A Model: Liquid Oral Solutions

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

Determination of
OPTIMIZATION OF A MONOPHASIC LIQUID ORAL DOSAGE FORM-SOLUTIONS
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 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
PAT &
Development of Feedback Controls
Implementation 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.

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) / New Drug
Control system
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 Solution

QTPP
QTPP Element Target Justification
Pharmaceutical equivalence requirement:
Dosage FORM Solution
same dosage form
Immediate release design needed to meet
Dosage DESIGN Immediate Release Formulation
label claims
Determination of Pharmaceutical equivalence requirement:
ROUTE of Administration Oral/ External
CQAs same route of administration
Pharmaceutical equivalence requirement:
Dosage STRENGTH x mg
same strength
Appearance
Assay
Content Uniformity
Drug Impurities
Quality Risk
Assessment of Product pH of System Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable
QUALITY Microbial Limits reference standards (i.e., identity, assay of drug, assay of preservatives, microbial load, purity & quality)
CMAs & ATTRIBUTES Antimicrobial content
CPPs Antioxidant content
Extractables
Viscosity/Specific Gravity
Container (Glass/Plastic/Metal) & Closure (Plastic/Metal/Rubber)
system should be qualified as suitable for drug product with Required to achieve the target shelf-life
PRIMARY & SECONDARY desired Compatibility & Stability. Should product from heat, and to ensure product integrity
DoE PACKAGING moisture, oxygen, carbon dioxide, light & microbial attack. during transportation, storage
& Development Plastic should not allow permeation, leaching, sorption, & during routine-use
of Design Space or any other chemical or physical deformation.
BE study is not required in Solution as drug is already Bioequivalence study is not required to meet
Pharmaco-KINETICS available in the solution form at the site of absorption required rate & extent of drug absorption
PAT
&Development Can be stored at real time storage condition as a normal
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 Hydrolysis, Oxidation, Photodegradation &
Microbial Growth. At least 12-months shelf-life is required at Equivalent to or better than
STABILITY & SHELF LIFE room temperature. At least 28 Days of in-Use Shelf Life is Reference Product shelf-life
Implementatn of
required during routine use of multidose product
Should possess acceptable taste, flavor, odour & attractable
Control PATIENT ACCEPTANCE & pleasant color most probably as similar with Reference Product. Required to achieve the desired patient
Strategy PATIENT COMPLIANCE Can be easily administered (pourable & palatable)/ used/
applied similarly with Reference Product labelling
acceptability & suitable compliance

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 Quality Attributes of
Target
Is this a
Justification
Drug Product CQA?
Physical Color, Odor and taste should Color, Odor & Taste are not directly linked to safety and efficacy. Therefore, they are not
Yes
Appearances acceptable to the patient. critical. But to ensure patient acceptability it should be similar with reference product
Though identification is critical for safety, it can be effectively controlled at drug
Positive for drug as per USP Monograph
Identification Yes* substance release stage. Formulation and process variables do not impact identity.
of Drug Substance
Therefore, this CQA will not be discussed during development.
Determination of Viscosity/ Specific gravity of the suspension should be balanced to make it possible to pour
Rheological
As per USP <911> for viscosity; conforms easily from container or to apply on the skin or to maintain optimum consistency to hold
CQAs properties (viscosity
/specific gravity)
to USP <841> for specific gravity
Yes
globules in emulsion to ensure PHYSICAL STABILITY. Formulation variables may have
impact on viscosity. Therefore, this CQA will be discussed during formulation development
Assay variability will affect SAFETY AND EFFICACY. Formulation & Process variables may
Assay 90.0 to 110.0 % of labeled claim. Yes
affect the assay of the drug product. Thus, assay will be evaluated throughout development.
Conforms to USP <905> Uniformity of Variability in content uniformity will affect SAFETY AND EFFICACY. Both formulation and
Weight Variation/
Quality Risk Dosage Units: 90.0-110.0 % of labeled Yes process variables may have impact on weight variation & content uniformity,
Content Uniformity
Assessment of claim with Acceptance Value: NMT 15.0; so this CQA will be evaluated throughout development.
CMAs & Liquid dosage forms are very liable to microbial attack as it contains mostly aqueous
As per USP <51> & As per In house vehicle /solvent. Formulation, compounding, packaging variables & environmental factors
CPPs Antimicrobial
specification according to Yes may impact on antimicrobial content. Thus to maintain the microbial quality of the product
preservative content
developmental & stability data throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus,
this CQA will be discussed throughout formulation & process development.
Liquid dosage forms are more prone to oxidation. Formulation, Compounding, Packaging
Antioxidant As per In house specification according Process variables & Environmental factors may impact on antioxidant content. Thus to
Yes
preservative content to developmental & stability data maintain the levels of oxidized impurities throughout shelf life & proposed in-use shelf life
DoE to ensure patient SAFETY. Thus, this CQA will be discussed throughout development.
& Development
of Design Space Formulation & Processing variables may affect the pH of the drug product having
pH of System Conforms to USP <791> Yes impact on SOLUBILITY & CHEMICAL STABILITY. Thus, pH of the formulation
will be evaluated throughout formulation & development .
Degradation products can impact safety and must be controlled based on compendia /
Impurities /
As per ICH Q3A& Q3B & ICH requirements or reference product characterization to ensure patient SAFETY.
Degradation Yes
USP <1086> Formulation and process variables can impact degradation products. Therefore,
Products
PAT degradation products will be assessed during product and process development.
&Development Microbial Load will impact patient SAFETY. Formulation, compounding,
of Feedback packaging variables & environmental factors may impact microbial limits. Thus to
Microbiological
Control system Conforms to USP <61 & 62> Yes maintain the microbial quality of the product throughout shelf life & proposed in-use
Limits
shelf life to ensure patient SAFETY. Thus, this CQA will be discussed
throughout formulation & process development.
Generally, development and stability data should show evidence that extractable from
Conforms to USP <660> for glass,
the container/closure systems are consistently below levels that are demonstrated to be
Extracta/,ble <661> for plastic & comparable to Yes*
acceptable and safe, elimination of this test can normally be accepted to ensure SAFETY
Implementatn of reference product
This should be reinvestigated if the container/closure system or formulation changes.
Control For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE
Strategy Dissolution
As per In house specification according
Yes*
Can be waived. Generally, in vivo BE studies are waived for solutions on the assumption
to developmental & stability data that release of the drug substance from the drug product is self-evident and that the
solutions do not contain any excipient that significantly affects drug absorption
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 Filtration in Colloid mill
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
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
BCS Class II/IV Low Solubility drug
be Reduced through
Particle Size DoE Optimization
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
QTPP Active Pharmaceutical Ingredient’s (API) Attributes
Required to be Optimized &/Or Controlled
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
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 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
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 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

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

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

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
Active Pharmaceutical Ingredient (API) Critical Material Attributes
Determination of
CQAs Polymorphic
To ensure batch to batch
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
Ranges studied at Actual data Proposed range for
FACTOR(s) CPPs PURPOSE of Control
LAB scale for EXHIBIT batches COMMERCIAL batch
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

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

A Model: Liquid Oral Solutions

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Copyright:

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A Model: Liquid Oral Solutions

Uploaded by

Copyright:

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Definition of

QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS

PAT Designed & Developed by

• Stable & Therapeutic

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QbD & Its Elements

Quality Risk Assessment of

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Designing of Experiments (DoE) & Design Space

PAT Process Analytical Technology (PAT)

Implementatn of Implementation of Control Strategy

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QUALITY TARGET PRODUCT PROFILE (QTPP)

Note: QTPP will be finalized -

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Definition of Quality Target Product Profile (QTPP) of Solution

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Critical Quality Attribute (CQA)

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Definition of Critical Quality Attributes (CQA) of Solution

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

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CQAs Physical Particle Microbial Moisture Residual

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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

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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

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© Created & Copyrighted by Shivang Chaudhary

Design of Experiments (DoE)

Definition of DoE For

Optimization of CMAs & CPPs OF

CQAs Solution Homogenization Process

CONTENT UNIFORMITY COMPROMISED

QUALITY COMPROMISED SAFETY COMPROMISED EFFICACY COMPROMISED

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Definition of DoE For

OBJECTIVE To Optimize CMAs & CPPs of Liquid Suspension Dosage Form

PAT Probability* Severity Detect ability* Score