FMEA, DoE & PAT : Three Inseparable Organs of Quality Risk Management (QRM) Body for Pharmaceutical Product Development with QbD

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


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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


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


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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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.


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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)



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



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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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)



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



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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


Significant Model Terms: A, C, A2


Significant Terms: A,B,C, AB, B2, C2


Significant Terms: A,B,C, A2, B2, C2

EXPERIMENTAL DESIGN

ANOVA DIAGNOSTI

CS

MODEL GRAPHS

DESIGN SPACE


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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)


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)


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


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CONTROL STRATEGY

PROCESS ANALYTICAL

TECHNOLOGY



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


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World FamousMcDonald’s French Fries

QRM/QbD EXAMPLEFROM FAST

FOOD INDUSTRY


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.


mailto:[email protected]

Health & Medicine

FMEA, DoE & PAT : Three Inseparable Organs of Quality Risk Management (QRM) Body for Pharmaceutical Product Development with QbD