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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 .
• 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 3g
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
?

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