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How To Define Design Space: Lynn Torbeck
How To Define Design Space: Lynn Torbeck
How To Define Design Space: Lynn Torbeck
Space
Lynn Torbeck
Overview
Regulatory Impact
Design space is proposed by the
applicant and is subject to regulatory
assessment and approval.
Working within the design space is not
considered a change.
Movement out of the design space is
considered to be a change and would
normally initiate a regulatory post
approval change process.
This is a big deal, it needs to be done
correctly !
The economic impact of this can be huge.
Potential Benefits
Real process understanding and
knowledge, not just tables of raw data.
Reduced rejects, deviations,
discrepancies, lost time, scrap and
rework.
Fewer 483 citations and warning letters.
Fewer investigations and CAPA.
Freedom to operate with design space
ICH Q8 Definition
The multidimensional combination
and interaction of input variables
and process parameters that have
been demonstrated to provide
assurance of quality.
This is not universally understood by all
parties involved. We need to harmonize
several viewpoints, statistical, scientific,
engineering and regulatory.
Deconstructing the
Definition
Need to deconstruct the definition to
get to a day to day working
Operational Definition that can be
implemented.
Need enough detail to write a
Standard Operating Procedure or SOP.
Need to see an example of what it
looks like.
Multidimensional
Also called multivariable or
multivariate
More than one variable at a time is
considered.
The practice of holding the world
constant while only considering onefactor-at-a-time has been shown to
be grossly inefficient and ineffective.
Interaction
Defined in the PAT guidance
Interactions essentially are the
inability of one factor to produce
the same effect on the response at
different levels of another factor.
Interactions are the joint action of
two or more factors working
together.
Example Interaction
ABInteractionEffect
70
A v era g eEffect
60
50
40
ALow
AHigh
30
20
10
0
0.5
1.5
BLowBHi gh
2.5
Input Variables
Input Variables:
The cause
Independent variable
Factor
Output Variables
The effect
Dependent variable
Responses
Assurance of Quality
Assurance is a high probability of
meeting:
Safety
Strength
Quality
Identity
Purity
Basic Science
Cause ?
Effect
3.
5.
Multiple Causes
Effects
R=
Independent
Factors
2.
4.
6.
Dependent
Responses
Design Space
Independent
Factor
Space
Dependent
Response
Space
Design Space
FACTOR SPACE
N dimension Xs
X1
RESPONSE SPACE
M dimension Ys
Y1
X2
Y2
X3
Y3
X4
Y4
X5
Y5
XN
YM
Factor Space
Potential Space Areas that could be
investigated
Uncertain Space Insufficient data for a
decision.
Unacceptable Space Factors and ranges
have been shown to not provide assurance of
SSQuIP.
Acceptable Space Data to demonstrate
assurance of SSQuIP.
Production Space Factors and ranges that
are selected for routine use.
Response Space
Potential space or Region of Interest
Uncertain Space, unknown responses
Unacceptable Space unacceptable
responses
Region of Operability, acceptable
responses
Production Space for manufacturing
Optimal Conditions or Control Space
Design
Space
Opt
Region of Interest
Region of operability
Uncertain space
Lactose
Mannitol
Lubricant
Steraric Acid
Mag Stearate
Disintegrant
Maze Starch
Microcrystalline Cell
Binder
PVP
Gelatine
Intact drug %
Content uniformity
Impurities
Moisture
Disintegration
Dissolution
Weight
Hardness
Friability
Stability
10-15 lbs
Temperature
220-240 degrees
Pressure
50-80 lbs
Concentration
10-12%
Yield
Percent converted
Impurity
pH
Color
Turbidity
Viscosity
Stability
Simple linear, y = a + bx
Quadric equation, y = a + bx + cx2
Mechanistic Models:
Model Prediction
Equations for critical factors and
the mechanistic connection with
the critical responses allow for the
prediction of the quality
characteristics in quantitative
terms.
Multidimensional in factors and
responses.
S.I.P.O.C. Model
Culture
Management
upplier
I nput
upplier
I nput
upplier
I nput
Facilities
Equipment
SPO's
People
rocess
Systems
Regulations
Measurement
Environment
utput
ustomer
utput
ustomer
utput
ustomer
Unknown
Controllable
Factors
Concomitant
Uncontrollable
Factors
Product
Process
Design
Controlled
Responses
Uncontrolled
Responses
Macro View
Mid-Level View
Pre-formulation / formulation studies
Pharmacology / toxicology
Animal studies
Product development
Process development
Clinical trials
Validation and process improvement
Dependent
Response
space
Existing Products
Design Space can be inferred by using
existing information and historical data .
Retrospective process capability studies.
Annual Product Review analysis
Comparison of historical data to specs
Risk management and assessment, Q9
Factor Space
ASTM E1325-2002
That portion of the experiment space
restricted to the range of levels of the
factors to be studied in the experiment
3-9 mins
Drying Temperature
40-100
Excipients Moisture
1.2-5 %
%Solvent
1-14 %
RESPONSE
SPACE
Impurity-1 %
Impurity-2 %
Intact drug %
Final moisture %
Factor Space
B
+1
+1
1.90
3.80
5.20
1.30
15.50
-1
0.70
5.20
0.80
20.70
-1
1.00
-1
1.00
-1
-1
0.80
6.10
-1
0.50
+1
0.60
C
Left Cube Is D = LOW
q62
+1
Right Cube is D = HIGH
A
+1
Design Space
Independent
Factor
Space
f(x)=?
Dependent
Response
space
2 Factor Interaction
Effects to Consider
Time * Temperature
Time * Moisture
Time * Solvent
Temperature * Moisture
Temperature * Solvent
Moisture * Solvent
DES I GN -E XP E RT Pl ot
Im purity - 1
X = A : T im e
Y = B: Te mp erat ure
B - 4 0.00 0
B + 10 0. 000
A ctual F a cto rs
C: Mo istu re = 3.1 0
D: S olv e nt = 7.5 0
In t e r a c t io n G r a p h
B : T e m p e ra t u re
2 0 .7
Im p u rity -1
1 5 .2 8 9 4
9 .8 7 8 8 9
4 .4 6 8 3 4
-0 . 9 4 2 2 2
3 .0 0
4 .5 0
6 .0 0
A : T im e
7 .5 0
9 .0 0
C- 1. 200
C+ 5 .00 0
Ac tua l F actor s
B: Tem p erat ure = 70. 00
D: So lv en t = 7.50
C : M o i st u re
2 0 .7
1 5 .4 3 1 2
Im purity -1
1 0 .1 6 2 4
4 .8 9 3 6 4
-0 . 3 7 5 1 5
3 .0 0
4 .5 0
6 .0 0
A : T im e
7 .5 0
9 .0 0
Imp ur ity -1
X = B: Tem per atur e
Y = C: Mo is ture
Design P oints
C- 1.200
C+ 5. 00 0
Act ual F act ors
A: Time = 6.00
D: S olv ent = 7. 50
C : M o i st u re
2 0 .7
1 5 .2 6 9 7
Im purity -1
DES IGN- EX PE RT P lo t
Temp*Moisture Interaction
Plot
In t e r a c t io n G r a p h
9 .8 3 9 5
4 .4 0 9 2 5
2
-1 . 0 2 1
4 0 .0 0
5 5 .0 0
7 0 .0 0
8 5 .0 0
B : T e m p e ra t u re
1 0 0 .0 0
Impurity-1
100.00
Temp
B : T em perature
85.00
4
70.00
2
55.00
40.00
3.00
4.50
Time
6.00
A: T im e
7.50
9.00
Time*Moisture Contour
Plot
0. 1
X1 = A : Time
X2 = C : Moist ure
A ctu al Fa ctor s
B: T
e m pe rat ure = 70. 00
D: S olv ent = 7.50
Impurity-1
5.00
Moisture
C : M ois ture
4.05
4
3.10
2.15
1
1.20
3.00
4.50
6.00
Time
A: T i m e
7.50
9.00
0. 1
X1 = B : T em pe ratur e
X2 = C: Moi stu re
Act ual F act ors
A: Tim e = 6 .00
D: Solv en t = 7 .50
Impurity-1
5.00
8
4.05
Moisture
C : M oisture
Temp*Moisture Contour
Plot
3.10
2.15
1.20
40.00
Temp
55.00
70.00
B: T em perature
85.00
100.00
Time*Temp Surface
Des ign-E xpe rt So f twar e
I mpur ity -1
20 .7
0. 1
X1 = A : Time
X2 = B : Tem pe ratu re
A ct ual F acto rs
C: Moist ure = 3 .10
D: S olven t = 7 .50
12
Im p u rity-1
100.00
9.00
85.00
7.50
70.00
B: Temperature
6.00
55.00
4.50
40.00
3.00
A: Time
Time*Moisture Surface
De sign- E xp ert S of twar e
Imp urity -1
20. 7
0. 1
X1 = A : T im e
X2 = C: Moi stu re
Act ual F act ors
B: Te mp era ture = 70. 00
D: Solv en t = 7 .50
9.1
Impurity-1
7.025
4.95
2.875
0.8
5.00
9.00
4.05
7.50
3.10
C: Moisture
6.00
2.15
4.50
1.20
3.00
A: Time
Temp*Moisture Surface
Des ign-E xpe rt So f twar e
I mpur ity -1
20 .7
0. 1
X1 = B : Tem pe ratu re
X2 = C: Mo is tu re
A ct ual F acto rs
A : T ime = 6. 00
D: S olven t = 7 .50
12
Im purity-1
5.00
100.00
4.05
85.00
3.10
C: Moisture
70.00
2.15
55.00
1.20
40.00
B: Temperature
3-9 mins
Drying Temperature
40-100
Excipients Moisture
1.2-5 %
%Solvent
1-14 %
RESPONSE
SPACE
Impurity-1 %
Impurity-2 %
Intact drug %
Final moisture %
Conclusions
FACTOR SPACE
Solvent, no effect
Time, decrease
Temp, decrease
Moisture,
decrease
RESPONSE SPACE
Impurity 1
Less than 1%
R2 = 0.95
-0.0057
-0.0058
+0.1994
+0.00061
-0.29386
-0.00502
+0.00713
Goal
Find a set of levels for Time,
Temperature, and Moisture that will
predict impurity of less than 1
percent. (Solvent doesnt matter.)
The combination of levels is the
design space for impurity 1.
Predictive Equation
Factor
Intercept
A-Time
B-Temperature
C-Moisture
AB
AC
BC
ABC
Impurity
1.0
Predictive Equation
Factor
Intercept
A-Time
B-Temperature
C-Moisture
AB
AC
BC
ABC
Impurity
1.0
Design Space
A ct ual F acto rs
C: Moist ure = 5 .00
D: S olven t = 7 .50
Overlay Plot
100.00
B : Temperature
85.00
70.00
55.00
Impurity-1: 1
40.00
3.00
4.50
6.00
A: T i me
7.50
9.00
Design Space
A ctu al Fa ctor s
C: Moistu re = 1. 20
D: S olven t = 7.50
Overlay Plot
100.00
B : Tem perature
85.00
70.00
Impurity-1: 1
55.00
40.00
3.00
4.50
6.00
A: T im e
7.50
9.00
Multidimensional
Specifications
Specifications should not be set one
factor at a time.
We need to consider all responses
together.
We need to do the same analysis for
impurity 2, intact drug and final moisture
and then overlay the four solutions to
find the design space that will meet all of
the criteria at the same time.
Scale-Up
Scale-up may not be linear
Assume that the basic equations will
apply
Assume the design space will be
somewhat robust and rugged.
Need to do confirmation
experiments to confirm assumptions.
Or reestablish the design space.