Three Inseparable Organs of Quality Risk Management Body
SHIVANG CHAUDHARYFormulation Scientist (Pharma-QbD Associate)
M.S. Pharm (Pharmaceutics)- NIPERP.G.D (Patents Law)- NALSAR
FMEA DoE
PAT
© Copyrighted by Shivang Chaudhary
Email ID: [email protected] No: +91-9904474045
Generic Immediate Release Uncoated Scored Tablet
© Copyrighted by Shivang Chaudhary€€
QRM/QbD EXAMPLE
FROM PHARMAINDUSTRY
Define QTPP (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)Considering QUALITY [Assay, Uniformity of Dosage units,], SAFETY [Impurities (Related substances), Residual Solvents, Microbiological limits], EFFICACY [Dissolution & Absorption] & MULTIDISCIPLINARY [Patient Acceptance & Compliance]
DoE & Generation of Design SpaceFor 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
Development of PAT SystemFor 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 based upon CONTINUAL RISK REVIEW & RISK COMMUNICATION BETWEEN PLANT, QA, QC, RA, R&D, AR&D during routine commercial manufacturing experience
CONTINUAL IMPROVEMENT
CONTROL STRATEGY
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
Quality Risk Assessment of CMAs & CPPs by(1) RISK IDENTIFICATION: by Ishikawa Fishbone (2) RISK ANALYSIS by Relative Risk based Matrix Analysis
(3) RISK EVALUATION by Failure Mode Effective Analysis
<<(QRM)>>
FMEA
DoE
PAT
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
PHARMACIST’S POINT OF
VIEW
PHYSICIAN’S POINT OF
VIEW
PATIENT’S POINT OF
VIEW
QTPP Element Target Justification
Pharmaco-KINETICS
Fasting Study and Fed BE Study90 % confidence interval of the PK parameters,
AUC0-2, AUC2-24, AUC0-∞ and Cmax, should fall within bioequivalence limits of 80-125
Bioequivalence requirement needed to ensure rapid onset and efficacy
QTPP Element Target Justification
EASE OF STORAGE & DISTRIBUTION
Can be stored at real time storage condition as a normal practice with desired stability & can be
distributed from the manufacturer to end user same as per Reference Product.
Required to handle the product easily with suitable accessibility
STABILITY & SHELF LIFEShould be stable against hydrolysis, oxidation, photo
degradation & microbial growth. At least 24-month shelf-life is required at room temperature
Equivalent to or better than Reference Product shelf-life
PATIENT ACCEPTANCE & PATIENT
COMPLIANCE
Should be suitably flavored & colored for possessing acceptable taste ( in case of soluble/ dispersible/
effervescent tablet) similar with Reference Product. Can be easily administered/used similar with
Reference Product labeling
Required to achieve the desired patient acceptability & suitable compliance
QTPP Element Target Justification
Dosage FORM TabletPharmaceutical equivalence requirement:
same dosage form
Dosage DESIGN Immediate Release Uncoated TabletImmediate release design needed to meet
label claims
ROUTE of Administration OralPharmaceutical equivalence requirement:
same route of administration
Dosage STRENGTH x mgPharmaceutical equivalence requirement:
same strength
Drug Product QUALITY
ATTRIBUTES
Description
Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable reference standards (i.e., identity, assay, purity and quality).
AssayUniformityImpuritiesDissolution
Microbiological Limits
Water ContentResidual Solvents
PRIMARY PACKAGINGPlastic Container & Closure/ Metal Blister system
should be qualified as suitable for drug product with desired appropriate compatibility & stability
Needed to achieve the target shelf-life and to ensure product integrity during shipping
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
MULTIDIS
CIPLINARY
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.Weight
Variation/
Content Uniformity
Conforms to USP <905> Uniformity of Dosage Units:
90.0-110.0 % of labeled claim with Acceptance Value: NMT
15.0; RSD : NMT 5.0%
YesVariability 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.
Water ContentAs per In house specification according to stability data
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
ImpuritiesAs per ICH Q3A& Q3B
Yes
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
Conforms to USP <467> option 1
Yes*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.
Microbiological Limits
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.
YesFailure 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.
Quality Attributes of Drug Product
TargetIs this a CQA?
Justification
Physical
Attributes
Appearance
Color and shape should acceptable to the patient. No
visual tablet defects should be observed.
Yes
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
Size Similar to reference product NoFor 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
Score configuration Scored Yes*
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..
Identification Positive for drug Yes*
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.
QUALITY SAFETY EFFICACY
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MILLING SCREEN SIZE (SIEVE NO:ASTM/BSS#)
BLENDER SPEED-RPM
ATOMIZATION PRESSURE
INLET AIR TEMPERATURE
RAW MATERIAL
DILUENT PSD & LOD
BINDER TYPE & CONC.
DISINTEGRANT CONC.
LUBRICANT CONC.SOLUTION SPRAYING RATE
COATING PAN SPEED
SOLUTION CONC.
GRANULATION & DRYING
LIQUID ADDITION RATE
ATOMIZATION AIR PRESSURE
INLET AIR TEMPERATURE
FLUIDIZATION AIR VELOCITY
IMPELLER/ MIXER SPEED
API PSD & SOLUBILITY
COMPRESSION FORCE
PRESS TURRET SPEED
PRECOMPRESSION FORCETEMPERATURE
RELATIVE HUMIDITY
COMPRESSIONCHOPPER/GRANULATOR SPEED
FEEDER SPEED
SIZING & BLENDING
COATING
ENVIRONMENT
TOTAL GRANULATION TIME
MILLING SPEED
BLENDING TIME
RISK IDENTIFICATI
ON
RISK ANALYSIS
RISK EVALUATION
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
CR
ITIC
AL M
ATER
IAL
AT
TR
IBU
TES
(C
MA
s)
FP CQAsParticle
size
Flow Propertie
s
Moisture content
Residual Solvent
Solid state
/Polymorph
Solubility
Process Impurity
Chemical
Stability
Physical Low Low Low Low High Low Low LowAssay Low Low Low Low Low Low High High
Uniformity High High Low Low Low Low Low LowImpurities Medium Low Medium Medium Low Low High HighDissolution High Low Low Low High High Low Low
FP CQAs Diluent BinderGranulating Agent
Disintegrant
Wetting Agent Glidant
Anti-adherant
Lubricant
Physical Low Low Low Low Low Low High HighAssay Medium Low Low Low Low Low Low Low
Uniformity High Low Low Low Low High Low LowImpurities Medium Low Low Low Medium Medium Low LowDissolution Low High High High High Low High High
CMAs of Active Pharmaceutical Ingredient
(API)
CMAs of Inactive Ingredient (Excipients)
RISK IDENTIFICATI
ON
RISK ANALYSIS
RISK EVALUATION
© Copyrighted by Shivang Chaudhary
Low Broadly acceptable risk. No further investigation is needed
MediumRisk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
RISK IDENTIFICATI
ON
RISK ANALYSIS
RISK EVALUATION
FM
EA
of
Acti
ve’s
C
MA
s
Physico- Chemical Property of Actives
Critical Material Attribute (CMAs)
Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
S P D RPN (=S*P*D)
Physical Property
Solid Sate Form
Different Polymorph/ form
Different Solubility of drug substance=Dissolution of drug product may be affected= Bioavailability/Efficacy may got compromised
4 4 4 64
Particle Size Distribution (PSD)
Higher PSD
BCS Class II/IV drug = Dissolution of drug product can be affected= Bioavailability/Efficacy may got compromised
4 4 4 64
Flow Properties
Poor flow
Poor blend uniformity in simple dry mixing process= uncertainty in uniformity of dosage units due to possible segregation = Quality may got compromised
4 4 3 48
Moisture content
High water content
Rate of degradation may be affected = Impurity profile may be affected = Safety may got compromised
3 2 2 12
HygroscopicityHigh water content
Rate of degradation may be affected = Impurity profile may be affected = Safety may got compromised
3 2 2 12
Residual Solvents
High residual solvent
Residual solvents are likely to interact with drug substance= Impurities may be affected = Safety may got compromised
3 2 2 12
Chemical Property
SolubilityDifferent Salt/ Form
Dissolution of the drug product can be affected = Bioavailability/Efficacy may got compromised
3 2 3 18
Process Impurities
Less PurityAssay & impurity profile of drug product may be affected = Quality & Safety may got compromised
3 2 3 18
Chemical Stability
poor
Susceptible to dry heat/oxidative/hydrolytic/UV light degradation- impurity profile may get affected = Quality & Safety may got compromised
3 2 3 18Probability* Severity** Detect ability*** ScoreVery Unlikely Minor Always Detected 01Occasional Moderate Regularly Detected 02Repeated Major Likely not Detected 03Regular Extreme Normally not Detected 04
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
RISK IDENTIFICATI
ON
RISK ANALYSIS
RISK EVALUATION
FM
EA
of
In
acti
ve's
C
MA
s
Excipient (Inactive ingredient)
Critical Material Attribute (CMAs)
Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
S P DRPN
(=S*P*D)
Diluent
Particle Size Distribution
Uneven
Flow properties of the blend may be affected (in dry mixing process) = Uniformity of dosage units may be affected = Quality/ Safety may got compromised
3 3 2 18
Moisture Content
HighImpurity profile may be affected (in case of moisture sensitive drugs) = Safety may got compromised
3 3 2 18
Amount of Binder
More than optimum
Produces hard granules= Produces tablet / capsule with greater disintegration time & retarded dissolution= Efficacy may got compromised
4 4 2 32Binder/ Granulating agent Less than
optimum
Loose granules will be formed, which may produce friable Tablet = Patient acceptance/ Patient compliance got compromised
4 4 2 32
DisintegrantAmount of Disintegrant
Less than optimum
Desired Dissolution cannot be achieved (in case of immediate release product)= Efficacy may got compromised
4 4 2 32
GlidantConcentration of Glidant
Less than optimum
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
3 3 2 18
Anti-adherant
Concentration of Anti-adherant
Less than optimum
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
3 3 2 18
LubricantConcentration of Lubricant
Less than optimum
Material get stuck to the surface of punches/toolings = Picking may be observed = Patient acceptance/ compliance may got compromised
3 3 2 18
Higher than Optimum
Hydrophobic lubricant may surface coat the drug particle = dissolution may got retarded = Efficacy may got compromised
3 3 3 27
Coloring/ Flavor/ Sweetener agent
Concentration
Lower than optimal
Shade variation/ Mottling may be observed = Patient compliance may got compromised
3 3 1 9
Higher than optimum
Safety may got compromised 3 3 3 27
Probability* Severity** Detect ability*** ScoreVery Unlikely Minor Always Detected 01Occasional Moderate Regularly Detected 02Repeated Major Likely not Detected 03Regular Extreme Normally not Detected 04
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
FP CQAs Co-sifting Blending
Rapid Mixing
Granulation
Fluid Bed Drying Sizing
Lubrication
Compression
Description Low Low Low Low High High HighAssay Medium High Low Low Medium High Low
Impurities Low Low Low High Low Low LowUniformity Medium High Low Low Medium High HighDissolution Low Low High Low Low High High
CPPs of Wet Granulation Process
CR
ITIC
AL
PR
OC
ESS
ING
PA
RA
METER
S (
CP
Ps)
RISK IDENTIFICATI
ON
RISK ANALYSIS
RISK EVALUATION
© Copyrighted by Shivang Chaudhary
Low Broadly acceptable risk. No further investigation is needed
MediumRisk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
RISK IDENTIFICATI
ON
RISK ANALYSIS
RISK EVALUATION
CR
ITIC
AL
PR
OC
ESS
ING
PA
RA
METER
S (
CP
Ps)
Unit Operations
Critical Process Parameter (CPPs)
Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
S P DRPN
(=S*P*D)
Sifting SiftingLargerSieve size.
Uneven PSD = Uncertainty in Uniformity 02 02 03 12
Granulation in Rapid Mixer Granulator
Dry MixingLower RPM & Shorter Time
Lesser No. of total Revolutions = Uncertainity in Uniformity
02 02 03 12
Rate of Impeller / Mixer
High RPM & Longer Time Produce Larger granules (forms
agglomerate/lumps)= Dissolution of Tablet / Capsule can be increased= Efficacy/ Bioavailability may got compromised
04 04 03 64
Rate of Chopper/ Granulator
Low RPM & Shorter Time
04 04 03 48
Binder-Granulating agent spraying rate
High RPM 04 04 03 48
Drying in Fluid Bed Drier
InletTemperature
High Product Temperature
Rate of degradation may be affected = Impurity profile may be affected
02 02 03 12
Fluidizing Air Flow rate
Higher CFMIncreased attrition & evaporation produces fines = process efficiency may be compromised
02 02 03 12
Sizing (Milling & Screening)
Comil SpeedIncrease Speed
Fines may be generated = Poor flow leads to uncertainty in uniformity of dosage units
02 02 03 12
Comil Screen Larger # Size
Uneven PSD leads to uncertainty in UniformityLarger granules = Dissolution may be increased
02 02 03 12
Lubrication & Blending
Blending RateHigh RPM & High Time
Increase No. of total Revolutions = Dissolution may be increased
02 02 03 12
Compression / Filling
Turret/ Feeder Speed
High SpeedWeight Variation may be observed= Uniformity of dosage units may be bargained
04 03 03 36
Compression Force /Tamping force
High ForceHardness of Tablet/ Slug will be increased = Disintegration/ Dissolution may be increased
04 03 02 24
Coating
Bed Temperature High Temp. Impurity profile affected 02 02 03 12Spraying rate Higher Rate Appearance affected 03 03 01 09
Atomizing Pressure Lower pressure
Appearance affected 02 02 01 04
Probability* Severity** Detect ability*** ScoreVery Unlikely Minor Always Detected 01Occasional Moderate Regularly Detected 02Repeated Major Likely not Detected 03Regular Extreme Normally not Detected 04
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
DESIGN: BOX-BEHNKENTOTAL RUNS: 17
ORDER: QUADRATICMODEL: POLYNOMIAL
NO. OF FACTORS: 3NO. OF LEVEL: 3
CMAs CPP CQAs
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
FOR OPTIMIZATIONS OF IR TABLET FORMULATION &
KNEADING IN GRANULATION PROCESS
Factor 1 Factor 2 Factor 3 Response 1 Response 2 Response 3Response
4
A:BINDER
B:DISINTEGRAN
TC:KNEADING
Time HARDNESS FRIABILITYDISINTEGRATION
TIMEDRUG
DISSOLVED
(in %) (in %)(in
minutes) (in N) (in %) (in min) (in %)1 4 3 2 46 0.24 5 952 4 5 4 52 0.21 5 973 4 1 4 55 0.18 9 874 4 3 6 58 0.16 7 915 7 3 4 70 0.11 6 996 7 1 6 72 0.10 11 907 7 3 4 68 0.10 6 1008 7 3 4 70 0.12 6 979 7 3 4 72 0.09 6 100
10 7 3 4 68 0.08 6 9911 7 1 2 65 0.13 10 9212 7 5 2 62 0.14 5 9813 7 5 6 74 0.09 6 9514 10 3 6 92 0.06 9 8215 10 5 4 86 0.07 4 8916 10 3 2 83 0.08 8 8817 10 1 4 88 0.08 12 86
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
KNEA
DING T
IME
(in m
inut
es))
-1 (1%)
0 (3%)
+1 (5%)
-1 (4%)
0 (7%)
+1 (10%)
xSUPER DISINTEGRANT (in % w/w/)
BIN
DER
(in
%w
/w)
-1 (2 min)
0 (4 min)
+1 (6 min)
(-1,0,+1
)
(0,-1,-1)
(+1,0,-1)
(0,+1,-1)
(-1,-1,0)
(-1,+1,0
)
(+1,+1,0)
(+1,-1,0)
(-1,0,+1
)
(0,-1,+1)
(0,+1,+1)
(+1,0,+1)
(0,0,0)
DESIGN: BOX-BEHNKEN NO. OF FACTORS :3NO. OF LEVELS :3TOTAL RUNS :17
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
HARDNESS =+69.60+17.25A-0.75B+5.00C+0.25AB-0.75AC+1.25BC
+1.08A2-0.42B2-0.93C2
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
DISINTEGRATION TIME =+6.00+0.87A-2.75B+0.63C-1.00AB-0.25AC+0.000BC
+0.37A2+1.13B2+0.88C2
DRUG DISSOLVED =+99.00-3.12A+3.00B-1.88C-1.75AB-0.50AC-0.25BC
-7.00A2-2.25B2-3.00C2
Analysis of Variance (ANOVA) For Each factor,
their interactions & curvatures on Individual
Response
Predicted Effect Equation of Each factor, their
interactions & curvatures on Individual Response
Model F-value: 128.93Model Value: Significant
Significant Model Terms: A, C
Model F-value: 27.49Model Value: Significant
Significant Model Terms: A, C, A2
Model F-value: 37.34Model Value: Significant
Significant Terms: A,B,C, AB, B2, C2
Model F-value: 23.67Model Value: Significant
Significant Terms: A,B,C, A2, B2, C2
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
© Copyrighted by Shivang Chaudhary
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audh
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
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)
2D Contour plots Plots for Individual Responses with respect to Binder(A) & Kneading Time(C)
2D
CO
NTO
UR
P
LO
TS
3D
R
ES
PO
NS
E
SU
RFA
CE
PLO
TS
4D
CU
BE
P
LO
TS
© Copyrighted by Shivang Chaudhary
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audh
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
Factors (Variables) Levels of Factors studied-1 0 +1
A BINDER (%) 3%w/w 5%w/w 7%w/wB DISINTEGRANT (%) 1%w/w 3%w/w 5%w/wC KNEADING TIME (min) 2min 4min 6min
Responses (Effects) Goal for Individual ResponsesY1 HARDNESS (N) To achieve tablet hardness in the range from 60 to 80NY2 FRIABILITY (%) To achieve minimum friability nearest to 0.00%Y3 DISINTEGRATION
(min)To achieve tablet DT in the range from 5 to 10 minutes
Y4 DISSOLUTION (%) To achieve maximum dissolution nearest to 100%
OV
ER
LAY
PLO
T W
ITH
S
WEET S
PO
T
© Copyrighted by Shivang Chaudhary
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audh
ary
CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
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)
2D Contour plots Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B)
2D
CO
NTO
UR
P
LO
TS
3D
R
ES
PO
NS
E
SU
RFA
CE
PLO
TS
4D
CU
BE
P
LO
TS
© Copyrighted by Shivang Chaudhary
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
EXPERIMENTAL DESIGN
ANOVA DIAGNOSTI
CS
MODEL GRAPHS
DESIGN SPACE
Factors (Variables) Levels of Factors studied-1 0 +1
A BINDER (%) 3%w/w 5%w/w 7%w/wB DISINTEGRANT (%) 1%w/w 3%w/w 5%w/wC KNEADING TIME (min) 2min 4min 6min
Responses (Effects) Goal for Individual ResponsesY1 HARDNESS (N) To achieve tablet hardness in the range from 60 to 80NY2 FRIABILITY (%) To achieve minimum friability nearest to 0.00%Y3 DISINTEGRATION
(min)To achieve tablet DT in the range from 5 to 10 minutes
Y4 DISSOLUTION (%) To achieve maximum dissolution nearest to 100%
OV
ER
LAY
PLO
T W
ITH
S
WEET S
PO
T
© Copyrighted by Shivang Chaudhary
© C
opyr
ight
ed b
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ivan
g Ch
audh
ary
CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
SIFTER FOR DELUMPING
RAPID MIXER GRANULATOR
FLUID BED DRYER
SIFTER CUM MULTI MILL
BIN BLENDER
COMPRESSION MACHINE
RATE OF DRY MIXING & GRANULATION
(Speed / Time) by In Line Lasentec FBRM or PVM & AES
(Acoustic Emission Spectroscopy) FOR GRANULES
API / EXCIPIENT PURITY by In Line BRUKER FT-NIR
API / EXCIPIENT PARTICLE SIZE DISTRIBUTION by In line Lasentec FBRM
RATE OF DRYING (Temperature / Time) FOR by In Line FT-NIR
RATE OF BLENDING (Speed/ Time) by
In Line FT-NIR
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
RATE OF SIZING / MILLING (Speed/ Force) by In Line
Lasentec FBRM FOR GRANULES OR At Line Malvern PSA
PAT FOR TABLET MANUFACTURING
LINE
© Copyrighted by Shivang Chaudhary
© C
opyr
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ivan
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audh
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CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
CONTROL OF CMAs
CONTROL OF CPPs
Factor(s) CMAsRanges
studied at lab scale
Actual data for Exhibit
batch
Proposed range for
Commercial batch
Purpose of control
API Attributes
Polymorphic Form 2Ө values Xx, yy, zz Xx, yy, zz Xx, yy, zzTo ensure batch to batch consistency in drug product Dissolution
Particle Size Distribution (PSD)
D25: NMT 10 um NMT 10 um NMT 10 um To ensure batch to batch consistency in Blend uniformity & Dissolution
D50: NMT 35 um NMT 35 um NMT 35 umD90: NMT 50 um NMT 50 um NMT 50 um
Excipient AttributesMicrocrystalline Cellulose (Avicel PH 102)
Particle Size distribution
d50: NMT 100 um
d50: NMT 100 um
d50: NMT 100 um To ensure consistency in dry
mixing for wet granulation Moisture content NMT 5.0% NMT 5.0% NMT 5.0%
Crospovidone (Polyplasdone XL 10)
Level in Formulation 4%-10% 7.5% 7.5% To ensure consistent disintegration of tablet into granulesSpecific surface area 1.2-1.4 m2/g 1.2-1.4m2/g 1.2-1.4m2/g
Polyvinylpyrolidone (Pladone K 29/32)
Level in Formulation 1-5% 2.5% 2.5% To give consistent binding functionality to granulesK Value 29-32 30 30
Colloidal silicone Dioxide (Aerosil 200 Pharma)
Specific surface area 175-225m2/g 200m2/g 200m2/gTo promote consistent flow property of granules from hopper to die
Magnesium Stearate(vegetable Grade)
Specific surface area 10-20m2/g 10-20m2/g 10-20m2/gTo ensure consistent lubrication &smooth ejection of tablet from die.
Factor(s) CPPsRanges
studied at lab scale
Actual data for Exhibit
batch
Proposed range for
Commercial batch
Purpose of control
Granulation Process
Pre-mixing time 10-20 min 15 min 15 min
To ensure IR granule CQAs (PSD & bulk as well as tapped density) are met consistently
Granulation fluid quantity
20-30% 25% 25%
Solution addition rate 2 min 2 min 2 min
Rate of Wet Mass Mixing & Granulation
2-6 min (Impeller: 50 rpm; Chopper: 1500 rpm)
4 min (Impeller: 50 rpm; Chopper: 1500 rpm)
4 min (Impeller: 50 rpm; Chopper: 1500 rpm)
Drying Process Drying temerature 40-50°C 45-55°C 45-55°C To ensure low water content in
order to prevent microbial growth & compression defectsWater Content 0.5-5.0% 1.5-3.0% 1.5-3.0%
Milling ProcessMilling Speed 800-1200 rpm 1000 rpm 1000 rpm To ensure IR granule PSD is met
consistentlyMill Screen Size 1-2 mm 1.5 mm 1.5 mm
Blending Process
Blending Rate in Pre Lubrication stage
50-150 revolutions (10 RPM, 5-15 min)
100 revolutions (10 RPM, 10 minutes)
100 revolutions (10 RPM, 10 minutes)
To ensure batch to batch consistancy in Blend Uniformity
Blending Rate in Pre Lubrication stage
30-70 revolutions (10 RPM, 3-7 minutes)
50 revolutions (10 RPM,5 minutes)
50 revolutions (10 RPM, 5 minutes)
Compression ProcessFeeder speed 3-7 RPM 3-7 RPM 3-7 RPM To ensure all tablet CQAs (Assay,
CU & drug release) are met consistently
Turret Speed 10-30 RPM 15-25 RPM 15-25 RPMCompression hardness 40-80N 50-70N 50-70N
© Copyrighted by Shivang Chaudhary
© C
opyr
ight
ed b
y Sh
ivan
g Ch
audh
ary
CONTINUAL IMPROVEMENT
CONTROL STRATEGY
PROCESS ANALYTICAL
TECHNOLOGY
DESIGN OF EXPERIMENTS
RISK ASSESSMENT OF CMAS &
CPPS
CRITICAL QUALITY
ATTRIBUTES
QUALITY TARGET
PRODUCT PROFILE
CONTINUAL RISK REVIEW & RISK COMMUNICATION BETWEEN
STACKHOLDERS OF:
MANUFACTURING PLANT
QUALITY ASSUARANCE
QUALITY CONTROL
REGULATORY AFFAIRS
FORMULATION R&D
ANALYTICAL R&D
DURING ROUTINE COMMERCIAL MANUFACTURING
© Copyrighted by Shivang Chaudhary
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World FamousMcDonald’s French Fries
QRM/QbD EXAMPLEFROM FAST
FOOD INDUSTRY
© Copyrighted by Shivang Chaudhary
1. 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.
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
FREEZING in freezer for
at least 4 hours
FINISHING (FINAL FRYING)
at 275-375 ͦC for about five minutes, gives golden brown color
Crispy & Soft Exterior
Fluffy & Intact Interior
Even Light Golden blond
Stay crisp & tasty for long time
CPPs
CQ
As
CMA
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
SHIVANG CHAUDHARYFormulation Scientist (Pharma-QbD Associate)M.S. Pharm (Pharmaceutics)- NIPER; P.G.D (Patents Law)- NALSAR
Email ID: [email protected] No: +91-9904474045
Focus on Quality, Not on Money;Quality Automatically Brings Money.
Thank You So much for Your Attention.
© Copyrighted by Shivang Chaudhary