CPP & Cqa PDF

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Quality by Design (QbD) Model for "LIQUID ORAL SOLUTION" © by Dr.

Shivang Chaudhary from QbD-Expert™
Article in Drug Development and Industrial Pharmacy · April 2016
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Definition of
QTPP A MODEL
QbD For SOLUTION

QUALITY BY DESIGN FOR FORMULATION DEVELOPMENT & PROCESS OPTIMIZATION
Determination of OF MONOPHASIC LIQUID ORAL DOSAGE FORM-SOLUTION
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development Designed & Developed by
of Feedback
Control system
SHIVANG CHAUDHARY
Chief Knowledge Officer (CKO) & Global Head Quality by Design at QbD Expert™
MS (Pharmaceutics), Ph.D. (Pharmaceutical Sciences), LSSMBB, EDMP (PM), PGDPL
Implementatn of
www.facebook.com/QbDExpert www.linkedin.com/groups/8264051
Control  +91 -9904474045, +91-8866327899
Strategy  qbdexpert@gmail.com
 www.qbdexpert.com
© Created & Copyrighted by Shivang Chaudhary.

Aim
Project
Goal
To Develop :
• Stable & Therapeutic

Equivalent (Pharmaceutical
Equivalent + Bioequivalent) IR
Generic Liquid Oral Solution
• 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
© Created & Copyrighted by Shivang Chaudhary
PAT &
Development of Feedback Controls
Implementation of
Control Strategy

Definition of
QTPP
Determination of
CQAs
What is the meaning of

Quality Risk
Assessment of
CMAs &
CPPs
Quality by Design?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

What is QbD?
Definition of
QTPP
Determination of Quality
CQAs 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
• to development
DoE • that begins with predefined objectives and
& Development
of Design Space • emphasizes product and process understanding
• and process control,
• based on sound science and quality risk management.
PAT
&Development
of Feedback
Control system
Implementatn of
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.

Definition of
QTPP
Determination of
CQAs
1
How to define
Quality Risk
Assessment of
CMAs &
CPPs
Target Product Profile?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

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:
• For Pharmaceutical Abbreviated New Drug Application (ANDA- Generics) QTPP will be finalized -on the basis of
Therapeutic Equivalence= Pharmaceutical Equivalence (same dosage form, route of administration, strength & same
quality) + Bio-Equivalence (same pharmacokinetics in terms of Cmax, AUC;
PAT
&Development
of Feedback • Thus QTPP of Generics will be defined based on the properties of the drug substance, characterization of the RLD
Control system
product, and consideration of the RLD label and intended patient population.
• For Pharmaceutical New Chemical Entities (NCE-Innovator) QTPP will be finalized on the basis of Therapeutic Safety &
Efficacy / New Drug Applications (NDA-Novel Drug Delivery Systems as compared to already approved & available
Implementatn of conventional dosage forms)
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 Solution

QTPP Therapeutic Equivalence = Pharmaceutical Equivalence + Bio-Equivalence
Of Generic Solution with Patient Compliance
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development PHARMACEUTICAL BIO- PATIENT
of Design Space
Equivalence Equivalence Compliance
Similar For oral solutions, elixirs, syrups, Primary PACKAGING:
tinctures, or other solubilized forms, in
Dosage FORM : Solution vivo BA and/or BE can be waived.
Container : (Glass/Plastic/Metal) &
PAT Dosage DESIGN : IR Generally, in vivo BE studies are waived Closure : (Plastic/Metal/Rubber)
&Development
of Feedback ROUTE of for solutions on the assumption that Ease of Storage & Distribution
Control system release of the drug substance from the Should be stable against hydrolysis, oxidation, photo
Administration : Oral drug product is self-evident and that degradation & microbial growth with at least 12
Dosage STRENGTH : x mg/ml the solutions do not contain any months long term stability at normal room
excipient that significantly affects drug temperature & 28 Days of in-Use Shelf Life
Drug Product QUALITY : absorption
Implementatn of Assay, Impurities, Patient Acceptance
Control Microbiological Limits, Antioxidant & Should possess acceptable flavor, taste & odor
Strategy Antimicrobial content, pH, Viscosity/ Patient Compliance
Sp. Gravity, Leachable/ Extractable within re-dispersible upon shaking/administered
acceptable limits of specification (pourable & palatable)/used/ applied similarly
Note: Plastic/ Rubber should not allow permeation, leaching, extraction or sorption with Reference Product labeling
Definition of
QTPP
Determination of
CQAs
2
How to determine
Quality Risk
Assessment of
CMAs &
CPPs
Critical Attributes of Quality?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

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 Solution

QTPP
Formulation & Process variables have direct impact on this CQA. This will remain as a target element of the drug product
 profile and should be investigated and discussed in detail in subsequent risk assessment and pharmaceutical development
!
Formulation and process variables are unlikely to impact this CQA. Therefore, the CQA will not be investigated and
discussed in detail in subsequent risk assessment and pharmaceutical development.
Determination of
CQAs Formulation & Process variables does not have any impact on this CQA.
 No need for any further investigation & discussion.
Physical Identification Assay

Quality Risk
Assessment of
 Attributes ! Positive for Drug Substance

Should be between
Color, Flavor, Taste , Viscosity But controlled at Drug
CMAs & USP <911> Density / Sp. Gravity Substance Release
90.0 to 110.0 % of
labeled claim to ensure
CPPs USP <841> should be mostly similar stage itself with at least safety & efficacy
to reference product to ensure two confirmatory tests
physical stability & Patient
Acceptance & Compliance
Assay of
DoE  Weight 
Preservative  Impurities
& Development
of Design Space
Variation Should be within limits as per
Should Conform to USP <905> As per USP <51> Should maintain ICH Q3A & Q3B OR Reference
Uniformity of Dosage Units: 90.0- the microbial quality of the product Product Characterization to
110.0 % of labeled claim with RSD: & to prevent oxidation throughout ensure chemical stability of
NMT 5.0% to ensure patient shelf life & proposed in-use shelf life formulation & patient Safety
Safety & product Efficacy to ensure patient safety.
PAT
Extractable Microbiological
 pH !
&Development
of Feedback
Control system
Should be within limits & Leachable  Limits
Should Conform to USP
specified in monograph Stability data should show evidence
<61 & 62>
conforms to USP <791> or as that extractable & leachable from the
But controlled at Drug
per reference product container/closure systems
Substance & Excipient
Implementatn of characterization to prevent are consistently below
Release stage itself to
Control precipitation, hydrolysis, acceptable levels, should conform to
ensure microbiological
Strategy oxidation & any other chemical USP <660> for glass, <661> for
stability & patient safety
incompatibility plastic, to ensure patient safety.

Definition of
QTPP
Determination of
CQAs
3
How to assess Risks associated with
Quality Risk
Assessment of
CMAs &
CPPs
Materials & Process?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
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 Controlled Solubilization Process Map
Critical Processing Critical Attributes of Manufacturing Quality Attributes of
Parameters Input Materials Process Steps Output Materials
Solvent source, purity, polarity, pH, Viscosity/sp.

Gravity, Volatility, Microbial content
Type of purification system Physical Attributes (color, odor, taste)
(ion exchange/reverse osmosis)
Type & Source of color/ flavor/ sweetener Vehicle Preparation & Storage Vehicle purity, Vehicle polarity
(natural/ semisynthetic/ synthetic),
Determination of Rate of filtration Organoleptic addition Vehicle pH, Vehicle Viscosity/sp. Gravity
Microbial content of color, flavor & sweetener
CQAs
Heating temperature & time Vehicle Volatility, Vehicle Microbial content
Type & Position of Impeller
Mixing Speed & Time
Drug substance PSD/SSA, Contact angle,

Vehicle purity, polarity, pH,
Viscosity, Rheology, Sp. Gravity/ Density, Physical Attributes
Volatility & Microbial content (Homogeneity#/Sedimentation*/Caking*)
Type & Concentration of Surfactant Assay, Uniformity of Dosage units,
Quality Risk
Concentration of preservative Controlled Solubilization by pH & Preservative content of system
Order of addition Source ,Concentration, Viscosity, pH &
Assessment of Microbial contents of hydrocolloids
Surfactants & Hydrocolloid Viscosity/Rheology, Specific Gravity/Density &
Heating temperature & Time Extractable volume of system,
CMAs & Type & Position of Impeller
Mixing Speed & Mixing Time
Particle Size distribution*, Zeta Potential*,
Redispersibility*,Microbial content of system
CPPs pH of buffer/salts,
Concentration of buffers/salts
Purity, Solubility, Compatibility,
Stability & Toxicity of Buffers/Salts
Physical Attributes (color, flavor. taste),
Vehicle purity, polarity, pH, Viscosity, Sp.
Assay, Impurity, Uniformity of Dosage units,
Gravity, Volatility, Microbial
Viscosity/Rheology, Specific Gravity/Density &
Physical Attributes , Assay, Impurity, pH &
DoE pH adjustment & Final Volume make Extractable volume of system,
Order of addition Preservative content of system
pH & Preservative content of system,
Heating temperature & Time Dissolution*, Reconstitution time** up with vehicle & final mixing Dissolution*, Reconstitution time**,
& Development
Type & Position of Impeller Dissolved Oxygen of system
of Design Space Mixing Speed & Mixing Time Microbial content of system
Physical Attributes (Clarity#, Homogeneity*),

Physical Attributes (clarity#/ Homogeneity*) Assay, Uniformity of Dosage units*, pH,
PAT Type & Principle of milling
Viscosity/Rheology, Specific Gravity/Density Ultra-Filtration
Impurity, Assay of Preservative content of
system, Particle Size distribution*, Zeta
&Development Milling speed Microbial content of system potential*, Redispersibility*, Dissolution*,
of Feedback Screen size of mill Reconstitution time**
Type & Size of Filter
Control system Rate of filtration
Physical Attributes (Clarity#, Homogeneity*),

Viscosity/Rheology, Specific Gravity/Density of Physical Attributes,
system, pH & Preservative content of system Assay, Impurity, Uniformity of dosage units*,
Dissolved Oxygen of system Uniformity of Weight**,
Implementatn of Microbial content of system Viscosity/Rheology, Specific Gravity/Density &
Control Filling rate

Material of container (Glass/Metal/ Plastic)
Material of closure (Metal/Plastic/Rubber)
Filling , Capping & Sealing with
nitrogen purging
Extractable volume of system,
pH & Preservative content of system,
Strategy
Capping & Sealing rate Dissolved / Headspace
Design & Size of container/closure
Nitrogen purging &/or sparging rate Oxygen content of system
Sealing rate after closure fitting Microbial content of system
Patient Acceptance & Compliance
# Applicable to Solution only; * Applicable to Suspension only; ** Applicable to reconstituted powder only
Environment (Temperature and RH)
RISK RISK RISK RISK
Definition of Identification of Risk Factors by

QTPP Ishikawa Fishbone Diagram
Determination of
CQAs
SOLUBILIZATION BY
SURFACTATNT
Quality Risk BODYING BY API PSD & SURFACE AREA

Assessment of HYDROCOLLOID&/OR
VOLUME MAKE UP INTERFACIAL TENSION OF SYSTEM
CMAs & FILTRATION,
FILLING & CAPPING
VISCOSITY OF SYSTEM
API AQUEOUS SOLUBILITY
CPPs COLLOID MILL MESH SIZE
TYPE OF HYDROCOLLOID
HYDROCOLLOID CONC.
TYPE & CONC. OF SURFACTANT
FILTER SCREEN SIZE CONC. OF COMPLEXING AGENTS
VEHICLE QUANTITY
FILRATION RATE TYPE & CONC. OF PRESERVATIVE
CO-SOLVENT QUANTITY
RATE OF FILLING STIRRING RATE STIRRING RATE (SPEED *TIME)
TARGET EXTRACTABLE VOL.
STIRRING RATE MATERIAL OF 1° PACKAGING
DoE NITROGEN PURGING RATE
BIOBURDEN
BUFFER CONCENTRATION HYDROCOLLOID SOURCE
& Development COLOR SOURCE & CONC.
of Design Space SURFACTANT SOURCE
RELATIVE HUMIDITY SWEETENERS SOURCE & CONC
API STABILITY
OXYGEN EXPOSURE FLAVORS SOURCE & CONC
API PURITY
LIGHT EXPOSURE STIRRING RATE
TEMPERATURE RAW
ADDITION OF MATERIAL
ENVIRONMENTAL ORGANOLEPTICS &
PAT FACTORS pH ADJUSTMENT
&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 Physical Particle Microbial Moisture Residual

FP CQAs Solubility* Volatility Purity Stability
Form size** Content content*** Solvent***
Appearance High Low Low Low Low Low Low Low Low
Assay Low Low Low Low High High Low Low Low
Uniformity of Content** Medium High High High Low Low Low Low Low
Quality Risk
Assessment of Uniformity of Weight Low Low Low Low Low Low Low Low Low
CMAs & Impurities Medium MEdium Low Low High High Low Low Medium
pH of System Low Low Low Low Low Medium Medium Low Low
CPPs Microbial Limits Low Low Low Low Low Low High Medium Low
Antimicrobial content Low Low Low Low Low Low High Low Low
Antioxidant content Low Low Low Low Low Low Low Low Low
Extractable Low Low High High Low Low Low Low Low
DoE Viscosity/specific gravity Low Low Low High Low Low Low Low Low
& Development Particle Size
of Design Space Low Medium Low Low Low Low Low Low Low
Distribution**
Dissolution** High High High Medium Low Medium Low Low Low
Redispersibility** Low High Low Low Low Low Low Low Low
Reconstitution time*** Low High High Low Low Low Low Low Low
** Applicable to Suspension only; *** Applicable to reconstituted powder only
PAT
&Development Low Broadly acceptable risk. No further investigation is needed
of Feedback
Control system 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.
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
Quantitative Failure Mode Effect Analysis (FMEA) of Detectability of Risk can
QTPP Active Pharmaceutical Ingredient’s (API) Attributes be increased through

In Line PAT System
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)
Different Solubility of drug substance may get affected=
Determination of Solid Sate
Form
Polymorph/ Dissolution of drug product may get affected= 2 4 of Risk
Probability 4 can 32
CQAs form Bioavailability/Efficacy may get compromised be Reduced through
BCS Class II/IV Low Solubility drug DoE Optimization
Particle Size
Distribution (PSD)
Higher PSD >> Dissolution of drug product may get affected 4 4 3 48
Physical >> Bioavailability/Efficacy may get compromised
Property Rate of degradation may get affected
High water
Moisture content
content
>> Impurity profile may get affected 2 3 2 12
>> Safety of the product may get compromised
Quality Risk Residual solvents are likely to interact with drug substance
Assessment of High residual
Residual Solvents >> Impurities profile may get affected 2 3 2 12
CMAs & solvent
>> Safety may get compromised
CPPs Solubility
Different Salt/ Dissolution of the drug product can be affected
2 3 4 24
Form >> Bioavailability/Efficacy may got compromised
Assay & Content Uniformity can be affected
Volatility High
>> Efficacy may get compromised 2 3 4 24
Chemical
Property Process Assay & impurity profile of drug product may be affected =
Impurities
Less Purity
Quality & Safety may got compromised 2 3 3 18
DoE Susceptible to dry heat/oxidative/hydrolytic/UV light
& Development Chemical
of Design Space Stability
poor degradation- impurity profile may get affected 2 3 3 18
Quality & Safety may got compromised
MICROBIAL LOAD may get increased during
Biological transportation, shipping, storage & in-use
Property
Microbial Content High
>> MICROBIOLOGICAL STABILITY may get compromised 2 3 4 24
>> SAFETY of patient may get compromised
PAT Probability* Severity** Detect ability*** Score

&Development Very Unlikely Minor Always Detected 01
of Feedback Occasional Moderate Regularly Detected 02
Control system 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
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
API Attributes which got RPN more than 30 were get highest priority among
Implementatn of
all the risks, they should be taken into consideration as most
Control
Strategy Critical Material Attributes of API , which were required
to be optimized &/or controlled
RISK RISK RISK RISK
Definition of
CRITICAL
Determination of
CQAs
CMAs of
API
Quality Risk
Assessment of
CMAs & A SOLID STATE FORM
CPPs
B PARTICLE SIZE
DoE
& 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 Inactive Ingredients’ (Excipients’) Attributes
Determination of
CQAs Surfactants Preservatives Organoleptic Additives

Solvents/ Hydrocolloid
(Solubilizing/ Buffering
FP CQAs Co-solvents/ (Suspending Anti Anti
Wetting agent Colors Flavors Sweeteners
Vehicles agent) Microbial Oxidant
agents)
Appearance High High High Low Low Low High Low Low
Quality Risk Assay High Low Low Low Low Low Low Low Low
Assessment of
Uniformity of Content** High High High Low Low Low Low Low Low
CMAs & Uniformity of Weight*** High Low Low Low Low Low Low Low Low
CPPs Impurities High Medium Low Medium Medium High Low Medium Low
pH of System High Low Low High Low Low Low Low Low
Microbial Limits High Low Medium Medium High Medium Medium Medium Medium
Antimicrobial content High Low Low High High Low Low Low Low
Antioxidant content High Low Low High Low High Low Low Low
DoE Extractable
& Development High High High Low Low Low Low Low Low
of Design Space Viscosity/specific gravity High Low High Low Low Low Low Low Low
Particle Size
Low High Low Low Low Low Low Low Low
Distribution**
Dissolution** Low High Low High Low Low Low Low Low
Redispersibility** High High High Low Low Low Low Low Low
PAT Reconstitution time*** High High High Low Low Low Low Low
&Development
of Feedback ** Applicable to Suspension only; *** Applicable to reconstituted powder only
Control system
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.
Implementatn of
Control
Strategy

RISK RISK RISK RISK
Definition of
Quantitative Failure Mode Effect Analysis (FMEA) 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
Determination of Quantity of optimum
DISTRIBUTED >> UNIFORMITY may get affected 3 3 3 27
>> SAFETY & EFFICACY may get compromised
Vehicles/ Solvents
CQAs Vehicle/ Solvent More than Product may get BULKIER to handle
4 3 2 24
optimum >> Patient ACCEPTANCE & COMPLIANCE may get compromised
Source of hydrocolloid is natural i.e. plant or animal based origin
Source of >> potential for microbial attack & growth
Hydrocolloid
Natural >> MICROBIOLOGICAL STABILITY may get compromised 3 3 4 36
Hydrocolloid >> SAFETY of the patient may get compromised
(Suspending VISCOSITY of dispersion medium may be too lower
agent as a Less than >> Rate of SEDIMENTATION will be high
Quality Risk optimum >> PHYSICAL STABILITY may get compromised 4 4 2 32
structured Concentration of >> SAFETY & EFFICACY may get compromised
Assessment of
vehicle) Hydrocolloid VISCOSITY of dispersion medium may be too higher
CMAs & More than
optimum
>> POUR ABILITY of the product may get compromised
>> PATIENT COMPLIANCE may get compromised
4 4 2 32
CPPs If surfactant is positively/ negatively CHARGED
>> INCOMPATIBLE with anionic/cationic drugs /preservatives / primary
Ionic Nature of Cationic/ Anionic
Surfactant in nature
packaging material 3 3 3 27
>> CHEMICAL / MICROBIOLOGICAL STABILITY may get compromised
>> SAFETY of the patient may get compromised
Drug Substance/ Preservatives may NOT getting
effectively SOLUBILIZED/ DISTRIBUTED within system 4 4 3 48
Surfactants (As a >>SAFETY & EFFICACY may get compromised
DoE Solubilizing/
Less than ZETA POTENTIAL of the system may be too low
& Development optimum >> Particles coalesce & flocculated suspension forms
agents) >> Suspension start to form SEDIMENT 4 4 2 32
of Design Space Concentration of >> PHYSICAL STABILITY may get compromised
Surfactant >> SAFETY & EFFICACY may get compromised
ZETA POTENTIAL of the system may be too high
>> Particles repel each other & forms deflocculated suspension which upon
More than
optimum
settled down invariably leads to form HARD CAKE 4 4 2 32
>> PHYSICAL STABILITY may get compromised
>> SAFETY & EFFICACY may get compromised
PAT Within
Neutral Range
SOLUBILITY of the weak acidic / weak basic drugs may get affected
>> EFFICACY may get compromised 3 3 3 27
&Development Buffering Agent pH of the Buffer STABILITY of pH sensitive drugs/ preservatives may get affected
of Feedback Within Acidic/
Control system Basic Range
>> CHEMICAL STABILITY may get compromised 3 3 3 27
MICROBIAL LOAD may get increased during transportation, storage & in-use
Concentration of Less than
Anti-Microbial
Anti-Microbial optimum
>> MICROBIOLOGICAL STABILITY may get compromised 3 3 4 36
LEVEL OF OXIDIZED IMPURITIES of the product may get increased during
Concentration of Less than transportation, storage & routine use
Anti-Oxidant
Anti-Oxidant optimum >> CHEMICAL STABILITY may get compromised 4 4 3 36
Implementatn of >> SAFETY of the patient may get compromised
Sweetener/ Concentration of
Control Flavoring agent Sweetener/ Flavor
Not optimum
Product TASTE may not be palatable & agree able
>> Patient COMPLIANCE may get compromised 4 4 2 32
Strategy Coloring agent
Concentration of
Not optimum
APPEARANCE of the product may not be pleasant
>> Patient ACCEPTANCE may get compromised 4 4 2 32
Coloring Agent

RISK RISK RISK RISK
Definition of
CRITICAL
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Excipients’ Attributes which got RPN more than 30 were get highest priority
Implementatn of
among all the risks, they should be taken into consideration as most
Control
Strategy Critical Material Attributes of Excipients, which were required
RISK RISK RISK RISK
Definition of
CRITICAL
Determination of
CQAs CMAs of
EXCIPIENTS
Quality Risk A SURFACTANT (%w/w)

Assessment of
CMAs &
B HYDROCOLLOID (%w/w)
CPPs
C ANTI MICROBIAL (%w/w)
DoE D ANTI OXIDANT (%w/w)

& Development
of Design Space
E SWEETENER (%w/w)
F FLAVOR (%w/w)
PAT COLOR (%w/w)

&Development G
of Feedback
Control system
Implementatn of
Control
Strategy

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

QTPP Processing Parameters
Determination of
CQAs Solvent/ Solubilizing of

Supporting in Organoleptic
Final Volume
Filling,
Vehicle Solids (API+ pH adjustment make up with Filtration in
FP CQAs Preparation & Preservative)
Structured additives
by buffering vehicle & Colloid mill
Capping &
Vehicle addition Sealing
storage by Surfactants mixing
Physical attributes High Medium High High Low High High Low
Assay Low High High Low Medium High High Medium
Quality Risk
Assessment of
Uniformity of Content** Low High High Low Low High High Low
CMAs & Uniformity of Weight*** Low Low Low Low Low Low Low High
Impurities High High Low Low High High Low High
CPPs pH of System High Medium Medium Medium High High Low High
Microbial Contents High Low High High Low High Low High
O2 in headspace/ dissolved O2 High High Low Low Low High Low High
Antimicrobial content Low Medium Low Low High High Low High
DoE Antioxidant content Low Medium Low Low High High Low High
& Development Extractable Low High High Low Low High Low High
of Design Space
Viscosity/specific gravity High Low High Low Low High Low Low
Particle Size Distribution** Low Low High Low Low Low High Low
Dissolution** Low High Low Low High High High Low
Redispersibility** Low High Low Low Low Low High Low
PAT Reconstitution time*** High High Low Low High High High Low
&Development ** Applicable to Suspension only; *** Applicable to reconstituted powder only
of Feedback
Control system
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.
Implementatn of
Control
Strategy

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

Failure Mode Effect on IP & FP CQAs with
Unit Critical Process RPN
(Critical respect to QTPP (Justification of P S D
Operations Parameter (CPPs) (=P*S*D)
Event) Failure Mode)
Rate of Addition Physical Attributes, Impurity profile & Microbial Load 2 3 4 24
Higher than Optimum may get affected >> Safety may get compromised
Determination of Filtration Rate 2 3 4 24
Vehicle/ Solvent Microbiological Stability may get affected
CQAs Preparation
Heating Rate (Temp*Time)
Lower than Optimum >> Safety may get compromised 3 3 4 36
Storage& Higher than Optimum
Impurity profile & Assay may get affected
3 3 4 36
distribution
Mixing Rate (Speed*Time) Content Uniformity & Assay may get affected
Lower than Optimum 3 3 4 36
with Co-Solvents >> Efficacy may get compromised
Order of addition Incorrect Physical Attributes, Zeta Potential, 2 3 4 24

Content Uniformity & ultimately Assay may get affected
Impeller Design & Position Improper 2 3 4 24
Quality Risk Solubilization of >> Sedimentation/Caking may be observed
>> Physical Stability may get compromised
Assessment of Solids (API+ Mixing Rate (Speed*Time) Lower than Optimum >> Safety & Efficacy may get compromised
3 3 4 36
CMAs & Preservative) by
Surfactants Impurity profile & ultimately Assay may get affected
CPPs Heating Rate (Temp*Time) Higher than optimum > Chemical Stability may get compromised
3 3 4 36
Order of Addition Incorrect Physical Attributes, Viscosity, SVR/SHR. Content 2 3 4 24

Supporting by Rate of Addition Higher than optimum Uniformity & Ultimately Assay may get affected 2 3 4 24
Structured >> Sedimentation/Caking may be observed
>> Physical Stability may get compromised
Vehicles Mixing Rate (Speed*Time) Lower than Optimum 3 3 4 36
>> Safety & Efficacy may get compromised
DoE Order of Addition Incorrect Physical Attributes (Color, Odor, Taste) , Content 3 3 3 27
& Development Organoleptic Uniformity & ultimately Assay may get affected
of Design Space Mixing Rate (Speed*Time) Lower than Optimum >> Safety & Efficacy may get compromised 3 3 3 27
addition >> Patient Compliance may get compromised
With mixing Impurity profile & Assay may get affected
Heating Rate (Temp*Time) Higher than optimum >> Safety may get compromised 3 3 3 27
Rate of Addition Higher than Optimum Physical Attributes, Particle Size Distribution, pH/ 2 3 4 24
Solubility, Content Uniformity & Assay may get affected
pH Adjustment Impeller Design & Position Improper >> Sedimentation/Caking may be observed
2 3 4 24
with Buffer
PAT &Final Volume
Mixing Rate (Speed*Time) Lower than Optimum >> Physical & Chemical Stability may get compromised
>> Safety & Efficacy may get compromised
3 3 4 36
&Development make up with Microbiological Stability may get affected
Lower than Optimum 3 3 4 36
of Feedback vehicle & final >> Safety may get compromised
Control system Heating Rate (Temp*Time) Impurity profile & Assay may get affected
mixing Higher than Optimum > Chemical Stability may get compromised 3 3 4 36
Type & Principle of Filter Improper Physical Attributes, Impurity profile, Microbial Load, 2 3 4 24
Ultrafiltration Filter Screen Size Incorrect Content Uniformity & ultimately Assay may get affected
in Colloid mill >> Physical Stability may get compromised 2 3 4 24
Rate of Filtration Higher than Optimum >> Quality, Safety & Efficacy may get compromised 3 3 4 36
Implementatn of Uniformity of Weight may get affected
Not Optimum 3 2 2 12
Control Filling , Capping
& Sealing with
Filling rate (Speed*Time)
Higher than Optimum
>> Patient Acceptance may get compromised
Dissolved / Headspace Oxygen may get increased 3 3 4 36

Strategy nitrogen purging Nitrogen purging rate Lower than optimum >>Oxidation Impurity profile & Assay may get affected
3 3 4 36
Capping & Sealing rate Lower than Optimum 3 3 4 36

RISK RISK RISK RISK
Definition of CRITICAL
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Process Parameters which got RPN more than 30 were get highest priority
Implementatn of
among all the risks, they should be taken into consideration as most
Control
Strategy Critical Process Parameters , which were required
RISK RISK RISK RISK
Definition of CRITICAL
Determination of CPPs of
CQAs CONTROLLED SOLUBILIZATION
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT A %SURFACTANT
&Development
of Feedback %HYDROCOLLOID
Control system B
C MIXING TIME
Implementatn of
Control
Strategy

Definition of
QTPP
Determination of
CQAs
4
How to evaluate & optimize risks by
Quality Risk
Assessment of
CMAs &
CPPs
Designing of Experiments?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
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 CONTROLLED SOLUBILIZATION(Contd…)
Optimization of CMAs & CPPs OF

Determination of
CQAs Solution Homogenization Process
Quality Risk
Assessment of
CMAs &
CPPs C STIRRING TIME
B HYDROCOLLOID
DoE A SURFACTANT
& Development
of Design Space
RISKS
PAT
&Development
of Feedback INADEQUATE VISCOSITY INADEQUATE ZETA POTENTIAL HIGH RATE OF SEDIMENTATION
Control system
CONTENT UNIFORMITY COMPROMISED
QUALITY COMPROMISED SAFETY COMPROMISED EFFICACY COMPROMISED

Implementatn of
Control
Strategy


OBJECTIVE To Optimize CMAs & CPPs of Liquid Suspension Dosage Form
Determination of
CQAs NO. OF FACTORS 3 NO. OF FACTORS 3
NO. OF LEVELS 3
Quality Risk
EXPERIMENTAL DESIGN SELECTED
Assessment of
“High”
CMAs & BOX BEHNKEN DESIGN
CPPs
STIRRING TIME
ADD. CENTER POINTS 2

Medium
TOTAL NO OF 12MP
DoE EXPERIMENTAL RUNS + 3CP
C
& Development
of Design Space (NO OF TRIALS) =15
“Low”
A SURFACTANT
PAT
&Development
of Feedback
Control system 3 NO. OF LEVELS
Factors (Variables) Levels of Factors Studied

-1 0 +1
Implementatn of A SURFACTANT (%) 0.50%w/w 1.00%w/w 1.50%w/w
Control B HYDROCOLLOID (%) 20%w/w 30%w/w 40%w/w
Strategy C STIRRING TIME (min) 30min 45min 60min


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 INDIVIDUAL RESPONSE BY QUADRATIC MODEL
Sedimentation Volume Ratio = Zeta potential=
+0.030-0.024A-0.089B-0.020C -44.67+12.00A+5.62B+0.38C-2.25 AB-0.25AC+1.00BC
+0.010AB+2.500E-003AC+2.500E-003BC+0.067A2+0.11B2+0.030C2 -6.92A2-2.67B2-1.17C2
Implementatn of
Control Viscosity = Content Uniformity=
Strategy +44.67+3.25A+8.38B+1.13C +1.73-0.20A-0.50B-0.15C
+0.000AB+0.050AC+0.000BC+0.41A2+0.76B2+0.26C2
-0.75AB-0.25AC+0.000BC-1.08A2-3.83B2+0.17C2


Responses (Effects) Goal for Individual Responses
Y1 Sedimentation Volume Ratio To achieve the minimum SVR i.e. NMT 0.1
Y2 Zeta Potential (mV) To achieve zeta potential of suspension in the range of -40 to -50 mv
Determination of Y3 Viscosity (cps) To achieve viscosity in the range of 40 to 50 cps
CQAs Y4 Content Uniformity (AV) To achieve minimum acceptance value in CU i.e. NMT 2.0
By Overlaying contour maps from each responses on top of each other, RSM was used to find 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
Factors (Variables) Knowledge Space Design Space Control Space

Implementatn of A SURFACTANT (%) 0.50-1.50 0.75-1.25 0.85-1.15
Control B HYDROCOLLOID (%) 20.0-40.0 27.5-37.5 30.0-35.0
Strategy C STIRRING TIME (min) 30-60 37-53 40-50


QTPP SWEETENER : FLAVOR : COLOR(Contd…)
Optimization of
Determination of Sweetener Flavor & Color
CQAs Ratio in liquid oral mixtures
Quality Risk
Assessment of
CMAs &
CPPs
3 COLORANT
DoE
& Development 2 FLAVOR
of Design Space
1 SWEETENER
PAT RISK
&Development
of Feedback
Control system
UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE
PATIENT ACCEPTANCE
Implementatn of COMPROMISED
Control
Strategy


OBJECTIVE To Optimize Sweetener : Flavor : Color ratio of Liquid Orals

Determination of
CQAs EXPERIMENTAL DESIGN SELECTED
D-OPTIMAL MIXTURE DESIGN
• During Optimization of sweetener, flavor & color in
SWEETENER
Quality Risk liquid orals; ultimate response to be measured was
Assessment of
CMAs & Patient Acceptability Score which was a function of
CPPs proportion of all 3 components in combination
• All 3 factors were components of a mixture, their
operating ranges were not same but their total
must be 2.0 %w/w of formulation & there were
upper bound constraints on the component
DoE
& Development proportions in the formulation mixture
of Design Space
• Thus, Constrained Mixture Design is selected, in
opposite to Simplex Mixture, as a special class of
RSM for optimization of proportions especially
applicable when there are upper or lower bound
PAT constraints on the component proportions.
&Development
of Feedback
Control system TOTAL NO OF EXP RUNS (TRIALS) 16
Factors (Variables) Lower Levels Higher Levels

A SWEETENER (%w/w) 1.00% 1.50%
Implementatn of B FLAVOR (%w/w) 0.50% 1.00%
Control C COLOR (%w/w) 0.00% 0.50%
Strategy


CMAs 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 SPECIAL CUBIC MODEL
Implementatn of Patient Acceptability Score= +3.79A+3.19B+2.67C+2.57AB+4.73AC+1.94BC+15.05ABC

Control
Strategy


Responses (Effects) Goal for Individual Responses

Y1 PATIENT ACCEPTANCE To achieve maximum Patient Acceptance Score as maximum as possible out of 10. &
Determination of SCORE NLT 4.5 out of 5.0
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 ultimate goals
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system

A SWEETENER (%w/w) 1.00-1.50% 1.10-1.35% 1.15-1.30%
Implementatn of B FLAVOR (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70%
Control C COLOR (%w/w) 0.00-0.50% 0.05-0.25% 0.10-0.20%
Strategy


QTPP PRESERVATIVE SYSTEM(Contd…)
Optimization of
Determination of
Preservative system for
CQAs In use Stability of Multidose Liquid Orals
Quality Risk
Assessment of
CMAs & C BUFFERING AGENT
CPPs
B ANTIOXIDANT
DoE A ANTIMICROBIAL
& Development
of Design Space
PAT RISKS
&Development
of Feedback
Control system
INADEQUATE ANTIMICROBIAL CONC. INADEQUATE ANTIOXIDANT CONC
MICROBIAL LOAD IN-USE OXIDATION IMPURITIES

Implementatn of
SAFETY COMPROMISED
Control
Strategy


OBJECTIVE To Optimize Preservative System for In Use Stability Of

Multi-dose Sterile Product (Injection, Eye/Ear Drops)
Determination of
CQAs
NO. OF FACTORS 3
NO. OF LEVELS 2
Quality Risk
Assessment of EXPERIMENTAL DESIGN SELECTED
CMAs &
CPPs 23 FULL FACTORIAL DESIGN WITH
BUFFERING AGENT
ADD. CENTER POINTS
ADD. CENTER POINTS 3

DoE
& Development TOTAL NO OF 23 + 3
of Design Space
EXPERIMENTAL RUNS
C
= 11
(NO OF TRIALS)
PAT
&Development A ANTIMICROBIAL
of Feedback
Control system
Factors (Variables) Levels of Factors studied

-1 Center point (0) +1
Implementatn of A Antimicrobial (%W/W) 0.005 0.010 0.015
Control B Antioxidant (%W/W) 0.050 0.100 0.150
Strategy C Buffering Agent (%W/W) 0.800 1.400 2.000


CMAs 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 LINEAR MODEL
REDUCTION in Microbial Load after 14 days =+99.42 +0.35A +0.075B +0.15C -0.050AB -0.075AC +0.025ABC
Implementatn of
Control OXIDIZED Impurities after 14 days=+0.46 -0.035A -0.18B -0.052C +7.50E-003AB +5.00E-003AC + 0.010BC -2.50E-003ABC
Strategy


Responses (Effects) 5 Goals for Individual Responses

Y1 Reduction in Microbial Load after 14D in use To achieve NLT 99.5% reduction in microbial load
Determination of
Y2 %Oxidized Impurities after 14D in use To minimize the level of oxidized impurities NMT 0.5%
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system

A Antimicrobial (%W/W) 0.005-0.015 0.010-0.015 0.012-0.015
B Antioxidant (%W/W) 0.050-0.150 0.080-0.150 0.100-0.150
Implementatn of C Buffering Agent (%W/W) 0.800-2.000 0.800-2.000 1.000-1.500
Control
Strategy

Definition of
QTPP
Determination of
CQAs
How to Identify & Optimize CMAs & CPPs of
Primary Packaging Process by Stability Studies?
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

IDENTIFICATION DESIGN OF ANALYSIS OF DEFINING OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN
SELECTION & OPTIMIZATION OF CMAs & CPPs OF
Determination of
LIQUID ORAL PACKAGING PROCESS
CQAs FOR LIQUID ORAL SOLUTION DOSAGE FORM DEVELOPMENT AS PER QbD
C CAP
Quality Risk
Assessment of B CAP LINER
LINER SEALING & CAPPING F
CMAs &
CPPs
POST-GASSING E
BOTTLE FILLING D
DoE
& Development A BOTTLE
of Design Space
RISKS
PAT COMPROMISE IN COMPROMISE IN COMPROMISE IN

&Development MECHANICAL STRENGTH PHYSICAL BARRIER CHEMICAL COMPATABILITY
of Feedback
Control system
FAILURE IN BUBBLE TEST, OOT / OOS IN WVTR, OTR, LTR OR OOS IN IMPURITY
VACUUM / PRESSURE DECAY MICROBIAL LOAD TESTS LIMITDURING SHELF LIFE
Implementatn of CHANCES OF DRUG PRODUCT PRODUCT EXPOSURE TO MOISTURE, COMPROMISE IN DRUG

Control INTEGRITY LOSS OXYGEN, LIGHT, MICROORGANISMS PRODUCT SHELF LIFE
Strategy
COMPROMISE IN QUALITY, SAFETY & EFFICACY

IDENTIFICATION DESIGN OF ANALYSIS OF VERIFICATION OF DEFINING OF
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Available Options of Primary Packaging Material
Determination of A Plastic HDPE B Plastic PP C Plastic PET
CQAs
Al CAP Al CAP Al CAP
Al Cap Liner 1 mil Al Cap Liner 1 mil Al Cap Liner 1 mil
Quality Risk
Assessment of
CMAs & Plastic HDPE Bottle Plastic PP Bottle Plastic PET Bottle
CPPs
D Glass USP IV F Glass USP II
Al CAP Al CAP
DoE Al Cap Liner 1 mil
& Development Al Cap Liner 1 mil
of Design Space
Glass USP IV Bottle Glass USP II Bottle
PAT
&Development
of Feedback G Glass USP I
Control system
Al CAP
Al Cap Liner 1 mil
Implementatn of
Control
Strategy
Glass USP I Bottle

Definition of
PDbD
Selection of Primary Packaging Material
Positive Control Test Pack (For Selection of Packaging material Negative
Tests (Plastic Plastic Plastic Glass Glass Control (Glass
HDPE) PP PET USP Type IV USP Type II USP Type I)
Determination of Barrier Properties
CQAs Oxygen Permeation High Moderate Low None None None
Water Vapor Permeation Low Very Low Very Low None None None
Resistance to Acids Fair Good Fair Fair Good Excellent
Resistance to Alkalis Good Very Good Good Very Poor Fair Excellent
Resistance to Alcohols Good Good Good Poor Excellent Excellent
Resistance to Mineral oils Fair Fair Good Fair Excellent Excellent
Quality Risk
Assessment of Resistance to Solvents Good Good Fair Poor Good Excellent
CMAs & Resistance to Heat Fair Good Fair Good Good Excellent
Resistance to Cold Excellent Fair Good Good Excellent Excellent
CPPs Resistance to Sunlight Fair Fair Fair Fair Fair Fair
Resistance to High Humidity Good Excellent Excellent Good Excellent Excellent
Processing / Storage Parameters
Colorless, Transparent, Transparent, Optically Clear, Optically Clear,
Clarity / Translucency Translucent
DoE Translucent Clear Clear Transparent Transparent
& Development Toughness / Impact Resistance Good Fair to Good Excellent Fair Fair Good
of Design Space Autoclavable / Sterilizable Yes Yes Yes Yes Yes Yes
Extractable / Leachable Low Low Moderate High Moderate Low
Weathering- Flaking –Alkalinity Low Low Moderate High Moderate Low
Breathing – Permeation – O2/CO2 High Moderate Low None None None
PAT
&Development
of Feedback
SELECTION CRITERIAS
Control system
MECHANICAL PHYSICAL CHEMICAL BIOLOGICAL ECONOMICAL
STRENGTH BARRIER COMPATABILITY SAFETY ACCEPTABLE
-Strong enough to Protection from Does not react with Extract able/ Leachable Total Cost,
Implementatn of withstand handling -heat & moisture -Product Contents Should be Unit Price acceptable
Control -should fit in -oxygen /any gas / vapor -Packing Ingredients -absent / within limits with comparable
Strategy packaging line -UV / Visible light -not impart its color odor -biological safe Advantages
-long life -microorganism taste to drug product -nontoxic

Definition of
PDbD
Comparative Accelerated Stability Study with different Packaging Material – Scale Up Batch
40°±2°C /75±5%RH for 3 Months
Initial Positive Test Pack (For Selection of Packaging material Negative
Specification-CQAs Analysis
Tests Control for Optimized Finished Product Formulation) Control
(Acceptance Criteria)
Determination of (0 Days) (Plastic Plastic Plastic Glass Glass (Glass
CQAs HDPE) PP PET USP Type IV USP Type II USP Type I)
Weathering
Physical Description Clear, Transparent Complies Complies Complies Complies Complies Complies
Flaking
Imp A1: NMT 0.5% 0.15 0.39 0.35 0.30 0.29 0.22 0.20
Related Substance Imp B2: NMT 0.5% 0.18 0.37 0.34 0.28 0.30 0.31 0.28
Quality Risk (Impurity) / HPLC Imp C3: NMT 0.5% 0.10 0.25 0.22 0.17 0.17 0.14 0.13
Assessment of Imp D4: NMT 0.5% 0.07 0.19 0.20 0.18 0.19 0.20 0.18
CMAs & Max UNK:NMT 0.5% 0.14 0.35 0.31 0.30 0.33 0.29 0.23
CPPs Total : NMT 3.0% 0.66 1.59 1.44 1.29 1.31 1.18 1.06
Assay
95% to 105% 98.8 96.7 97.1 97.6 97.5 98.2 98.4
(API)
Assay
90% to 110% 99.7 85.6 87.6 89.5 92.1 98.4 98.9
(Antimicrobial)
DoE Assay
90% to 110% 98.6 83.4 86.5 87.3 96.1 97.6 97.8
& Development (Antioxidant)
of Design Space
pH of system 6.5-7.5 7.1 6.8 6.6 6.9 8.4 7.3 7.2
Microbial Contents Absent Absent Absent Absent Absent Absent Absent Absent
Viscosity 40-50 cps 46 cps 44 cps 44 cps 42 cps 46 cps 47 cps 45 cps
Specific Gravity 0.9-1.2 g/ml 1.1 g/ml 1.0 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml
Extractable / Na2O, CaO,
PAT Leachable
Within Limits /
Absent Absent Absent DMT, EG K2O, BaO,
Na2O, CaO B2O3, Na2O
&Development Nontoxic-safe (<10 ppm) (<5 ppm)
of Feedback Constituents Al2O3, B2O3
Control system 1Impurity 2Impurity 3Impurity
generated due to oxidation generated due to temperature effect generated due to moisture effect 4 Impurity generated due to light exposure
Here , Drug Substance in Liquid formulation is susceptible to oxidation, hydrolysis, temperature, light, pH Change & Microbial Growth.
(A) Plastic containers possess major problems due to high permeability of gases & vapors & sorption of preservatives & flavors by packaging material itself.
(B) While Soda Lime Glass containers in damp atmosphere moisture condenses on the surface of glass container & extracts weekly bonded alkali ions. When the surface
Implementatn of becomes dry in high temperate atmosphere, white deposit of alkali carbonate is produced by reaction with CO2 from the air. If the film is allowed to remain, further
Control condensation dissolves away some of the silica with a loss of surface brilliance or clarity, known as “weathering”. This silica rich layer on the surface of the glass container fall
away & can be seen as glistering flakes in the contents. Known as “Flaking”.
Strategy Thus, with respect to (i) Physical Appearance / Clarity (ii) Assay of API & Preservatives (iii) impurities generated upon storage (iv) pH Change (iv) extractable & leachable
profiling ; Treated Sulphured Soda Lime Glass (USP Type II) with high hydrolytic resistance due to surface treatment (dealkalized by SO2) was selected as primary pack

Definition of
PDbD
Accelerated Stability Study with Finalized Primary Pack : USP Type II Glass– Exhibit Batch
Initial Analysis 40°±2°C /75±5%RH up to 6 Months:

Specification-CQAs
Tests in USP Type II Glass with Al Cap & Al Liner Pack
(Acceptance Criteria) (0 Days)
1 Month 2 Months 3 Months 6 Months
Determination of
Description Clear, Transparent Complies Complies Complies Complies Complies
CQAs Imp A1:
NMT 0.5% 0.14 0.16 0.19 0.22 0.25
Imp B2: NMT 0.5% 0.17 0.23 0.28 0.31 0.34
Related Substance
Imp C3: NMT 0.5% 0.10 0.16 0.13 0.14 0.16
(Impurity) / HPLC
Imp D4: NMT 0.5% 0.08 0.14 0.18 0.20 0.23
Max Unk :NMT 0.5% 0.15 0.21 0.26 0.29 0.32
Quality Risk
Assessment of Total : NMT 3.0% 0.68 0.82 1.02 1.18 1.37
CMAs & Assay (API) 95% to 105% 98.8 98.6 98.5 98.2 97.9
CPPs Assay (Anti Microbial) 90% to 110% 99.5 99.1 98.8 98.6 98.2
Assay (Anti Oxidant) 90% to 110% 98.7 98.3 97.9 97.6 97.3
pH of system 6.5-7.5 7.1 7.1 7.2 7.2 7.3
Microbial Contents Absent Absent Absent Absent Absent Absent
Viscosity / Rheology 40-50 cps 45 cps 44 cps 44 cps 46 cps 47 cps
DoE Density / Sp. Gravity 0.9-1.2 gm/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml
& Development Na2O Na2O, CaO
of Design Space Extractable / Leachable Absent Absent Absent Absent
(Very Low) (Very Low)
1Impurity generated due to oxidation 2Impurity generated due to temperature effect 3Impurity generated due to moisture effect 4 Impurity generated due to light exposure
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

Definition of
PDbD
Implementation of Controls for Packaging of– Commercial Batches
Ranges studied at Actual data Proposed range for

CPAs / CPPs PURPOSE of Control
LAB scale for EXHIBIT batches COMMERCIAL batch
Container
Determination of
USP Type II Glass USP Type II Glass USP Type II Glass To ensure Mechanical Strength,
CQAs Material (Treated Sulphured (Treated Sulphured (Treated Sulphured Physical Barrier & Chemical
Soda Lime Glass) Soda Lime Glass) Soda Lime Glass) Compatibility for target shelf
life of drug product during
Capacity 200 ml 200 ml 200 ml transportation, storage or
routine-use
Quality Risk Closure
Assessment of
CMAs & Cap
Aluminum Cap
22 mm
Aluminum Cap
22 mm
Aluminum Cap
22 mm
To ensure Physical Barrier &
Chemical Compatibility for
CPPs target shelf life of drug product
Two Piece Re-sealable Two Piece Re-sealable Two Piece Re-sealable
Cap Liner during transportation,
Al Cap Liner 1 mil Al Cap Liner 1 mil Al Cap Liner 1 mil
storage or routine-use
Processing Parameters
DoE Volumetric Filling Volumetric Filling Volumetric Filling
To ensure batch to batch
& Development Method of Filling with by Positive by Positive by Positive
of Design Space
Mechanism Displacement Displacement Displacement consistency in bottle pack
Piston Action Piston Action Piston Action without any Mechanical
damage, Physical Leakage or
30-50 bottles / min 30-50 bottles / min to 30-50 bottles / min to
Rate of Filling Chemical Incompatibility to
to prevent Foaming prevent Foaming prevent Foaming
achieve target shelf life of drug
Post-gassing With N2 purging With N2 purging With N2 purging
PAT Induction Sealing Induction Sealing Induction Sealing
product during transportation,
&Development Cap Liner Sealing storage or routine-use
of Feedback (20-60 bottles/min) (20-60 bottles/min) (20-60 bottles/min)
Control system
Environmental Conditions
Temperature 21-25°C 21-25°C 21-25°C To ensure batch to batch
Humidity 20-40 % RH 20-30 % RH 20-30 % RH uniformity in surrounding
Under Nitrogen Under Nitrogen Under Nitrogen environmental factors during
O2 or N2 on line processing of packaging
Implementatn of Laminar Flow Laminar Flow Laminar Flow
Control Packaging Under Packaging Under Packaging Under
to provide protection from
temperature, moisture,
Strategy UV- Visible Light
Sodium Vapor Lamp Sodium Vapor Lamp Sodium Vapor Lamp light & oxidation

Definition of
QTPP
Determination of
CQAs
5
How to control risks by
Quality Risk
Assessment of
CMAs &
CPPs
Process Analytical Technology?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
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 SOLUTION MANUFACTURING (Contd…)
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
VEHICLE PREPARATION WITH CONTROLLED SOLUBILIZATION pH & VOLUME MAKE UP WITH
SWEETENER, FLAVOR & COLOR WITH HEATING & MIXING VEHICLE & STORAGE
A B C
Implementatn of
Control
Strategy CRITICAL PROCESSING STEPS


API / EXCIPIENT PURITY API / EXCIPIENT PARTICLE
At line UV/ HPLC/ GC, SIZE DISTRIBUTION TEMPERATURE &
On line LOD/ HMB or W/KF At line Malvern Particle Size RELATIVE HUMIDITY
Analyzer OR On Line At Line
Sieve Shaker Analysis Thermo-hygrometer
Determination of
On Line On Line
CQAs pH Meter Viscometer
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
VEHICLE PREPARATION CONTROLLED SOLUBILIZATION pH & VOLUME MAKE & STORAGE
of Feedback
Control system Bulk Uniformity by At line Bulk Uniformity by At line Precipitation analyzed by
UV-VISIBLE/ IR,-RAMAN UV-VISIBLE/ IR,-RAMAN At Line Malvern PSA or
HPLC/ GC Spectroscopy HPLC/ GC Spectroscopy Online SVR/ SHR/ DF
Risk Analysis of CMAs & CPPs with respect to CQAs at Raw Scale Developmental level
Implementatn of
by ON LINE / AT LINE Analyzers for Prediction of Real Time Data &
Control Designing of Control Strategies at Commercial Scale
Strategy


API / EXCIPIENT PURITY API / EXCIPIENT PARTICLE TEMPERATURE &
In Line FT-NIR SIZE DISTRIBUTION RELATIVE HUMIDITY
In line FBRM In Line
Thermo-hygrometer
Determination of
In Line In Line
CQAs pH Meter Viscometer
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
VEHICLE PREPARATION CONTROLLED SOLUBILIZATION pH & VOLUME MAKE & STORAGE
of Feedback
Control system Bulk Uniformity by In line Bruker Bulk Uniformity by In line Bruker Precipitation analyzed by
FT-NIR Spectroscopy for FT-NIR Spectroscopy for In Line Lasentec FBRM or
homogenized state of solution homogenized state of solution Particle Video Monitoring
Real Time Data Analysis at Scale UP-Exhibit Manufacturing Scale

Implementatn of
by IN LINE analyzers with auto-sensors & Real time data comparison with Raw scale data
Control
for Finalization of Control Strategies at Commercial Scale
Strategy


Auto-controlling of Auto-controlling of Auto-controlling of
DISSOLVED OXYGEN HEADSPACE OXYGEN TEMPERATURE &
by adjusting Vacuum by adjusting Vacuum RELATIVE HUMIDITY
Pressure & Stirring Time Pressure & N2 Purging Air Handling Unit
(AHU)
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
Auto controlling of Auto controlling of Auto Maintaining of
of Feedback
Control system VEHICLE PREPARATION CONTROLLED SOLUBILIZATION PHYSICAL & CHEMICAL STABILITY
Bulk Uniformity by adjusting Bulk Uniformity by adjusting By adjusting
Heating Temperature Heating Temperature Stirring Speed
Heating Time Heating Time Stirring Time
Mixing Speed Mixing Speed Storage Temperature
Mixing Time Mixing Time Dissolved & Headspace Oxygen
Implementatn of
Application of Auto-controllers at real time Manufacturing scale
Control For Continuously attaining Acceptable ranges of CMAs & CPPs
Strategy with respect to desired CQAs

Definition of
QTPP
Determination of
CQAs
6
How to
Quality Risk
Assessment of
CMAs &
CPPs
Implement Controls
for Commercial Manufacturing?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy

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
FACTOR(s) CMAs PURPOSE of Control
Active Pharmaceutical Ingredient (API) Critical Material Attributes
Determination of
CQAs Polymorphic
2Ө values x, y, z x, y, z x, y, z consistency in
Form
Dissolution
EXCIPIENT Critical Material Attributes

Quality Risk To ensure consistence
Assessment of UV/RO Filtered UV/RO Filtered UV/RO Filtered
Vehicle Grade compatibility, purity &
CMAs & Purified Water Purified Water Purified Water
Microbial Stability
CPPs
Type (Tween 80) Non-ionic Non-ionic Non-ionic
Surfactant
Concentration (%w/w) 0.50-1.50 0.75-1.25 0.85-1.15 To ensure batch to batch
consistency in solubility,
DoE pour ability, Physical
& Development Source (CMA) Semisynthetic Semisynthetic Semisynthetic Stability & Compatibility
of Design Space Hydrocolloid
Concentration (%w/w) 20.0-40.0 27.5-37.5 30.0-35.0
Sweetener Concentration (%w/w) 1.00-1.50% 1.10-1.35% 1.15-1.30%

PAT consistent Patient
&Development Flavor Concentration (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70%
of Feedback Acceptance &
Control system Compliance
Color Concentration (%w/w) 0.00-0.50% 0.05-0.25% 0.10-0.20%
Anti-Microbial Concentration (%w/w) 0.005-0.015 0.010-0.015 0.012-0.015

Implementatn of
Anti-Oxidant Concentration (%w/w) 0.050-0.150 0.080-0.150 0.100-0.150 consistency Chemical &
Control Microbiological stability
Strategy Buffer Concentration (%w/w) 0.800-2.000 0.800-2.000 1.000-1.500

CONTROL OF CONTROL OF
CMAs CPPs
Definition of CONTROL STRATEGY For

QTPP Critical Processing Parameters
FACTOR(s) CPPs PURPOSE of Control
To ensure consistence
Determination of Vehicle/ Solvent Heating Temperature 60-80°C 63-77°C 65-75°C
compatibility,
CQAs Preparation
acceptability, purity &
with Sweetener,
Microbial Stability
Flavor, Color
Mixing Time 30-60 min 35-55 min 45 min
Quality Risk
Assessment of Controlled Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch
CMAs & Solubilization by consistency in Solubility,
Surfactant & Pour ability, Physical
CPPs hydrocolloids Mixing Time 30-60 min 37-53 min 40-45 min Stability & Compatibility
pH Adjustment
with Buffer Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch
DoE &Final Volume consistency Chemical &
& Development
of Design Space make up Microbiological stability
with vehicle
Mixing Time 30-60 min 37-53 min 40-45 min
& final Mixing
Particulate Matter 5 micron with 3 micron 3 micron

PAT Screen Size vacuum with vacuum with vacuum
&Development Ultrafiltration
of Feedback purity to warrant Safety
Control system Microbial Filter 0.3 micron 0.2 micron 0.2 micron
Screen Size vacuum filter vacuum filter vacuum filter
Temperature 21-25°C 21-25°C 21-25°C

Implementatn of Filling,
To ensure Chemical
Control Capping &
Vacuum Pressure Stability
Sealing
Strategy with Nitrogen NLT 29.5” NLT 29.5” NLT 29.5”
Purging

Controls for
Definition of Critical Material Attributes
QTPP Critical Processing Parameters
2.0
0.50
0.045 0.050
100
5.0
100
5.0
100
0.45
1.9
4.5
4.5
Determination of
90
90
90
CQAs
0.040
0.40
1.8
4.0
4.0
80
80
80
75˚C
0.035
1.7
0.35
3.5
70
70
3.5
70
Quality Risk
Assessment of
CMAs & 65˚C
0.30
0.025 0.030
1.6
3.0
60
60
3.0
CPPs
60
0.25
1.5
2.5
50
50
2.5
50
45 min
DoE
0.020
0.20
1.4
2.0
40
40
2.0
40
& Development
of Design Space 35% 40 min
0.15% 1.5% 1.30 %
0.015
0.015%
0.15
1.3
1.5
30
1.5
30
30
30%
1.0%
0.01
PAT
1.2
0.10
1.0
0.012%
1.0
20
20
20
&Development 0.10% 1.0%
of Feedback 0.8% 1.15 %
0.000 0.005
Control system
0.05
1.1
0.5
0. 5
10
10
10
0.00
0.0
0
1
0
0
0
Implementatn of
Control Surfactant Hydrocolloid Anti Anti Buffer Sweetener Controlled Controlled
Strategy Microbial Oxidant Solubilization
Temperature
Solubilization
Stirring Time

Controls for
Definition of Critical Quality Attributes of
QTPP In Process Intermediates & Finished Product
150
150
150
150
2.0
1.5
10
1.5
1.4 g/mL
140
140
140
140
1.8
9
Determination of
1.4
1.4
CQAs
130
130
130
130
1.6
1.3
8
1.3
7.5
1.2 cP
120
120
120
120
7
1.4
1.2
1.2
Quality Risk 1.2 g/mL
Assessment of
CMAs & 110% 110% 110% 110% 6.5
110
110
110
110
1.2
1.1
6
CPPs
1.1
1%
100
100
100
100
1.0
1.0
1.0
5
1.0 cP
DoE
0.9
90
90
0.8
90
90
0.9
& Development 90% 90%
of Design Space 90% 90%
0.8
0.8
0.6
80
80
80
80
0.7
0.7
PAT
70
70
70
70
0.4
2
&Development
of Feedback
Control system
0.6
0.2
60
60
0.6
60
60
0.5
50
50
50
50
0.5
0
Implementatn of 0%
Control API Assay Total Weight Anti Anti pH Viscosity Density / Sp.
Strategy Impurities Variation Microbial Oxidant Gravity

Assay assay

7
How to manage quality throughout
Product Life Cycle
By continual improvement?
Management of
Product
Life
Cycle
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.
“Continual Trend Analysis” in Process Control Charts
Assessment of Common (Chance) Cause Vs. Special (Assignable) Cause
WECO Rules for signaling "Out of Control"

4
Upper Control Limit Assignable Cause
Any Point bove +3 Sigma
3 +3σ Limit
Mean or Range of Characteristic Quality
2 Out of the 3 Consecutive Points above +2 Sigma & below +3 sigma

2 +2σ Limit
4 Out of the 5 Consecutive Points above +1 Sigma & below +2 sigma
1 +1σ Limit
Common Causes
8 Consecutive Points or 10 out of 11 points or 12 out of 14 points
Central Line or 14 out of 17 points or 16 out of 20 points fall on same Side of Control Line
0 0
0 1 8 Consecutive Points or2 10 out of 11 points or 12
3 out of 14 points or 14 4
out of 17 points or 16 out5 of 20 points 6
fall on same Side of Control Line
-1 -1σ Limit
4 Out of the 5 Consecutive Points below -1 Sigma & above -2 sigma
-2 -2σ Limit
2 Out of the 3 Consecutive Points below -2 Sigma & above -3 sigma
-3 -3σ Limit
Lower Control Limit Any Point below -3 Sigma
Assignable Cause
-4
Sample Number
Management of
Product Other Trend Rules: 6 consecutive points in a row trending up OR down (same side)
Life 14 consecutive points in a row alternating up & down (same side)
Cycle 8 consecutive points in a row more than 1σ from center line (either side)
15 consecutive points in a row within 1σ of center line (either side)
Process Variations
Common (Chance) Cause Vs. Special (Assignable) Cause
Common Cause Chance

cause/ Non-Assignable
cause (NOISE) Special Cause /
Assignable cause
(Signal)
Phenomena constantly active
within the system;
New, surprise, unanticipated,
emergent or previously neglected
Natural Predictable Pattern of phenomena within the system
variation, within a historic
experience base Unnatural unpredictable pattern
of variation, outside historic
experiment base.
Inappropriate procedures/ SOP
Poor design &
Poor maintenance of machines Operator absent
Poor working conditions
Substandard raw materials Poor adjustment of equipment
Measurement error Operator falls asleep
Vibration in industrial processes Faulty controllers
Ambient temperature / humidity Machine malfunction
Insufficient training
Normal wear and tear Fall of ground
Variability in settings Computer crash
Computer response time Poor batch of raw material
Power surges
Management of
Product
Life
Cycle
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

Conclusion
Risk Reduction For Critical Material Attributes of API
BEFORE
Detectability of Solid State

form was increased by
AFTER
including pXRD test at drug

substance release stage itself
Probability of undesired PSD

was reduced by implementing
IVIVC during development
Detectability of desired PSD

was increased by
implementing Malvern &
FBRM at release
Detectability of content
Justification for uniformity was increased by
Risk implementing in line FT-NIR
Reduction during mixing stage
  
Conclusion
Risk Reduction For Critical Material Attributes of Excipients
BEFORE
Probabilities of POOR
WETTING of API was reduced
by optimizing ranges of
Surfactant via DoE generated
Design Space (DS)
Probability of Flocculation &

AFTER
Caking was reduced by

optimizing ranges of
Disintegrant via DoE / DS
Probabilities of increased
Sedimentation was reduced by
Hydrocolloid via DoE generated
Design Space (DS)
Probability of Microbial
Spoilage upon storage was
reduced by optimizing ranges
of Anti-microbial via DoE / DS
Justification for
Risk Probability of Oxidation
upon storage was reduced by
Reduction 
    optimizing ranges of Anti-
Oxidant via DoE / DS

Conclusion
Risk Reduction For Critical Processing Parameters of Tableting
BEFORE
Detectability of Solvent/
Vehicle Purity was increased
by utilizing inline FT-NIR PAT
Probability of poor wetting,

flocculation, sedimentation &
caking were reduced by
Surfactant, Electrolyte &
AFTER
Hydrocolloid via DoE

generated Design Space (DS)
Detectability of Content
Uniformity was increased by
utilizing inline FT-NIR PAT
Detectability of pH was
increased by inline pH Meter
Detectability of Desired
Particle Size Distribution was
increased by utilizing FBRM/
PVM Sensors as PAT Tool
Justification for
Risk Detectability of online
dissolved / headspace O2 & pH
Reduction
     
during filling & packaging was
increased by utilizing in line
DO meter & pH meter as PAT
“Quality doesn’t cost, it always pays”
© Created & Copyrighted by

SHIVANG CHAUDHARY
Chief Knowledge Officer (CKO) & Global Head Quality by Design at QbD Expert™
MS (Pharmaceutics), Ph.D. (Pharmaceutical Sciences), LSSMBB, EDMP (PM), PGDPL
www.facebook.com/QbDExpert www.linkedin.com/groups/8264051
 +91 -9904474045, +91-8866327899
 qbdexpert@gmail.com
 www.qbdexpert.com
View publication stats © Created & Copyrighted by Shivang Chaudhary.

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Quality by Design (QbD) Model for "LIQUID ORAL SOLUTION" © by Dr.

Article in Drug Development and Industrial Pharmacy · April 2016

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QbD For SOLUTION

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• Stable & Therapeutic

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QbD & Its Elements

Quality Risk Assessment of

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What is the meaning of

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Designing of Experiments (DoE) & Design Space

PAT Process Analytical Technology (PAT)

Implementatn of Implementation of Control Strategy

© Created & Copyrighted by Shivang Chaudhary.

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QUALITY TARGET PRODUCT PROFILE (QTPP)

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Definition of Quality Target Product Profile (QTPP) of Solution

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Critical Quality Attribute (CQA)

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Definition of Critical Quality Attributes (CQA) of Solution

Physical Identification Assay

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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

Solvent source, purity, polarity, pH, Viscosity/sp.

Drug substance PSD/SSA, Contact angle,

Physical Attributes (Clarity#, Homogeneity*),

Physical Attributes (Clarity#, Homogeneity*),

Control Filling rate

Definition of Identification of Risk Factors by

Quality Risk BODYING BY API PSD & SURFACE AREA

© Created & Copyrighted by Shivang Chaudhary.

CQAs Physical Particle Microbial Moisture Residual

© Created & Copyrighted by Shivang Chaudhary.

QTPP Active Pharmaceutical Ingredient’s (API) Attributes be increased through

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

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CQAs Surfactants Preservatives Organoleptic Additives

© Created & Copyrighted by Shivang Chaudhary.

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Quality Risk A SURFACTANT (%w/w)

DoE D ANTI OXIDANT (%w/w)

PAT COLOR (%w/w)

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Definition of Qualitative Risk based Matrix Analysis of

CQAs Solvent/ Solubilizing of

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Definition of Quantitative Failure Mode Effect Analysis (FMEA) of

Order of addition Incorrect Physical Attributes, Zeta Potential, 2 3 4 24

Order of Addition Incorrect Physical Attributes, Viscosity, SVR/SHR. Content 2 3 4 24

Dissolved / Headspace Oxygen may get increased 3 3 4 36

© Created & Copyrighted by Shivang Chaudhary.

© Created & Copyrighted by Shivang Chaudhary.

PAT Probability* Severity Detect ability* Score