How to Define Design

Space
Lynn Torbeck

Overview

Why is a definition important?

Definitions of Design Space.
Deconstructing Q8 Definition.
Basic science, Cause and Effect
SIPOC Process Analysis
Three Levels of Application.
Case Study with Example.

Why is this Important?

ICH Q8 is in its final version.
Design Space is defined in Q8.
Many presenters are using the term.
All are repeating the same definition.
Many presenters dont understand the
statistical implications of the issue.
Need for a detailed Operational
Definition

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

For all measured quality

characteristics.

Basic Science

Cause ?
Effect

Critical Cause and Effect

1.

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

Conceptual Design Space

Design
Space

Opt

Region of Interest

Region of operability
Uncertain space

Tablet Process Example

Filler

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

Chemical Process Example

Catalyst

10-15 lbs

Temperature

220-240 degrees

Pressure

50-80 lbs

Concentration

10-12%

Yield
Percent converted
Impurity
pH
Color
Turbidity
Viscosity
Stability

Statistical Design Space

The mathematically and
statistically defined combination of
Factor Space and Response Space
that results in a system, product or
process that consistently meets its
quality characteristics, SSQuIP,
with a high degree of assurance.
LDT

Modeling the World

All Models are wrong, but some
are useful. G. E. P. Box
Empirical Models:

Simple linear, y = a + bx
Quadric equation, y = a + bx + cx2

Mechanistic Models:

A physical or chemical equation.

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

The Whole New Product Development Cycle

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

Micro Level View:

Design Space
Independent
Factor
Space

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

AKA, Design Regions

The Cambridge Dictionary of Statistics.

B. S. Everitt, Cambridge University Press

Quick Dry Example

Five batches of product had been
lost to an impurity exceeding the
criteria
The criteria for impurity 1 was NMT
1.0%
Four factors studied.
Four responses.

Quick Dry Example

FACTOR SPACE
Drying time

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

Process understanding is cause and effect quantitated.

We find a mathematical and statistical formula that
describes the relationship between factor space and
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

Time*Temp Interaction Plot

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

DE SIG N- EXP ERT P lot

Im pur it y -1
X = A: Ti me
Y = C : M oistu re

Time* Moisture Interaction

Plot
In t e r a c t io n G r a p h

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

Time*Temp Contour Plot

Desi gn-E xp ert S of twa re
Im pur it y- 1
2 0.7
0 .1
X1 = A : Tim e
X2 = B : Tem pe rat ure
A ctu al Fa c tors
C: Moistu re = 3. 10
D: S olv e nt = 7 .50

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

De si gn-E xper t S of t ware

I mpur it y- 1
20. 7

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

De sign- E xp ert S of twar e

Imp urity -1
De sign P oin ts
20. 7

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

Quick Dry Example

FACTOR SPACE
Drying time

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

f(Xi) Design Space

Impurity =
+0.6079
+Time
*
+Temperature *
+Moisture
*
+Time*Temp *
+Time*Moist *
+Temp*Moist *
+T*T*M
*

-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

Coefficient Factor Level

0.607940
-0.005702
4
-0.005813
70
0.199410
1
0.000614
280
-0.293860
4
-0.005018
70
0.007127
280

Impurity
1.0

Predictive Equation
Factor
Intercept
A-Time
B-Temperature
C-Moisture
AB
AC
BC
ABC

Coefficient Factor Level

0.607940
-0.005702
9
-0.005813
43
0.199410
5
0.000614
387
-0.293860
45
-0.005018
215
0.007127
1935

Impurity
1.0

Des ign-E xpe rt So f twar e

Ov erl ay P lo t
I mpur ity -1
X1 = A : Time
X2 = B : Tem pe ratu re

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

Desi gn-E xper t S of t ware

Ov erl ay P lot
I mpur ity- 1
X1 = A : Time
X2 = B : Tem perat ure

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.

Design Space Conclusions

ICH Q8 and the FDA are asking for
designed experiments and predictive
equations for each aspect of a new
product.
Descriptions need to be mathematical
and statistical equations.
Empirical equations are the most
common, but a few mechanistic
equations may be possible.

Design Space Conclusions

This is a new and perhaps confusing
issue for the pharmaceutical industry.
To implement this approach will require
designed experiments with overlays of
multiple responses for each new
product.
Sometimes retrospective studies of
existing products can be done with
historical data.