Quality by Design - QbD Model for Liquid Oral "SUSPENSION"
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Transcript of Quality by Design - QbD Model for Liquid Oral "SUSPENSION"
QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION OF A BIPHASIC LIQUID ORAL DOSAGE FORM-SUSPENSION
A MODEL
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Copyrighted by Shivang Chaudhary
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
+91 -9904474045, +91-7567297579 [email protected]
https://in.linkedin.com/in/shivangchaudhary
facebook.com/QbD.PAT.Pharmaceutical.Development
Designed & Developed by
© Created & Copyrighted by Shivang Chaudhary
Aim
• Stable & Therapeutic Equivalent (Pharmaceutical Equivalent + Bioequivalent) IR Generic Liquid Oral Suspension
• Robust & Rugged Reproducible Manufacturing Process
• with a Control Strategy that ensures the quality & performance of the drug product
as per Quality by Design
To Develop :
Project
Goal
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
© Created & Copyrighted by Shivang Chaudhary
© Created & Copyrighted by Shivang Chaudhary
iNSIDES
Targeting
Bullets
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
What is the meaning of
Quality by Design?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
Quality by Design (QbD) A SYSTEMATIC approach • to development • that begins with predefined objectives and • emphasizes product and process understanding • and process control,
• based on sound science and quality risk management.
Quality The suitability of either a drug substance or a drug product for its intended use.
What is QbD?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Define QTPP (Quality Target Product Profile) On the basis of THERAPEUTIC EQUIVALENCE for Generic Drug Product = PHARMACEUTICAL EQUIVALENCE (same dosage form, route of administration, strength & same quality) + BIO-EQUIVALENCE (same pharmacokinetics in terms of Cmax, AUC to reference product)
Determine CQAs (Critical Quality Attributes) Considering QUALITY [Assay, Uniformity of Dosage units,], SAFETY [Impurities (Related substances), Residual Solvents, Microbiological limits], EFFICACY [Dissolution & Absorption] & MULTIDISCIPLINARY [Patient Acceptance & Compliance]
Designing of Experiments (DoE) & Design Space For SCREENING & OPTIMIZATION of CMAs & CPPs with respect to CQAs by superimposing contour plot to generate OVERLAY PLOT (Proven acceptable Ranges & Edges of failure ) based upon desired ranges of Responses
Process Analytical Technology (PAT) For continuous automatic IN LINE analyzing & FEED BACK controlling critical processing through timely measurements of CMA & CPAS by INLINE ANALYZERS WITH AUTO SENSORS with the ultimate goal of consistently ensuring finished product quality with respect to desired CQAs
Implementation of Control Strategy For CONTROLS OF CMAs, CPPs within Specifications, by Real Time Release Testing, Online Monitoring System, Inline PAT Analyzers based upon previous results on development, Scale Up. Exhibit/ Validation batches.
Quality Risk Assessment of CMAs & CPPs with CQAs (1) RISK IDENTIFICATION: by Ishikawa Fishbone (2) RISK ANALYSIS by Relative Risk based Matrix Analysis (3) RISK EVALUATION by Failure Mode Effective Analysis
© Created & Copyrighted by Shivang Chaudhary
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to define
Target Product Profile?
1
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
QUALITY TARGET PRODUCT PROFILE (QTPP) A Prospective Summary of • 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. 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;
• Thus QTPP of Generics will be defined based on the properties of the drug substance, characterization of the RLD 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
conventional dosage forms)
What is QTPP?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Pharmaco-KINETICS
Fasting Study and/or Fed BE Study 90 % confidence interval of the PK parameters, AUC0-t, ,
AUC0-∞ and Cmax, should fall within bioequivalence limits of 80-125 with reference product
Bioequivalence requirement needed
to meet required rate & extent of drug absorption
EASE OF STORAGE & DISTRIBUTION
Can be stored at real time storage condition as a normal practice with desired stability & can be distributed
from the manufacturer to end user same as per Reference Product.
Required to handle the product easily with suitable accessibility
STABILITY & SHELF LIFE Should be stable against hydrolysis, oxidation, photo degradation & microbial growth. At least 24-month
shelf-life is required at room temperature
Equivalent to or better than Reference Product shelf-life
PATIENT ACCEPTANCE & PATIENT COMPLIANCE
Should be suitably flavored & colored for possessing acceptable taste ( in case of soluble/ dispersible/
effervescent tablet) similar with Reference Product. Can be easily administered/used similar with
Reference Product labeling
Required to achieve the desired patient acceptability & suitable compliance
PATIENT’S POINT OF VIEW
PHYSICIAN”s POINT OF VIEW
PHARMACIST’s POINT OF VIEW
Quality Target Product Profile (QTPP) of Suspension
© Created & Copyrighted by Shivang Chaudhary
Similar Dosage FORM : Suspension
Dosage DESIGN : IR
ROUTE of Administration : Oral
Dosage STRENGTH : x mg/ml
Drug Product QUALITY : Assay, Uniformity, Impurities, Dissolution, Microbiological Limits, Antioxidant content, Antimicrobial content, PSD, pH, Viscosity/ Sp. Gravity, Leachable/ Extractable within acceptable limits of specification
Therapeutic Equivalence = Pharmaceutical Equivalence + Bio-Equivalence Of Generic Suspension with Patient Compliance
PHARMACEUTICAL Equivalence
BIO- Equivalence
PATIENT Compliance
Similar Pharmacokinetics: Rate of Absorption AUC0-t, , AUC0-∞
Extent of Absorption: Cmax
90 % CI of these PK Parameters should fall within bioequivalence limits of 80-125 with reference product
Primary PACKAGING: Container : (Glass/Plastic/Metal) & Closure : (Plastic/Metal/Rubber)
Ease of Storage & Distribution Should be stable against sedimentation, caking, hydrolysis, oxidation, photo degradation & microbial growth with at least 12 months stability at normal room temperature & 28 Days of in-Use Shelf Life
Patient Acceptance Should possess acceptable flavor, taste & odor
Patient Compliance re-dispersible upon shaking/administered (pourable & palatable)/used/ applied similarly with Reference Product labeling Note: Plastic/ Rubber should not allow permeation, leaching, extraction or sorption
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to determine
Critical Attributes of Quality?
2
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Critical Quality Attribute (CQA) A CQA is a • Physical, • Chemical, • Biological, or • Microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. Note: CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) & Finished drug product. on the basis of Quality [Assay, Uniformity of Dosage units, Redispersibility, Reconstitution time, Aerodynamic property], Safety [Impurities (Related substances), Residual Solvents, Osmolarity & Isotonicity, Microbiological limits, Sterility & Particulate matter], Efficacy [Diffusion, Dissolution & Permeation] & Multidisciplinary [Patient Acceptance & Compliance]. Identification of critical quality attributes (CQAs) was based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute of the drug product.
What is CQA?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Critical Quality Attributes (CQA) of Suspension
EFFICACY SAFETY QUALITY MULTI DISCIPLINARY
© Created & Copyrighted by Shivang Chaudhary
PSD & Dissolution
Assay Physical Attributes
Identification
Content Uniformity
Assay of Preservative
Extractable & Leachable
Microbiological Limits
!
!
!
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.
Formulation & Process variables does not have any impact on this CQA. No need for any further investigation & discussion.
pH & Impurities
Should be between 90.0 to 110.0 % of labeled claim to ensure safety & efficacy
Should Conform to USP <905> Uniformity of Dosage Units: 85.0-115.0 % of labeled claim with AV:
NMT 15.0 to ensure patient Safety & product Efficacy
As per USP <51> Should maintain the microbial quality of the product & to prevent oxidation throughout
shelf life & proposed in-use shelf life to ensure patient safety.
Should be within limits as per ICH Q3A & Q3B OR Reference Product Characterization to ensure chemical stability of
formulation & patient Safety
Stability data should show evidence that extractable &
leachable from the container/closure systems
are consistently below acceptable levels to ensure
patient safety.
Should Conform to USP <61 & 62> But controlled at Drug Substance & Excipient Release stage itself to ensure microbiological stability & patient safety
NLT 85 % (Q) of labeled amount of drug / single dose should be dissolved within 30 mins. in pH 1.2- 0.1N HCl (500 ml), USP Apparatus II paddle),
50 rpm to ensure desired bioavailability & efficacy
Positive for Drug Substance But controlled at Drug Substance Release stage itself
Color, Flavor, Taste , Viscosity USP <911> / Sp. Gravity USP <841> & Re-dispersibility should be mostly
similar to reference product to ensure physical stability & Patient
Acceptance & Compliance
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to assess Risks associated with
Materials & Process?
3
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Critical Material Attribute (CMA) Independent formulation variables i.e. physicochemical properties
of active(drug substance) & inactive ingredients(excipients)
• affecting CQAs of semi-finished and/or finished drug product
Critical Process Parameter (CPP) Independent process parameters
• most likely to affect the CQAs of an intermediate or finished drug
product & therefore should be monitored or controlled
• to ensure the process produces the desired quality product.
Note: Risk related to individual CMAs &/or CPPs will be identified, analyzed qualitatively & then evaluated
quantitatively in order to reduce the probability of risk through optimization by DoE &/or inline detection by PAT.
What is CMA & CPP?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
RISK EVALUATION
RISK ANALYSIS
RISK IDENTIFICATION
Identification of Factors involved in
Controlled Flocculation Process Map
Vehicle Preparation & Storage Organoleptic addition
Controlled Flocculation by Surfactants & Hydrocolloid
pH adjustment & Final Volume make up with vehicle & final mixing
Type of purification system (ion exchange/reverse osmosis)
Rate of filtration Heating temperature & time Type & Position of Impeller
Mixing Speed & Time
Order of addition Heating temperature & Time Type & Position of Impeller
Mixing Speed & Mixing Time
Physical Attributes (color, odor, taste) Vehicle purity, Vehicle polarity
Vehicle pH, Vehicle Viscosity/sp. Gravity Vehicle Volatility, Vehicle Microbial content
Physical Attributes (color, flavor. taste), Assay, Impurity, Uniformity of Dosage units,
Viscosity/Rheology, Specific Gravity/Density & Extractable volume of system,
pH & Preservative content of system, Dissolution*, Reconstitution time**,
Dissolved Oxygen of system Microbial content of system
Critical Processing Parameters
Critical Attributes of Input Materials
Manufacturing Process Steps
Quality Attributes of Output Materials
Solvent source, purity, polarity, pH, Viscosity/sp. Gravity, Volatility, Microbial content
Type & Source of color/ flavor/ sweetener (natural/ semisynthetic/ synthetic),
Microbial content of color, flavor & sweetener
Order of addition Heating temperature & Time Type & Position of Impeller
Mixing Speed & Mixing Time
pH of buffer/salts, Concentration of buffers/salts
Purity, Solubility, Compatibility, Stability & Toxicity of Buffers/Salts
Vehicle purity, polarity, pH, Viscosity, Sp. Gravity, Volatility, Microbial
Physical Attributes , Assay, Impurity, pH & Preservative content of system
Dissolution*, Reconstitution time**
Filtration in Colloid mill Type & Principle of milling
Milling speed Screen size of mill
Type & Size of Filter Rate of filtration
Physical Attributes (clarity#/ Homogeneity*) Assay, Impurity, Uniformity of Dosage units, Viscosity/Rheology, Specific Gravity/Density
Microbial content of system
Filling , Capping & Sealing with nitrogen purging
Filling rate Capping & Sealing rate
Nitrogen purging &/or sparging rate Sealing rate after closure fitting
Physical Attributes, Assay, Impurity, Uniformity of dosage units*,
Uniformity of Weight**, Viscosity/Rheology, Specific Gravity/Density &
Extractable volume of system, pH & Preservative content of system,
Dissolved / Headspace Oxygen content of system
Microbial content of system Patient Acceptance & Compliance
Physical Attributes (Clarity#, Homogeneity*), Assay, Impurity, Uniformity of Dosage units,
Viscosity/Rheology, Specific Gravity/Density of system, pH & Preservative content of system
Dissolved Oxygen of system Microbial content of system
Material of container (Glass/Metal/ Plastic) Material of closure (Metal/Plastic/Rubber)
Design & Size of container/closure
Drug substance PSD/SSA, Contact angle, Vehicle purity, polarity, pH,
Viscosity, Rheology, Sp. Gravity/ Density, Volatility & Microbial content
Type & Concentration of Surfactant Concentration of preservative
Source ,Concentration, Viscosity, pH & Microbial contents of hydrocolloids
# Applicable to Solution only; * Applicable to Suspension only; ** Applicable to reconstituted powder only
Physical Attributes (Clarity#, Homogeneity*), Assay, Uniformity of Dosage units*, pH,
Impurity, Assay of Preservative content of system, Particle Size distribution*, Zeta
potential*, Redispersibility*, Dissolution*, Reconstitution time**
Physical Attributes (Homogeneity#/Sedimentation*/Caking*)
Assay, Uniformity of Dosage units, pH & Preservative content of system
Viscosity/Rheology, Specific Gravity/Density & Extractable volume of system,
Particle Size distribution*, Zeta Potential*, Redispersibility*,Microbial content of system
Environment (Temperature and RH)
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
RISK EVALUATION
RISK ANALYSIS
RISK IDENTIFICATION
Identification of Risk Factors by
Ishikawa Fishbone Diagram
RAW MATERIAL
API STABILITY
HYDROCOLLOID SOURCE
SURFACTANT SOURCE
SOLUBILIZATION BY SURFACTATNT
BODYING BY HYDROCOLLOID&/OR
VOLUME MAKE UP
MATERIAL OF 1° PACKAGING
FILTRATION, FILLING, CAPPING & SEALING
COLLOID MILL MESH SIZE
FILTER SCREEN SIZE
EXTRACTABLE/LEACHABLE
NITROGEN PURGING RATE BUFFER CONCENTRATION
COLOR SOURCE & CONC.
STIRRING RATE
FLAVORS SOURCE & CONC
SWEETENERS SOURCE & CONC
VEHICLE QUANTITY
HYDROCOLLOID CONC.
TYPE OF HYDROCOLLOID TYPE & CONC. OF SURFACTANT
TYPE & CONC. OF PRESERVATIVE
STIRRING RATE
API PSD & SURFACE AREA
pH ADJUSTMENT & ADDITION OF
ORGANOLEPTICS
FILRATION RATE
STIRRING RATE (SPEED *TIME)
CO-SOLVENT QUANTITY
STIRRING RATE
RATE OF FILLING & SEALING
VISCOSITY OF SYSTEM API AQUEOUS SOLUBILITY
INTERFACIAL TENSION OF SYSTEM
BIOBURDEN
OXYGEN EXPOSURE
ENVIRONMENTAL FACTORS
LIGHT EXPOSURE
RELATIVE HUMIDITY
TEMPERATURE
CONC. OF COMPLEXING AGENTS
API PURITY
FP CQAs Physical
Form Particle
size** Solubility* Volatility Purity Stability
Microbial Content
Moisture content***
Residual 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 Uniformity of Weight*** Low Medium Low Low Low Low Low Low Low
Impurities Medium Medium Low Low High High Low Medium Medium pH of System Low Low Low Low Low Medium Medium Low Low
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 Medium Low Low
Extractable Low Low High High Low Low Low Low Low Viscosity/specific gravity Low Low Low High Low Low Low Low Low
Particle Size Distribution** Low High Low Low Low Low Low Low Low
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
Low Broadly acceptable risk. No further investigation is needed
Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of Active Pharmaceutical Ingredient’s (API) Attributes
© Created & Copyrighted by Shivang Chaudhary
Physico- Chemical Property of Actives
Critical Material Attribute (CMAs)
Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
P S D RPN (=P*S*D)
Physical Property
Solid Sate Form
Different Polymorph/ form
Solubility of drug substance may get affected= >> Dissolution of drug product may get affected >> BIOAVAILABILITY-EFFICACY may get compromised
2 4 4 32
Particle Size Distribution (PSD)
Higher PSD BCS Class II/IV Low Solubility drug >> Dissolution of drug product may get affected >> BIOAVAILABILITY/EFFICACY may get compromised
4 4 3 48
Moisture content High water content
Rate of degradation may get affected >> Impurity profile may get affected >> SAFETY of the product may get compromised
2 3 2 12
Residual Solvents High residual solvent
Residual solvents are likely to interact with drug substance >> Impurities profile may get affected >> SAFETY may get compromised
2 3 2 12
Chemical Property
Solubility Different Salt/ Form
Dissolution of the drug product may get affected >> BIOAVAILABILITY-EFFICACY may got compromised
2 3 4 24
Volatility High Assay & Content Uniformity may be affected >> EFFICACY may get compromised
2 3 4 24
Process Impurities
Less Purity Assay & impurity profile of drug product may be affected = >> Quality & SAFETY may got compromised
2 3 3 18
Chemical Stability
poor Susceptible to dry heat/oxidative/hydrolytic/UV light degradation- impurity profile may get affected >> Quality & SAFETY may got compromised
2 3 3 18
Biological Property
Microbial Content High
MICROBIAL LOAD may get increased during transportation, shipping, storage & in-use >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of patient may get compromised
2 3 4 24
Probability* Severity** Detect ability*** Score Very Unlikely Minor Always Detected 01 Occasional Moderate Regularly Detected 02 Repeated Major Likely not Detected 03 Regular Extreme Normally not Detected 04
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
Score based on
LIKELY SEVERITY IMPACT ON DRUG
PRODUCT CQA.
Score based on
PROBABILITY FOR OCCURANCE
OF FAILURE
Score based on
PROBABILITY OF FAILURE OF DETECTION.
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK IDENTIFICATION
RISK ASSESSMENT
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Active Pharmaceutical Ingredient’s (API) Attributes
Probability of Risk can be Reduced through
DoE Optimization
Detectability of Risk can be increased through In Line PAT System
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Active Pharmaceutical Ingredient’s (API) Attributes Required to be Optimized &/Or Controlled
API Attributes which got RPN more than 30 were get highest priority among all the risks, they should be taken into consideration as most
Critical Material Attributes of API , which were required to be optimized &/or controlled
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Active Pharmaceutical Ingredient’s (API) Attributes Required to be Optimized &/Or Controlled
B
A SOLID STATE FORM
PARTICLE SIZE
CMAs of
API
FP CQAs Solvents/
Co-solvents/ Vehicles
Surfactants (Solubilizing
/ Wetting agents)
Hydrocolloid (Suspending
agent)
Buffering agent
Preservatives Organoleptic Additives
Anti Microbial
Anti Oxidant
Colors Flavors Sweeteners
Appearance High High High Low Low Low High Low Low Assay High High High Low Low Low Low Low Low
Uniformity of Content** High High High Low Low Low Low Low Low Uniformity of Weight*** Low Low Low Low Low Low Low Low Low
Impurities High Medium Low High Medium Medium Medium Medium Medium pH of System High Low Low High Low Low Low Low Low
Microbial Limits Medium Low Medium Low High Low Medium Medium Medium Antimicrobial content Low Low Low High High Medium Low Low Low Antioxidant content Low Low Low High Medium High Low Low Low
Extractable High High Low Low Low Low Low Low Low Viscosity/specific gravity High Low High Low Low Low Low Low Low
Particle Size Distribution** Low High Low Low Low Low Low Low Low
Dissolution** Low High Low High Low Low Low Low Low Redispersibility** High High High Low Low Low Low Low Low
Reconstitution time*** High High High Low Low Low Low Low
Low Broadly acceptable risk. No further investigation is needed
Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of
Inactive Ingredients’ (Excipients’) Attributes
© Created & Copyrighted by Shivang Chaudhary
Excipient CMAs Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
P S D RPN
(=P*S*D)
Solvents/ Co-solvents/ Vehicles
Quantity of Vehicle/ Solvent
Less than optimum Drug Substance may NOT get completely SOLUBILIZED or uniformly DISTRIBUTED >> CONTENT UNIFORMITY may get affected >> SAFETY & EFFICACY may get compromised
3 3 3 27
More than optimum Product may get BULKIER to handle >> Patient ACCEPTANCE & COMPLIANCE may get compromised 4 3 2 24
Source of Vehicle/ Solvents/ Co-solvents
Natural without purification
Source of VEHICLE is natural i.e. PLANT OR ANIMAL BASED ORIGIN >> Potential for microbial attack & growth >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
2 3 4 24
Surfactants (As a Solubilizing/ Wetting agents)
Ionic Nature of Surfactant
Cationic/ Anionic in nature
If surfactant is positively/ negatively CHARGED >> INCOMPATIBLE with anionic/cationic drugs /preservatives / primary packaging material >> CHEMICAL / MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
3 3 3 27
Concentration of Surfactant
Less than optimum
Drug Substance/ Preservatives may NOT getting effectively SOLUBILIZED/ DISTRIBUTED within system >>SAFETY & EFFICACY may get compromised 3 4 4 48 ZETA POTENTIAL of the system may be too low >> Particles COALESCE & flocculated suspension forms >> Suspension start to form REDISPERSIBLE SEDIMENT >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
3 4 4 48
More than optimum
ZETA POTENTIAL of the system may be too high >> Particles REPEL each other & forms deflocculated suspension which upon settled down invariably leads to form HARD CAKE >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
3 4 4 48
Electrolytes (As a Controlled Flocculating Agent)
Concentration of Electrolytes
Less than optimum
VERY LOOSE FLOCS will be formed through reducing forces of repulsion >> Particles repel each other & forms deflocculated suspension which upon settled down invariably leads to form HARD CAKE >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
3 4 4 48
More than optimum
HARD BOUND FLOCS will be formed by increasing forces of coalescence >> Particles COALESCE & flocculated suspension forms >> Suspension start to form REDISPERSIBLE SEDIMENT >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
3 4 4 48
Hydrocolloid (As a Supporting Structured Vehicle)
Source of Hydrocolloid
Natural Source of hydrocolloid is natural i.e. PLANT OR ANIMAL BASED ORIGIN >> Potential for microbial attack & growth >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
2 3 4 24
Concentration of Hydrocolloid
Less than optimum
VISCOSITY of dispersion medium may be too low >> Rate of SEDIMENTATION will be high >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
3 4 4 48
More than optimum VISCOSITY of dispersion medium may be too high >> POUR ABILITY of the product may get compromised >> PATIENT COMPLIANCE may get compromised
3 3 2 18
Buffering Agent pH of the Buffer
Within Neutral Range
SOLUBILITY of the weak acidic / weak basic drugs may get affected >> EFFICACY may get compromised 3 3 3 27
Within Acidic/ Basic Range
CHEMICAL STABILITY of pH sensitive drugs/ preservatives may get affected >> SAFETY of patient may get compromised 3 3 3 27
Anti-Microbial Concentration of Anti-Microbial
Less than optimum MICROBIAL LOAD may get increased during transportation, storage & in-use >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of patient may get compromised
3 3 4 36
Anti-Oxidant Concentration of Anti-Oxidant
Less than optimum LEVEL OF OXIDIZED IMPURITIES of the product may get increased >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
3 3 4 36
Sweetener/ Flavoring agent
Concentration of Sweetener/ Flavor
Not optimum Product TASTE may not be palatable & agree able >> Patient COMPLIANCE may get compromised 3 3 2 18
Coloring agent Concentration of Coloring Agent
Not optimum APPEARANCE of the product may not be pleasant >> Patient ACCEPTANCE may get compromised 3 3 2 18
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK ASSESSMENT
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Inactive Ingredients’ (Excipients’) Attributes
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Inactive Ingredients’ (Excipients’) Attributes Required to be Optimized &/Or Controlled
Excipients’ Attributes which got RPN more than 30 were get highest priority among all the risks, they should be taken into consideration as most
Critical Material Attributes of Excipients, which were required to be optimized &/or controlled
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
B
A
HYDROCOLLOID (%w/w)
SURFACTANT (%w/w)
RISK EVALUATION
RISK ASSESSMENT
CMAs of
EXCIPIENTS
CRITICAL
Inactive Ingredients’ (Excipients’) Attributes Required to be Optimized &/Or Controlled
D
C ANTI MICROBIAL (%w/w)
ANTI OXIDANT (%w/w)
F
E SWEETENER (%w/w)
FLAVOR (%w/w)
G COLOR (%w/w)
FP CQAs
Solvent/ Vehicle
Preparation & storage
Solubilizing*/ Wetting** of Solids (API+ Preservative)
by Surfactants
Controlled Flocculation
by Electrolytes
Bodying with Hydrocolloid
Organoleptic additives addition
pH adjustment by buffering
Final Volume make up
with vehicle & mixing
Filtration*/ Milling** in Colloid mill
Filling & Capping
Physical attributes High High High High High Low High High Low Assay Low High High High Low Medium High High Medium
Uniformity of Content** Low High High High Low Low High High Low Uniformity of Weight*** Low Low Low Low Low Low Low Low High
Impurities High High Low Low Low High High Low High pH of System High Medium High Medium Medium High High Low High
Microbial Contents High Low Low Medium Medium Low Medium Low High O2 in headspace/ dissolved O2 High High Low Low Low Low High Low High
Antimicrobial content Low Medium High Low Low High High Low High Antioxidant content Low Medium High Low Low High High Low High
Extractable Low High Medium Low Low High High Low High Viscosity/specific gravity High Low Low High Low Low High Low Low
Particle Size Distribution** Low Low High High Low Low Low High Low Dissolution** Low High Low Low Low High High High Low
Redispersibility** Low High Low Low Low Low Low High Low Reconstitution time*** High High Low Low Low High High High Low
Low Broadly acceptable risk. No further investigation is needed
Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of Processing Parameters
© Created & Copyrighted by Shivang Chaudhary
Unit Operations
Critical Process Parameter (CPPs)
Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
P S D RPN
(=P*S*D)
Solvent/ Vehicle Preparation with organoleptics & storage
Rate of Addition Higher than Optimum
Physical Attributes, Impurity profile & Microbial Load may get affected >> Safety may get compromised
2 3 4 24 Filtration Rate 2 3 4 24
Heating Rate (Temp*Time) Lower than Optimum Physical Attributes may get affected
>> Safety may get compromised 3 3 3 27
Higher than Optimum
Impurity profile & Assay may get affected >> Safety may get compromised 3 3 3 27
Mixing Rate (Speed*Time) with Co-Solvents
Lower than Optimum
Physical Attributes (Color, Odor, Taste) , Content Uniformity & ultimately Assay may get affected >> Safety & Efficacy may get compromised >> PATIENT COMPLIANCE may get compromised
3 3 3 27
Wetting* of Solids (API+ Preservative) by Surfactants
Order of addition Incorrect Physical Attributes, ZETA POTENTIAL, Content Uniformity & ultimately Assay may get affected >> Sedimentation/Caking may be observed >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
2 3 4 24 Impeller Design & Position Improper 2 3 4 24
Mixing Rate (Speed*Time) Lower than Optimum 3 3 4 36
Heating Rate (Temp*Time) Higher than optimum
Impurity profile & ultimately Assay may get affected >> CHEMICAL STABILITY may get compromised >> SAFETY may get compromised
3 3 4 36
Controlled Flocculation by Surfactants / Electrolytes / Polymers
Order of Addition Incorrect Physical Attributes, Particle Size Distribution (flocks) Content Uniformity & ultimately Assay may get affected >> Sedimentation/Caking may be observed >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
2 3 4 24
Mixing Rate (Speed*Time) Lower than Optimum 3 4 4 48
Bodying with Hydrocolloid*
Order of Addition Incorrect Physical Attributes, VISCOSITY, SVR/SHR. Content Uniformity & Ultimately Assay may get affected >> Sedimentation/Caking may be observed >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
2 3 4 24
Rate of Addition Higher than optimum
2 3 4 24
Mixing Rate (Speed*Time) Lower than Optimum 3 3 4 36
pH Adjustment with Buffer &Final Volume make up with vehicle & final mixing
Rate of Addition Higher than Optimum
Physical Attributes, Particle Size Distribution, pH/ Solubility, Content Uniformity & Assay may get affected >> Sedimentation/Caking may be observed >> PHYSICAL & CHEMICAL STABILITY may get compromised >> Safety & Efficacy may get compromised
2 3 4 24
Impeller Design & Position Improper 2 3 4 24 Mixing Rate (Speed*Time) Lower than Optimum 3 3 4 36
Heating Rate (Temp*Time)
Lower than Optimum Microbiological Stability may get affected >> Safety may get compromised 3 3 4 36
Higher than Optimum
Impurity profile & Assay may get affected > CHEMICAL STABILITY may get compromised >> SAFETY may get compromised
3 3 4 36
MicroMilling** in Colloid mill
Type & Principle of Mill Improper Physical Attributes, Impurity profile, Microbial Load, Content Uniformity & ultimately Assay may get affected >> PHYSICAL STABILITY may get compromised >> Quality, SAFETY & EFFICACY may get compromised
2 3 4 24 Filter/ Mill Screen Size Incorrect 2 3 4 24
Rate of Milling Higher than Optimum 3 3 3 27
Filling , Capping & Sealing with nitrogen purging
Filling rate (Speed*Time) Not Optimum Uniformity of Weight may get affected
>> PATIENT ACCEPTANCE may get compromised 3 2 2 12
Higher than Optimum Dissolved / Headspace Oxygen may get increased
>>Oxidation Impurity profile & Assay may get affected >> Safety may get compromised
3 3 4 36
Nitrogen purging rate Lower than optimum 3 3 4 36 Capping & Sealing rate Lower than Optimum 3 3 4 36
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK IDENTIFICATION
RISK ASSESSMENT
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Processing Parameters
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Processing Parameters Required to be Optimized &/Or Controlled
Process Parameters which got RPN more than 30 were get highest priority among all the risks, they should be taken into consideration as most
Critical Process Parameters , which were required to be optimized &/or controlled
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
%HYDROCOLLOID
%SURFACTANT
MIXING TIME C
B
A
CPPs of
CONTROLLED SOLUBILIZATION
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Processing Parameters Required to be Optimized &/Or Controlled
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to evaluate & optimize risks by
Designing of Experiments?
4
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Design Space The Multidimensional Combination & Interaction of • Critical Material Attributes and • Critical Process Parameters that have been demonstrated to provide assurance of quality. Note: Working within the design space is not considered as a change. Movement out of the design space is considered to be a change
Design of Experiments (DoE) A Systematic Series of Experiments, • In which purposeful changes are made to input factors to identify
causes for significant changes in the output responses & • Determining the relationship between factors & responses to
evaluate all the potential factors simultaneously, systematically and speedily;
• With complete understanding of the process to assist in better product development & subsequent process scale-up With pretending the finished product quality & performance.
What is DoE & DS?
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
DESIGN OF EXPERIMMENTS
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
© Created & Copyrighted by Shivang Chaudhary
DoE For
CONTROLLED FLOCCULATION(Contd…)
Optimization of CMAs & CPPs OF
Suspension Homogenization Process
QUALITY COMPROMISED EFFICACY COMPROMISED SAFETY COMPROMISED
INADEQUATE ZETA POTENTIAL
RISKS
INADEQUATE VISCOSITY HIGH RATE OF SEDIMENTATION
CONTENT UNIFORMITY COMPROMISED
A
B
C STIRRING TIME
HYDROCOLLOID
SURFACTANT
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
© Created & Copyrighted by Shivang Chaudhary
NO. OF FACTORS
NO. OF LEVELS
EXPERIMENTAL DESIGN SELECTED
ADD. CENTER POINTS
TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
3
3
BOX BEHNKEN DESIGN
2
12MP + 3CP
=15
To Optimize CMAs & CPPs of Liquid Suspension Dosage Form OBJECTIVE
NO. OF FACTORS
NO. OF LEVELS
3
3
A SURFACTANT
C
STIR
RIN
G T
IME
“High”
Medium
“Low”
Factors (Variables) Levels of Factors Studied -1 0 +1
A SURFACTANT (%) 0.50%w/w 1.00%w/w 1.50%w/w B HYDROCOLLOID (%) 20%w/w 30%w/w 40%w/w C STIRRING TIME (min) 30min 45min 60min
DoE For
CONTROLLED FLOCCULATION(Contd…)
DEVELOPMENT OF DESIGN SPACE
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
© Created & Copyrighted by Shivang Chaudhary
PREDICTION EFFECT EQUATION OF INDIVIDUAL RESPONSE BY QUADRATIC MODEL
CMAs CPP CQAs
Sedimentation Volume Ratio = +0.030-0.024A-0.089B-0.020C
+0.010AB+2.500E-003AC+2.500E-003BC+0.067A2+0.11B2+0.030C2
Zeta potential= -44.67+12.00A+5.62B+0.38C-2.25 AB-0.25AC+1.00BC
-6.92A2-2.67B2-1.17C2
Viscosity = +44.67+3.25A+8.38B+1.13C
-0.75AB-0.25AC+0.000BC-1.08A2-3.83B2+0.17C2
Content Uniformity= +1.73-0.20A-0.50B-0.15C
+0.000AB+0.050AC+0.000BC+0.41A2+0.76B2+0.26C2
DoE For
CONTROLLED FLOCCULATION(Contd…)
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
© Created & Copyrighted by Shivang Chaudhary
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 Y3 Viscosity (cps) To achieve viscosity in the range of 40 to 50 cps Y4 Content Uniformity (AV) To achieve minimum acceptance value in CU i.e. NMT 2.0
Factors (Variables) Knowledge Space Design Space Control Space A SURFACTANT (%) 0.50-1.50 0.75-1.25 0.85-1.15 B HYDROCOLLOID (%) 20.0-40.0 27.5-37.5 30.0-35.0 C STIRRING TIME (min) 30-60 37-53 40-50
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
DoE For
CONTROLLED FLOCCULATION(Contd…)
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
DESIGN OF EXPERIMMENTS
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
© Created & Copyrighted by Shivang Chaudhary
DoE For
SWEETENER : FLAVOR : COLOR(Contd…)
Optimization of
Sweetener Flavor & Color Ratio in liquid oral mixtures
RISK
UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE
PATIENT ACCEPTANCE COMPROMISED
FLAVOR
SWEETENER 1
2
3 COLORANT
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
© Created & Copyrighted by Shivang Chaudhary
DoE For
SWEETENER : FLAVOR : COLOR(Contd…)
16
OBJECTIVE To Optimize Sweetener : Flavor : Color ratio of Liquid Orals
EXPERIMENTAL DESIGN SELECTED
D-OPTIMAL MIXTURE DESIGN
TOTAL NO OF EXP RUNS (TRIALS)
Factors (Variables) Lower Levels Higher Levels A SWEETENER (%w/w) 1.00% 1.50% B FLAVOR (%w/w) 0.50% 1.00% C COLOR (%w/w) 0.00% 0.50%
• During Optimization of sweetener, flavor & color in liquid orals; ultimate response to be measured was Patient Acceptability Score which was a function of 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 proportions in the formulation mixture
• 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 constraints on the component proportions.
SWE
ETE
NE
R
DEVELOPMENT OF DESIGN SPACE
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
© Created & Copyrighted by Shivang Chaudhary
DoE For
SWEETENER : FLAVOR : COLOR(Contd…)
PREDICTION EFFECT EQUATION OF EACH FACTOR BY SPECIAL CUBIC MODEL
CQAs CMAs
Patient Acceptability Score= +3.79A+3.19B+2.67C+2.57AB+4.73AC+1.94BC+15.05ABC
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
© Created & Copyrighted by Shivang Chaudhary
DoE For
SWEETENER : FLAVOR : COLOR(Contd…)
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
Responses (Effects) Goal for Individual Responses Y1 PATIENT ACCEPTANCE
SCORE To achieve maximum Patient Acceptance Score as maximum as possible out of 10. & NLT 4.5 out of 5.0
Factors (Variables) Knowledge Space Design Space Control Space A SWEETENER (%w/w) 1.00-1.50% 1.10-1.35% 1.15-1.30% B FLAVOR (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70% C COLOR (%w/w) 0.00-0.50% 0.05-0.25% 0.10-0.20%
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
DESIGN OF EXPERIMMENTS
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
© Created & Copyrighted by Shivang Chaudhary
DoE For
PRESERVATIVE SYSTEM(Contd…)
Optimization of
Preservative system for In use Stability of Multidose Liquid Orals
INADEQUATE ANTIMICROBIAL CONC. INADEQUATE ANTIOXIDANT CONC
MICROBIAL LOAD IN-USE OXIDATION IMPURITIES
ANTIMICROBIAL A
B ANTIOXIDANT
C BUFFERING AGENT
RISKS
SAFETY COMPROMISED
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
© Created & Copyrighted by Shivang Chaudhary
DoE For
PRESERVATIVE SYSTEM(Contd…)
Factors (Variables) Levels of Factors studied -1 Center point (0) +1
A Antimicrobial (%W/W) 0.005 0.010 0.015 B Antioxidant (%W/W) 0.050 0.100 0.150 C Buffering Agent (%W/W) 0.800 1.400 2.000
NO. OF FACTORS
NO. OF LEVELS
EXPERIMENTAL DESIGN SELECTED
ADD. CENTER POINTS
TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
3
2
23 FULL FACTORIAL DESIGN WITH ADD. CENTER POINTS
3
23 + 3 = 11
OBJECTIVE To Optimize Preservative System for In Use Stability Of Multi-dose Sterile Product (Injection, Eye/Ear Drops)
A ANTIMICROBIAL
C
BU
FF
ER
ING
AG
EN
T
DEVELOPMENT OF DESIGN SPACE
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
© Created & Copyrighted by Shivang Chaudhary
DoE For
PRESERVATIVE SYSTEM(Contd…)
CQAs CMAs
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
OXIDIZED Impurities after 14 days=+0.46 -0.035A -0.18B -0.052C +7.50E-003AB +5.00E-003AC + 0.010BC -2.50E-003ABC
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
© Created & Copyrighted by Shivang Chaudhary
DoE For
PRESERVATIVE SYSTEM(Contd…)
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
Y2 %Oxidized Impurities after 14D in use To minimize the level of oxidized impurities NMT 0.5%
Factors (Variables) Knowledge Space Design Space Control Space 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 C Buffering Agent (%W/W) 0.800-2.000 0.800-2.000 1.000-1.500
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to Identify & Optimize CMAs & CPPs of Primary Packaging Process by Stability Studies?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISKS
COMPROMISE IN MECHANICAL STRENGTH
COMPROMISE IN PHYSICAL BARRIER
COMPROMISE IN CHEMICAL COMPATABILITY
A
C
PACKAGING DEVELOPMENT bY DESIGN
© Created & Copyrighted by Shivang Chaudhary
DEFINING OF PACK CONTROLS
DEFINING OF PACK CONTROLS
ANALYSIS OF STABILITY DATA
DESIGN OF $TABILITY STUDY
IDENTIFICATION OF PACK CQAs
FOR LIQUID ORAL SUPENSION DOSAGE FORM DEVELOPMENT AS PER QbD
SELECTION & OPTIMIZATION OF CMAs & CPPs OF LIQUID ORAL PACKAGING PROCESS
F
E
D BOTTLE FILLING
LINER SEALING & CAPPING
POST-GASSING
CHANCES OF DRUG PRODUCT INTEGRITY LOSS
PRODUCT EXPOSURE TO MOISTURE, OXYGEN, LIGHT, MICROORGANISMS
COMPROMISE IN DRUG PRODUCT SHELF LIFE
COMPROMISE IN QUALITY, SAFETY & EFFICACY
OOT / OOS IN WVTR, OTR, LTR OR MICROBIAL LOAD TESTS
OOS IN IMPURITY LIMITDURING SHELF LIFE
FAILURE IN BUBBLE TEST, VACUUM / PRESSURE DECAY
PDbD
BOTTLE
CAP
B CAP LINER
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
Al CAP
Glass USP IV Bottle
A Plastic HDPE C Plastic PET B Plastic PP
D Glass USP IV
DEFINING OF PACK CONTROLS
VERIFICATION OF PACK CONTROLS
ANALYSIS OF STABILITY DATA
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
PDbD
Available Options of Primary Packaging Material
PACKAGING DEVELOPMENT bY DESIGN (Contd)
F Glass USP II
G Glass USP I
Al CAP
Glass USP II Bottle
Al CAP
Glass USP I Bottle
PP CAP
Plastic HDPE Bottle
PvDC Liner 75 gauge
PP CAP
Plastic PP Bottle
PP CAP
Plastic PET Bottle
PvDC Liner 75 gauge PvDC Liner 75 gauge
PvDC Liner 75 gauge PvDC Liner 75 gauge
PvDC Liner 75 gauge
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
DEFINING OF PACK CONTROLS
VERIFICATION OF PACK CONTROLS
ANALYSIS OF STABILITY DATA
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
Tests Positive Control
(Plastic HDPE)
Test Pack (For Selection of Packaging material with PVdC Cap liner & PP Cap)
Negative Control (Glass
USP Type I) Plastic O-PP
Plastic A-PET
Plastic C-PET
Glass USP Type IV
Barrier Properties Oxygen Permeation High Moderate Low Very Low None None Water Vapor Permeation Low Low Very Low Very Low None None Resistance to Acids Fair Good Fair Fair Fair Excellent Resistance to Alkalis Good Very Good Good Good Very Poor Excellent Resistance to Alcohols Good Good Good Good Poor Excellent Resistance to Mineral oils Fair Fair Good Good Fair Excellent Resistance to Solvents Good Good Fair Good Poor Excellent Resistance to Heat Fair Good Fair Good Good Excellent Resistance to Cold Excellent Fair Good Good Good Excellent Resistance to Sunlight Fair Fair Fair Fair Fair Fair Resistance to High Humidity Good Excellent Excellent Excellent Good Excellent Processing / Storage Parameters
Clarity / Translucency Colorless,
Translucent Transparent,
Clear Transparent,
Clear Transparent,
Clear Translucent
Optically Clear, Transparent
Toughness / Impact Resistance Good Fair to Good Good Very Good Fair Good Autoclavable / Sterilizable Yes Yes Yes Yes Yes Yes Extractable / Leachable Low Low Moderate Moderate Very High Low Weathering- Flaking –Alkalinity Low Low Moderate Moderate Very High Low Breathing – Permeation – O2/CO2 High Moderate Low Low None None
ECONOMICAL ACCEPTABLE
MECHANICAL STRENGTH
SELECTION CRITERIAS
CHEMICAL COMPATABILITY
PHYSICAL BARRIER
Protection from -heat & moisture -oxygen /any gas / vapor -UV / Visible light -microorganism
Does not react with -Product Contents -Packing Ingredients -not impart its color odor taste to drug product
-Strong enough to withstand handling -should fit in packaging line -long life
Total Cost, Unit Price acceptable with comparable Advantages
PDbD
Selection of Primary Packaging Material
PACKAGING DEVELOPMENT bY DESIGN (Contd)
BIOLOGICAL SAFETY
Extract able/ Leachable Should be -absent / within limits -biological safe -nontoxic
Here , Drug Substance in Liquid formulation is susceptible to oxidation, hydrolysis, temperature, light, pH Change & Microbial Growth. (A) Plastic containers possess potential problems of high permeability of gases & vapors & sorption of preservatives & flavors by packaging material itself. (B) Moisture condenses on the surface of General Purpose Soda Lime Glass container in moist atmosphere & extracts weekly bonded alkali ions. When the surface 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 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”. Thus, with respect to (i) Physical Appearance (ii) Assay of API & Preservatives (iii) impurities generated upon storage (iv) pH Change (iv) extractable & leachable profiling ; Crystalline Poly Ethylene Terephthalate (C-PET) [due to least permeability, sorption & extractable] with PVdC Liner & PP Cap was selected as primary pack
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
DEFINING OF PACK CONTROLS
VERIFICATION OF PACK CONTROLS
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
ANALYSIS OF STABILITY DATA
1Impurity generated due to oxidation 2Impurity generated due to temperature effect 3Impurity generated due to moisture effect 4 Impurity generated due to light exposure
Tests Specification-CQAs (Acceptance Criteria)
Initial Analysis
(0 Days)
40°±2°C /75±5%RH for 3 Months Positive Control (Plastic HDPE)
Test Pack (For Selection of Packaging material for optimized formula with PVdC Cap liner & PP Cap)
Negative Control (Glass
USP Type I) Plastic
PP Plastic A-PET
Plastic C-PET
Glass USP Type IV
Physical Description Clear, Transparent Complies Complies Complies Complies Complies Weathering
Flaking Complies
Related Substance (Impurity) / HPLC
Imp A1: NMT 0.5% 0.15 0.39 0.35 0.30 0.24 0.29 0.20 Imp B2: NMT 0.5% 0.18 0.37 0.34 0.28 0.22 0.30 0.28 Imp C3: NMT 0.5% 0.10 0.25 0.22 0.17 0.14 0.17 0.13 Imp D4: NMT 0.5% 0.07 0.19 0.20 0.18 0.18 0.19 0.18 Max UNK:NMT 0.5% 0.14 0.35 0.31 0.30 0.27 0.33 0.23 Total : NMT 3.0% 0.66 1.59 1.44 1.29 1.11 1.31 1.06
Assay (API)
95% to 105% 98.8 96.7 97.1 97.6 98.1 97.5 98.4
Assay (Antimicrobial)
90% to 110% 99.7 89.6 91.6 93.9 97.4 94.1 98.9
Assay (Antioxidant)
90% to 110% 98.6 84.4 90.5 92.3 96.5 96.1 97.8
pH of system 6.5-7.5 7.1 6.8 6.6 6.9 7.1 8.4 7.2 Microbial Contents Absent Absent Absent Absent Absent Absent Absent Absent Viscosity 40-50 cps 46 cps 44 cps 44 cps 42 cps 42 cps 46 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 / Leachable Constituents
Within Limits / Nontoxic-safe
Absent Absent Absent DMT, EG Absent Na2O, CaO, K2O, BaO, Al2O3, B2O3
B2O3, Na2O (<5 ppm)
PDbD
Comparative Accelerated Stability Study with different Packaging Material – Scale Up Batch
PACKAGING DEVELOPMENT bY DESIGN (Contd)
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
DEFINING OF PACK CONTROLS
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
ANALYSIS OF STABILITY DATA
VERIFICATION OF PACK CONTROLS
Tests Specification-CQAs (Acceptance Criteria)
Initial Analysis
(0 Days)
40°±2°C /75±5%RH up to 6 Months: in C-PET Bottle-PP Cap-PVdC Liner
1 Month 2 Months 3 Months 6 Months
Description Clear, Transparent Complies Complies Complies Complies Complies
Related Substance (Impurity) / HPLC
Imp A1: NMT 0.5% 0.14 0.19 0.22 0.26 0.28
Imp B2: NMT 0.5% 0.17 0.20 0.21 0.22 0.24
Imp C3: NMT 0.5% 0.10 0.12 0.12 0.14 0.15
Imp D4: NMT 0.5% 0.08 0.13 0.15 0.18 0.20
Max Unk :NMT 0.5% 0.15 0.21 0.25 0.28 0.30
Total : NMT 3.0% 0.68 0.90 1.02 1.14 1.25
Assay (API) 95% to 105% 98.9 98.6 98.2 97.9 97.4
Assay (Anti Microbial) 90% to 110% 99.5 99.1 98.6 97.9 97.6
Assay (Anti Oxidant) 90% to 110% 98.7 98.3 97.2 96.5 96.2
pH of system 6.5-7.5 7.1 7.1 6.9 7.0 6.8
Microbial Contents Absent Absent Absent Absent Absent Absent
Viscosity / Rheology 40-50 cps 46 cps 44 cps 44 cps 43 cps 47 cps
Density / Sp. Gravity 0.9-1.2 gm/cc 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml
Extractable / Leachable Absent Absent Absent Absent Absent Absent
PDbD PACKAGING DEVELOPMENT bY DESIGN (Contd)
Accelerated Stability Study with Finalized Primary Pack : C-PET Bottle-PP Cap-PVdC Liner– Exhibit Batch
1Impurity generated due to oxidation 2Impurity generated due to temperature effect 3Impurity generated due to moisture effect 4 Impurity generated due to light exposure
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
ANALYSIS OF STABILITY DATA
VERIFICATION OF PACK CONTROLS
DEFINING OF PACK CONTROLS
CPAs / CPPs Ranges studied at
LAB scale Actual data
for EXHIBIT batches Proposed range for
COMMERCIAL batch PURPOSE of Control
Container
Material C-PET
Crystalline Poly Ethylene Teraphthalate
C-PET Crystalline Poly Ethylene
Teraphthalate
C-PET Crystalline Poly Ethylene
Teraphthalate
To ensure Mechanical Strength, Physical Barrier & Chemical Compatibility for target shelf life of drug product during transportation, storage or routine-use
Capacity 250 ml 250 ml 250 ml
Closure
Cap Polypropylene PP Cap
22 mm Polypropylene PP Cap
22 mm Polypropylene PP Cap
22 mm To ensure Physical Barrier & Chemical Compatibility for target shelf life of drug product during transportation, storage or routine-use
Cap Liner Two Piece Re-sealable
PVdC Cap Liner 75 gauge
Two Piece Re-sealable PVdC Cap Liner
75 gauge
Two Piece Re-sealable Aluminum Cap Liner
75 gauge
Processing Parameters
Method of Filling with Mechanism
Volumetric Filling by Positive
Displacement Piston Action
Volumetric Filling by Positive
Displacement Piston Action
Volumetric Filling by Positive
Displacement Piston Action
To ensure batch to batch consistency in bottle pack without any Mechanical damage, Physical Leakage or Chemical Incompatibility to achieve target shelf life of drug product during transportation, storage or routine-use
Rate of Filling 30-50 bottles / min to prevent Foaming
30-50 bottles / min to prevent Foaming
30-50 bottles / min to prevent Foaming
Post-gassing With N2 purging With N2 purging With N2 purging
Cap Liner Sealing Induction Sealing
(20-60 bottles/min) Induction Sealing
(20-60 bottles/min) Induction Sealing
(20-60 bottles/min) Environmental Conditions
Temperature 21-25°C 21-25°C 21-25°C To ensure batch to batch uniformity in surrounding environmental factors during on line processing of packaging to provide protection from temperature, moisture, light & oxidation
Humidity 20-40 % RH 20-30 % RH 20-30 % RH
O2 or N2 Under Nitrogen Laminar Flow
Under Nitrogen Laminar Flow
Under Nitrogen Laminar Flow
UV- Visible Light Packaging Under
Sodium Vapor Lamp Packaging Under
Sodium Vapor Lamp Packaging Under
Sodium Vapor Lamp
PDbD PACKAGING DEVELOPMENT bY DESIGN (Contd) Implementation of Controls for Packaging of– Commercial Batches
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to control risks by
Process Analytical Technology?
5
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Process Analytical Technology (PAT) A System for- • Designing, • Analysing & • Controlling Manufacturing through Timely Measurements (i.e., during processing) of Critical Quality and Performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. Note: Through PAT, Online Feedback Controlling System for each & individual CMAs &/or CPPs will be developed through designing of controls by analysis at line/ on line/ in line analyser system
What is PAT?
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
CONTROLLING PHASE
ANALYZING PHASE
DESIGNING PHASE
IDENTIFICATION OF CRITICAL STEPs
VEHICLE PREPARATION WITH SWEETENER, FLAVOR & COLOR
pH & VOLUME MAKE UP WITH VEHICLE & STORAGE
CONTROLLED FLOCCULATION WITH HEATING & MIXING
A B C
CRITICAL PROCESSING STEPS
PAT For
SUSPENSION MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Risk Analysis of CMAs & CPPs with respect to CQAs at Raw Scale Developmental level by ON LINE / AT LINE Analyzers for Prediction of Real Time Data &
Designing of Control Strategies at Commercial Scale
CONTROLLING PHASE
ANALYZING PHASE
IDENTIFICATION OF CRITICAL STEPs
DESIGNING PHASE
TEMPERATURE &
RELATIVE HUMIDITY
At Line
Thermo-hygrometer
API / EXCIPIENT PURITY
At line UV/ HPLC/ GC,
On line LOD/ HMB or W/KF
API / EXCIPIENT PARTICLE
SIZE DISTRIBUTION
At line Malvern Particle Size
Analyzer OR On Line
Sieve Shaker Analysis
RATE OF CONTROLLED FLOCCULATION OR EFFECTIVE PRECIPITATION by In Line Lasentec FBRM or PVM FOR SUSPENSIONS /
EMULSIONS OR At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests
RATE OF SEDIMENTATION FOR PHYSICAL STABILITY by
In Line Lasentec FBRM or PVM OR
At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests
RATE OF STIRRING FOR COMPLETE HOMOGENIZED STATE by In Line BRUKER FT-NIR FOR HOMOGENIZED
STATE OF SOLUTION
VEHICLE PREPARATION
Bulk Uniformity by At line
UV-VISIBLE/ IR,-RAMAN
HPLC/ GC Spectroscopy
CONTROLLED FLOCCULATION
Bulk Uniformity by At line
UV-VISIBLE/ IR,-RAMAN
HPLC/ GC Spectroscopy
pH & VOLUME MAKE & STORAGE
Precipitation analyzed by
At Line Malvern PSA or
Online SVR/ SHR/ DF
On Line
pH Meter
On Line
Viscometer
PAT For
SUSPENSION MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CRITICAL STEPs
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Real Time Data Analysis at Scale UP-Exhibit Manufacturing Scale by IN LINE analyzers with auto-sensors & Real time data comparison with Raw scale data
for Finalization of Control Strategies at Commercial Scale
CONTROLLING PHASE
DESIGNING PHASE
ANALYZING PHASE
TEMPERATURE &
RELATIVE HUMIDITY
In Line
Thermo-hygrometer
API / EXCIPIENT PURITY
In Line FT-NIR
API / EXCIPIENT PARTICLE
SIZE DISTRIBUTION
In line FBRM
RATE OF CONTROLLED FLOCCULATION OR EFFECTIVE PRECIPITATION by In Line Lasentec FBRM or PVM FOR SUSPENSIONS /
EMULSIONS OR At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests
RATE OF SEDIMENTATION FOR PHYSICAL STABILITY by
In Line Lasentec FBRM or PVM OR
At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests
RATE OF STIRRING FOR COMPLETE HOMOGENIZED STATE by In Line BRUKER FT-NIR FOR HOMOGENIZED
STATE OF SOLUTION
VEHICLE PREPARATION
Bulk Uniformity by In line Bruker
FT-NIR Spectroscopy for
homogenized state of solution
CONTROLLED FLOCCULATION
Bulk Uniformity by In line Bruker
FT-NIR Spectroscopy for
homogenized state of solution
pH & VOLUME MAKE & STORAGE
Precipitation analyzed by
In Line Lasentec FBRM or
Particle Video Monitoring
In Line
pH Meter
In Line
Viscometer
PAT For
SUSPENSION MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CRITICAL STEPs
DESIGNING PHASE
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Application of Auto-controllers at real time Manufacturing scale For Continuously attaining Acceptable ranges of CMAs & CPPs
with respect to desired CQAs
A DEVELOPED PAT SYSTEM FOR CONTINUOS AUTOMATIC ANALYSING & CONTROLLING MANUFACTURING THROUGH TIMELY MEASUREMENTS OF CQA & CPPs WITH THE ULTIMATE GOAL OF CONSISTANTLY ENSURING FINISHED PRODUCT QUALITY AT REAL TIME COMMERCIAL SCALE
ANALYZING PHASE
CONTROLLING PHASE
Auto-controlling of
TEMPERATURE &
RELATIVE HUMIDITY
Air Handling Unit
(AHU)
Auto controlling of
VEHICLE PREPARATION
Bulk Uniformity by adjusting
Heating Temperature
Heating Time
Mixing Speed
Mixing Time
Auto controlling of
CONTROLLED FLOCCULATION
Bulk Uniformity by adjusting
Heating Temperature
Heating Time
Mixing Speed
Mixing Time
Auto Maintaining of
PHYSICAL & CHEMICAL STABILITY
By adjusting
Stirring Speed
Stirring Time
Storage Temperature
Dissolved & Headspace Oxygen
Auto-controlling of
DISSOLVED OXYGEN
by adjusting Vacuum
Pressure & Stirring Time
Auto-controlling of
HEADSPACE OXYGEN
by adjusting Vacuum
Pressure & N2 Purging
PAT For
SUSPENSION MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
How to
Implement Controls
6
for Commercial Manufacturing?
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Control Strategy A planned set of controls for CMAs & CPPs- derived from current product and process understanding • During Lab Scale Developmental Stage • Scaled Up Exhibit-Submission Stage that ensures process performance and product quality • During Commercial Stage
Note: For finalizing & implementation of Control Strategy for each & individual CMAs &/or CPPs; ranges 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
What is Control Strategy?
© Created & Copyrighted by Shivang Chaudhary
CONTROL OF CPPs
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
FACTOR(s) CMAs Ranges studied at
LAB scale Actual data
for EXHIBIT batches Proposed range for
COMMERCIAL batch PURPOSE of Control
Active Pharmaceutical Ingredient (API) Critical Material Attributes
Polymorphic Form
2Ө values x, y, z x, y, z x, y, z To ensure batch to batch consistency in Dissolution
Particle Size Distribution
(PSD)
D10: NMT x um NMT x um NMT x um To ensure batch to batch consistency in Blend Uniformity (BU), Content Uniformity (CU) & Dissolution
D50: NMT y um NMT y um NMT y um
D90: NMT z um NMT z um NMT z um
EXCIPIENT Critical Material Attributes
Vehicle Grade UV/RO Filtered Purified Water
UV/RO Filtered Purified Water
UV/RO Filtered Purified Water
To ensure consistence compatibility, purity & Microbial Stability
Surfactant Type (Tween 80) Non-ionic Non-ionic Non-ionic
To ensure batch to batch consistency in solubility, pour ability, Physical Stability & Compatibility
Concentration (%w/w) 0.50-1.50 0.75-1.25 0.85-1.15
Hydrocolloid Source (CMA) Semisynthetic Semisynthetic Semisynthetic
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% To ensure batch to batch consistent Patient Acceptance & Compliance
Flavor Concentration (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70%
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 To ensure batch to batch consistency Chemical & Microbiological stability
Anti-Oxidant Concentration (%w/w) 0.050-0.150 0.080-0.150 0.100-0.150
Buffer Concentration (%w/w) 0.800-2.000 0.800-2.000 1.000-1.500
CONTROL OF CMAs
CONTROL STRATEGY For
Critical Material Attributes
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
FACTOR(s) CPPs Ranges studied at
LAB scale Actual data
for EXHIBIT batches Proposed range for
COMMERCIAL batch PURPOSE of Control
Vehicle/ Solvent Preparation
with Sweetener, Flavor, Color
Heating Temperature 60-80°C 63-77°C 65-75°C To ensure consistence Compatibility, Acceptability, purity & Microbial Stability
Mixing Time 30-60 min 35-55 min 45 min
Controlled Solubilization by
Surfactant & hydrocolloids
Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch consistency in solubility, pour ability, Physical Stability & Compatibility
Mixing Time 30-60 min 37-53 min 40-45 min
pH Adjustment with Buffer
&Final Volume make up
with vehicle & final Mixing
Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch consistency Chemical & Microbiological stability
Mixing Time 30-60 min 37-53 min 40-45 min
Ultrafiltration
Particulate Matter Screen Size
5 micron with vacuum
5 micron with vacuum
5 micron with vacuum
To ensure batch to batch purity to warrent Safety
Microbial Filter Screen Size
0.3 micron vacuum filter
0.2 micron vacuum filter
0.2 micron vacuum filter
Filling, Capping &
Sealing
Temperature 21-25°C 21-25°C
21-25°C
To ensure Chemical Stability Vacuum Pressure
with Nitrogen Purging
NLT 29.5” NLT 29.5” NLT 29.5”
CONTROL OF CMAs
CONTROL OF CPPs
CONTROL STRATEGY For
Critical Processing Parameters
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Surfactant Electrolyte Hydrocolloid Anti Microbial
Anti Oxidant
Buffer Controlled Flocculation
Temperature
Controlled Flocculation Stirring Time
0.8%
1.0%
0.20 %
30%
35%
0.015%
0.10%
0.15%
1.0%
1.5%
65˚C
40 min
45 min
0.25 %
0.012%
0
1
0
20
30
40
5
0
60
7
0
80
9
0
10
0
0
0
.5
1.0
1
.5
2.0
2
.5
3.0
3
.5
4.0
4
.5
5.0
0
0
.1
0.2
0
.3
0.4
0
.5
0.6
0.7
0
.8
0.9
1
.0
0.0
00
0
.00
5
0
.01
0.0
15
0.0
20
0
.02
5
0.0
30
0.0
35
0
.04
0
0.0
45
0
.05
0
0.0
0. 5
1
.0
1.5
2
.0
2.5
3
.0
3.5
4
.0
4.5
5
.0
Controls for Critical Material Attributes
Critical Processing Parameters
0
1
0
20
30
40
5
0
60
7
0
80
9
0
10
0
0.0
0
0
.05
0.1
0
0.1
5
0
.20
0.2
5
0
.30
0.3
5
0
.40
0.4
5
0
.50
0
1
0
20
30
40
5
0
60
7
0
80
9
0
10
0
75˚C
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Viscosity Assay Impurities pH Content Uniformity
PSD D90 Dissolution in 30 min
1.0 cP
90%
110%
1%
6.5
7.5
0 AV
10 AV
25 um
0 um
85%
100%
1.2 cP
0%
0
1
0
20
30
40
5
0
60
7
0
80
9
0
10
0
0.5
0
.6
0
.7
0.8
0
.9
1.0
1
.1
1.2
1
.3
1.4
1
.5
50
6
0
7
0
80
90
1
00
11
0
12
0
13
0
14
0
1
50
0
0
.2
0.4
0
.6
0.8
1
.0
1.2
1
.4
1.6
1
.8
2.0
Controls for Critical Quality Attributes of
In Process Intermediates & Finished Product
0
1
2
3
4
5
6
7
8
9
1
0
Preservative Content
90%
110%
50
6
0
7
0
80
90
1
00
11
0
12
0
13
0
14
0
1
50
0
1
0
20
30
40
5
0
60
7
0
80
9
0
10
0
0
1
0
20
30
40
5
0
60
7
0
80
9
0
10
0
Management of
Product Life
Cycle
© Created & Copyrighted by Shivang Chaudhary
How to manage quality throughout
Product Life Cycle
7
By continual improvement?
During Routine Commercial Manufacturing Continual
Risk Review & Risk Communication between Stockholders of:
MANUFACTURING PLANT
QUALITY ASSUARANCE
QUALITY CONTROL
REGULATORY AFFAIRS
FORMULATION R&D
ANALYTICAL R&D
For continual assurance that the process remains in a state of control (the validated state) during commercial manufacture.
For Excellent Product
Lifecycle Management Management of
Product Life
Cycle
What is Continual Improvement?
© Created & Copyrighted by Shivang Chaudhary
Throughout the product lifecycle, the manufacturing process performance will be monitored to ensure that 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 to correct, anticipate, and prevent future problems so that the process remains in control.
© Created & Copyrighted by Shivang Chaudhary
-4
-3
-2
-1
0
1
2
3
4
0 1 2 3 4 5 6
Mea
n o
r R
ange
of
Ch
arac
teri
stic
Qu
alit
y
Sample Number
WECO Rules for signaling "Out of Control"
2 Out of the 3 Consecutive Points above +2 Sigma & below +3 sigma
4 Out of the 5 Consecutive Points above +1 Sigma & below +2 sigma
8 Consecutive Points or 10 out of 11 points or 12 out of 14 points or 14 out of 17 points or 16 out of 20 points fall on same Side of Control Line
2 Out of the 3 Consecutive Points below -2 Sigma & above -3 sigma
4 Out of the 5 Consecutive Points below -1 Sigma & above -2 sigma
8 Consecutive Points or 10 out of 11 points or 12 out of 14 points or 14 out of 17 points or 16 out of 20 points fall on same Side of Control Line
+3σ Limit
+1σ Limit
0
-1σ Limit
-2σ Limit
-3σ Limit
Management of
Product Life
Cycle
Any Point bove +3 Sigma
Any Point below -3 Sigma
+2σ Limit
Upper Control Limit
Lower Control Limit
Central Line
Other Trend Rules: 6 consecutive points in a row trending up OR down (same side) 14 consecutive points in a row alternating up & down (same side) 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)
“Continual Trend Analysis” in Process Control Charts Assessment of Common (Chance) Cause Vs. Special (Assignable) Cause
Special Cause
Special Cause
Co
mm
on
Cau
ses
Type of variation Synonyms
Common cause
Chance cause Non-assignable cause Noise Natural pattern
Special cause Assignable cause Signal Unnatural pattern
Management of
Product Life
Cycle
Process Variations Common (Chance) Cause Vs. Special (Assignable) Cause
Common Cause Chance cause/ Non-Assignable
cause (NOISE) Special Cause / Assignable cause
(Signal)
Operator absent
Poor adjustment of equipment
Operator falls asleep
Faulty controllers
Machine malfunction
Fall of ground
Computer crash
Poor batch of raw material
Power surges
Unnatural unpredictable pattern of variation, outside historic
experiment base.
New, surprise, unanticipated, emergent or previously neglected
phenomena within the system
Inappropriate procedures/ SOP Poor design &
Poor maintenance of machines Poor working conditions
Substandard raw materials Measurement error
Vibration in industrial processes Ambient temperature / humidity
Insufficient training Normal wear and tear Variability in settings
Computer response time
Natural Predictable Pattern of variation, within a historic
experience base
Phenomena constantly active within the system;
© Created & Copyrighted by Shivang Chaudhary
© Created & Copyrighted by Shivang Chaudhary
Conclusion
Detectability of Risk was increased by implementation of automatic inline
Process Analytical Technology (PAT)
RPN = Severity * Probability * Detectability
Severity of Risks could Not be reduced
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.
Probability of Risk occurrence was reduced by systematic series of experiments through
Designing of Experiments (DoE)
which ensured timely measurement of critical quality and performance attributes of raw and
in-process materials or parameters to control the quality of finished product.
which generated safe & optimized ranges of CMAs & CPPs with respect to desired CQAs par overlaid DESIGN SPACE, where all the desired
in process & finished product CQAs are met simultaneously.
Justification for
Risk Reduction
© Created & Copyrighted by Shivang Chaudhary
Conclusion
Justification for
Risk Reduction
BEF
OR
E A
FTER
Detectability of Solid State form was increased by
including pXRD test at drug substance release stage itself
Detectability of content uniformity was increased by implementing in line FT-NIR
during mixing stage
Detectability of desired PSD was increased by
implementing Malvern & FBRM at release
Risk Reduction For Critical Material Attributes of API
Probability of undesired PSD was reduced by implementing
IVIVC during development
© Created & Copyrighted by Shivang Chaudhary
Conclusion
Justification for
Risk Reduction
BEF
OR
E A
FTER
Probabilities of Poor Wetting of API & Preservatives was
reduced by optimizing ranges of Surfactant via DoE
generated Design Space (DS)
Probability of Flocculation & Caking was reduced by
optimizing ranges of surfactant / electrolyte via DoE / DS
Probabilities of increased Sedimentation rate was
reduced by optimizing ranges of Hydrocolloid via DoE
generated Design Space (DS)
Risk Reduction For Critical Material Attributes of Excipients
Probability of Microbial Spoilage upon storage was
reduced by optimizing ranges of Anti-microbial via DoE / DS
Probability of Oxidation upon storage was reduced by
optimizing ranges of Anti-Oxidant via DoE / DS
© Created & Copyrighted by Shivang Chaudhary
Conclusion
Justification for
Risk Reduction
BEF
OR
E A
FTER
Probability of poor wetting, flocculation, sedimentation &
caking were reduced by optimizing ranges of
Surfactant, Electrolyte & Hydrocolloid via DoE
generated Design Space (DS)
Detectability of Desired Particle Size Distribution was increased by utilizing FBRM/
PVM Sensors as PAT Tool
Detectability of Content Uniformity was increased by
utilizing inline FT-NIR PAT
Detectability of online impurity during filling &
packaging was increased by utilizing in line FT-NIR & DO meter & pH meter as PAT
Detectability of Solvent/ Vehicle Purity was increased by utilizing inline FT-NIR PAT
Risk Reduction For Critical Processing Parameters of Tableting
Detectability of pH was increased by inline pH Meter
© Created & Copyrighted by Shivang Chaudhary
Conclusion
Detectability of Risk was increased by implementation of automatic inline
Process Analytical Technology (PAT)
RPN = Severity * Probability * Detectability
Severity of Risks could Not be reduced
Probability of Risk occurrence was reduced by systematic series of experiments through
Designing of Experiments (DoE)
which ensured timely measurement of critical quality and performance attributes of raw and
in-process materials or parameters to control the in-process quality
of finished product.
which generated safe & optimized ranges of CMAs & CPPs with respect to desired CQAs par overlaid DESIGN SPACE, where all the desired
in process & finished product CQAs are met simultaneously.
QTPP was defined based upon the Voice of the Customers [Requirements of Pharmacist (Pharmaceutical Equivalence), Physician (Bioequivalence) & Patient Acceptance & Compliance]
From the targets defined in QTPP, required in-process & finished product specifications were determined in the form of in process
& finished product CQAs
With respect to CQAs, Risk associated with
each CMAs & CPPs were extensively
analyzed out by FMEA, which decided “which risk should get first priority?” based upon Severity * Probability * Detectability of individual risk.
Severity of Risks could not be reduced. Probability of Risk occurrence was reduced by
systematic series of experiments through DoE & Stability Studies; while Detectability of Risk was increased by online/ inline/ at line
PAT tools
During Commercial Manufacturing, Continual Risk Review & Communication was done between Stakeholders of R&D & Production for
Continual Improvement by Trend Analysis in Control Charts with Cp, Cpk for Product Lifecycle Management
Target Quality
A planned set of controls for CMAs & CPPs were derived from Lab Scale Developmental batch & Scaled Up Exhibit batches, which were verified by Process Performance indices (Pp, Ppk)
© Created & Copyrighted by Shivang Chaudhary
© Copyrighted by Shivang Chaudhary
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
+91 -9904474045, +91-7567297579 [email protected]
https://in.linkedin.com/in/shivangchaudhary
facebook.com/QbD.PAT.Pharmaceutical.Development
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“Quality doesn’t costs, it always pays”