A Model: Solid Oral Hard Gelatin Capsule

Definition of
QTPP A MODEL
QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION

Determination of OF ENCAPSULETED SOLID ORAL DOSAGE FORM-HARD GELATIN CAPSULE
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT Designed & Developed by

&Development
of Feedback
Control system
Formulation Engineer (QbD/PAT System Developer & Implementer)

MS (Pharmaceutics)- National Institute of Pharmaceutical Education & Research (NIPER), INDIA
PGD (Patents Law)- National academy of Legal Studies & Research (NALSAR), INDIA
Implementatn of facebook.com/QbD.PAT.Pharmaceutical.Development
Control https://in.linkedin.com/in/shivangchaudhary
Strategy  +91 -9904474045, +91-7567297579
© Copyrighted by Shivang Chaudhary
 shivaniper@gmail.com
© Created & Copyrighted by Shivang Chaudhary
Aim
Project
Goal
To Develop :
• Stable & Therapeutic

Equivalent (Pharmaceutical
Equivalent + Bioequivalent) IR
Generic HG Capsule Formulation
• Robust & Rugged Reproducible
Manufacturing Process
• with a Control Strategy that ensures
the quality & performance of the drug
product as per Quality by Design

iNSIDES
Targeting
Bullets
QbD & Its Elements
Definition of QTPP
Determination of CQAs
Quality Risk Assessment of

CMAs & CPPs
DoE &
Development of Design Space
PAT &
Development of Feedback Controls
Implementation of
Control Strategy

What is QbD?
Definition of
QTPP
Determination of
CQAs Quality
The suitability of either a drug substance or a drug product
for its intended use.
Quality Risk
Assessment of
CMAs &
CPPs
Quality by Design (QbD)
A SYSTEMATIC approach
DoE • to development
& Development
of Design Space • that begins with predefined objectives and
• emphasizes product and process understanding
• and process control,
PAT • based on sound science and quality risk management.
&Development
of Feedback
Control system
Note: “Quality doesn’t costs, it always pays” & “Quality does not happen accidently,
Implementatn of Quality must be designed in by planning, not tested in afterwards.“
Control
Strategy

Definition of
Define QTPP (Quality Target Product Profile)
On the basis of THERAPEUTIC EQUIVALENCE for Generic Drug Product
QTPP = PHARMACEUTICAL EQUIVALENCE (same dosage form, route of administration, strength & same quality)
+ BIO-EQUIVALENCE (same pharmacokinetics in terms of Cmax, AUC to reference product)
Determination of
Determine CQAs (Critical Quality Attributes)
Considering QUALITY [Assay, Uniformity of Dosage units,], SAFETY [Impurities (Related substances),
CQAs Residual Solvents, Microbiological limits], EFFICACY [Dissolution & Absorption] &
MULTIDISCIPLINARY [Patient Acceptance & Compliance]
Quality Risk
Assessment of
Quality Risk Assessment of CMAs & CPPs with CQAs
(1) RISK IDENTIFICATION: by Ishikawa Fishbone
CMAs & (2) RISK ANALYSIS by Relative Risk based Matrix Analysis
CPPs (3) RISK EVALUATION by Failure Mode Effective Analysis
Designing of Experiments (DoE) & Design Space

DoE For SCREENING & OPTIMIZATION of CMAs & CPPs with respect to CQAs by
& Development superimposing contour plot to generate OVERLAY PLOT (Proven acceptable
of Design Space
Ranges & Edges of failure ) based upon desired ranges of Responses
PAT Process Analytical Technology (PAT)

&Development For continuous automatic IN LINE analyzing & FEED BACK controlling critical processing through
of Feedback timely measurements of CMA & CPAS by INLINE ANALYZERS WITH AUTO SENSORS with the ultimate goal of
Control system consistently ensuring finished product quality with respect to desired CQAs
Implementatn of Implementation of Control Strategy

Control For CONTROLS OF CMAs, CPPs within Specifications, by
Real Time Release Testing, Online Monitoring System, Inline PAT Analyzers
Strategy based upon previous results on development, Scale Up. Exhibit/ Validation batches.

What is QTPP?
Definition of
QTPP
Determination of
CQAs
QUALITY TARGET PRODUCT PROFILE (QTPP)

Quality Risk
Assessment of A Prospective Summary of
CMAs &
CPPs
• the quality characteristics of a drug product
• that IDEALLY will be achieved to ensure the desired quality,
• taking into account Safety & Efficacy of the drug product.
DoE
& Development
of Design Space
Note: QTPP will be finalized -

• On the basis of Therapeutic Equivalence for Pharmaceutical Abbreviated New Drug Application (ANDA- Generics)=
Pharmaceutical Equivalence (same dosage form, route of administration, strength & same quality) + Bio-Equivalence
(same pharmacokinetics in terms of Cmax, AUC;
PAT
&Development
of Feedback • On the basis of Therapeutic Safety & Efficacy for Pharmaceutical New Chemical Entities (NCE-Innovator) /
Control system
New Drug Applications (NDA-Novel Drug Delivery Systems as compared to already approved & available
conventional dosage forms)
Implementatn of
Control
Strategy

PHARMACIST’s PHYSICIAN”s PATIENT’S
POINT OF VIEW POINT OF VIEW POINT OF VIEW
Definition of Quality Target Product Profile (QTPP) of HGC

QTPP QTPP Element Target Justification
Pharmaceutical equivalence requirement:
Dosage FORM Hard Gelatin Capsule
same dosage form
Immediate release design needed to meet
Dosage DESIGN Immediate Release / Modified Release Formulation
label claims
Determination of ROUTE of Administration Oral
same route of administration
CQAs Dosage STRENGTH x mg
same strength
Description
Assay
Uniformity
Drug Product Impurities
Quality Risk Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable
Assessment of QUALITY Dissolution
reference standards (i.e., identity, assay, purity & quality).
CMAs & ATTRIBUTES Microbiological
Limits
CPPs Water Content
Residual Solvents
Plastic Container & Closure/ Metal Blister system should be
Required to achieve the target shelf-life
qualified as suitable for drug product with desired
and to ensure product integrity
PRIMARY PACKAGING appropriate compatibility & stability. Should
during transportation, storage
DoE protect product from heat, moisture,
& during routine-use
& Development oxygen, light & microbial attack.
of Design Space
Fasting Study and/or Fed BE Study

Bioequivalence requirement needed to
90 % confidence interval of the PK parameters, AUC0-t, ,
Pharmaco-KINETICS meet required rate & extent of
AUC0-∞ and Cmax, should fall within bioequivalence limits
drug absorption
of 80-125 with reference product
PAT Can be stored at real time storage condition as a normal
&Development
of Feedback EASE OF STORAGE & practice with desired stability & can be distributed Required to handle the product easily
Control system DISTRIBUTION 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
STABILITY & SHELF LIFE degradation & microbial growth. At least 24-month
Reference Product shelf-life
shelf-life is required at room temperature
Implementatn of Should be suitably colored for possessing
PATIENT ACCEPTANCE & Required to achieve the desired patient
Control PATIENT COMPLIANCE
acceptableshade similar with Reference Product.
Can be easily administered/used similar with acceptability & suitable compliance
Strategy Reference Product labeling

What is CQA?
Definition of
QTPP
Determination of
CQAs
Critical Quality Attribute (CQA)

A CQA is a
Quality Risk
Assessment of
• Physical,
CMAs &
CPPs • Chemical,
• Biological, or
• Microbiological property or characteristic
DoE that should be within an appropriate limit, range, or distribution
& Development
of Design Space
to ensure the desired product quality.
PAT Note: CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) & Finished
&Development
of Feedback drug product. On the basis of Quality [Assay, Uniformity of Dosage units, Redispersibility, Reconstitution time, Aerodynamic
Control system
property], Safety [Impurities (Related substances), Residual Solvents, Osmolarity & Isotonicity, Microbiological limits, Sterility
& Particulate matter], Efficacy [Diffusion, Dissolution & Permeation] & Multidisciplinary [Patient Acceptance & Compliance].
Implementatn of
Control
Strategy

MULTI
QUALITY SAFETY EFFICACY
DISCIPLINARY
Definition of Critical Quality Attributes (CQA) of HGC

QTPP
Quality Attributes Is this a
Target Justification
of Drug Product CQA?
Color and shape should acceptable
to the patient. No visual tablet Yes To ensure PATIENT ACCEPTABILITY comparable to reference product
Physical
defects should be observed.
Attributes
To ensure PATIENT COMPLIANCE with treatment regimens &
Determination of Size Similar to reference product No
for comparable EASE OF SWALLOWING
CQAs Though identification is critical for SAFETY AND EFFICACY, this CQA can be
Identification Positive for Drug Substance Yes*
effectively controlled & monitored at drug substance release.
Assay variability will affect SAFETY AND EFFICACY. Process variables

90.0 to 110.0 % of
Assay Yes may affect the assay of the drug product. Thus, assay will be evaluated
Quality Risk labeled claim.
Assessment of throughout formulation and process development.
CMAs & Weight Variation/
Conforms to USP <905> Uniformity
of Dosage Units: 90.0-110.0 % of
Variability in content uniformity will affect SAFETY AND EFFICACY.
CPPs Content Uniformity labeled claim with AV:
Yes Both formulation and process variables may impact content uniformity, so this
CQA will be evaluated throughout formulation and process development.
NMT 15.0; RSD : NMT 5.0%
As per In house specification If drug is sensitive to moisture, it will impact stability & ultimately SAFETY &
Water Content Yes
according to stability data EFFICACY. If drug is not sensitive to moisture, it will not impact stability
DoE
& Development
of Design Space Degradation products can impact SAFETY and must be controlled based on
As per compendia/ICH requirements or reference product characterization to
Impurities ICH Q3A& Q3B Yes limit patient exposure. Formulation and process variables may 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
Residual Conforms to USP
PAT Solvents <467> option 1
Yes* controlled during drug substance & drug product manufacturing by drying,
&Development Therefore, Formulation and Process variables are unlikely to impact this CQA.
of Feedback
Control system Microbial Load will impact patient SAFETY, but as it will be primarily
Microbiological Conforms to USP
Yes* controlled during drug substance & drug product manufacturing,
Limits <61 & 62>
Therefore, Formulation and Process variables are unlikely to impact this CQA.
NLT X % (Q) of labeled amount of

Failure to meet the dissolution specification can impact bioavailability
Implementatn of drug is dissolved in y Minutes in
Dissolution Yes (EFFICACY). Both formulation and process variables affect the dissolution profile.
Control pH Z buffer, 900 ml,
This CQA will be investigated throughout formulation and process development.
Apparatus I/II, 50/100 rpm.
Strategy

What is CMA & CPP?
Definition of
QTPP
Determination of
CQAs
Critical Material Attribute (CMA)

Quality Risk
Independent formulation variables i.e. physicochemical properties
Assessment of
CMAs & of active(drug substance) & inactive ingredients(excipients)
CPPs
• affecting CQAs of semi-finished and/or finished drug product
DoE
& Development
of Design Space Critical Process Parameter (CPP)
Independent process parameters
• most likely to affect the CQAs of an intermediate or finished drug
PAT
&Development
of Feedback product & therefore should be monitored or controlled
Control system
• to ensure the process produces the desired quality product.
Implementatn of Note: Risk related to individual CMAs &/or CPPs will be identified, analyzed qualitatively & then evaluated
Control quantitatively in order to reduce the probability of risk through optimization by DoE &/or inline detection by PAT.
Strategy

RISK RISK RISK RISK
IDENTIFICATION ANALYSIS EVALUATION ASSESSMENT
Definition of Identification of Factors involved in

QTPP Fluid Bed Granulation Process Map
Critical Processing Critical Attributes of Manufacturing Quality Attributes of
Parameters Input Materials Process Steps Output Materials
Drug PSD & Flow ability

Determination of Screen Type & Screen Size Powder PSD
Excipient PSD & Flow ability Screening
Mill Type (cone mill)
CQAs Mill Speed
Excipient BD TD
Excipient Moisture Content
(Co-Sifting/ Co-Milling)
Powder Flow ability
Powder Bulk Density
Excipient lot to lot variability
Inlet air Volume,

Inlet Air temperature, Fluid Bed Mixing, Granule PSD
Quality Risk Powder PSD
Assessment of
Spray Rate per nozzle, Fluid Bed Granulation &
Powder Flow ability Granule Flow ability
Nozzle diameter and numbers,
CMAs & Atomization air pressure,, Powder Bulk Density Fluid Bed Drying Granule LOD
CPPs Capacity utilized,

Filter type & shake
interval/duration
Granule4 PSD Granule PSD

Mill type Sizing
Granule Flow ability Granule Flow ability
DoE Blade configuration orientation
Oscillation degree / speed Granule LOD (Milling / Sifting) Granule Assay
& Development Screen type/ Screen size
of Design Space
Number of recycles
Granule PSD & Flow ability

Blender Type & Fill Level Granule Assay Blend Assay
Order of Addition Lubricant/ Glidant Lubrication Blend Uniformity
PAT Rotation speed & Time specific surface area
Anti-adherant PSD
Blend BD/TD
&Development Number of Revolution Blend Compressibility
of Feedback Drum to hopper transfer
Control system
Appearance, Dimensions,
Filing speed (RPM/SPM) Weight variation
Feed Frame paddle speed (individual/composite),
Feeder Fill depth Blend Assay & Uniformity Hardness, Friability,
Implementatn of
Capsule Filling Assay, Content Uniformity
Taping Force Blend BD/TD
Control Filling principle Blend Compressibility Impurities- Related
Substances(RS)
Strategy (Dosator/Tamping)
Hopper Design & Fill level Disintegration Time,
Total Run Time Dissolution (% Drug Release)
Environment (Temperature and RH)
RISK RISK RISK RISK
Definition of Identification of Risk Factors by

QTPP Ishikawa Fishbone Diagram
Determination of
CQAs
FLUID BED
GRANULATION
LIQUID ADDITION RATE

ENCAPSULATION
Quality Risk ATOMIZATION AIR PRESSURE
Assessment of BD/TD/ FLOW OF MATERIAL
CMAs & MOISTURE OF GELATIN SHELL
FLUIDIZATION AIR VELOCITY
INLET AIR TEMPERATURE

CPPs
ENVIRONMENT
FILLING PRINCIPLE
(DOSATOR/ TAMPING) PRODUCT TEMPERATURE
TEMPERATURE DOSING DISK SIZE
OUTLET AIR TEMPERATURE
RELATIVE HUMIDITY DOSING DISK SPEED
PRESERVATIVE TYPE & CONC.
TAMPING FORCE
COLOR SOURCE & CONC.
GLIDANT CONC. GELATIN: GLYCERINE RATIO.
DoE INLET AIR TEMPERATURE BLENDING TIME
BLENDER SPEED-RPM
GELATIN: WATER RATIO.
& Development INLET AIR VOLUME/ FLOW GELATIN: TYPE & CONC.
of Design Space PRINCIPLE OF BLENDING
SOLUTION SPRAYING RATE BINDER TYPE & CONC.
MILLING SCREEN SIZE
COATING PAN SPEED DILUENT PSD & WATER
MILLING SPEED
SOLUTION CONC/ VISCOSITY API PSD & WATER CONTENT
PRINCIPLE OF MILLING
RAW
SIZING & MATERIAL
DEDUSTING & BLENDING
POLISHING
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
Qualitative Risk based Matrix Analysis of
QTPP Active Pharmaceutical Ingredient’s (API) Attributes
Determination of
CQAs
Quality Risk Solid state Particle Size Flow Hygro- Moisture Residual Process Chemical
Assessment of FP CQAs Solubility
/Polymorph Distribution Properties Scopicity content Solvent Impurity Stability
CMAs & Physical High Low Low High Low Low Low Low Low
CPPs Assay Low Low Low Low Low Low Low High High
Uniformity Low High High Low Low Low Low Low Low
Impurities Low Medium Low High Medium Medium Low High High
Dissolution High* High* Low Low Low Low High* Low Low
DoE
& Development Low Broadly acceptable risk. No further investigation is needed
of Design Space
Medium Risk 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.
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
Quantitative Failure Mode Effect Analysis (FMEA) of
Failure Mode
Critical Material Effect on IP & FP CQAs with respect to QTPP
Property (Critical P S D RPN (=P*S*D)
Attribute (CMAs) (Justification of Failure Mode)
Event)
Different Solubility of drug substance may get affected=
Solid Sate
Determination of Polymorph/ >> Dissolution of drug product may get affected 2 4 4 32
Form
CQAs form >> BIOAVAILABILITY-EFFICACY may get compromised
BCS Class II/IV Low Solubility drug
Particle Size
Higher PSD >> Dissolution of drug product may get affected 4 4 3 48
Distribution (PSD)
>> BIOAVAILABILITY/EFFICACY may get compromised
Poor blend uniformity in simple dry mixing process=
Flow
Poor flow uncertainty in uniformity of dosage units due to possible 4 4 3 48
Properties
Physical segregation = Quality may got compromised
Quality Risk Property Rate of degradation may be affected
Assessment of High water
Hygroscopicity = Impurity profile may be affected 3 4 2 36
CMAs & content
= Safety may got compromised
CPPs Moisture content
High water
Rate of degradation may get affected
>> Impurity profile may get affected 3 4 2 36
content
>> SAFETY of the product may get compromised
Residual solvents are likely to interact with drug
High residual
Residual Solvents substance >> Impurities profile may get affected 2 3 3 18
solvent
>> SAFETY may get compromised
DoE Solubility
Different Salt/
Form
Dissolution of the drug product may get affected
>> BIOAVAILABILITY-EFFICACY may got compromised
2 3 4 24
& Development
of Design Space Process Assay & impurity profile of drug product may be
Chemical Less Purity 2 3 3 18
Impurities affected = >> Quality & SAFETY may got compromised
Property
Susceptible to dry heat/oxidative/hydrolytic/UV light
Chemical
poor degradation- impurity profile may get affected 2 3 3 18
Stability
>> Quality & SAFETY may got compromised
PAT Probability* Severity** Detect ability*** Score

&Development Very Unlikely Minor Always Detected 01
of Feedback
Control system Occasional Moderate Regularly Detected 02
Repeated Major Likely not Detected 03
Regular Extreme Normally not Detected 04
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
Implementatn of
Control Score based on Score based on Score based on
Strategy PROBABILITY
FOR OCCURANCE
LIKELY SEVERITY PROBABILITY OF
IMPACT ON DRUG FAILURE OF
OF FAILURE PRODUCT CQA. DETECTION.
RISK RISK RISK RISK
Definition of
CRITICAL
Required to be Optimized &/Or Controlled
Determination of
CQAs CMAs of
API
Quality Risk A SOLID STATE FORM

Assessment of
CMAs & PARTICLE SIZE
B
CPPs
C FLOW PROPERTY
D HYGROSCOPICITY
DoE
& Development
of Design Space E MOISTURE CONTENT
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
QTPP Shell-Inactive Ingredients’ (Excipients’) Attributes
Determination of
CQAs
Quality Risk FP CQAs Gelatin Plasticizers Water Preservative Colorant Opacifier

Assessment of
Physical High High High Low High High
CMAs & Assay Low Low Low Low Low Low
CPPs Uniformity Low Low Low Low Low Low
Impurities High Medium High Medium Low Low
Dissolution High High High Low Low Low
Low
DoE Broadly acceptable risk. No further investigation is needed
& Development Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
of Design Space High Risk is unacceptable. Further investigation is needed to reduce the risk.
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
Critical
Excipient Failure Mode
Material Effect on IP & FP CQAs with respect to QTPP
(Inactive (Critical P S D RPN (=P*S*D)
Attribute (Justification of Failure Mode)
ingredient) Event)
(CMAs)
Low cohesive strength of cross linking of shell
Determination of Bloom or Lower than
>> PHYSICAL STABILITY may get affected 4 4 2 32
Gel Strength optimum< 150g
CQAs >> Patient Acceptance may get compromised
Capsule shell may get brittle & hard
Viscosity of Higher than
>> Disintegration/Dissolution of the shell may get affected 4 4 2 32
Gelatin Solution Optimum <25mp >> Bioavailability-EFFICACY may get compromised
Capsule shell may get BRITTLE & HARD
Gelatin Less than >> Physical Properties of Shell may get altered
>> Disintegration/Dissolution of the shell may get affected
4 4 3 48
optimum
>> Bioavailability-EFFICACY may get compromised
Quality Risk Moisture Content LEVEL OF IMPURITIES of the Hygroscopic/
Assessment of Higher than Moisture sensitive product may get increased
3 4 3 36
CMAs & optimum >> CHEMICAL STABILITY may get compromised
>> SAFETY of the patient may get compromised
CPPs Less than
>> Physical Properties of Shell may get altered
Ratio of Dry 4 4 3 48
optimum >> Disintegration/Dissolution of the shell may get affected
Plasticizer to Dry
Plasticizers >> Bioavailability-EFFICACY may get compromised
Gelatin (0.4/1, LEVEL OF IMPURITIES of the product may get increased
0.6/1.0, 0.8/1.0) Higher than
>> CHEMICAL STABILITY may get compromised 3 3 3 27
optimum >> SAFETY of the patient may get compromised
DoE Less than
>> Physical Properties of Shell may get altered
& Development 4 4 3 48
of Design Space optimum >> Disintegration/Dissolution of the shell may get affected
Ratio of Water to
>> Bioavailability-EFFICACY may get compromised
Water Dry Gelatin (0.7, LEVEL OF IMPURITIES of the Hygroscopic/
1.0, 1.3) Higher than Moisture sensitive product may get increased
>> CHEMICAL STABILITY may get compromised
3 4 3 36
optimum
>> SAFETY of the patient may get compromised
MICROBIAL LOAD may get increased during
Concentration of Less than
PAT Anti-Microbial
Anti-Microbial optimum
transportation, storage & in-use
>> MICROBIOLOGICAL STABILITY may get compromised
2 3 4 24
&Development >> SAFETY of patient may get compromised
of Feedback LEVEL OF OXIDIZED IMPURITIES of the product may get increased
Control system Concentration of Less than
Anti-Oxidant >> CHEMICAL STABILITY may get compromised 2 3 3 18
Anti-Oxidant optimum >> SAFETY of the patient may get compromised
Lower than Shade variation/ Mottling may be observed
3 3 2 18
Concentration of optimal >> Patient ACCEPTNCE/ COMPLIANCE nay get compromised
Colorant Probability of impurity formation with FD&C Certified Dyes get
Colorant
Fe >15 ppm increased due to REDOX Potential of Iron Itself >> Safety may got 3 3 3 27
Implementatn of compromised
Control Concentration of
Lower than
optimal
Shine variation/ Mottling may be observed
>> Patient ACCEPTNCE/ COMPLIANCE nay get compromised
3 3 2 18
Opacifier
Strategy Opacifier Higher than
Safety may got compromised 2 3 3 18
optimum

RISK RISK RISK RISK
Definition of
CRITICAL
Determination of
CQAs
CMAs of
SHELL EXCIPIENTS
Quality Risk
Assessment of
A BLOOM/GEL STRENGTH
CMAs &
CPPs B VISCOSITY OF GELATIN
C MOISTURE CONTENT
DoE D GLYCERINE: DRY GELATIN

& Development
of Design Space
E WATER : DRY GELATIN
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
QTPP Fill-Inactive Ingredients’ (Excipients’) Attributes
Determination of
CQAs
Risk Based MATRIX ANALYSIS for CMAs of

INACTIVE FILL MATERIAL
Quality Risk
Assessment of Granulating Wetting Anti-
FP CQAs Diluent Binder Disintegrant Glidant Lubricant
CMAs & Agent Agent adherant
CPPs Physical Low Low Low Low Low Low High High
Assay Medium Low Low Low Low Low Low Low
Uniformity High Low Low Low Low High Low Low
Impurities Medium Low Low Low Medium Medium Low Low
Dissolution Low High High High High Low High High
DoE
& Development Low Broadly acceptable risk. No further investigation is needed
of Design Space
Medium Risk 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.
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
Critical
Excipient Failure Mode
Material Effect on IP & FP CQAs with respect to QTPP
(Inactive (Critical P S D RPN (=P*S*D)
Attribute (Justification of Failure Mode)
ingredient) Event)
Determination of (CMAs)
CQAs
Flow properties of the blend may be affected (in dry
Particle Size
Not Optimum mixing process) >> Uniformity of dosage units may be 3 4 3 36
Distribution
affected >> Safety may got compromised
Diluent/ Filler
Impurity profile may be affected (in case of moisture
Moisture Content High 3 4 3 36
sensitive drugs) >> Safety may got compromised
Quality Risk
Assessment of
Produces hard granules/pellets
CMAs & More than
>> Greater disintegration time & retarded dissolution 3 3 3 27
optimum
CPPs Binder/ >> Efficacy may got compromised
Granulating Amount of Binder
agent Flow properties of the blend may be affected (in dry
Less than
mixing process)>> Uniformity of dosage units may be 3 3 3 27
optimum
affected >> Safety may got compromised
DoE Amount of Less than

Desired disintegration-Dissolution cannot be achieved (in
& Development Disintegrant case of immediate release product) 3 3 3 27
of Design Space Disintegrant optimum
>> Efficacy may got compromised
Wetting Agent/ Amount of Less than Desired Dissolution cannot be achieved in case of
3 3 3 27
surfactant Surfactant optimum hydrophobic drugs >> Efficacy may got compromised
Flow of granules or powder from hopper to die by reducing

PAT Glidant
Concentration of Less than friction between particles may be affected
4 4 2 32
&Development Glidant optimum >> Uniformity of dosage units may affected
of Feedback >> Quality may got compromised
Control system
Ejection of finished product from tooling may be difficult=

Less than Material get stuck to the surface of filling die
4 4 2 32
optimum >> STICKING may be observed = patient acceptance/
Concentration of compliance may got compromised
Anti-adherant
Implementatn of Anti-adherant
Control Higher than
Hydrophobic anti-adherant may surface coat the drug
particle >> DISSOLUTION may got retarded = Efficacy 4 4 2 32
Strategy Optimum
may got compromised

RISK RISK RISK RISK
Definition of
CRITICAL
Determination of
CQAs CMAs of
FILL EXCIPIENTS
Quality Risk
Assessment of
CMAs & A DILUENT PSD
CPPs
B DILUENT MOISTURE
C GLIDANT CONC.
DoE
& Development
of Design Space D ANTI-ADHERANT CONC.
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of Qualitative Risk based Matrix Analysis of

QTPP Processing Parameters
DRY MIXING BLENDING-
LUBRICATION FOR FILL MATERIAL PREPARATION
FP CQAs Co-sifting Blending Lubrication
Determination of Description Low Low High
CQAs Assay Medium High Low
Impurities Low Low Low
Uniformity Medium High Low
Dissolution Low Low High
Quality Risk
Assessment of
CMAs & HARD GELATIN CAPSULE SHELL PREPARATION
CPPs (MOLD PIN DIPPING TECHNIQUE)
FP CQAs Dipping Spinning Drying Striping Trimming Joining
Description Low Low High Medium High Low
Assay Low Low Low Low Low Low
Impurities Low Low High Low Low Low
DoE Uniformity Low Low Low Low Low Low
& Development
of Design Space Dissolution Medium High Low Low Low Low
HARD GELATIN CAPSULE FILLING

(ENCAPSULATION PROCESS)
PAT Filling of Capsules
&Development Loading of Empty Separation of Cap Locking of Cleaning/ DE Polishing &
of Feedback FP CQAs by Tamping/
Control system Capsule Shell from Body Capsules dusting brushing
Dosator
Description Low Low High High High High
Assay Low Low Low Low Low Low
Impurities Low Low Low Low High Low
Implementatn of Uniformity Low Low High Low Low Low
Control Dissolution Low Low High High Low Low
Strategy

RISK RISK RISK RISK
Definition of Quantitative Failure Mode Effect Analysis (FMEA) of

Unit Critical Process Failure Mode Effect on IP & FP CQAs with respect to QTPP RPN
P S D
Operations Parameter (CPPs) (Critical Event) (Justification of Failure Mode) (=P*S*D)
Determination of FILL MATERIAL PREPARATION (DRY MIXING-BLENDING)

CQAs Screening Co-Sifting
Larger Uneven PSD = Uncertainty in CONTENT Uniformity
2 3 3 18
Sieve size >> SAFETY may get compromised
Spraying rate Higher Agglomerates may be produced >> Dissolution profiling 3 4 4 48
Fluid Bed Atomizing pressure Lower may get affected >> BA-EFFICACY may get compromised 3 3 4 36
Granulation Fines may get produced >> Chances of Segregation >> CU may get
Fluidization velocity Higher affected >> SAFETY may get compromised 3 3 4 36
Quality Risk Blending Rate (No of Low RPM & Low Lesser No. of total Revolutions >> Uncertainty in Uniformity
Assessment of Dry Mixing 3 3 4 36
RPM * Time) Time >> SAFETY may get compromised
CMAs & Lubrication
Blending Rate (No of High RPM & High Dissolution profiling may get retarded
3 3 4 36
CPPs RPM *Time) Time >> BIOAVAILABILITY/ EFFICACY may get compromised
SHELL MATERIAL PREPARATION (MOLD PIN DIPPING TECHNIQUE)
Appearance (Gelatin Shell Thickness Uniformity),

Dipping &
Rotation Speed Not Optimum Disintegration - Dissolution profiling may get affected 3 3 3 27
Spinning
DoE >> EFFICACY & Patient ACCEPTANCE may get affected
& Development
of Design Space
Lower than Moisture content in shell may be higher & DEFORM
3 3 4 36
Inlet Optimum >> PHYSICAL & CHEMICAL STABILITY may get affected
Temperature of
Drying Heating &
Cooling Capsule Shell may get BRITTLE & HARD
Higher than
>> Disintegration-Dissolution may get retarded 3 3 4 36
PAT Air optimum
>> BIO AVAILABILITY-EFFICACY may get compromised
&Development
of Feedback
Control system
Higher than Chances of Shell damage during striping by jaws
Striping Force 2 3 3 18
optimum >> Patient ACCEPTANCE may get compromised
Stripping &
Trimming
Higher than Disintegration time & pattern may get affected
Trimming Length 2 3 3 18
Implementatn of
optimum >> BIO AVAILABILITY-EFFICACY may get compromised
Control Joining of Cap Higher than Chances of Shell damage by tamping pins
Strategy from Body
Pressing Force
optimum >> Patient ACCEPTANCE may get compromised
2 3 2 12

RISK RISK RISK RISK
Definition of Quantitative Failure Mode Effect Analysis (FMEA) of

Unit Critical Process Failure Mode Effect on IP & FP CQAs with respect to QTPP RPN
P S D
Operations Parameter (CPPs) (Critical Event) (Justification of Failure Mode) (=P*S*D)
Determination of
HARD GELATIN CAPSULE FILLING PROCESS (ENCAPSULATION)
Vacuum pressure in PINHOLES & CRACKS occurs when the dome of the
CQAs Loading &
separation of cap-
Higher than
capsule body fractures due to excessive vacuum 2 3 2 12
Separation optimum
body during separation.
DOSATOR & Not Suitable for powder having low BD & TD
3 3 3 27
Piston System (COHESIVE BULK POWDERS)
Filling Principle
Quality Risk TAMPING & Not suitable for material having high BD & TD
Assessment of 3 3 3 27
Dosing Disc (FREE FLOWING GRANULES / PELLETS)
CMAs &
CPPs Hardness of PLUG, Weight Variation may get affected
Dosing Disk Size Incorrect >> Disintegration/ Dissolution & Uniformity may get 3 3 4 36
Filling of
affected >> SAFETY &EFFICACY may get compromised
Capsules
(Encapsulation)
Appearance (CRACKS), Weight Variation may be
Feeder / Dosing
DoE Disk Speed
Higher than optimum observed >> Uniformity of dosage units may get affected 3 4 4 48
& Development >> SAFETY & EFFICACY may get compromised
of Design Space
Appearance (BENT) , Hardness of Slug / PLUG may get

Higher than
Tamping Force affected >> Disintegration/ Dissolution may get affected 3 4 4 48
optimum
>> BIOAVAILABILITY/ EFFICACY may get compromised
PAT Body Joining Pins Incorrect setting

&Development Physical LOCKING LENGTH may get affected
of Feedback Locking of Pin Size/
Incorrect >> DENTS/ TELESCOPE/ SPILT may be observed portion 3 3 3 27
Control system Capsules Configuration
>> Patient ACCEPTANCE may get compromised
Bushings Misalignment
Higher than
Spraying Rate
Cleaning & optimum Physical Appearance (Foreign particles/ dirt) may get
3 3 3 27
Polishing Lower than affected >> Patient ACCEPTANCE may get compromised
Implementatn of Rotational Speed
optimum
Control Temperature Higher (>25°C) Impurity profiling may get affected 3 4 4 48
Strategy Environmental
Factors
>> CHEMICAL STABILITY may get compromised
Relative Humidity Higher (>40%RH) >> SAFETY may get compromised 3 4 4 48

RISK RISK RISK RISK
Definition of CRITICAL
CPPs of CPPs of
Determination of
CQAs
FLUID BED GRANULATION DRY MIXING-LUBRICATION
A SPRAYING RATE A BLENDING SPEED

Quality Risk
Assessment of
B ATOMIZATION PRESSURE
CMAs & B BLENDING TIME
CPPs
C FLUIDIZATION VELOCITY
DoE
& Development
of Design Space
CPPs of
HARD GELATIN ENCAPSULATION
PAT A GLIDANT CONCENTRATION

&Development
of Feedback
Control system
B ANTI ADHERANT CONC.
C FILLING RATE
Implementatn of
Control
Strategy

What is DoE & DS?
Definition of
QTPP
Design of Experiments (DoE)

Determination of
CQAs
A Systematic Series of Experiments,
• In which purposeful changes are made to input factors to identify
Quality Risk causes for significant changes in the output responses &
Assessment of
CMAs & • Determining the relationship between factors & responses to
CPPs evaluate all the potential factors simultaneously, systematically and
speedily;
• With complete understanding of the process to assist in better
DoE
& Development
of Design Space
product development & subsequent process scale-up With
pretending the finished product quality & performance.
Design Space
PAT
&Development
of Feedback
The Multidimensional Combination & Interaction of
Control system
• Critical Material Attributes and
• Critical Process Parameters
Implementatn of
that have been demonstrated to provide assurance of quality.
Control
Strategy Note: Working within the design space is not considered as a change.
Movement out of the design space is considered to be a change
IDENTIFICATION DESIGN OF ANALYSIS OF DEVELOPMENT
OF CMAs/CPPs EXPERIMMENTS RESPONSES OF DESIGN SPACE
Definition of DoE For

QTPP FLUID BED GRANULATION (Contd…)
Optimization of CPPs of
Determination of FLUID BED TOP SPRAY GRANULATION PROCESS
CQAs
Quality Risk A BINDER SPRAYING RATE

Assessment of
CMAs &
B ATOMIZATION AIR PRESSURE
CPPs
C FLUIDIZATION AIR VELOCITY
DoE
& Development
of Design Space
RISKS
HIGHER %FINES HIGHER %AGGLOMERATES
PAT SOFT GRANULES HARD GRANULES

&Development
of Feedback
Control system
LOWER HARDNESS INADEQUATE DISINTEGRATION
HIGH FRIABILITY INADEQUATE DISSOLUTION

Implementatn of
Control QUALITY COMPROMISED EFFICACY COMPROMISED
Strategy


QTPP FLUID BED GRANULATION(Contd…)
OBJECTIVE To Optimize CPPs of Fluid Bed Granulation Process
Determination of
NO. OF FACTORS 3
CQAs
NO. OF LEVELS 5
Quality Risk
EXPERIMENTAL DESIGN
Assessment of SELECTED
FLUIDIZATION AIR VELOCITY
CMAs &
CPPs CIRCUMSCRIBED CENTRAL
COMPOSITE RSM for 3 factors
ADD. CENTER POINTS 5

DoE
& Development
of Design Space
TOTAL NO OF 8 fp
C
EXPERIMENTAL RUNS +6 sp
(NO OF TRIALS) +6 cp
=20
PAT
&Development A BINDER SPRAYING RATE
of Feedback
Control system
Factors (Variables) Levels of Factors studied

-α -1 0 +1 +α
Implementatn of A Binder Spraying Rate (gm/min) 1.64gm/min 3 gm/min 5 gm/min 7 gm/min 8.36gm/min
Control B Atomization Pressure (bar) 0.32bar 1 bar 2 bar 3 bar 3.68bar
Strategy C Fluidization Air Velocity (cfm) 32.96cfm 50 cfm 75 cfm 100 cfm 117.04cfm


CPPs CQAs
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
PREDICTION EFFECT EQUATION OF EACH FACTOR BY QUADRATIC MODEL
Agglomerates (%w/w) = +2.21+1.61A-0.34B-0.20C-0.16AB-0.14AC Fines (%w/w) = +2.00-0.25A+1.78B+0.35C-

Implementatn of +0.038BC+0.65A2 +0.14B2+0.082C2 0.012AB+0.013AC+0.16BC+0.22A2+0.59B2+0.22C2
Control
Strategy %Process Efficiency (%) = +97.18+1.76A+0.52B-5.83C+0.50AB+0.50AC-0.50BC-1.92A2-1.39B2-3.69C2


Responses (Effects) Goal for Individual Responses
Y1 Agglomerates (%w/w) Agglomerates should NMT 2.5%w/w
Y2 Fines (%w/w) Fines should NMT 2.5%w/w
Determination of
Y3 Process Efficiency (%) To achieve the maximum process efficiency (%yield) NLT 95%w/w
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of Factors (Variables) Knowledge Space Design Space Control Space

Control A Spraying Rate (gm/min) 3-7 3.50-5.50 4.00-5.00
Strategy B Atomization Pressure (bar) 1-3 1.25-2.25 1.50-2.00
C Fluidization Air Velocity (cfm) 50-100 55-75 60-70

QTPP DRY MIXING- BLENDING (Contd…)
Optimization of CPPs of
Determination of
DRY MIXING- BLENDING PROCESS
CQAs
Quality Risk
Assessment of
CMAs &
CPPs BLENDING TIME
2
1 BLENDING SPEED
DoE
& Development
of Design Space
RISKS
PAT
&Development
of Feedback
Control system
INAPPROPRIATE BLENDING SPEED &/OR TIME
BLEND UNIFORMITY COMPROMISED
Implementatn of CONTENT UNIFORMITY COMPROMISED

Control
Strategy


OBJECTIVE To Optimize Critical Processing Parameters of Dry Mixing Process
Determination of
CQAs NO. OF FACTORS 2 EXPERIMENTAL DESIGN SELECTED
32 FULL FACTORIAL DESIGN
• In Dry Mixing Process, 2 Processing Parameters

Quality Risk
Assessment of
“High” were critical & required to be optimized
CMAs & • Moreover, It was required to investigate
CPPs interactive & quadratic relationship between
BLENDING TIME
factors & response to find out optimum ranges

“Medium” • Thus, 3 Level FFD is a time & cost effective best
option for optimization of 2 factors.
DoE • However 3 Level FFD facilitates investigation of
& Development
of Design Space interactive & quadratic relationship of factors &
B
“Low” response in the terms of multiplied 2FI & squared

main effects in the quadratic model equation
PAT A BLENDING SPEED

TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
&Development
of Feedback
Control system
3 NO. OF LEVELS Lf = 32 FP = 9
Factors (Variables) Levels of Factors studied

Implementatn of 0 1 2
Control A Blending Speed (in RPM) 8 10 12
Strategy B Blending Time (in minutes) 5 10 15


CPPs CQAs
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Prediction Effect Equation On Individual Response by QUADRATIC MODEL
Average Assay of Blend Uniformity =+99.61 +0.78A+2.32B-0.95AB-1.52A2-2.22B2

Implementatn of
Control RSD Of Blend Uniformity=+1.94-0.47A-1.45B+0.53AB+1.13A2+1.98B2
Strategy


Responses (Effects) Goals for Individual Responses
Y1 Avg. Assay of BU (%) To achieve average assay of BU in the range from 98 to 102%
Determination of Y2 RSD of BU(%) To achieve minimum variability in BU i.e. NMT2.0%
CQAs By Overlaying contour maps from each responses on top of each other, RSM was used to find out the IDEAL “WINDOW”
of operability-Design Space per proven acceptable ranges & Edges of Failure with respect to individual goals
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of Factors (Variables) Knowledge Space Design Space Control Space

Control A Blending Speed (RPM) 8.0-12.0 9.15-11.35 9.5-11.0
Strategy B Blending Time (minutes) 5.0-15.0 10.0-13.5 10.0-12.0


QTPP HARD GELATIN CAPSULE ENCAPSULATION
(Contd…)
Optimization of CMAs & CPPs of

Determination of
CQAs HARD GELATIN CAPSULE ENCAPSULATION PROCESS
Quality Risk
Assessment of
CMAs &
CPPs
A GLIDANT
B ANTIADHERANT
DoE
& Development
of Design Space
C FILLING RATE
PAT RISKS
&Development
of Feedback
Control system
INAPPROPRIATE FLOW PROPERTY & FILLING RATE INADEQUATE DISINTEGRATION
WEIGHT VARIATION & CONTENT NON UNIFORMITY INADEQUATE DISSOLUTION

Implementatn of
Control QUALITY COMPROMISED SAFETY COMPROMISED EFFICACY COMPROMISED
Strategy


(Contd…)
OBJECTIVE To Optimize CMAs & CPPs of Hard Gelatin Capsule Encapsulation.
Determination of
CQAs NO. OF FACTORS 3 EXPERIMENTAL DESIGN SELECTED
BOX BEHNKEN DESIGN
• In Hard Gelatin Encapsulation, 2 different

Quality Risk
Assessment of CMAs & 1 CPP required to be optimized. Due
CMAs & “High” to 3 factors, more no. of runs were required
CPPs for optimization in the case of CCD.
• Moreover, Here Region of Interest & Region
FILLING RATE
of Operability was nearly the same

Medium • Thus, BBD is an economic alternative to CCD
DoE for optimization of 3 factors simultaneously
& Development at 3 levels providing strong coefficient
C
of Design Space
estimates near the center of design space,
where presumed optimum with nearly same
“Low”
region of interest & region of operability.
A GLIDANT
PAT TOTAL NO OF EXPERIMENTAL RUNS (TRIALS) $
&Development
of Feedback
Control system
3 NO. OF LEVELS 12MP + 3CP =15
Factors (Variables) Levels of Factors Studied

-1 0 +1
Implementatn of A Glidant (%w/w) 0.10%w/w 0.25%w/w 0.40%w/w
Control B Lubricant (%w/w) 0.50%w/w 1.25%w/w 2.00%w/w
Strategy C Filling Rate (SPM) 50SPM 65SPM 80SPM


(Contd…)
CMAs CPP CQAs
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
PREDICTION EFFECT EQUATION OF EACH FACTOR BY QUADRATIC MODEL
Weight Variation =+1.53-0.21A-0.11B+0.37C- Content Uniformity=+3.03-0.35A-0.16B+0.74C-0.025AB-

0.025AC-0.025BC+0.28A2+0.18B2+0.91C2 0.075AC+0.61A2+0.43B2+1.83C2
Implementatn of
Control Disintegration Time =+3.23-0.21A+0.82B-0.16C- %Drug Dissolved in 30 minutes =+95.67+2.00A-
Strategy 0.17AB-0.050AC-0.075BC+0.66A2+1.03B2+0.058C2 4.25B+1.50C+1.00AB-0.50AC+0.50BC-4.58A2-7.08B2-0.083C2


(Contd…)
Responses (Effects) Goal for Individual Responses
Y1 Weight Variation Relative Standard Deviation in WV test should NMT 2.0%
Determination of
Y2 Content Uniformity Acceptance Value in CU test should NMT 4.0
CQAs Y3 Disintegration To achieve complete disintegration (no residue) within 5 minutes
Y Dissolution To achieve at least 95% drug release within 30 minutes
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Factors (Variables) Knowledge Space Design Space Control Space

Implementatn of A Glidant (%) 0.10-0.50 0.18-0.36 0.20-0.30
Control B Anti-adheant (%) 0.50-2.00 0.70-1.30 0.80-1.20
Strategy C Filling Rate (SPM) 50-80 58-72 60-70

What is PAT?
Definition of
QTPP
Determination of
CQAs
Process Analytical Technology (PAT)

Quality Risk
Assessment of
A System for-
CMAs & • Designing,
CPPs
• Analysing &
• Controlling Manufacturing
DoE
through Timely Measurements (i.e., during processing) of Critical Quality
& Development
of Design Space and Performance attributes of raw and in-process materials and
processes with the goal of ensuring final product quality.
PAT
&Development
of Feedback Note: Through PAT, Online Feedback Controlling System for each & individual CMAs &/or CPPs will be
Control system
developed through designing of controls by analysis at line/ on line/ in line analyser system
Implementatn of
Control
Strategy

IDENTIFICATION OF DESIGNING ANALYZING CONTROLLING
CRITICAL STEPs PHASE PHASE PHASE
Definition of PAT For

QTPP HARD GELATIN CAPSULE MANUFACTURING (Contd…)
AUTOMATIC CAPSULE
SHELL CONVEYING
Determination of SYSTEM AUTOMATIC
CQAs PRODUCT
CONVEYING SYSTEM
Quality Risk
Assessment of
CMAs & CAPSULE ORIENTS &
CAP/ BODY SEPARATES
FILLING STATION
BY TAMPING /
CPPs AUTOMATIC
PRODUCT
BY VACUUM SYSTEM DOSATOR SYSTEM
ELEVATOR SYSTEM
INLINE METAL
DETECTOR SYSTEM
DoE
& Development DEDUSTING &
of Design Space POLISHING
AUTOMATIC
CAPSULE FILLING SYSTEM
MACHINE
MINI CAPSULE
BIN BLENDER SORTER
FOR PRODUCT AIR DISPLACEMENT
MIXING UNIT
PAT EMPTY CAPSULE
EMPTY CAPSULE
ELIMINATOR by
&Development SHELL ELEVATOR VACCUM
of Feedback INLINE WEIGH
Control system CHECKING SYSTEM
DRY LOADING OF EMPTY SEPARATION OF FILLING OF CLOSING OF DE CLEANING &

CAPSULES CAP FROM BODY CAPSULES SORTINGREADY
CAPSULE
Implementatn of MIXING CAPSULES
DUSTING POLISHING
FOR PACKING
Control
Strategy A B C D E F G H
CRITICAL PROCESSING STEPS © Created & Copyrighted by Shivang Chaudhary


API / EXCIPIENT PURITY

Determination of analyzed by
CQAs At line UV/ HPLC/ GC,
On line LOD/ HMB or W/KF
API / EXCIPIENT PARTICLE

TEMPERATURE &
SIZE DISTRIBUTION
RELATIVE HUMIDITY
analyzed by At line Malvern
by At Line Thermo-
Particle Size Analyzer
hygrometer
OR On Line
Quality Risk Sieve Shaker Analysis
Assessment of
CMAs & MOISTURE CONTENT of
EMPTY CAPSULE SHELLS by
CPPs On line Halogen Moisture
Balance or At line
Water by KF
ONLINE METAL
DETECTOR SYSTEM
DoE
& Development
of Design Space
PAT BLENDING &

LUBRICATION ONLINE GROUP ONLINE GROUP ONLINE VISUAL INSPECTION
&Development Blend Uniformity WEIGHT WEIGHT FOR DEDUSTING, POLISHING
CAPSULE FILLING
of Feedback analyzed by At line CHECKING of CHECKING of & SORTING OF UNFILLED/
On Line Weight Variation &
Control system UV/HPLC system Empty Capsules Filled Capsules DEFECTIVE CAPSULES
Disintegration Testing
Implementatn of CAPSULE READY

FOR PACKING
Control
Strategy Risk Analysis of CMAs & CPPs with respect to CQAs at Raw Scale Developmental level
by ON LINE / AT LINE Analyzers for Prediction of Real Time Data &
Designing of Control Strategies at Commercial Scale

Determination of API / EXCIPIENT PURITY

CQAs analyzed by In line
Bruker FT NIR
API / EXCIPIENT PARTICLE

SIZE DISTRIBUTION TEMPERATURE &
by In Line Lasentec RELATIVE HUMIDITY
Focused Beam Reflectance by In Line Thermo-
Measurement (FBRM) hygrometer
Quality Risk
Assessment of
CMAs & MOISTURE CONTENT
CPPs OF EMPTY CAPSULE SHELLS
by Inline Bruker/ MT
FT_NIR System
INLINE METAL
DETECTOR SYSTEM
DoE
& Development IN LINE
of Design Space DEDUSTING &
POLISHING
SYSTEM
IN LINE MINI
CAPSULE
SORTER
WEIGHT VARIATION
PAT WEIGHT VARIATION
CONTENT UNIFORMITY
of Filled Capsules
IN LINE
EMPTY CAPSULE
&Development BLEND UNIFORMITY of Empty Capsules by In line ELIMINATOR by
of Feedback analyzed by In line Shells by In line analyzed by In Line Bruker FT-NIR Check Weigher VACCUM
Control system Bruker FT-NIR Check Weigher based on Gravimetric
based on Gravimetric EMFR System
EMFR System

FOR PACKING
Control Real Time Data Analysis at Scale UP-Exhibit Manufacturing Scale
Strategy by IN LINE analyzers with auto-sensors & Real time data comparison with Raw scale data
for Finalization of Control Strategies at Commercial Scale

Determination of
CQAs
Auto-controlling of
TEMPERATURE &
RELATIVE HUMIDITY
Air Handling Unit
Quality Risk (AHU)
Assessment of
CMAs &
CPPs
INLINE METAL
DETECTOR SYSTEM
Auto controlling
DoE ON/OFF System of
Machine
& Development IN LINE
of Design Space DEDUSTING &
POLISHING
SYSTEM
IN LINE MINI
CAPSULE
SORTER
Auto-controlling of
PAT Auto controlling of
BLEND UNIFORMITY
Auto Controlling of
EMPTY CAPSULE
FILLED CAPSULE WEIGHT &
PLUG HARDNESS by adjusting
INLINE WEIGHT
IN LINE EMPTY
CAPSULE
&Development CHECKING SYSTEM ELIMINATOR
by adjusting SHELL WEIGHT by Filing Turret Speed,
of Feedback auto controlling by VACCUM
Rotation Speed * adjusting Feeder Feed Frame Paddle speed
Control system Turret Speed of
Rotation Time = Speed for Empty Tamping Force, Dosator
Filled Capsules
Number of Revolutions Capsule shells Piston Stroke Volume

FOR PACKING
Control
Strategy Application of Auto-controllers at real time Manufacturing scale
For Continuously attaining Acceptable ranges of CMAs & CPPs with respect to desired CQAs
What is Control Strategy?
Definition of
QTPP
Determination of
CQAs
Control Strategy
Quality Risk
Assessment of
A planned set of controls for CMAs & CPPs-
CMAs & derived from current product and process understanding
CPPs
• During Lab Scale Developmental Stage
• Scaled Up Exhibit-Submission Stage
DoE that ensures process performance and product quality
& Development
of Design Space
• During Commercial Stage
PAT
&Development Note: For finalizing & implementation of Control Strategy for each & individual CMAs &/or CPPs; ranges
of Feedback
Control system studied at lab scale developmental stage will be compared with pilot plant scale up & pivotal
scale exhibit batches to ensure consistent quality of finished product
Implementatn of
Control
Strategy

CONTROL OF CONTROL OF
CMAs CPPs
Definition of CONTROL STRATEGY For

QTPP Critical Material Attributes
Ranges studied at Actual data Proposed range for
FACTOR(s) CMAs PURPOSE of Control
LAB scale for EXHIBIT batches COMMERCIAL batch
API- Critical Material Attributes
Polymorphic To ensure batch to batch
Determination of 2Ө values x, y, z x, y, z x, y, z
Form consistency in Dissolution
CQAs D10: NMT x um NMT x um NMT x um To ensure batch to batch
Particle Size D50: NMT y um NMT y um NMT y um consistency in Blend
Distribution Uniformity (BU), Content
(PSD) D90: NMT z um NMT z um NMT z um Uniformity (CU) &
Dissolution
Quality Risk To ensure batch to batch
Assessment of
Density or Bulk Density (BD) & BD: NLT 0.35gm/cc BD: NLT 0.40gm/cc BD: NLT 0.40gm/cc consistency good Flow
CMAs & Flow Property Tapped Density (TD) TD: NLT 0.45gm/cc TD: NLT 0.50gm/cc TD: NLT 0.50gm/cc Property in order to
CPPs ensure BU & CU.
To prevent physical or
Water Moisture Content NMT 3%w/w NMT 2.5%w/w NMT 2%w/w chemical reaction of API
with capsule shell.
FILL-EXCIPIENT Critical Material Attributes
DoE Microcrystalline 60#: ≥ 10%w/w 60#: ≥ 10%w/w 60#: ≥ 10%w/w To ensure batch to batch
& Development Particle Size Distribution
of Design Space Cellulose 100#: ≥ 50%w/w 100#: ≥ 50%w/w 100#: ≥ 50%w/w consistency in BU & CU
(Avicel PH during dry mixing for wet
200) Moisture Content NMT 5.0% NMT 3.0% NMT 2.0% granulation
Level in Formulation 4-10%w/w 7.5%w/w 6-8%w/w To give consistent binding
Polyvinylpyroli
functionality to granules
done (Pladone
PAT K 29/32)
K Value 29-32 29-32 29-32 to warrant hardness &
&Development
of Feedback
friability
Control system Colloidal Concentration (%w/w) 0.10-0.50 0.18-0.36 0.20-0.30 To promote consistent
Silicone Dioxide
flow property of granules
(Aerosil Specific surface area 175-225 m2/g 180-220 m2/g 185-215 m2/g
from hopper to die.
200 Pharma)
Concentration (%w/w) 0.50-2.00 0.70-1.30 0.80-1.20 To ensure consistent
Implementatn of Purified Talc
lubrication & smooth
Control (Vegetable
Specific surface area 10-20 m2/g 10-20 m2/g 10-20 m2/g ejection of compressed
Grade)
Strategy tablet from die.

CMAs CPPs

QTPP Critical Material Attributes
FACTOR(s) CMAs PURPOSE of Control
SHELL-EXCIPIENT Critical Material Attributes
Determination of
Type of Gelatin Type A (Acid bone) Type A (Acid bone) Type A (Acid bone)
pH 3.8–5.5 4.0–5.0 4.0-5.0
CQAs
Isoelectric point 6.0-9.5 7.0-9.0 7.0-9.0 To ensure batch to batch
Bloom or Gel Strength consistency in Cohesive
(weight in gms required strength of Cross linking
to move a plastic that occurs between
Quality Risk plunger i.e. 0.5 inches in gelatin molecules in
Assessment of
150-250 gm 170-240 gm 180-230 gm empty gelatin shell
diameter 4 mm into
CMAs & 62/3% gelatin gel that in order to ensure
GELATIN
CPPs as a base
has been held at 10°C physical strength
for 17 hours)
Concentration (%w/w) 35-45% 36-44% 38-42%
To ensure batch to
Viscosity of 62/3%
batch consistency of
DoE Gelatin Solution 2.7-3.7 mPa 2.7-3.2 mPa 2.7-3.0 mPa
Molecular Chain length
& Development at 60°C
of Design Space for Mfg. consistency
To prevent physical or
Moisture Content 10-15%w/w 12-15%w/w 12-15%w/w chemical reaction of API
with empty capsule shell
Glycerin as a Dry Glycerine to To prevent softening
PAT PLASTICIZER Dry Gelatin Ratio
0.25-0.55 0.30-0.50 0.35-0.45
(tacky) or hardening
&Development
of Feedback Water to (brittleness) of shell
0.70-1.30 0.90-1.10 0.90-1.10
Control system WATER as Dry Gelatin Ratio retarded dissolution &
solvent handling problems during
Concentration (%w/w) 30-50% 35-45% 38-42%
processing/ packaging
To prevent chemical
Implementatn of Iron Content in reaction with certain
Control IRON NMT 15 ppm NMT 12 ppm NMT 10ppm
raw gelatin FD&C dyes & organic
Strategy compound

CMAs CPPs

QTPP Critical Processing Parameters
FACTOR(s) CPPs PURPOSE of Control
FILL MATERIAL PREPARATION (DRY MIXING-BLENDING)
30# 30# 30# To ensure PSD consistency
Determination of
Co-Sifting Screen Mesh # Size
(NMT 5% ≥ 600um (NMT 3% ≥ 600um (NMT 1% ≥ 600um to prevent segregation
CQAs Inlet Air Temperature 25-40°C 28-37°C 30-35°C To ensure batch to batch
Binder Spraying Rate 3-7 gm/min 3.50-5.50 gm/min 4.0-5.0 gm/min consistency in PSD, BD &
Fluid Bed
GRANULATION
Atomization Pressure 1-3 bar 1.25-2.25 bar 1.50-2.00 bar TD in order to warrant
Fluidization Velocity 50-100 cfm 55-75 cfm 60-70 cfm Uniform Flow property, BU,
Fill Level (%v/v) 30-70% 40-60% 45-55% CU & Desired Dissolution
Quality Risk Blending Speed 8.0-12.0 RPM 9.5-11.5 RPM 9.5-11.0 RPM To ensure batch to batch
Assessment of Blending &
Blending Time 5.0-15.0 Min 11.0 Min 10.0-12.0 Min consistency in Blend
CMAs & Lubrication
Fill Level (%v/v) 30-70% 40-60% 45-55% Uniformity & Dissolution
CPPs SHELL MATERIAL PREPARATION (MOLD PIN DIPPING TECHNIQUE)
SPINNING Rotation Speed X-Y RPM (X+3) – (Y-3) RPM (X+5) – (Y-5) RPM To prevent softening
(tacky) or hardening
DRYING Inlet Air Temperature 20°-30°C 23°-28°C 23°C-28°C (brittleness) of shell &
handling problems .
DoE HARD GELATIN CAPSULE FILLING PROCESS (ENCAPSULATION)
& Development
of Design Space TAMPING & TAMPING & TAMPING &
Filling Principle To ensure batch to batch
Dosing Disc Dosing Disc Dosing Disc consistency in Weight
Dosing Disk Size Size “1” Size “1” Size “1” variation in order to
Filling Rate 50-80 58-72 60-70 ensure Content Uniformity
Hard Gelatin Turret Speed 10-40 RPM 10-30 RPM 15-25 RPM without any crack
PAT Capsule FILLING To ensure batch to batch
&Development
of Feedback
& LOCKING consistency in Hardness of
Control system plug & Dissolution in order
Tamping Force 0.5-3.0 kN 1.0-2.0 kN 1.0-1.5 kN
to Dissolution without any
defects (Bent/ Dents/
Telescope/ Spilt )
++ ++ ++ ++
De-dusting & Liquid Spraying Rate X-Y gm/min X -Y gm/min X -Y gm/min To ensure batch to batch
Implementatn of
POLISHING Pan Rotation Speed 3-10 RPM 3-8 RPM 4-7RPM consistency in Appearance
Control Temperature 21°C-25°C 21°C-25°C 21°C-25°C To ensure batch to batch
Strategy ENVIRONMEN
Physical & Chemical
TAL Factors Relative Humidity <40%RH <30 %RH <30 %RH
Stability
Conclusion
Through QbD, Risk associated with each & every CMAs & CPPs
with respect to CQAs identified from QTPP were effectively & extensively assessed
out by FMEA (Failure Mode Effective Analysis), which decided “which risk should get
first priority?” based upon Severity * Probability * Detectability of individual risk.
Severity of Risks could Not be reduced
RPN = Probability * Severity * Detectability

Probability of Risk occurrence was reduced Detectability of Risk was increased by
by systematic series of experiments through implementation of automatic inline
Designing of Experiments (DoE) Process Analytical Technology (PAT)
which generated safe & optimized ranges of which ensured timely measurement of critical
CMAs & CPPs with respect to desired CQAs par quality and performance attributes of raw and
overlaid DESIGN SPACE, where all the desired in-process materials or parameters
in process & finished product CQAs are to control the quality
met simultaneously. of finished product.
Justification for
Risk
Reduction

What is Continual Improvement?
During Routine
Commercial Manufacturing Continual
Risk Review & Risk Communication
between Stockholders of:
FORMULATION
R&D
QUALITY ANALYTICAL
CONTROL R&D
QUALITY REGULATORY
ASSUARANCE AFFAIRS
MANUFACTURING
PLANT
For continual assurance that the process remains in a state of control
(the validated state) during commercial manufacture.
For Excellent Product
Management of
Lifecycle Management
Product Throughout the product lifecycle, the manufacturing process performance will be monitored to ensure that
Life it is working as anticipated to deliver the product with desired quality attributes. Process stability and process capability
will be evaluated. If any unexpected process variability is detected, appropriate actions will be taken
Cycle to correct, anticipate, and prevent future problems so that the process remains in control.
“Quality doesn’t costs, it always pays”
Created & Copyrighted by
Formulation Engineer (QbD/PAT System Developer & Implementer)

MS (Pharmaceutics)- National Institute of Pharmaceutical Education & Research (NIPER), INDIA
PGD (Patents Law)- National academy of Legal Studies & Research (NALSAR), INDIA
facebook.com/QbD.PAT.Pharmaceutical.Development
https://in.linkedin.com/in/shivangchaudhary
 +91 -9904474045, +91-7567297579
© Copyrighted by Shivang Chaudhary
 shivaniper@gmail.com

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Definition of

QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION

PAT Designed & Developed by

Formulation Engineer (QbD/PAT System Developer & Implementer)

• Stable & Therapeutic

© Created & Copyrighted by Shivang Chaudhary

QbD & Its Elements

Quality Risk Assessment of

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Designing of Experiments (DoE) & Design Space

PAT Process Analytical Technology (PAT)

Implementatn of Implementation of Control Strategy

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QUALITY TARGET PRODUCT PROFILE (QTPP)

Note: QTPP will be finalized -

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Definition of Quality Target Product Profile (QTPP) of HGC

Fasting Study and/or Fed BE Study

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Critical Quality Attribute (CQA)

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Definition of Critical Quality Attributes (CQA) of HGC

Assay variability will affect SAFETY AND EFFICACY. Process variables

NLT X % (Q) of labeled amount of

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Critical Material Attribute (CMA)

• to ensure the process produces the desired quality product.

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Definition of Identification of Factors involved in

Drug PSD & Flow ability

Inlet air Volume,

CPPs Capacity utilized,

Granule4 PSD Granule PSD

Granule PSD & Flow ability

Definition of Identification of Risk Factors by

LIQUID ADDITION RATE

INLET AIR TEMPERATURE

© Created & Copyrighted by Shivang Chaudhary

© Created & Copyrighted by Shivang Chaudhary

PAT Probability* Severity** Detect ability*** Score

Quality Risk A SOLID STATE FORM

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Quality Risk FP CQAs Gelatin Plasticizers Water Preservative Colorant Opacifier

© Created & Copyrighted by Shivang Chaudhary

© Created & Copyrighted by Shivang Chaudhary

DoE D GLYCERINE: DRY GELATIN

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Risk Based MATRIX ANALYSIS for CMAs of

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DoE Amount of Less than

Flow of granules or powder from hopper to die by reducing

Ejection of finished product from tooling may be difficult=

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© Created & Copyrighted by Shivang Chaudhary

Definition of Qualitative Risk based Matrix Analysis of

HARD GELATIN CAPSULE FILLING

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Definition of Quantitative Failure Mode Effect Analysis (FMEA) of

Determination of FILL MATERIAL PREPARATION (DRY MIXING-BLENDING)

Appearance (Gelatin Shell Thickness Uniformity),

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Definition of Quantitative Failure Mode Effect Analysis (FMEA) of

PAT Probability* Severity Detect ability* Score