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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 .
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
Definition of Starting Materials
Starting Material
Manufacturer
Starting material
Active substance
Starting Material Supplier
Starting Material
Manufacturer
IntermediateStarting Material
Manufacturer
Errors in communication
Not samedefined SM
Different quality control standards
Considers their processes confidential
Definition of Starting Materials
Formation of stereochemical center
All significant impurities from Step 4-6
A or D as Starting Material?
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
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
Definition of Starting MaterialsSecond example:
Proposed SM
Concerns regarding (genotoxic) impurities in Step 4
Indicates that the proposed SM (E) should be redefined to D
Definition of Starting Materials
Proposed SMImpurities from the manufacture of D should be insignificant.
All significant impurities from Step 4-6
Information on the manufacturing process for D important?
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:
Purification
Starting Material Active Substance
”?” One step
R4
R1
R2
R3
CH3
R5
R1
R2
R3
CH3
Insufficient control of impurities
Stereochemistry based on SM man. process
Definition of Starting Materials
Examples:
Typical daily dose is 3g
SM
Latanoprost
O CH3
O CH3
OH
OH
OH
Necessity to include a large part of the manufacturing process within GMP?
Definition of Starting Materials
Examples:
BenzydamineSM
Definition of Starting Materials
Examples: N-nitrosoamine genotoxic?
BenzydamineSM
Indicates that the N-nitrosoamine and control of related impurities should be included in the manufacturing process.
N-nitrosoamine
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?
• …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…
• …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…
NH4Cl
Traditional?
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 RequirementsICH 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 RequirementsICH 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
Quality Attributes:• S-enantiomer
Potentially Critical Process parameters:• Solvent ratio• Temperature Critical?- Yes
Acceptable limit 0.3%
Design Space & Documentation Requirements
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 of Experiments at laboratoty scale (10g):
Design Space & Documentation Requirements
Parameters Attribute
Solvent ratio S-enantiomer
1:3 0.13%
1:2 0.18%
1:1 0.25%
2:1 0.38%
Design of Experiments at laboratoty scale (10g):
10:30 10:20 10:10 20:100
0.1
0.2
0.3
0.4
Design Space & Documentation Requirements
Design of Experiments at laboratoty scale (10g):
Impu
rity
Con
tent
(%)
Solvent ratio
Design Space & Documentation Requirements
Parameter Operational Range Target Criticality
Solvent ratio 1:3 to 1:1 1:1 Critical Process Parameter
Temperature 20-60°C 25°C Non-Critical Process Parameter
Should also be included in S.2.2 Description of Manufacturing Process
Design Space & Documentation Requirements
Temperature
Sol
vent
ratio
pH
Second example: Design of Experiments for three process parameters
S-enantiomer above 0.3%
S-enantiomer below 0.3%
Design Space & Documentation Requirements
Temperature
Sol
vent
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
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 RequirementsSummary 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
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
Design Space & Documentation Requirements
Design Space & Documentation Requirements
?