A Model: Solid Oral Soft Gelatin Capsules

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

Determination of
OF ENCAPSULETED SOLID ORAL DOSAGE FORM-SOFT GELATIN CAPSULES
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 SG 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 SGC

QTPP QTPP Element Target Justification
Pharmaceutical equivalence requirement:
Dosage FORM Soft 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 Bio-equivalenceStudy
Bioequivalence requirement needed
90 % confidence interval of the PK parameters, AUC0-t, ,
Pharmaco-KINETICS to 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 flavored & colored for possessing
Control PATIENT ACCEPTANCE &
acceptable taste ( in case of soluble/ dispersible/
effervescent tablet) similar with Reference Product.
Required to achieve the desired patient
Strategy PATIENT COMPLIANCE
Can be easily administered/used similar with
acceptability & suitable compliance
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 SGC

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
Quality Risk Assay Yes may affect the assay of the drug product. Thus, assay will be evaluated
Assessment of labeled claim.
throughout formulation and process development.
CMAs & Conforms to USP <905> Uniformity
Variability in content uniformity will affect SAFETY AND EFFICACY.
CPPs Weight Variation/ of Dosage Units: 90.0-110.0 % of
Yes Both formulation and process variables may impact content uniformity, so this
Content Uniformity labeled claim with AV:
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.
PAT Residual Conforms to USP
Residual solvents can impact SAFETY, but as it will be primarily
&Development Yes* controlled during drug substance & drug product manufacturing by drying,
of Feedback Solvents <467> option 1
Therefore, Formulation and Process variables are unlikely to impact this CQA.
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.
Implementatn of NLT X % (Q) of labeled amount of

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

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
Identification of Factors involved in
SOFTGEL CAPSULE ENCAPSULATION Process Map
Definition of
QTPP
Processing Input Materials Manufacturing Quality Attributes of
Parameters Attributes Process Steps Output Materials4
Type, pH, Iso electric point,
Bloom Strength, Viscosity &
Moisture content, Microbial GEL MASS Assay, Impurities,
Melting Temperature & Time Content of GELATIN GEL MASS PREPARATION Appearance, Bulk Uniformity
Determination of
Type of Homogenizer Dry Glycerin to Gelatin Ratio, (SHELL) Viscosity/ Rheology, Sp. Gr /
CQAs Homogenization Speed & Time Water to Gelatin Ratio, Density, Moisture Content,
De-aeration Stirring time & Preservative concentration Residual Solvent
Deaeration Vacuum pressure
Drug substance PSD, Specific
Surface area, Hygroscopicity,
Moisture Content. Vehicle FILL MATERIAL Assay, Related
Quality Risk Type of Mill & Mixer purity, polarity, pH, Viscosity, Substances, Moisture Content
Assessment of Milling / Homogenization Rate Specific Gravity, Volatility, FILL MATERIAL Residual Solvents, Bulk
CMAs & Heating Temperature & Time Surfactant concentration
Preservative concentration
PREPARATION (DRUG) Uniformity, Viscosity/ Rheology
Specific . Gravity / Density
CPPs De-aeration Stirring time
Deaeration Vacuum pressure
Physical Attributes (Ribbon
Appearance, Bulk Uniformity,
Gap between Spreader Box & Thickness, Seal Thickness),
Viscosity/ Rheology, Sp. Gr / SPREADING OF GEL MASS
Rotating Drum Disintegration time,
Density, Moisture Content,
Rotating Drum Temperature Residual Solvent of GEL MASS INTO UNIFORM RIBBON Dissolution, Assay, Impurities,
DoE Rotating Drum Speed Uniformity of Dosage units,
& Development Ribbon Thickness
of Design Space Assay, RS, Moisture Content, Physical Attributes
Residual Solvents, Bulk (Appearance (Overfill/ Under
Uniformity of FILL MATERIAL fill/ entrapped Air bubble )
Stroke Volume Adjustment Viscosity/ Rheology METERING & FILLING Assay, Impurities (RS),
Die Roller Speed Specific Gravity/ Density Weight Variation,
Die Roller Temperature Uniformity of Dosage units,
PAT Disintegration Time,
Dissolution profiling
&Development Fill Material Bulk Uniformity
of Feedback
Control system
Viscosity/ Rheology,
CUTTING & SEALING Physical Attributes, Assay,
Die Roller Gap Specific Gravity / Density
Related Substances,
Die Roller Temperature (Dimensions/ Defects),
Seal thickness
Naphtha wash Spraying Rate
Type & Solubility of Lubricant Physical Attributes (color,
Primary Tunnel Drying
Implementatn of Moisture Content & Residual flavor. Taste, Assay, Impurity,
Temperature & Rotation Speed WASHING & DRYING
Control Secondary Tray Drying Area
Solvent of Filled Capsule Residual Moisture Content,
Residual Solvent
Strategy Temperature & Humidity
Secondary Tray Drying Period
Environment (Temperature & RH)
RISK RISK RISK RISK
Definition of Identification of Risk Factors by

QTPP Ishikawa Fishbone Diagram
Determination of
CQAs MATERIAL
ATTRIBUTES
API PSD & WATER CONTENT
ENCAPSULATION IONIC NATURE OF SURFACTANT
DENSITY/SP.GRAVITY & SOLVENT TYPE & CONC

Quality Risk VISCOSITYOF SOLUTION
Assessment of
STROKE VOLUME CO-SOLVENT TYPE & CONC
CMAs & ENVIRONMENT
RIBBON THICKNESS TYPE OF GELATIN
CPPs TEMPERATURE
DIE ROLLER SPEED
SOURCE OF GELATIN
ROLLER GAP/ THICKNESS
RELATIVE
CUTTING/ SEALING TEMP. STORAGE & MAINTENANCE TEMP.
HUMIDITY
SEAL THICKNESS/ INTEGRITYPRESERVATIVE TYPE & CONC.
SURFACTANT CONC.
COLOR SOURCE & CONC.
DoE SHELL RESIDUAL MOISTURE HOMOGENIZATION TIME
WATER: GELATIN RATIO
& Development TOTALEXPOSURE TIME HOMOGENIZATION SPEED
of Design Space GLYCERIN: GELATIN RATIO.
TRAY DRYING HUMIDITY NO OF RECYCLES
VACUUM PRESSURE
TRAY DRYING TEMP. COLLOID MILL SPEED
GELATIN MELTING TEMP.
INFRARED DOSE COLLOID MILL SCREEN SIZE
GELATIN MASS
DRUG SOLUTION/ PREPARATION
WASHING &
SUSPENSION
PAT
DRYING
PREPARATION
&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
Solid state Particle Size Hygro Moisture Residual Process Chemical

Quality Risk FP CQAs Solubility
Assessment of /Polymorph Distribution Scopicity content Solvent Impurity Stability
CMAs & Physical High Low High Low Low High Low Low
CPPs Assay Low Low Low Low Low High High High
Uniformity Low High Low Low Low High Low Low
Impurities Low Medium High Medium Medium Low High High
Dissolution High* High* 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
Physico- Critical
Failure Mode
Chemical Material Effect on IP & FP CQAs with respect to QTPP
(Critical P S D RPN (=P*S*D)
Property of Attribute (Justification of Failure Mode)
Event)
Actives (CMAs)
Determination of
Different Solubility of drug substance may get affected=
CQAs Solid Sate
Form
Polymorph/ >> Dissolution of drug product may get affected 2 4 4 32
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
Rate of degradation may be affected
Physical High water
Quality Risk Hygroscopicity = Impurity profile may be affected 3 4 3 36
Property content
Assessment of = Safety may got compromised
CMAs & High water
Rate of degradation of moisture sensitive API may get
Moisture content affected >> Impurity profile may get affected 3 4 3 36
CPPs content
>> SAFETY may get compromised
Residual solvents are likely to interact with drug substance
High residual
Residual Solvents >> Impurities profile may get affected 2 3 3 18
solvent
>> SAFETY may get compromised
Different Salt/ Dissolution of the drug product may get affected
Solubility 2 4 4 32
DoE Form >> BIOAVAILABILITY-EFFICACY may got compromised
Assay & Content Uniformity may be affected
& Development Volatility High 2 3 4 24
of Design Space >> EFFICACY may get compromised
Chemical
Process Assay & impurity profile of drug product may be affected =
Property Less Purity 2 3 3 18
Impurities >> Quality & SAFETY may got compromised
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
of Feedback Very Unlikely Minor Always Detected 01
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
Assessment of
A SOLID STATE FORM
CMAs &
CPPs B PARTICLE SIZE
C SOLUBILITY
DoE D HYGROSCOPICITY
& 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
FP CQAs Gelatin Plasticizers Water Preservative Colorant Opacifier

Quality Risk
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 Broadly acceptable risk. No further investigation is needed

DoE Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
& Development
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 Gel Lower than
>> PHYSICAL STABILITY may get affected 4 4 2 32
CQAs Strength optimum< 150g >> Patient Acceptance may get compromised
Capsule shell may get brittle & hard
Viscosity (38±2 Higher than
>> Disintegration/Dissolution of the shell may get affected 4 4 2 32
milipose) 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
Moisture Content >> Bioavailability-EFFICACY may get compromised
Quality Risk LEVEL OF IMPURITIES of the Hygroscopic/
Assessment of (NMT 12-15%w/w)
Higher than Moisture sensitive product may get increased
CMAs & optimum >> CHEMICAL STABILITY may get compromised
3 4 3 36
>> SAFETY of the patient may get compromised
CPPs Capsule shell may get BRITTLE & HARD
Ratio of Dry Less than >> Physical Properties of Shell may get altered
>> Disintegration/Dissolution of the shell may get affected
4 4 3 48
Plasticizer to Dry optimum
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 Capsule shell may get BRITTLE & HARD
& Development Less than >> Physical Properties of Shell may get altered
of Design Space >> Disintegration/Dissolution of the shell may get affected
4 4 3 48
Ratio of Water to optimum
>> 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
MICROBIAL LOAD may get increased during
PAT Anti-Microbial
Concentration of
Anti-Microbial
Less than
optimum
transportation, storage & in-use
>> MICROBIOLOGICAL STABILITY may get compromised
2 3 4 24
&Development
of Feedback >> SAFETY of patient may get compromised
Control system LEVEL OF OXIDIZED IMPURITIES of the product may get increased
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 Lower than Shine variation/ Mottling may be observed
3 3 2 18
Concentration of optimal >> Patient ACCEPTNCE/ COMPLIANCE nay get compromised
Strategy Opacifier
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 MATERIAL 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
Surfactants Preservatives Organoleptic Additives

Solvents/ Hydrocolloid
(Solubilizing/ Buffering
Quality Risk FP CQAs Co-solvents/ (Suspending Anti Anti
Assessment of Wetting agent Colors Flavors Sweeteners
Vehicles agent) Microbial Oxidant
CMAs & agents)
CPPs Physical High High High Low Low Low High Low Low
Assay High Low Low Low Low Low Low Low Low
Uniformity High Low Low Low Low Low Low Low Low
Impurities High Medium Low Medium Medium Medium Low Medium Low
Dissolution Low High Low Medium Low Low Low Low Low
DoE
& Development
of Design Space Low Broadly acceptable risk. No further investigation is needed
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
Excipient Critical Failure Mode
Effect on IP & FP CQAs with respect to QTPP
(Inactive Material (Critical P S D RPN (=P*S*D)
(Justification of Failure Mode)
ingredient) Attribute Event)
Drug Substance may NOT get completely SOLUBILIZED or uniformly
Less than
DISTRIBUTED >> CONTENT UNIFORMITY may get affected 3 3 3 27
Quantity of optimum >> SAFETY & EFFICACY may get compromised
Determination of Vehicle/ Solvent
Solvents/ Co- More than Product may get BULKIER to handle
4 3 2 24
CQAs solvents/ Vehicles optimum >> Patient ACCEPTANCE & COMPLIANCE may get compromised
Source of VEHICLE is natural i.e. PLANT OR ANIMAL BASED ORIGIN
Source of Vehicle/
Natural without >> Potential for microbial attack & growth
Solvents/ Co- >> MICROBIOLOGICAL STABILITY may get compromised 2 3 4 24
purification
solvents >> SAFETY of the patient may get compromised
If surfactant is positively/ negatively CHARGED
Ionic Nature of Cationic/ Anionic >> INCOMPATIBLE with anionic/cationic drugs /preservatives /
primary packaging material >> CHEMICAL / MICROBIOLOGICAL STABILITY 3 3 3 27
Surfactant in nature
may get compromised >> SAFETY of the patient may get compromised
Quality Risk Drug Substance/ Preservatives may NOT getting effectively SOLUBILIZED/
Assessment of DISTRIBUTED within system >>SAFETY & EFFICACY may get compromised 3 4 4 48
Surfactants (As a
CMAs & Solubilizing/
Less than
optimum
ZETA POTENTIAL of the system may be too low
>> Particles COALESCE & flocculated suspension forms >> Suspension start to
3 4 4 48
Wetting agents) Concentration of
CPPs Surfactant
form REDISPERSIBLE SEDIMENT >> PHYSICAL STABILITY may get
compromised >> SAFETY & EFFICACY may get compromised
ZETA POTENTIAL of the system may be too high
More than >> Particles REPEL each other & forms deflocculated suspension which upon
settled down invariably leads to form HARD CAKE >> PHYSICAL STABILITY 3 4 4 48
optimum
may get compromised >> SAFETY & EFFICACY may get compromised
VERY LOOSE FLOCS will be formed through reducing forces of repulsion
Less than >> Particles repel each other & forms deflocculated suspension which upon
Electrolytes (As a 3 4 4 48
DoE Controlled Concentration of
optimum settled down invariably leads to form HARD CAKE >> PHYSICAL STABILITY
may get compromised >> SAFETY & EFFICACY may get compromised
& Development Flocculating Electrolytes HARD BOUND FLOCS will be formed by increasing forces of coalescence
of Design Space More than >> Particles COALESCE & flocculated suspension forms >> Suspension start to
Agent) form REDISPERSIBLE SEDIMENT >> PHYSICAL STABILITY may get 3 4 4 48
optimum
compromised >> SAFETY & EFFICACY may get compromised
Source of hydrocolloid is natural i.e. PLANT OR ANIMAL BASED ORIGIN
Source of
Natural >> Potential for microbial attack & growth >> MICROBIOLOGICAL STABILITY 2 3 4 24
Hydrocolloid may get compromised >> SAFETY of the patient may get compromised
Hydrocolloid (As VISCOSITY of dispersion medium may be too low
a Supporting Less than >> Rate of SEDIMENTATION will be high
3 4 4 48
PAT Structured
Vehicle)
Concentration of
Hydrocolloid
optimum >> PHYSICAL STABILITY may get compromised
>> SAFETY & EFFICACY may get compromised
&Development More than VISCOSITY of dispersion medium may be too high
of Feedback >> POUR ABILITY of the product may get compromised 3 3 2 18
optimum >> PATIENT COMPLIANCE may get compromised
Control system
Within SOLUBILITY of the weak acidic / weak basic drugs may get affected
>> EFFICACY may get compromised 3 3 3 27
Neutral Range
Buffering Agent pH of the Buffer
Within Acidic/ CHEMICAL STABILITY of pH sensitive drugs/ preservatives may get affected
>> SAFETY of patient may get compromised 3 3 3 27
Basic Range
MICROBIAL LOAD may get increased during transportation, storage & in-use
Concentration of Less than
Anti-Microbial >> MICROBIOLOGICAL STABILITY may get compromised 3 3 4 36
Implementatn of Anti-Microbial optimum >> SAFETY of patient may get compromised
Control Anti-Oxidant
Concentration of
Anti-Oxidant
Less than
optimum
LEVEL OF OXIDIZED IMPURITIES of the product may get increased >>
CHEMICAL STABILITY may get compromised 3 3 4 36
Strategy Concentration of
APPEARANCE of the product may not be pleasant
Coloring agent
Coloring Agent
Not optimum >> Patient ACCEPTANCE may get compromised 3 3 2 18

RISK RISK RISK RISK
Definition of
CRITICAL
Determination of
CQAs
CMAs of
FILL MATERIAL EXCIPIENTS
Quality Risk
Assessment of A VEHICLE/ SOLVENT QTY
CMAs &
CPPs B SURFACTANT CONC
C HYDROCOLLOID CONC.
DoE D PRESERVATIVE CONC.

& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

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

QTPP SGC Manufacturing Processing Steps
SHELL MATERIAL PREPARATION
Melting of Gelatin Base Mixing with Plasticizer, Maintenance & Storage
FP CQAs under vacuum Preservative, Colorant of Soft Gelatin Shell
Determination of
(29.5"Hg) at 93°C & Opacifier Material at 60°C
CQAs Description High High Low
Assay Low Low Low
Impurities High Low High
Uniformity Low Low Low
Dissolution Low High High
Quality Risk
Assessment of
CMAs & FILL MATERIAL PREPARATION
CPPs
Initial Mixing with Milling or De aeration of Drug
FP CQAs
Surfactant or Hydrocolloid Homogenization Solution/ Suspension at 60°C
Description Low Low High
Assay Medium High High
DoE Impurities Low Low High
& Development
of Design Space
Uniformity Medium High High
Dissolution Low Low Low
CAPSULE FILLING (ENCAPSULATION) PROCESS

PAT Metering/Stroke Injecting & Filling of
Cutting of Ribbons &
Washing in
&Development Spreading of Gelatin Sealing of Capsules by
of Feedback adjustment of Drug Product into Gelatin Naphthbath & Drying
Control system FP CQAs Film as a Uniform mechanical pressure
Solution/ Suspension Die pocket under in Infrared dryer &
Ribbon on die rolls & heating
to be filled pressure then Tray Dryer
of ribbons
Description High Low High High High
Assay Low Low Low Low Low
Implementatn of Impurities Low Low Low Low Low
Control Uniformity Low High High Low Low
Strategy Dissolution High Low Low Low Low

RISK RISK RISK RISK

QTPP Processing Parameters
Critical Process Failure Mode Effect on IP & FP CQAs with respect to QTPP RPN
Unit Operations P S D
Parameter (CPPs) (CriticalEvent) (Justification of Failure Mode) (=P*S*D)
SHELL MATERIAL PREPARATION
Determination of Impurity profile & Physical Attributes may get affected

Melting Rate Higher than
CQAs Melting of Gelatin
(Temperature * Time) optimum >> SAFETY & PATIENT ACCEPTANCE may get compromised
Base under vacuum

Oxidized Impurity profile may increased due to air entrapment >>
Lower than
Vacuum Pressure CHEMICAL STABILITY may get compromised 2 3 4 24
optimum >> SAFETY may get compromised
Mixing with Physical Attributes (FLEXIBILITY, TENSILE STRENGTH, appearance)

Quality Risk
Assessment of Plasticizer, Water Mixing Rate Lower than & Disintegration-Dissolution profiling may get affected >> PHYSICAL
3 3 3 27
Preservative & (Speed * Time) optimum STABILITY & BIOAVAILABILITY may get compromised >> SAFETY &
CMAs & Colorant EFFICACY may get compromised
CPPs Temperature Higher(>25°C) 3 4 4 48

Impurity profiling may get affected
Storage of
>> CHEMICAL STABILITY may get compromised
Soft Gel mass Relative Humidity Higher (>40%RH) >> SAFETY may get compromised 3 4 4 48
FILL MATERIAL PREPARATION
DoE Physical Attributes, ZETA POTENTIAL, VISCOSITY, Fill Weight

& Development Mixing Rate Lower than Variation, Content Uniformity & ultimately Assay may get affected
of Design Space 3 3 3 27
Initial Mixing with (Speed * Time) optimum >> PHYSICAL STABILITY may get compromised
Surfactant or
Hydrocolloid
Impurity profile & ultimately Assay may get affected
Heating Rate Higher than
(Temp*Time) optimum >> SAFETY may get compromised
PAT Screen/ Mesh Size Incorrect Physical Attributes, PARTICLE SIZE DISTRIBUTION, Fill Weight
3 3 3 27
&Development Homogenization / Variation, Content Uniformity & ultimately Assay may get affected
of Feedback Rate of Milling / Higher than
Control system
Milling >> PHYSICAL STABILITY may get compromised 3 3 3 27
Homogenization optimum >> SAFETY & EFFICACY may get compromised
Physical Attributes (Appearance) may get affected

Stirring Rate Lower than
>> PHYSICAL STABILITY may get compromised 3 3 2 18
(Speed* Time) optimum >> PATIENT ACCEPTANCE may get compromised
De aeration of Drug
Implementatn of
Solution/ Suspension Air entrapment-Oxidized Impurity profile, Fill Weight variation-
Control Vacuum Pressure
Lower than Content uniformity & ultimately Assay may get affected
2 3 4 24
optimum >> CHEMICAL STABILITY may get compromised
Strategy >> SAFETY & EFFICACY may get compromised

RISK RISK RISK RISK

Critical Process Failure Mode Effect on IP & FP CQAs with respect to QTPP RPN
Unit Operations P S D
Parameter (CPPs) (CriticalEvent) (Justification of Failure Mode) (=P*S*D)
ROTARY DIE ENCAPSULATION PROCESS
Determination of Rotating Drum Higher than Physical STRENGTH (Firm Appearance) may be affected
3 3 2 18
Temperature optimum >> PATIENT COMPLIANCE may get compromised
CQAs Spreading of
Gelatin layer into
uniform ribbon Physical SEAL THICKNESS & Dissolution profiling may get affected
Higher than
Ribbon Thickness >> BIOAVAILABILITY may get compromised 3 4 4 48
Optimum >> SAFETY & EFFICACY may get compromised
Quality Risk
Assessment of
CMAs & Metering of Drug
Solution/ Suspension
Stroke Volume
adjustment
Lower than
optimum
Uniformity of Fill Weight & CONTENT may get affected
3 3 3 27
CPPs
Higher than Fill Weight Variation, Content Uniformity & ultimately Assay may get
Die Roller Speed 3 4 4 48
optimum affected >> SAFETY & EFFICACY may get compromised
Injecting & Filling of
DoE Product into Gelatin
Die pocket
& Development Impurity profile & ultimately Assay may get affected
of Design Space
Higher than
Die Roller Temperature >> CHEMICAL STABILITY may get compromised 3 4 4 48
optimum >> SAFETY may get compromised
Die Roller Gap Higher 3 3 2 18

Cutting of Ribbons Physical Strength (SEAL THICKNESS) may get affected
PAT & Sealing of
Capsules
>> PHYSICAL STABILITY may get compromised
>> PATIENT ACCEPTANCE may get compromised
&Development Die Roller Temperature Lower 3 3 2 18
of Feedback
Control system
Higher than Physical Attributes (POLISHED Appearance) may get affected

Spraying Rate 3 3 2 18
optimum >> PATIENT ACCEPTANCE may get compromised
Washing &
Implementatn of Drying
Control Drying Rate (Temp/
Not optimum
Physical Attributes & Impurity profiling may get affected
3 3 3 27
Dose * Time) >> PATIENT ACCEPTANCE & SAFETY may get compromised
Strategy

RISK RISK RISK RISK
Definition of CRITICAL
Determination of
CQAs
Quality Risk
Assessment of
CMAs & MELTING/ HEATING
CPPs 1 TEMPERATURE
DoE
& Development GELATIN LAYER
of Design Space 2 THICKNESS
PAT
&Development
of Feedback ROTARY
Control system
3 DIE
SPEED
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 CMAs of SHELL MATERIAL EXCIPIENTs
Determination of
Optimization of CMAs of
CQAs SoftGel Shell Material Excipients
Quality Risk
Assessment of
CMAs & 2 GLYCERINE : DRY GELATIN RATIO
CPPs
1 WATER : DRY GELATIN RATIO
DoE
& Development
of Design Space
RISKS
PAT
&Development
of Feedback
Control system
LONGER DISINTEGRATION TIME
DRUG RELEASE SUSTAINED
Implementatn of ACTION DELAYED

Control
Strategy


QTPP CMAs of SHELL MATERIAL EXCIPIENTs (Contd…)
OBJECTIVE To Optimize Critical Formulation Variables of Soft Gelatin Capsule Shell
Determination of
CQAs
NO. OF FACTORS 2
NO. OF LEVELS 3
Quality Risk
Assessment of EXPERIMENTAL DESIGN
CMAs &
WATER : GLYCERINE
SELECTED
CPPs
32 FULL FACTORIAL DESIGN
ADD. CENTER POINTS 2

DoE
B
& Development
of Design Space
TOTAL NO OF 32 FP
EXPERIMENTAL RUNS =9
(NO OF TRIALS)
PAT
&Development
of Feedback A WATER : GELATIN
Control system
Factors (Variables) Levels of Factors studied

0 1 2
Implementatn of A Water: Dry Gelatin Ratio 0.70 1.00 1.30
Control B Glycerine: Dry Gelatin Ratio 0.30 1.05 1.80
Strategy


CMAs CQA
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, THEIR INTERACTIONS & CURVATURES

ON INDIVIDUAL RESPONSE BY QUADRATIC MODEL
Implementatn of
Control DISINTEGRATION TIME=+11.22 -7.67A +4.83B -0.50AB +3.67A2 +1.17B2
Strategy


DISINTEGRATION TIME Goals for Individual Responses

Y1 Disintegration Time To achieve disintegration of soft gelatin capsule within 10 minutes
Determination of
CQAs
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 Water: Dry Gelatin Ratio 0.70-1.30 0.87-1.30 0.90-1.10
Control B Glycerine: Dry Gelatin Ratio 0.30-1.80 0.30-1.45 0.60-0.80
Strategy


QTPP SOFT GELATIN CAPSULE ENCAPSULATION
Optimization of CPPs of
Determination of
CQAs
Soft Gelatin Capsule
Encapsulation Process
1 MELTING/ HEATING
Quality Risk
Assessment of TEMPERATURE
CMAs &
CPPs GELATIN
2 LAYER
THICKNESS
DoE ROTARY
& Development
of Design Space 3 DIE
SPEED
PAT RISKS
&Development
of Feedback
Control system
IMPROPER MACHINE SPEED THICKENED SOFTGEL LAYER HIGHER TEMPERATURE
WEIGHT VARIATION INADEQUATE DRUG RELEASE IN-PROCESS IMPURITIES

Implementatn of
Control QUALITY COMPROMISED EFFICACY COMPROMISED SAFETY COMPROMISED
Strategy


(Contd…)
OBJECTIVE To Optimize CPPs of Encapsulation Process for Soft Gelatin Capsule
Determination of
CQAs NO. OF FACTORS 3
NO. OF LEVELS 5
Quality Risk EXPERIMENTAL DESIGN

Assessment of
SELECTED
CMAs &
CPPs CIRCUMSCRIBED CENTRAL
ROTARY DIE SPEED
COMPOSITE RSM WITH

FRACTIONAL FACTORIAL
(SCALE DOWN CCD)
DoE
& Development
of Design Space ADD. CENTER POINTS 4
C
TOTAL NO OF 4 ffp
EXPERIMENTAL RUNS + 6sp
(NO OF TRIALS) + 5cp
PAT =15
&Development A MELTING TEMPERATURE
of Feedback
Control system

-α -1 0 +1 +α
Implementatn of A Melting/ Heating Temperature (°C) 52.9 55.0 60.0 65.0 67.1
Control B Gelatin Layer Thickness (mm) 0.46 0.50 0.60 0.70 0.74
Strategy C Rotary Die Speed (RPM) 1.59 2.00 3.00 4.00 4.41


(Contd…)
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
WEIGHT VARIATION =++1.29-0.035A+0.11B+0.71C -0.043AB+0.46AC +0.015BC+0.17A2 +0.22B2+0.79C2
Implementatn of DISSOLUTION AT 30 MINS=+97.96-1.06A-4.60B-0.35C-0.85AB-0.60AC-2.56BC-1.69A2-6.69B2-1.69C2

Control
Strategy %TOTAL IMPURITIES =+1.50+0.95A+0.14B-0.14C-0.041AB-8.579E-003AC+0.25BC+0.32A2+0.044B2-6.481E-003C2


QTPP SOFT GELAIN CAPSULE ENCAPSULATION
(Contd…)
Responses (Effects) Goal for Individual Responses
Y1 Weight variation (%) Weight variation should not be more than i.e. NMT 1.5%RSD
Determination of Y2 Drug Dissolved at 30 min %Drug dissolved should not be less than 95%
CQAs Y3 Total Impurities (%) Total Impurities should not be increased more than 1.5%w/w
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 Melting/ Heating Temperature (°C) 53-67 55-60 56-60
Strategy B Gelatin Layer Thickness (mm) 0.46-0.74 0.54-0.62 0.55-0.60
C Rotary Die Speed (RPM) 1.6-4.4 2.75-3.25 2.80-3.20


QTPP SOFT GELATIN CAPSULE DRYING
Determination of Optimization of CPPs of

CQAs
Secondary Tray Drying Process
Quality Risk
Assessment of
CMAs &
CPPs B EXPOSURE TIME
DoE A DRYING TEMPERATURE

& Development
of Design Space
RISKS
PAT
&Development
of Feedback
Control system INADEQUATE EXPOSURE HIGH TEMPERATURE
MICROBIAL LOAD INPROCESS IMPURITIES
Implementatn of SAFETY COMPROMISED

Control
Strategy


(Contd…)
OBJECTIVE To Optimize Critical Processing Parameters of Secondary Tray Drying for SGC.
Determination of
CQAs
NO. OF FACTORS 2
NO. OF LEVELS 3
Quality Risk
Assessment of
CMAs & EXPERIMENTAL DESIGN
SELECTED
CPPs
EXPOSURE TIME
32 FULL FACTORIAL DESIGN
DoE ADD. CENTER POINTS 0

& Development
B
of Design Space
TOTAL NO OF 32 FP
EXPERIMENTAL RUNS =9
(NO OF TRIALS)
PAT
&Development
of Feedback
Control system A DRYING TEMPERATURE

0 1 2
Implementatn of
A Drying Temperature 0.70 1.00 1.30
Control
B Exposure Time 0.30 1.05 1.80
Strategy


(Contd…)
CPPs CQA
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
Residual Moisture =++7.90-0.83A-1.52B-0.15AB+0.40A2-0.15B2

Implementatn of
Control Impurities=+0.93+0.32A+0.28B-0.025AB+0.15A2+0.15B2
Strategy


(Contd…)
Responses (Effects) Goals for Individual Responses
Determination of Y1 Residual Moisture (%) To achieve residual moisture in the range between 6.0% to 8.0%
CQAs Y2 Impurities(%) To achieve minimum in process impurities i.e. NMT 1.0%
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 Drying TEMPERATURE (C) 21.0-25.0 21.5-23.5 22.0-23.0
B Drying TIME (hours) 24.0-48.0 34.0-42.0 35.0-40.0
Strategy

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 SOFT GEL CAPSULE MANUFACTURING (Contd…)
GELATIN
MIXER /MELTER MEDICINE HOPPER
MEDICINE PUMP
Determination of
CQAs
GELATIN
A PREPARATION DRUG MATERIAL
D PREPARATION
Quality Risk
Assessment of
CMAs &
METERING OF
CPPs E DRUG MATERIAL
MELTING
JACKET
MELTING
JACKET
INJECTION
SPREADING
B WEDGE
DoE OF GELATIN
& Development RIBBON
of Design Space F
CUTTING SPREADER
SPREADER BOX
LUBRICATION
BOX LUBRICATION ROLLERS
ROLLERS
DIE DIE
ROLLER ROLLER
PAT COOLING CAPSULE COOLING

&Development G SEALING
DRUM
of Feedback DRUM
Control system
CONVEYER ROLL
NAPHTHA COOLING
COOLING H BATH WASHING FAN
Implementatn of FAN
Control
Strategy COOILING 1 ° FLUID BED TUNNEL
C I
OF RIBBON & 2° TRAY DRYING


API / EXCIPIENT PURITY
analyzed by
GELATIN At line UV/ HPLC/ GC,
MIXER /MELTER MEDICINE HOPPER On line LOD/ HMB or W/KF
MEDICINE PUMP API / EXCIPIENT PARTICLE

Determination of SIZE DISTRIBUTION TEMPERATURE &
analyzed by At line Malvern
CQAs Particle Size Analyzer
RELATIVE HUMIDITY
by At Line Thermo-
MOISTURE CONTENT of OR On Line hygrometer
GEL MASS by At line Sieve Shaker Analysis
Toluene Distillation
Method HOMOGENEITY off FILL
analyzed by At line
UV/ HPLC system
VISCOSITY of GEL MASS
Quality Risk by On line Brookfield
Assessment of SPECIFIC GRAVITY
Viscometer
CMAs & Of fill material analyzed by
online Sp. Gravity bottle
CPPs
MELTING
JACKET
MELTING
JACKET
INJECTION
WEDGE
DoE
& Development
of Design Space
SPREADER
SPREADER BOX
RIBBON THICKNESS LUBRICATION
BOX LUBRICATION
by On line Digital Stage ROLLERS
ROLLERS
Microscopy & Calipers DIE DIE
ROLLER ROLLER
PAT COOLING
SEAL THICKNESS
by On line Digital Stage
CAPSULE FILL WEIGHT by
On Line Weight Variation &
COOLING
&Development DRUM
DRUM Microscopy & Calipers Disintegration Testing
of Feedback
Control system
ONLINE VISUAL INSPECTION

CONVEYER ROLL
for cleaning, polishing & COOLING
COOLING sorting of unfilled/ half FAN
Implementatn of FAN filled/ defective capsules
Control RESIDUAL MOISTURE OF
Strategy Risk Analysis of CMAs & CPPs with respect to CQAs at Raw Scale Developmental level FILLED CAPSULES
by ON LINE / AT LINE Analyzers for Prediction of Real Time Data & by At line Toluene
Distillation Method
Designing of Control Strategies at Commercial Scale

API / EXCIPIENT PURITY
GELATIN analyzed by
MIXER /MELTER MEDICINE HOPPER In line Bruker FT-NIR
MEDICINE PUMP API / EXCIPIENT PARTICLE

Determination of SIZE DISTRIBUTION TEMPERATURE &
analyzed by In line
CQAs Lasentec Focused Beam
RELATIVE HUMIDITY
by In Line Thermo-
MOISTURE CONTENT of Reflectance Measurement hygrometer
GEL MASS by Inline Bruker/ (FBRM)
MT FT_NIR System
HOMOGENEITY off FILL
VISCOSITY of GEL MASS analyzed by In Line
by In line Viscometer Bruketr FT_NIR
Quality Risk
Assessment of SPECIFIC GRAVITY SPECIFIC GRAVITY
CMAs & Of GEL MASS analyzed by

inline hydrometer
Of FILL MATERIAL
analyzed by inline
CPPs hydrometer
MELTING
JACKET
MELTING
JACKET
INJECTION
WEDGE
DoE
& Development
of Design Space
SPREADER
SPREADER BOX
RIBBON THICKNESS LUBRICATION
BOX LUBRICATION
by In line Digital HD ROLLERS
ROLLERS
Microscopy & Video DIE DIE
Monitoring ROLLER ROLLER
PAT COOLING
SEAL THICKNESS
by In line Digital HD
CAPSULE FILL WEIGHT
by In line Check Weigher
COOLING
&Development DRUM
DRUM Microscopy & Video based on Gravimetric
of Feedback
Control system Monitoring EMFR System
CONTENT UNIFORMITY
analyzed by In Line Bruker FT-NIR
DIAMETER SORTER for inline
CONVEYER ROLL sorting of under/ overfill capsules
COOLING
COOLING FAN
COLOR SORTER for inline sorting of
Implementatn of FAN
defective capsules with air bubbles
Control Real Time Data Analysis at Scale UP-Exhibit Manufacturing Scale RESIDUAL MOISTURE OF
Strategy by IN LINE analyzers with auto-sensors & Real time data comparison with Raw scale data
FILLED CAPSULES by In line
Bruker FT-NIR
for Finalization of Control Strategies at Commercial Scale

GELATIN
MIXER /MELTER MEDICINE HOPPER
MEDICINE PUMP
Determination of Auto-controlling of
CQAs TEMPERATURE &

RELATIVE HUMIDITY
Air Handling Unit
(AHU)
Auto Controlling of
HOMOGENEITY off FILL
By adjusting Homogenizer
Quality Risk Mixing Speed &
Assessment of Mixing Time
CMAs &
CPPs
MELTING
JACKET
MELTING
JACKET
INJECTION
WEDGE
DoE
& Development
of Design Space
SPREADER
SPREADER BOX
Auto Controlling of LUBRICATION
BOX LUBRICATION
RIBBON THICKNESS ROLLERS
ROLLERS
by adjusting Gap between DIE DIE
spreader box & rotating ROLLER ROLLER
cooling drum
PAT COOLING
Auto controlling of
SEAL THICKNESS
Auto-controlling of
FILLED CAPSULE WEIGHT &
COOLING
&Development DRUM
DRUM by adjusting Gap by adjusting
of Feedback
Control system between Die Rollers Die Roller Speed,
Rotating Drum Speed
CONVEYER ROLL Auto-controlling of

RESIDUAL MOISTURE COOLING
COOLING FAN
by adjusting
Implementatn of FAN
Drying Temperature
Control Drying Time
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
SHELL-EXCIPIENT Critical Material Attributes
Type of Gelatin Type A (Acid bone) Type A (Acid bone) Type A (Acid bone) To ensure batch to batch
Determination of
pH 3.8–5.5 4.0–5.0 4.0-5.0 consistency in Cohesive
CQAs Isoelectric point 6.0-9.5 7.0-9.0 7.0-9.0 strength of Cross linking
Bloom or Gel Strength that occurs between
(weight in gms gelatin molecules in
required to move a empty gelatin shell
plastic plunger i.e. 0.5 150-250 gm 180-250 gm 190-210 gm in order to ensure
Quality Risk Gelatin physical strength
inches in diameter 4
Assessment of as a base
mm into 62/3% gelatin
CMAs & gel at 10°C for 17 hrs
CPPs Concentration (%w/w) 35-45% 36-44% 38-42%
Viscosity of To ensure batch to
62/3% Gelatin 2.7-3.7 mPa 2.7-3.2 mPa 2.7-3.0 mPa batch consistency of
Solution at 60°C Molecular Chain length
TSE/BSE Free Free Free To ensure Safety
DoE Dry Glycerine to To prevent softening
& Development Glycerine as a 0.65-0.95 0.70-0.90 0.75-0.85
of Design Space Dry Gelatin Ratio (tacky) or hardening
Plasticizer
Concentration (%w/w) 15-25% 16-24% 18-22% (brittleness) of shell
Water to retarded dissolution &
Water as a 0.70-1.30 0.90-1.10 0.90-1.10
Dry Gelatin Ratio handling problems during
Solvent
Concentration (%w/w) 30-50% 35-45% 38-42% processing/ packaging
PAT Iron content in Iron Content in
To prevent chemical
&Development NMT 15 ppm NMT 12 ppm NMT 10ppm reaction with dyes &
of Feedback raw gelatin raw gelatin
Control system organic compound
Iron Oxide
Concentration (%w/w) 0.10-0.40% 0.15-0.35% 0.20-0.30%
as a Color To ensure patient
Titanium Dioxide acceptance & compliance
as an Opacifier
Implementatn of
Benzyl Alcohol as To ensure microbiological
Control Anti Microbial
stability to ensure safety
Strategy BHT as an
To ensure chemical
Anti Oxidant stability to ensure safety

CMAs CPPs

QTPP Critical Material Attributes

FACTOR(s) CMAs PURPOSE of Control
Determination of
API- Critical Material Attributes
CQAs Polymorphic To ensure batch to batch
2Ө values x, y, z x, y, z x, y, z
Form consistency in Dissolution
D10: NMT x um NMT x um NMT x um To ensure batch to batch
Particle Size
consistency in Bulk
Distribution D50: NMT y um NMT y um NMT y um
Uniformity, CU &
Quality Risk (PSD) D90: NMT z um NMT z um NMT z um
Assessment of Dissolution
CMAs & To ensure batch to batch
Sp. Gravity/
CPPs Density
Specific Gravity
consistency in bulk
uniformity of API in order
to control 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
DoE with capsule shell.
& Development
of Design Space FILL-EXCIPIENT Critical Material Attributes
Sp. Gravity/ Density 0.916–0.922 0.916–0.922 0.916–0.922 To ensure desirable
pour ability, smooth
Soybean Oil as Viscosity at 25°C 40-60 mPa s 45-55 mPa s 46-54 mPa s
processing, uniform
a Solvent cum Saponification Value 180-200 188-195 188-195
mixing to ensure bulk
PAT VEHICLE Surface Tension 25 dyn/cm at 20°C. 25 dyn/cm at 20°C. 25 dyn/cm at 20°C. uniformity & content
&Development
of Feedback Interfacial Tension 50 dyn/cm at 20°C. 50 dyn/cm at 20°C. 50 dyn/cm at 20°C. uniformity.
Control system
Ethanol as a To ensure batch to batch
Sp. Gravity/ Density 0.805–0.816 gm/ml 0.809–0.816 gm/ ml 0.809–0.816 gm/ml
CO-SOLVENT consistency in bulk
%Assay 95.1–96.9% 95.5-96.5% 95.1–96.9% uniformity of API in order
Span 80 as to control CU
Implementatn of Concentration (%w/w) 0.05-0.25 % 0.10-0.20 % 0.12-0.18 %
Co-Surfactant
Control To prevent oxidation of
BHT as an
Strategy Anti-oxidant
Concentration (%w/w) 0.005-0.02% 0.01-0.02% 0.015-0.020% content during storage,
transportation & in-use

CMAs CPPs

QTPP Critical Processing Parameters
FACTOR(s) CPPs PURPOSE of Control
FILL MATERIAL PREPARATION
Heating Heating Temp 50°-70°C 55°-65°C 57°-63°C To ensure batch to batch
Determination of
Mixing Speed Medium Medium Medium homogeneity in order to
CQAs Mixing
Mixing Time 30-60 min 40-50 min 45-50 min ensure Content Uniformity
SOFT GEL MASS PREPARATION
Mixing Speed Medium Medium Medium To ensure batch to batch
Mixing
Mixing Time 20-40 min 25-35 min 25-35 min consistency in color
Melting Temp 53°-67°C 55°-60°C 56°-60°C uniformity with minimum
Quality Risk Melting
Assessment of Melting Time 150-210 min 160-200 min 170-190 min in-process impurities
CMAs & To ensure acceptable
appearance, uniform fill
CPPs Deaeration Vacuum Pressure NLT 29.5” Hg NLT 29.5” Hg NLT 29.5” Hg
weight & protection from
oxidation of fill material
SOFT GELATIN CAPSULE FILLING PROCESS (ROTARY DIE ENCAPSULATION)
Rotating Drum
SPREADING of 10°-15°C 12°-15°C 13°-14°C To ensure batch to batch
DoE Gel mass into
Cooling Temperature
460-740 μm 540-620 μm 550-600 μm consistency in Weight
& Development RIBBON Ribbon Thickness
of Design Space (0.46-0.74 mm) (0.54-0.62 mm) (0.55-0.60 mm) variation & Disintegration
in order to ensure
150-250 μm 170-230 μm 180- 220 μm
INJECTING of Seal Thickness minimum variation in CU &
(0.15-0.25mm) (0.17-0.23 mm) (0.18-0.22 mm)
Drug Material Desired Dissolution
Rotary Die Speed 1.6-6.4 RPM 2.75-3.25 RPM 2.80-3.20 RPM
without any defects
SEALING Die Roller temperature 35°-40°C 36°-40°C 37°-40°C
PAT 1° Fluid Bed Tumbler
25-35°C 27-33°C 28-32°C To ensure maximum
&Development
of Feedback
IR Drying Temp.
water removal in order to
Control system 1° Fluid Bed Tumbler
30-60 min 35-55 min 40-50 min expedite drying process
Washing & IR Drying Rate Time
DRYING 2° Tray Drying To ensure 6-10% residual
21.0-25.0°C 21.5-23.5°C 22.0-23.0°C
Temperature moisture content in
2° Tray Drying capsule at equilibrium with
Implementatn of 24.0-48.0 hours 34.0-42.0 hours 35.0-40.0 hours
Time 20 to 30%RH at 21-24’C
Control Temperature 21°C-25°C 21°C-25°C 21°C-25°C To ensure batch to batch
ENVIRONMEN
Strategy TAL Factors Relative Humidity <40%RH <30 %RH <30 %RH
Physical & Chemical
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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© Created & Copyrighted by Shivang Chaudhary

Designing of Experiments (DoE) & Design Space

PAT Process Analytical Technology (PAT)

Implementatn of Implementation of Control Strategy

© Created & Copyrighted by Shivang Chaudhary

QUALITY TARGET PRODUCT PROFILE (QTPP)

Note: QTPP will be finalized -

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Definition of Quality Target Product Profile (QTPP) of SGC

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Critical Quality Attribute (CQA)

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Definition of Critical Quality Attributes (CQA) of SGC

Assay variability will affect SAFETY AND EFFICACY. Process variables

Implementatn of NLT X % (Q) of labeled amount of

© Created & Copyrighted by Shivang Chaudhary

Critical Material Attribute (CMA)

• to ensure the process produces the desired quality product.

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Definition of Identification of Risk Factors by

API PSD & WATER CONTENT

ENCAPSULATION IONIC NATURE OF SURFACTANT

DENSITY/SP.GRAVITY & SOLVENT TYPE & CONC

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Solid state Particle Size Hygro Moisture Residual Process Chemical

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© Created & Copyrighted by Shivang Chaudhary

FP CQAs Gelatin Plasticizers Water Preservative Colorant Opacifier

Low Broadly acceptable risk. No further investigation is needed

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© Created & Copyrighted by Shivang Chaudhary

DoE D GLYCERINE: DRY GELATIN

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Surfactants Preservatives Organoleptic Additives

© Created & Copyrighted by Shivang Chaudhary

© Created & Copyrighted by Shivang Chaudhary

DoE D PRESERVATIVE CONC.

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Definition of Qualitative Risk based Matrix Analysis of

CAPSULE FILLING (ENCAPSULATION) PROCESS

© Created & Copyrighted by Shivang Chaudhary

Definition of Qualitative Risk based Matrix Analysis of

Determination of Impurity profile & Physical Attributes may get affected

Base under vacuum

Mixing with Physical Attributes (FLEXIBILITY, TENSILE STRENGTH, appearance)

CPPs Temperature Higher(>25°C) 3 4 4 48

FILL MATERIAL PREPARATION

DoE Physical Attributes, ZETA POTENTIAL, VISCOSITY, Fill Weight

Physical Attributes (Appearance) may get affected

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Definition of Qualitative Risk based Matrix Analysis of

Die Roller Gap Higher 3 3 2 18

Higher than Physical Attributes (POLISHED Appearance) may get affected

© Created & Copyrighted by Shivang Chaudhary