dokumentasjonskrav Andreas Sundgren LMI 17. april 2012 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. 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 . • No GMP requirements • No detailed description • MA holder might have limited access to documentation • Limited change control Starting Material • GMP requirements • Detailed documentation • MA holder has access to relevant documentation • Full change control Active Substance Definition of Starting Materials Different quality control standards Not same defined SM Starting Material Manufacturer Starting Material Manufacturer Intermediate Starting Material Manufacturer Errors in communication Considers their processes confidential Starting material Starting Material Supplier Active substance Definition of Starting Materials A or D as Starting Material? Formation of stereochemical center All significant impurities from Step 4-6 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. Definition of Starting Materials A or D as Starting Material? Stereochemistry controlled by the manufacturing process Indicates that A should be defined as Starting Material Identity not fully controlled by Specifications E, F etc Definition of Starting Materials Second example: Indicates that the proposed SM (E) should be redefined to D Concerns regarding (genotoxic) impurities in Step 4 Proposed SM Definition of Starting Materials Impurities from the manufacture of D should be insignificant. Proposed SM Information on the manufacturing process for D important? All significant impurities from Step 4-6 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 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 Definition of Starting Materials Examples: Insufficient control of impurities R 4 R 5 H 3C H 3C Stereochemistry based on SM man. process ”?” R R R 3 One step R 2 1 Starting Material R R 3 2 1 Active Substance Purification Definition of Starting Materials Examples: O CH3 O HO CH3 SM HO HO Latanoprost Necessity to include a large part of the manufacturing process within GMP? Typical daily dose is 3g Definition of Starting Materials Examples: SM Benzydamine Definition of Starting Materials Examples: N-nitrosoamine genotoxic? Indicates that the N-nitrosoamine and control of related impurities should be included in the manufacturing process. SM N-nitrosoamine Benzydamine 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 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.” • 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? 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. Design Space & Documentation Requirements Traditional vs. Enhanced? NH4Cl • …4 kg of NH4Cl is added to the reaction mixture… • …4-5 kg of NH4Cl is added to the reaction mixture… • …NH4Cl is added to the reaction mixture until a pH of 5-6 is obtained… Traditional? • …1-8 kg of NH4Cl is added to the reaction mixture… • …NH4Cl (8 kg MAX) is added to the reaction mixture… • …NH4Cl is added to the reaction mixture… Enhanced? 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. 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 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 Design Space & Documentation Requirements Identify Quality Attributes Critical Quality Attributes? Identify potentially Critical Process Parameters Experimental data and/or scientific discussion Critical Process Parameters? Design Space & Documentation Requirements R-enantiomer Potentially Critical Process parameters: •Solvent ratio •Temperature Quality Attributes: •S-enantiomer Critical?- Yes Acceptable limit 0.3% Design Space & Documentation Requirements Design of Experiments at laboratoty scale (10g): Process Parameter Critical Attribute Solvent ratio Temperature S-enantiomer 1:3 20°C 0.13% 3:1 20°C 0.41% 1:3 60°C 0.11% 3:1 60°C 0.43% Design Space & Documentation Requirements Design of Experiments at laboratoty scale (10g): Parameters Attribute Solvent ratio S-enantiomer 1:3 0.13% 1:2 0.18% 1:1 0.25% 2:1 0.38% Design Space & Documentation Requirements Design of Experiments at laboratoty scale (10g): Impurity Content (%) 0.4 0.3 0.2 0.1 0 10:30 10:20 Solvent ratio 10:10 20:10 Design Space & Documentation Requirements Parameter Operational Range Target Criticality Solvent ratio 1:3 to 1:1 1:1 Temperature 20-60°C 25°C Critical Process Parameter Non-Critical Process Parameter Should also be included in S.2.2 Description of Manufacturing Process Design Space & Documentation Requirements Second example: Design of Experiments for three process parameters Solvent ratio S-enantiomer above 0.3% S-enantiomer below 0.3% Temperature Design Space & Documentation Requirements Solvent ratio Second example: Design of Experiments for three process parameters Operational boundaries should be included in section S.2.2 and could be presented as a; Above 0.3% • figure • function Below 0.3% or • range Temperature 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 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 Design Space & Documentation Requirements Wrong category Type IB change in the manufacturing process 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… Most likely not acceptable 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… Design Space & Documentation Requirements Design Space & Documentation Requirements ?