Quality by Design - QbD Model for "Liquid Oral Solution"
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Transcript of Quality by Design - QbD Model for "Liquid Oral Solution"
QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION OF A MONOPHASIC LIQUID ORAL DOSAGE FORM-SOLUTIONS
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 Solution
• 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
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
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: 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;
• On the basis of Therapeutic Safety & Efficacy for Pharmaceutical New Chemical Entities (NCE-Innovator) / 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 BE study is not required in Solution as drug is already available in the solution form at the site of absorption
Bioequivalence study is not required 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 Hydrolysis, Oxidation, Photodegradation & Microbial Growth. At least 12-months shelf-life is required at room temperature. At least 28 Days of in-Use Shelf Life is
required during routine use of multidose product
Equivalent to or better than Reference Product shelf-life
PATIENT ACCEPTANCE & PATIENT COMPLIANCE
Should possess acceptable taste, flavor, odour & attractable pleasant color most probably as similar with Reference Product. Can be easily administered (pourable & palatable)/ used/
applied similarly with Reference Product labelling
Required to achieve the desired patient acceptability & suitable compliance
QTPP Element Target Justification
Dosage FORM Solution Pharmaceutical equivalence requirement:
same dosage form
Dosage DESIGN Immediate Release Formulation Immediate release design needed to meet
label claims
ROUTE of Administration Oral/ External Pharmaceutical equivalence requirement:
same route of administration
Dosage STRENGTH x mg Pharmaceutical equivalence requirement:
same strength
Drug Product
QUALITY ATTRIBUTES
Appearance
Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable reference standards (i.e., identity, assay of drug, assay of preservatives, microbial load, purity & quality)
Assay Content Uniformity Impurities pH of System Microbial Limits Antimicrobial content Antioxidant content Extractables Viscosity/Specific Gravity
PRIMARY & SECONDARY PACKAGING
Container (Glass/Plastic/Metal) & Closure (Plastic/Metal/Rubber) system should be qualified as suitable for drug product with
desired Compatibility & Stability. Should product from heat, moisture, oxygen, carbon dioxide, light & microbial attack.
Plastic should not allow permeation, leaching, sorption, or any other chemical or physical deformation.
Required to achieve the target shelf-life and to ensure product integrity during transportation, storage
& during routine-use
PATIENT’S POINT OF VIEW
PHYSICIAN”s POINT OF VIEW
PHARMACIST’s POINT OF VIEW
Quality Target Product Profile (QTPP) of Solution
© 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
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].
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 Quality Attributes of
Drug Product Target
Is this a CQA?
Justification
Physical Appearances
Color, Odor and taste should acceptable to the patient.
Yes Color, Odor & Taste are not directly linked to safety and efficacy. Therefore, they are not critical. But to ensure patient acceptability it should be similar with reference product
Identification Positive for drug as per USP Monograph
of Drug Substance Yes*
Though identification is critical for safety, it can be effectively controlled at drug substance release stage. Formulation and process variables do not impact identity.
Therefore, this CQA will not be discussed during development.
Rheological properties (viscosity /specific gravity)
As per USP <911> for viscosity; conforms to USP <841> for specific gravity
Yes
Viscosity/ Specific gravity of the suspension should be balanced to make it possible to pour easily from container or to apply on the skin or to maintain optimum consistency to hold globules in emulsion to ensure PHYSICAL STABILITY. Formulation variables may have impact on viscosity. Therefore, this CQA will be discussed during formulation development
Assay 90.0 to 110.0 % of labeled claim. Yes Assay variability will affect SAFETY AND EFFICACY. Formulation & Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout development.
Weight Variation/ Content Uniformity
Conforms to USP <905> Uniformity of Dosage Units: 90.0-110.0 % of labeled
claim with Acceptance Value: NMT 15.0; Yes
Variability in content uniformity will affect SAFETY AND EFFICACY. Both formulation and process variables may have impact on weight variation & content uniformity,
so this CQA will be evaluated throughout development.
Antimicrobial preservative content
As per USP <51> & As per In house specification according to
developmental & stability data Yes
Liquid dosage forms are very liable to microbial attack as it contains mostly aqueous vehicle /solvent. Formulation, compounding, packaging variables & environmental factors
may impact on antimicrobial content. Thus to maintain the microbial quality of the product throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus,
this CQA will be discussed throughout formulation & process development.
Antioxidant preservative content
As per In house specification according to developmental & stability data
Yes
Liquid dosage forms are more prone to oxidation. Formulation, Compounding, Packaging Process variables & Environmental factors may impact on antioxidant content. Thus to
maintain the levels of oxidized impurities throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus, this CQA will be discussed throughout development.
pH of System Conforms to USP <791> Yes Formulation & Processing variables may affect the pH of the drug product having
impact on SOLUBILITY & CHEMICAL STABILITY. Thus, pH of the formulation will be evaluated throughout formulation & development .
Impurities / Degradation
Products
As per ICH Q3A& Q3B & USP <1086>
Yes
Degradation products can impact safety and must be controlled based on compendia / ICH requirements or reference product characterization to ensure patient SAFETY.
Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development.
Microbiological Limits
Conforms to USP <61 & 62> Yes
Microbial Load will impact patient SAFETY. Formulation, compounding, packaging variables & environmental factors may impact microbial limits. Thus to
maintain the microbial quality of the product throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus, this CQA will be discussed
throughout formulation & process development.
Extracta/,ble Conforms to USP <660> for glass, <661> for plastic & comparable to
reference product Yes*
Generally, development and stability data should show evidence that extractable from the container/closure systems are consistently below levels that are demonstrated to be
acceptable and safe, elimination of this test can normally be accepted to ensure SAFETY This should be reinvestigated if the container/closure system or formulation changes.
Dissolution As per In house specification according
to developmental & stability data Yes*
For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE Can be waived. Generally, in vivo BE studies are waived for solutions on the assumption
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
Critical Quality Attributes (CQA) of Solution
EFFICACY SAFETY QUALITY MULTI DISCIPLINARY
© 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
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 Solubilization Process Map
Vehicle Preparation & Storage Organoleptic addition
Controlled Solubilization 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
COLLOID MILL MESH SIZE
FILTER SCREEN SIZE
TARGET EXTRACTABLE VOL.
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
ADDITION OF ORGANOLEPTICS & pH ADJUSTMENT
FILRATION RATE
STIRRING RATE (SPEED *TIME)
CO-SOLVENT QUANTITY
STIRRING RATE
RATE OF FILLING
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
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
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 Low Low Low Low Low Low Low Low
Impurities Medium MEdium Low Low High High Low Low 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 Low 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 Medium 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.
© Created & Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of Active Pharmaceutical Ingredient’s (API) Attributes
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 can be affected >> Bioavailability/Efficacy may got compromised 2 3 4 24
Volatility High Assay & Content Uniformity can 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
© Created & Copyrighted by Shivang Chaudhary
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
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 Low Low Low Low Low Low Low Low
Uniformity of Content** High High High Low Low Low Low Low Low Uniformity of Weight*** High Low Low Low Low Low Low Low Low
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
Extractable High High High 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
© Created & Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of
Inactive Ingredients’ (Excipients’) Attributes
Excipient (Inactive ingredient)
Critical Material Attribute
Failure Mode (Critical Event)
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
P S D RPN (=P*S*D)
Vehicles/ Solvents Quantity of Vehicle/ Solvent
Less than optimum
Drug Substance may NOT get completely SOLUBILIZED or uniformly DISTRIBUTED >> 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 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
3 3 4 36 Hydrocolloid (Suspending agent as a structured vehicle)
Concentration of Hydrocolloid
Less than optimum
VISCOSITY of dispersion medium may be too lower >> Rate of SEDIMENTATION will be high >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
4 4 2 32
More than optimum
VISCOSITY of dispersion medium may be too higher >> POUR ABILITY of the product may get compromised >> PATIENT COMPLIANCE may get compromised
4 4 2 32
Surfactants (As a Solubilizing/ 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
4 4 3 48 ZETA POTENTIAL of the system may be too low >> Particles coalesce & flocculated suspension forms >> Suspension start to form SEDIMENT >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised
4 4 2 32
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
4 4 2 32
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
STABILITY of pH sensitive drugs/ preservatives may get affected >> CHEMICAL STABILITY may get compromised >> 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 during transportation, storage & routine use >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
4 4 3 36
Sweetener/ Flavoring agent
Concentration of Sweetener/ Flavor
Not optimum Product TASTE may not be palatable & agree able >> Patient COMPLIANCE may get compromised 4 4 2 32
Coloring agent Concentration of Coloring Agent
Not optimum APPEARANCE of the product may not be pleasant >> Patient ACCEPTANCE may get compromised 4 4 2 32
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.
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 IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Inactive Ingredients’ (Excipients’) Attributes
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 of Solids (API+
Preservative) by Surfactants
Supporting in Structured
Vehicle
Organoleptic additives addition
pH adjustment by buffering
Final Volume make up with
vehicle & mixing
Filtration in Colloid mill
Filling, Capping &
Sealing
Physical attributes High Medium High High Low High High Low Assay Low High High Low Medium High High Medium
Uniformity of Content** Low High High Low Low High High Low Uniformity of Weight*** Low Low Low Low Low Low Low High
Impurities High High Low Low High High Low High 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 Antioxidant content Low Medium Low Low High High Low High
Extractable Low High High Low Low High Low High 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 Reconstitution time*** High High 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
© Created & Copyrighted by Shivang Chaudhary
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of Processing Parameters
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)
Vehicle/ Solvent Preparation Storage& distribution
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 Microbiological Stability may get affected
>> Safety may get compromised 3 3 4 36
Higher than Optimum Impurity profile & Assay may get affected >> Safety may get compromised 3 3 4 36
Mixing Rate (Speed*Time) with Co-Solvents
Lower than Optimum Content Uniformity & Assay may get affected >> Efficacy may get compromised 3 3 4 36
Solubilization 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
Supporting by Structured Vehicles
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
Organoleptic addition With mixing
Order of Addition Incorrect 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
Mixing Rate (Speed*Time) Lower than Optimum 3 3 3 27
Heating Rate (Temp*Time) Higher than optimum Impurity profile & Assay may get affected >> Safety may get compromised 3 3 3 27
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
Ultrafiltration in Colloid mill
Type & Principle of Filter 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 Screen Size Incorrect 2 3 4 24 Rate of Filtration Higher than Optimum 3 3 4 36
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
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ASSESSMENT
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Processing Parameters
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
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 SOLUBILIZATION(Contd…)
Optimization of CMAs & CPPs OF
Solution 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
DoE For
CONTROLLED SOLUBILIZATION(Contd…)
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
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
CONTROLLED SOLUBILIZATION(Contd…)
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
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
CONTROLLED SOLUBILIZATION(Contd…)
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
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
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 SOLUBILIZATION WITH HEATING & MIXING
A B C
CRITICAL PROCESSING STEPS
PAT For
SOLUTION 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
PAT For
SOLUTION MANUFACTURING (Contd…)
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 SOLUBILIZATION
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
© 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
PAT For
SOLUTION MANUFACTURING (Contd…)
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 SOLUBILIZATION
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
© 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 SOLUBILIZATION
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
SOLUTION MANUFACTURING (Contd…)
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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?
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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
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
3 micron with vacuum
3 micron with vacuum
To ensure batch to batch purity to warrant 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
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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
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
© 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”