1. FMEA
DoE
PAT
Three Inseparable Organs of
Quality Risk Management Body
SHIVANG CHAUDHARY
Formulation Scientist (Pharma-QbD Associate)
M.S. Pharm (Pharmaceutics)- NIPER
P.G.D (Patents Law)- NALSAR
Email ID: shivaniper@gmail.com
Contact No: +91-9904474045
© Copyrighted by Shivang Chaudhary

2. QRM/QbD
EXAMPLE
FROM PHARMA
INDUSTRY
Generic Immediate Release
Uncoated Scored Tablet
© Copyrighted by Shivang Chaudhary€€

3. Define QTPP (Quality Target Product Profile)
QUALITY TARGET
PRODUCT PROFILE
On the basis of THERAPEUTIC EQUIVALENCE for Generic Drug Product
= PHARMACEUTICAL EQUIVALENCE (same dosage form, route of administration, strength & same quality)
+ BIO-EQUIVALENCE (same pharmacokinetics in terms of Cmax, AUC to reference product)
Determine CQAs (Critical Quality Attributes)
CRITICAL QUALITY
ATTRIBUTES
Considering QUALITY [Assay, Uniformity of Dosage units,], SAFETY [Impurities (Related substances),
Residual Solvents, Microbiological limits], EFFICACY [Dissolution & Absorption] &
MULTIDISCIPLINARY [Patient Acceptance & Compliance]
Quality Risk Assessment of CMAs & CPPs by
DESIGN OF
EXPERIMENTS
PROCESS
ANALYTICAL
TECHNOLOGY
CONTROL
STRATEGY
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
(1) RISK IDENTIFICATION: by Ishikawa Fishbone
(2) RISK ANALYSIS by Relative Risk based Matrix Analysis
(3) RISK EVALUATION by Failure Mode Effective Analysis
DoE & Generation of Design Space
DoE
For SCREENING & OPTIMIZATION of CMAs & CPPs with respect to CQAs by
superimposing contour plot to generate OVERLAY PLOT (Proven acceptable
Ranges & Edges of failure ) based upon desired ranges of Responses
PAT
Development of PAT System
For continuous automatic analyzing & controlling critical processing through timely
measurements of CMA & CPAS by INLINE ANALYZERS WITH AUTO SENSORS with the
ultimate goal of consistently ensuring finished product quality with respect to desired CQAs
Implementation of Control Strategy
For CONTROLS OF CMAs, CPPs within Specifications, by Real Time Release
Testing, Online Monitoring System * Inline PAT Analyzers [based upon previous
results on development, Scale Up. Exhibit/ Validation batches]
Continual Improvement
CONTINUAL
IMPROVEMENT
FMEA
based upon CONTINUAL RISK REVIEW & RISK COMMUNICATION
BETWEEN PLANT, QA, QC, RA, R&D, AR&D during routine
commercial manufacturing experience
© Copyrighted by Shivang Chaudhary
<<(QRM)>>

4. PHARMACIST’S
POINT OF VIEW
QUALITY TARGET
PRODUCT PROFILE
PHYSICIAN’S
POINT OF VIEW
PATIENT’S POINT
OF VIEW
QTPP Element
Dosage FORM
© Copyrighted by Shivang Chaudhary
PROCESS
ANALYTICAL
TECHNOLOGY
Oral
Dosage STRENGTH
DESIGN OF
EXPERIMENTS
Immediate Release Uncoated Tablet
ROUTE of Administration
RISK ASSESSMENT
OF CMAS & CPPS
Tablet
Dosage DESIGN
CRITICAL QUALITY
ATTRIBUTES
Target
x mg
Drug Product
QUALITY
ATTRIBUTES
Description
Assay
Uniformity
Impurities
Dissolution
Microbiological
Limits
Water Content
Residual Solvents
PRIMARY PACKAGING
QTPP Element
Pharmaco-KINETICS
QTPP Element
CONTROL
STRATEGY
EASE OF STORAGE &
DISTRIBUTION
STABILITY & SHELF LIFE
CONTINUAL
IMPROVEMENT
PATIENT ACCEPTANCE &
PATIENT COMPLIANCE
Justification
Pharmaceutical equivalence requirement:
same dosage form
Immediate release design needed to meet
label claims
Pharmaceutical equivalence requirement:
same route of administration
Pharmaceutical equivalence requirement:
same strength
Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable
reference standards (i.e., identity, assay, purity and quality).
Plastic Container & Closure/ Metal Blister system
Needed to achieve the target shelf-life and
should be qualified as suitable for drug product with
to ensure product integrity during shipping
desired appropriate compatibility & stability
Target
Fasting Study and Fed BE Study
90 % confidence interval of the PK parameters,
AUC0-2, AUC2-24, AUC0-∞ and Cmax, should fall
within bioequivalence limits of 80-125
Justification
Bioequivalence requirement needed to
ensure rapid onset and efficacy
Target
Justification
Can be stored at real time storage condition as a
normal practice with desired stability & can be
Required to handle the product easily
distributed from the manufacturer to end user same
with suitable accessibility
as per Reference Product.
Should be stable against hydrolysis, oxidation, photo
Equivalent to or better than
degradation & microbial growth. At least 24-month
Reference Product shelf-life
shelf-life is required at room temperature
Should be suitably flavored & colored for possessing
acceptable taste ( in case of soluble/ dispersible/
Required to achieve the desired patient
effervescent tablet) similar with Reference Product.
acceptability & suitable compliance
Can be easily administered/used similar with
Reference Product labeling
© Copyrighted by Shivang Chaudhary

5. MULTIDIS
CIPLINARY
QUALITY TARGET
PRODUCT PROFILE
Quality Attributes of
Drug Product
QUALITY
SAFETY
EFFICACY
Yes
Size
Similar to reference product
No
Scored
Yes*
Identification
Positive for drug
Yes*
Assay
90.0 to 110.0 % of labeled claim.
Yes
Assay variability will affect safety and efficacy. Process variables may affect the
assay of the drug product. Thus, assay will be evaluated throughout formulation
and process development.
Yes
Variability in content uniformity will affect safety and efficacy. Both formulation
and process variables impact content uniformity, so this CQA will be evaluated
throughout formulation and process development.
Yes
if drug is sensitive to moisture, it will impact stability & ultimately safety &
efficacy. If drug is not sensitive to moisture, it will not impact stability
Physical
Attribut
es
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
PROCESS
ANALYTICAL
TECHNOLOGY
Color and shape should acceptable to
the patient. No visual tablet defects
should be observed.
Score
configuration
DESIGN OF
EXPERIMENTS
Is this a
CQA?
Appearance
CRITICAL QUALITY
ATTRIBUTES
Target
Conforms to USP <905> Uniformity of
Weight Variation/
Dosage Units: 90.0-110.0 % of
Content Uniformity labeled claim with Acceptance Value:
NMT 15.0; RSD : NMT 5.0%
Water Content
Impurities
As per In house specification
according to stability data
As per ICH Q3A& Q3B
Yes
Justification
Color, shape and appearance are not directly linked to safety and efficacy.
Therefore, they are not critical. But to ensure patient acceptability it should be
similar with reference product
For comparable ease of swallowing as well as patient acceptance and
compliance with treatment regimens, the target for tablet dimensions is set
similar to the reference product
If reference product is a scored tablet; then, the generic tablet should be
scored. Score configuration is also critical for half-dosing & ease of splitting for
generic drug product design..
Though identification is critical for safety and efficacy, this CQA can be
effectively controlled by the quality management system and will be monitored
at drug product release. Formulation and process variables do not impact
identity. Therefore, this CQA will not be discussed during formulation and
process development.
Degradation products can impact safety and must be controlled based on
compendial/ICH requirements or reference product characterization to limit
patient exposure. The limit for total impurities is also based on reference
product analysis. The target for any unknown impurity is set according to the
ICH identification threshold for this drug product. Formulation and process
variables can impact degradation products. Therefore, degradation products will
be assessed during product and process development.
Residual solvents can impact safety, but as it will be primarily controlled during
drug substance & drug product manufacturing by drying, so Formulation and
process variables are unlikely to impact this CQA.
CONTINUAL
IMPROVEMENT
Residual Solvents
Conforms to USP <467> option 1
Yes*
Microbiological
Limits
CONTROL
STRATEGY
Conforms to USP <61 & 62>
Yes*
Non-compliance with microbial limits will impact patient safety, but as it will be
primarily controlled during drug substance & drug product manufacturing, so
formulation and process variables are unlikely to impact this CQA.
Dissolution
NLT X % (Q) of labeled amount of
drug is dissolved in y Minutes in pH Z
buffer, 900 ml, Apparatus I/II,
50/100 rpm.
Yes
Failure to meet the dissolution specification can impact bioavailability (efficacy).
Both formulation and process variables affect the dissolution profile. This CQA
will be investigated throughout formulation and process development.
© Copyrighted by Shivang Chaudhary

6. RISK
IDENTIFICATION
QUALITY TARGET
PRODUCT PROFILE
RISK
ANALYSIS
RISK
EVALUATION
CRITICAL QUALITY
ATTRIBUTES
GRANULATION &
DRYING
RISK ASSESSMENT
OF CMAS & CPPS
PROCESS
ANALYTICAL
TECHNOLOGY
© Copyrighted by Shivang Chaudhary
DESIGN OF
EXPERIMENTS
IMPELLER/ MIXER SPEED
CHOPPER/GRANULATOR SPEED
COMPRESSION
LIQUID ADDITION RATE
FEEDER SPEED
TOTAL GRANULATION TIME
PRESS TURRET SPEED
ENVIRONMENT
PRECOMPRESSION FORCE
TEMPERATURE
FLUIDIZATION AIR VELOCITY
COMPRESSION FORCE
RELATIVE
HUMIDITY
ATOMIZATION AIR PRESSURE
INLET AIR TEMPERATURE
API PSD & SOLUBILITY
MILLING SPEED
INLET AIR TEMPERATURE
ATOMIZATION PRESSURE
DILUENT PSD & LOD
MILLING SCREEN SIZE
(SIEVE NO:ASTM/BSS#)
SOLUTION SPRAYING RATE
COATING PAN SPEED
SOLUTION CONC.
BINDER TYPE & CONC.
BLENDER SPEED-RPM
BLENDING TIME
DISINTEGRANT CONC.
LUBRICANT CONC.
RAW
MATERIAL
SIZING &
BLENDING
COATING
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

7. RISK
IDENTIFICATION
QUALITY TARGET
PRODUCT PROFILE
RISK
ANALYSIS
RISK
EVALUATION
CRITICAL QUALITY
ATTRIBUTES
RISK ASSESSMENT
OF CMAS & CPPS
PROCESS
ANALYTICAL
TECHNOLOGY
© Copyrighted by Shivang Chaudhary
DESIGN OF
EXPERIMENTS
Physical
Assay
Uniformity
Impurities
Dissolution
Particle
size
Low
Low
High
Medium
High
Flow
Properties
Low
Low
High
Low
Low
FP CQAs
Diluent
Binder
Physical
Assay
Uniformity
Impurities
Dissolution
Low
Medium
High
Medium
Low
Low
Low
Low
Low
High
FP CQAs
Residual
Solvent
Low
Low
Low
Medium
Low
Granulating
Disintegrant
Agent
Low
Low
Low
Low
Low
Low
Low
Low
High
High
Solid state
Solubility
/Polymorph
High
Low
Low
Low
Low
Low
Low
Low
High
High
Wetting
Agent
Low
Low
Low
Medium
High
Glidant
Low
Low
High
Medium
Low
Process
Impurity
Low
High
Low
High
Low
Antiadherant
High
Low
Low
Low
High
Chemical
Stability
Low
High
Low
High
Low
Lubricant
High
Low
Low
Low
High
CMAs of Inactive Ingredient
(Excipients)
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
Moisture
content
Low
Low
Low
Medium
Low
Low
Medium
High
Broadly acceptable risk. No further investigation is needed
Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
Risk is unacceptable. Further investigation is needed to reduce the risk.
© Copyrighted by Shivang Chaudhary
CRITICAL MATERIAL
ATTRIBUTES (CMAs)
CMAs of Active Pharmaceutical
Ingredient (API)

8. QUALITY TARGET
PRODUCT PROFILE
PhysicoChemical
Property of
Actives
Failure
Mode
(Critical
Event)
Solid Sate
Form
CRITICAL QUALITY
ATTRIBUTES
Critical
Material
Attribute
(CMAs)
Different
Polymorph/
form
CONTROL
STRATEGY
© Copyrighted by Shivang Chaudhary
PROCESS
ANALYTICAL
TECHNOLOGY
High water
content
Hygroscopicity
High water
content
Residual Solvents
High residual
solvent
Solubility
Chemical
Property
Poor flow
Different Salt/
Form
Process
Impurities
Less Purity
Chemical
Stability
DESIGN OF
EXPERIMENTS
Flow
Properties
Moisture content
Physical
Property
RISK
EVALUATION
Effect on IP & FP CQAs with respect to
QTPP (Justification of Failure Mode)
Particle Size
Higher PSD
Distribution (PSD)
RISK ASSESSMENT
OF CMAS & CPPS
RISK
ANALYSIS
poor
Different Solubility of drug substance=
Dissolution of drug product may be affected=
Bioavailability/Efficacy may got compromised
BCS Class II/IV drug = Dissolution of drug product can
be affected= Bioavailability/Efficacy
may got compromised
Poor blend uniformity in simple dry mixing process=
uncertainty in uniformity of dosage units due to
possible segregation = Quality may got compromised
Rate of degradation may be affected
= Impurity profile may be affected
= Safety may got compromised
Rate of degradation may be affected
= Impurity profile may be affected
= Safety may got compromised
Residual solvents are likely to interact with drug
substance= Impurities may be affected
= Safety may got compromised
Dissolution of the drug product can be affected =
Bioavailability/Efficacy may got compromised
Assay & impurity profile of drug product may be
affected = Quality & Safety may got compromised
Susceptible to dry heat/oxidative/hydrolytic/UV light
degradation- impurity profile may get affected =
Quality & Safety may got compromised
Probability*
Severity**
Detect ability***
Very Unlikely
Occasional
Repeated
Regular
Minor
Moderate
Major
Extreme
Always Detected
Regularly Detected
Likely not Detected
Normally not Detected
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary
S
P
D
RPN
(=S*P*D)
4
4
4
64
4
4
4
64
4
4
3
48
3
2
2
12
3
2
2
12
3
2
2
12
3
2
3
18
3
2
3
18
3
2
3
18
Score
01
02
03
04
FMEA of Active’s CMAs
RISK
IDENTIFICATION

9. QUALITY TARGET
PRODUCT PROFILE
Critical
Excipient
Material
(Inactive
Attribute
ingredient)
(CMAs)
CRITICAL QUALITY
ATTRIBUTES
Particle Size
Distribution
Failure
Mode
(Critical
Event)
Uneven
Diluent
Moisture Content High
DESIGN OF
EXPERIMENTS
PROCESS
ANALYTICAL
TECHNOLOGY
CONTROL
STRATEGY
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
More than
optimum
Binder/
Granulating
agent
Amount of
Binder
Disintegrant
Amount of
Disintegrant
Less than
optimum
Glidant
Concentration of
Glidant
Less than
optimum
Anti-adherant
Concentration of
Anti-adherant
Less than
optimum
Lubricant
Coloring/
Flavor/
Sweetener
agent
Concentration of
Lubricant
Concentration
Less than
optimum
Less than
optimum
Higher than
Optimum
Lower than
optimal
Higher than
optimum
RISK
ANALYSIS
Effect on IP & FP CQAs with respect
to QTPP (Justification of Failure
Mode)
Flow properties of the blend may be affected (in dry
mixing process) = Uniformity of dosage units may be
affected = Quality/ Safety may got compromised
Impurity profile may be affected (in case of
moisture sensitive drugs) = Safety may got
compromised
Produces hard granules= Produces tablet / capsule
with greater disintegration time & retarded
dissolution= Efficacy may got compromised
Loose granules will be formed, which may produce
friable Tablet = Patient acceptance/ Patient
compliance got compromised
Desired Dissolution cannot be achieved (in case of
immediate release product)
= Efficacy may got compromised
Flow of granules or powder from hopper to die by
reducing friction between particles may be affected =
= Uniformity of dosage units may affected
=Quality may got compromised
Ejection of finished product from tooling may be
difficult= Material get stuck to the surface of filling
die= Sticking may be observed = patient acceptance/
compliance may got compromised
Material get stuck to the surface of punches/toolings
= Picking may be observed = Patient acceptance/
compliance may got compromised
Hydrophobic lubricant may surface coat the drug
particle = dissolution may got retarded = Efficacy
may got compromised
Shade variation/ Mottling may be observed =
Patient compliance may got compromised
Safety may got compromised
Probability*
CONTINUAL
IMPROVEMENT
RISK
EVALUATION
Severity**
Detect ability***
Very Unlikely
Occasional
Repeated
Regular
Minor
Moderate
Major
Extreme
Always Detected
Regularly Detected
Likely not Detected
Normally not Detected
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
© Copyrighted by Shivang Chaudhary
S
P
D
RPN
(=S*P*D)
3
3
2
18
3
3
2
18
4
4
2
32
4
4
2
32
4
4
2
32
3
3
2
18
3
3
2
18
3
3
2
18
3
3
3
27
3
3
1
9
3
3
3
27
Score
01
02
03
04
FMEA of In active's CMAs
RISK
IDENTIFICATION

10. RISK
IDENTIFICATION
QUALITY TARGET
PRODUCT PROFILE
RISK
ANALYSIS
RISK
EVALUATION
CRITICAL QUALITY
ATTRIBUTES
PROCESS
ANALYTICAL
TECHNOLOGY
CPPs of Wet
Granulation Process
FP CQAs
Co-sifting
Blending
Description
Assay
Impurities
Uniformity
Dissolution
Low
Medium
Low
Medium
Low
Low
High
Low
High
Low
Rapid Mixing
Granulation
Low
Low
Low
Low
High
Fluid Bed
Drying
Low
Low
High
Low
Low
Sizing
High
Medium
Low
Medium
Low
Lubrication Compression
High
High
Low
High
High
High
Low
Low
High
High
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
Low
Medium
High
Broadly acceptable risk. No further investigation is needed
Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
Risk is unacceptable. Further investigation is needed to reduce the risk.
© Copyrighted by Shivang Chaudhary
CRITICAL PROCESSING
PARAMETERS (CPPs)
DESIGN OF
EXPERIMENTS
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS

11. QUALITY TARGET
PRODUCT PROFILE
Unit
Operations
Critical Process
Parameter
(CPPs)
Sifting
CRITICAL QUALITY
ATTRIBUTES
Sifting
Dry Mixing
DESIGN OF
EXPERIMENTS
PROCESS
ANALYTICAL
TECHNOLOGY
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
Granulation in
Rapid Mixer
Granulator
Drying in Fluid
Bed Drier
Sizing
(Milling &
Screening)
Lubrication &
Blending
Compression /
Filling
Coating
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
Rate of
Impeller / Mixer
Rate of Chopper/
Granulator
Binder-Granulating
agent spraying rate
Inlet
Temperature
Fluidizing Air
Flow rate
RISK
EVALUATION
Failure Mode
Effect on IP & FP CQAs with respect to
(Critical
QTPP (Justification of Failure Mode)
Event)
Larger
Sieve size.
Lower RPM &
Shorter Time
High RPM &
Longer Time
Low RPM &
Shorter Time
High RPM
High Product
Temperature
Higher CFM
Comil Speed
Increase Speed
Comil Screen
Larger # Size
Blending Rate
High RPM &
High Time
Turret/
Feeder Speed
Compression Force
/Tamping force
Bed Temperature
Spraying rate
Atomizing Pressure
RISK
ANALYSIS
High Speed
High Force
High Temp.
Higher Rate
Lower pressure
S
P
D
RPN
(=S*P*D)
Uneven PSD = Uncertainty in Uniformity
02
02
03
12
Lesser No. of total Revolutions =
Uncertainity in Uniformity
02
02
03
12
04
04
03
64
04
04
03
48
04
04
03
48
02
02
03
12
02
02
03
12
02
02
03
12
02
02
03
12
02
02
03
12
04
03
03
36
04
03
02
24
02
03
02
02
03
02
03
01
01
12
09
04
Produce Larger granules (forms
agglomerate/lumps)= Dissolution of Tablet /
Capsule can be increased= Efficacy/
Bioavailability may got compromised
Rate of degradation may be affected =
Impurity profile may be affected
Increased attrition & evaporation produces
fines = process efficiency may be compromised
Fines may be generated = Poor flow leads to
uncertainty in uniformity of dosage units
Uneven PSD leads to uncertainty in Uniformity
Larger granules = Dissolution may be increased
Increase No. of total Revolutions =
Dissolution may be increased
Weight Variation may be observed=
Uniformity of dosage units may be bargained
Hardness of Tablet/ Slug will be increased =
Disintegration/ Dissolution may be increased
Impurity profile affected
Appearance affected
Appearance affected
Probability*
Severity**
Detect ability***
Very Unlikely
Occasional
Repeated
Regular
Minor
Moderate
Major
Extreme
Always Detected
Regularly Detected
Likely not Detected
Normally not Detected
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
© Copyrighted by Shivang Chaudhary
Score
01
02
03
04
CRITICAL PROCESSING
PARAMETERS (CPPs)
RISK
IDENTIFICATION

12. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
DESIGN
SPACE
FOR OPTIMIZATIONS OF
IR TABLET FORMULATION &
KNEADING IN GRANULATION PROCESS
CRITICAL QUALITY
ATTRIBUTES
NO. OF FACTORS: 3
NO. OF LEVEL: 3
CMAs
DESIGN OF
EXPERIMENTS
PROCESS
ANALYTICAL
TECHNOLOGY
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CPP
CQAs
Factor 1
Factor 2
Factor 3
Response 1
A:
B:
C:KNEADING
BINDER DISINTEGRANT
Time
HARDNESS
(in %)
(in %)
(in minutes)
(in N)
4
3
2
46
4
5
4
52
4
1
4
55
4
3
6
58
7
3
4
70
7
1
6
72
7
3
4
68
7
3
4
70
7
3
4
72
7
3
4
68
7
1
2
65
7
5
2
62
7
5
6
74
10
3
6
92
10
5
4
86
10
3
2
83
10
1
4
88
Response 2
Response 3
Response 4
DISINTEGRATION
DRUG
FRIABILITY
TIME
DISSOLVED
(in %)
(in min)
(in %)
0.24
5
95
0.21
5
97
0.18
9
87
0.16
7
91
0.11
6
99
0.10
11
90
0.10
6
100
0.12
6
97
0.09
6
100
0.08
6
99
0.13
10
92
0.14
5
98
0.09
6
95
0.06
9
82
0.07
4
89
0.08
8
88
0.08
12
86
DESIGN: BOX-BEHNKEN
TOTAL RUNS: 17
ORDER: QUADRATIC
MODEL: POLYNOMIAL
© Copyrighted by Shivang Chaudhary

13. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
DESIGN: BOX-BEHNKEN
CRITICAL QUALITY
ATTRIBUTES
DESIGN
SPACE
NO. OF FACTORS :3
NO. OF LEVELS :3
TOTAL RUNS
:17
(0,+1,+1)
(-1,0,+1)
PROCESS
ANALYTICAL
TECHNOLOGY
0
(7%)
(0,-1,+1)
(+1,+1,0)
(-1,+1,0)
BINDER (in %w/w)
DESIGN OF
EXPERIMENTS
+1
(10%)
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
(+1,0,+1)
(0,0,0)
(+1,-1,0)
(-1,-1,0)
+1 (6 min)
(0,+1,-1)
0 (4 min)
(-1,0,+1)
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
-1
(4%)
(+1,0,-1)
-1 (2 min)
(0,-1,-1)
SUPER DISINTEGRANT (in % w/w/)
-1
(1%)
0
(3%)
© Copyrighted by Shivang Chaudhary
x
+1
(5%)

14. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
CRITICAL QUALITY
ATTRIBUTES
Analysis of Variance (ANOVA)
For Each factor, their
interactions & curvatures on
Individual Response
RISK ASSESSMENT
OF CMAS & CPPS
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
DESIGN
SPACE
Predicted Effect Equation
of Each factor, their
interactions & curvatures
on Individual Response
© Copyrighted by Shivang Chaudhary
PROCESS
ANALYTICAL
TECHNOLOGY
HARDNESS =
+69.60+17.25A-0.75B+5.00C+0.25AB-0.75AC+1.25BC
+1.08A2-0.42B2-0.93C2
Model F-value: 27.49
Model Value: Significant
Significant Model Terms: A, C, A2
FRIABILITY =
+0.100-0.063A+2.500E-003B-0.023C-0.010AB+
0.015AC-5.000E-003BC+0.027A2+7.500E-003B2+7.500E-003C2
Model F-value: 37.34
Model Value: Significant
Significant Terms: A,B,C, AB, B2, C2
DISINTEGRATION TIME =
+6.00+0.87A-2.75B+0.63C-1.00AB-0.25AC+0.000BC
+0.37A2+1.13B2+0.88C2
Model F-value: 23.67
Model Value: Significant
Significant Terms: A,B,C, A2, B2, C2
DESIGN OF
EXPERIMENTS
Model F-value: 128.93
Model Value: Significant
Significant Model Terms: A, C
DRUG DISSOLVED =
+99.00-3.12A+3.00B-1.88C-1.75AB-0.50AC-0.25BC
-7.00A2-2.25B2-3.00C2
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

15. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
DESIGN
SPACE
2D Contour plots Plots for Individual Responses with respect to Binder(A) & Kneading Time(C)
2D CONTOUR
PLOTS
CRITICAL QUALITY
ATTRIBUTES
PROCESS
ANALYTICAL
TECHNOLOGY
3D RESPONSE
SURFACE PLOTS
3D Response Surface Methodology (RSM) Plots for Individual Responses with respect to Binder(A) & Kneading Time (C)
4D Cube Plots for Individual Responses with respect to Binder(A) & Kneading Time(C)
4D CUBE
PLOTS
DESIGN OF
EXPERIMENTS
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

16. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
Factors (Variables)
A
BINDER (%)
B
DISINTEGRANT (%)
C
KNEADING TIME (min)
Responses (Effects)
Y1
HARDNESS (N)
Y2
FRIABILITY (%)
Y3
DISINTEGRATION (min)
Y4
DISSOLUTION (%)
CRITICAL QUALITY
ATTRIBUTES
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
Levels of Factors studied
0
5%w/w
3%w/w
4min
Goal for Individual Responses
To achieve tablet hardness in the range from 60 to 80N
To achieve minimum friability nearest to 0.00%
To achieve tablet DT in the range from 5 to 10 minutes
To achieve maximum dissolution nearest to 100%
-1
3%w/w
1%w/w
2min
DESIGN
SPACE
+1
7%w/w
5%w/w
6min
PROCESS
ANALYTICAL
TECHNOLOGY
OVERLAY PLOT WITH
SWEET SPOT
DESIGN OF
EXPERIMENTS
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

17. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
DESIGN
SPACE
2D Contour plots Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B)
2D CONTOUR
PLOTS
CRITICAL QUALITY
ATTRIBUTES
PROCESS
ANALYTICAL
TECHNOLOGY
3D RESPONSE
SURFACE PLOTS
3D Response Surface Methodology (RSM) Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B)
4D Cube Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B)
4D CUBE
PLOTS
DESIGN OF
EXPERIMENTS
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

18. EXPERIMENTAL
DESIGN
QUALITY TARGET
PRODUCT PROFILE
Factors (Variables)
A
BINDER (%)
B
DISINTEGRANT (%)
C
KNEADING TIME (min)
Responses (Effects)
Y1
HARDNESS (N)
Y2
FRIABILITY (%)
Y3
DISINTEGRATION (min)
Y4
DISSOLUTION (%)
CRITICAL QUALITY
ATTRIBUTES
ANOVA
DIAGNOSTICS
MODEL
GRAPHS
Levels of Factors studied
0
5%w/w
3%w/w
4min
Goal for Individual Responses
To achieve tablet hardness in the range from 60 to 80N
To achieve minimum friability nearest to 0.00%
To achieve tablet DT in the range from 5 to 10 minutes
To achieve maximum dissolution nearest to 100%
-1
3%w/w
1%w/w
2min
DESIGN
SPACE
+1
7%w/w
5%w/w
6min
PROCESS
ANALYTICAL
TECHNOLOGY
OVERLAY PLOT WITH
SWEET SPOT
DESIGN OF
EXPERIMENTS
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

19. PAT FOR
TABLET MANUFACTURING LINE
QUALITY TARGET
PRODUCT PROFILE
CRITICAL QUALITY
ATTRIBUTES
API / EXCIPIENT
PURITY by In Line
BRUKER FT-NIR
API / EXCIPIENT PARTICLE
SIZE DISTRIBUTION by
In line Lasentec FBRM
DESIGN OF
EXPERIMENTS
PROCESS
ANALYTICAL
TECHNOLOGY
CONTROL
STRATEGY
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
RAPID MIXER
GRANULATOR
FLUID BED
DRYER
SIFTER CUM
MULTI MILL
SIFTER FOR
DELUMPING
BIN BLENDER
COMPRESSION
MACHINE
RATE OF DRY MIXING &
RATE OF DRYING (Temperature /
RATE OF BLENDING
GRANULATION
Time) FOR by In Line FT-NIR
(Speed/ Time) by
(Speed / Time) by In Line
In Line FT-NIR
Lasentec FBRM or PVM & AES
(Acoustic Emission Spectroscopy)
FOR GRANULES
RATE OF SIZING / MILLING
(Speed/ Force) by In Line
Lasentec FBRM FOR GRANULES
OR At Line Malvern PSA
© Copyrighted by Shivang Chaudhary
RATE OF COMPRESSION (Speed
& Hardness ) by In Line
Compression Force Sensor with
Servo motor in Se-Jong/Fette for
Auto matic control of Weight &
Hardness OR
Bruker Tandem FT-NIR

20. CONTROL OF
CMAs
QUALITY TARGET
PRODUCT PROFILE
Factor(s)
CMAs
CONTROL OF
CPPs
Ranges studied at Actual data for Proposed range for
lab scale
Exhibit batch
Commercial batch
Purpose of control
API Attributes
Polymorphic Form
CRITICAL QUALITY
ATTRIBUTES
DESIGN OF
EXPERIMENTS
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
Xx, yy, zz
2Ө values
D25:
Particle Size Distribution
D50:
(PSD)
D90:
Excipient Attributes
Microcrystalline Cellulose Particle Size distribution
(Avicel PH 102)
Moisture content
Crospovidone
Level in Formulation
(Polyplasdone XL 10)
Specific surface area
Polyvinylpyrolidone
Level in Formulation
(Pladone K 29/32)
K Value
Colloidal silicone Dioxide
Specific surface area
(Aerosil 200 Pharma)
Magnesium Stearate
Specific surface area
(vegetable Grade)
Factor(s)
CPPs
Pre-mixing time
Granulation fluid
quantity
Solution addition rate
Xx, yy, zz
Xx, yy, zz
To ensure batch to batch consistency
in drug product Dissolution
NMT 10 um
NMT 35 um
NMT 50 um
NMT 10 um
NMT 35 um
NMT 50 um
NMT 10 um
NMT 35 um
NMT 50 um
To ensure batch to batch consistency
in Blend uniformity & Dissolution
d50: NMT 100 um
NMT 5.0%
4%-10%
1.2-1.4 m2/g
1-5%
29-32
d50: NMT 100 um
NMT 5.0%
7.5%
1.2-1.4m2/g
2.5%
30
d50: NMT 100 um
NMT 5.0%
7.5%
1.2-1.4m2/g
2.5%
30
175-225m2/g
200m2/g
200m2/g
10-20m2/g
10-20m2/g
10-20m2/g
Ranges studied at Actual data for Proposed range for
lab scale
Exhibit batch
Commercial batch
10-20 min
15 min
15 min
Granulation Process
2 min
4 min
(Impeller: 50
rpm; Chopper:
1500 rpm)
45-55°C
2 min
4 min
(Impeller: 50
rpm; Chopper:
1500 rpm)
45-55°C
Water Content
0.5-5.0%
1.5-3.0%
1.5-3.0%
Milling Speed
Mill Screen Size
800-1200 rpm
1-2 mm
50-150
revolutions (10
RPM, 5-15 min)
30-70 revolutions
(10 RPM,
3-7 minutes)
3-7 RPM
10-30 RPM
40-80N
1000 rpm
1.5 mm
100 revolutions
(10 RPM,
10 minutes)
50 revolutions
(10 RPM,
5 minutes)
3-7 RPM
15-25 RPM
50-70N
Milling Process
1000 rpm
1.5 mm
100 revolutions
(10 RPM,
10 minutes)
50 revolutions
(10 RPM,
5 minutes)
3-7 RPM
15-25 RPM
50-70N
Blending Rate in Pre
Lubrication stage
Blending Process
Blending Rate in Pre
Lubrication stage
CONTINUAL
IMPROVEMENT
Compression Process
Purpose of control
25%
2 min
2-6 min
(Impeller: 50
rpm; Chopper:
1500 rpm)
40-50°C
Rate of Wet Mass
Mixing & Granulation
Drying Process
CONTROL
STRATEGY
25%
Drying temerature
PROCESS
ANALYTICAL
TECHNOLOGY
20-30%
To ensure consistency in dry mixing for
wet granulation
To ensure consistent disintegration of
tablet into granules
To give consistent binding
functionality to granules
To promote consistent flow property
of granules from hopper to die
To ensure consistent lubrication
&smooth ejection of tablet from die.
Feeder speed
Turret Speed
Compression hardness
© Copyrighted by Shivang Chaudhary
To ensure IR granule CQAs (PSD &
bulk as well as tapped density) are
met consistently
To ensure low water content in order
to prevent microbial growth &
compression defects
To ensure IR granule PSD is met
consistently
To ensure batch to batch consistancy
in Blend Uniformity
To ensure all tablet CQAs (Assay, CU
& drug release) are met consistently

21. QUALITY TARGET
PRODUCT PROFILE
CONTINUAL RISK REVIEW & RISK
COMMUNICATION BETWEEN
STACKHOLDERS OF:
CRITICAL QUALITY
ATTRIBUTES
REGULATORY
AFFAIRS
DESIGN OF
EXPERIMENTS
PROCESS
ANALYTICAL
TECHNOLOGY
CONTROL
STRATEGY
© Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
OF CMAS & CPPS
FORMULATION
R&D
QUALITY
CONTROL
ANALYTICAL
R&D
QUALITY
ASSUARANCE
MANUFACTURING
PLANT
DURING ROUTINE COMMERCIAL
MANUFACTURING
CONTINUAL
IMPROVEMENT
© Copyrighted by Shivang Chaudhary

22. QRM/QbD
EXAMPLE
FROM FAST FOOD
INDUSTRY
World Famous
McDonald’s French Fries
© Copyrighted by Shivang Chaudhary

23. CMA
McDonald’s passion for quality meant that every single
ingredient was tested, tasted and perfected to fit the
operating system
2.
Special varieties of potato, like the “RUSSET BURBANK”
which is chosen for its quality, taste and long shape
when cut
3.
100 Circle Farms grows the perfect potatoes in circles so
big around, they’re visible from space.
CQAs
1.
Even Light
Golden blond
Crispy & Soft
Exterior
Fluffy & Intact
Interior
Stay crisp & tasty
for long time
FREEZING
in freezer for
at least 4 hours
FINISHING
(FINAL FRYING)
at 275-375ͦC for about
five minutes, gives
golden brown color
CPPs
Washing &
Peeling of Potatoes
RINSING &
PLACING
in Water-Vinegar mixture
to remove extra starch
for at least 12 hours
BLANCHING
(PRE FRYING)
for 45 to 60 seconds
at 390 degrees in
canola blend oil
Average McDonald's restaurants in the US sells 87,600 pounds of fries per year, 1.05 billion pounds of French fries nationwide.
© Copyrighted by Shivang Chaudhary

24. Focus on Quality, Not on Money;
Quality Automatically Brings Money.
Thank You So much for Your Attention.
SHIVANG CHAUDHARY
Formulation Scientist (Pharma-QbD Associate)
M.S. Pharm (Pharmaceutics)- NIPER; P.G.D (Patents Law)- NALSAR
Email ID: shivaniper@gmail.com
Contact No: +91-9904474045
© Copyrighted by Shivang Chaudhary