Definition of
QTPP
Determination of
A MODEL
QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION OF A BIPHASIC LIQUID ORAL DOSAGE FORM-SUSPENSION
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
Designed & Developed by
&Development of Feedback Control system
Formulation Engineer (QbD/PAT System Developer & Implementer) MS (Pharmaceutics)- National Institute of Pharmaceutical Education & Research (NIPER), INDIA PGD (Patents Law)- National academy of Legal Studies & Research (NALSAR), INDIA Implementatn of
Control Strategy
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[email protected]
© Created & Copyrighted by Shivang Chaudhary
Aim Project
Goal
To Develop : •
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
© Created & Copyrighted by Shivang Chaudhary
iNSIDES Targeting
Bullets
QbD & Its Elements
Definition of QTPP
Determination of CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE &
Development of Design Space © Created & Copyrighted by Shivang Chaudhary
PAT &
Development of Feedback Controls Implementation of
Control Strategy © Created & Copyrighted by Shivang Chaudhary
Definition of
QTPP
Determination of
CQAs
What is the meaning of
Quality Risk Assessment of
CMAs & CPPs
Quality by Design?
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
What is QbD? Definition of
QTPP
Determination of
CQAs
Quality The suitability of either a drug substance or a drug product for its intended use.
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
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.
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
Definition of
QTPP
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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]
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
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.
© Created & Copyrighted by Shivang Chaudhary
Definition of
QTPP
Determination of
CQAs
1 How to define
Quality Risk Assessment of
CMAs & CPPs
Target Product Profile?
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
What is QTPP? Definition of
QTPP
Determination of
CQAs
QUALITY TARGET PRODUCT PROFILE (QTPP) Quality Risk Assessment of
CMAs & CPPs
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.
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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)
© Created & Copyrighted by Shivang Chaudhary
PHARMACIST’s POINT OF VIEW Definition of
QTPP
PHYSICIAN”s POINT OF VIEW
PATIENT’S POINT OF VIEW
Quality Target Product Profile (QTPP) of Suspension Therapeutic Equivalence = Pharmaceutical Equivalence + Bio-Equivalence Of Generic Suspension
with Patient Compliance
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
PHARMACEUTICAL Equivalence Similar Dosage FORM : Suspension Dosage DESIGN : IR ROUTE of Administration : Oral Dosage STRENGTH : x mg/ml Drug Product QUALITY :
BIOEquivalence 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
Assay, Uniformity, Impurities, Dissolution, Microbiological Limits, Antioxidant content, Antimicrobial content, PSD, pH, Viscosity/ Sp. Gravity, Leachable/ Extractable within acceptable limits of specification Note: Plastic/ Rubber should not allow permeation, leaching, extraction or sorption
PATIENT Compliance 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 © Created & Copyrighted by Shivang Chaudhary with Reference Product labeling
Definition of
QTPP
Determination of
CQAs
2 How to determine
Quality Risk Assessment of
CMAs & CPPs
Critical Attributes of Quality?
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
What is CQA? Definition of
QTPP
Determination of
CQAs
Critical Quality Attribute (CQA) Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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.
© Created & Copyrighted by Shivang Chaudhary
MULTI DISCIPLINARY
QTPP
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
EFFICACY
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
CQAs
SAFETY
Critical Quality Attributes (CQA) of Suspension
Definition of
Determination of
QUALITY
!
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.
Physical Attributes
!
Identification
Assay of Preservative
Positive for Drug Substance But controlled at Drug Substance Release stage itself
Color, Flavor, Taste , Viscosity USP / Sp. Gravity USP & Re-dispersibility should be mostly similar to reference product to ensure physical stability & Patient Acceptance & Compliance
Content Uniformity
Should Conform to USP Uniformity of Dosage Units: 85.0115.0 % of labeled claim with AV: NMT 15.0 to ensure patient Safety & product Efficacy
PSD & Dissolution 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
As per USP Should maintain the microbial quality of the product & to prevent oxidation throughout shelf life & proposed in-use shelf life to ensure patient safety.
!
Extractable & Leachable
Stability data should show evidence that extractable & leachable from the container/closure systems are consistently below acceptable levels to ensure patient safety.
Assay Should be between 90.0 to 110.0 % of labeled claim to ensure safety & efficacy
& Impurities pH Should be within limits as per
ICH Q3A & Q3B OR Reference Product Characterization to ensure chemical stability of formulation & patient Safety
Microbiological Limits Should Conform to USP But controlled at Drug Substance & Excipient Release stage itself to ensure microbiological stability & patient safety © Created & Copyrighted by Shivang Chaudhary
Definition of
QTPP
Determination of
CQAs
3 How to assess Risks associated with
Quality Risk Assessment of
CMAs & CPPs
Materials & Process?
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
What is CMA & CPP? Definition of
QTPP
Determination of
CQAs
Critical Material Attribute (CMA) Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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.
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
Critical Processing Parameters
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
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
Order of addition Heating temperature & Time Type & Position of Impeller Mixing Speed & Mixing Time
Type & Principle of milling Milling speed Screen size of mill Type & Size of Filter Rate of filtration
Implementatn of
Control Strategy
RISK ASSESSMENT
Controlled Flocculation Process Map
QTPP
CQAs
RISK EVALUATION
Identification of Factors involved in
Definition of
Determination of
RISK ANALYSIS
Filling rate Capping & Sealing rate Nitrogen purging &/or sparging rate Sealing rate after closure fitting
Critical Attributes of Input 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
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
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**
Physical Attributes (clarity#/ Homogeneity*) Assay, Impurity, Uniformity of Dosage units, Viscosity/Rheology, Specific Gravity/Density Microbial content of system
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
# Applicable to Solution only; * Applicable to Suspension only; ** Applicable to reconstituted powder only Environment (Temperature and RH)
Manufacturing Process Steps
Vehicle Preparation & Storage Organoleptic addition
Controlled Flocculation by Surfactants & Hydrocolloid
pH adjustment & Final Volume make up with vehicle & final mixing
Filtration in Colloid mill
Filling , Capping & Sealing with nitrogen purging
Quality Attributes of Output Materials
Physical Attributes (color, odor, taste) Vehicle purity, Vehicle polarity Vehicle pH, Vehicle Viscosity/sp. Gravity Vehicle Volatility, Vehicle Microbial content
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
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
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, 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
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION Definition of
QTPP
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
Identification of Risk Factors by
Ishikawa Fishbone Diagram
Determination of
CQAs SOLUBILIZATION BY SURFACTATNT BODYING BY HYDROCOLLOID&/OR VOLUME MAKE UP VISCOSITY OF SYSTEM
Quality Risk Assessment of
CMAs & CPPs
FILTRATION, FILLING, CAPPING & SEALING COLLOID MILL MESH SIZE FILTER SCREEN SIZE
VEHICLE QUANTITY
FILRATION RATE
EXTRACTABLE/LEACHABLE
& Development of Design Space
NITROGEN PURGING RATE
HYDROCOLLOID SOURCE
COLOR SOURCE & CONC.
OXYGEN EXPOSURE
SURFACTANT SOURCE
SWEETENERS SOURCE & CONC FLAVORS SOURCE & CONC
LIGHT EXPOSURE TEMPERATURE
PAT
MATERIAL OF 1° PACKAGING
BUFFER CONCENTRATION
RELATIVE HUMIDITY
TYPE & CONC. OF SURFACTANT CONC. OF COMPLEXING AGENTS
STIRRING RATE (SPEED *TIME)
STIRRING RATE
STIRRING RATE
BIOBURDEN
ENVIRONMENTAL FACTORS
INTERFACIAL TENSION OF SYSTEM API AQUEOUS SOLUBILITY
TYPE & CONC. OF PRESERVATIVE
CO-SOLVENT QUANTITY
RATE OF FILLING & SEALING
DoE
TYPE OF HYDROCOLLOID HYDROCOLLOID CONC.
API PSD & SURFACE AREA
STIRRING RATE pH ADJUSTMENT & ADDITION OF ORGANOLEPTICS
API STABILITY API PURITY RAW MATERIAL
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION Definition of
QTPP
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
Qualitative Risk based Matrix Analysis of
Active Pharmaceutical Ingredient’s (API) Attributes
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
FP CQAs
Appearance Assay Uniformity of Content** Uniformity of Weight*** Impurities pH of System Microbial Limits Antimicrobial content Antioxidant content Extractable Viscosity/specific gravity Particle Size Distribution** Dissolution* Redispersibility** Reconstitution time*** Low Medium High
Physical Form High Low Medium Low Medium Low Low Low Low Low Low
Particle size** Low Low High Medium Medium Low Low Low Low Low Low
Low High Low Low
Solubility* Volatility
Purity
Stability
Microbial Moisture Residual Content content*** Solvent*** Low Low Low Low Low Low Low Low Low Low Low Low Low Medium Medium Medium Low Low High Medium Low High Low Low Medium Low Low Low Low Low Low Low Low
Low Low High Low Low Low Low Low Low High Low
Low Low High Low Low Low Low Low Low High High
Low High Low Low High Low Low Low Low Low Low
Low High Low Low High Medium Low Low Low Low Low
High
Low
Low
Low
Low
Low
Low
Low
High High High
High Low High
Medium Low Low
Low Low Low
Medium Low Low
Low Low Low
Low Low Low
Low Low Low
Broadly acceptable risk. No further investigation is needed Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk. Risk is unacceptable. Further investigation is needed to reduce the risk.
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ASSESSMENT Detectability of Risk can be increased through In Line PAT System
Active Pharmaceutical Ingredient’s (API) Attributes
QTPP
PhysicoChemical Property of Actives Determination of
CQAs Physical Property Quality Risk Assessment of
CMAs & CPPs Chemical Property
DoE
& Development of Design Space
Biological Property
PAT
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of
Definition of
&Development of Feedback Control system
RISK ANALYSIS
Critical Material Attribute (CMAs)
Failure Mode Effect on IP & FP CQAs with respect to QTPP (Critical (Justification of Failure Mode) Event)
Solid Sate Form
Different Polymorph/ form
Particle Size Distribution (PSD)
Higher PSD
Moisture content
High water content
Residual Solvents
High residual solvent
Solubility
Different Salt/ Form
Volatility
High
Process Impurities
Less Purity
Chemical Stability
poor
Microbial Content
High
P
S
Solubility of drug substance may get affected= Probability2of Risk4can >> Dissolution of drug product may get affected >> BIOAVAILABILITY-EFFICACY may get compromised be Reduced through DoE Optimization BCS Class II/IV Low Solubility drug >> Dissolution of drug product may get affected 4 4 >> BIOAVAILABILITY/EFFICACY may get compromised Rate of degradation may get affected >> Impurity profile may get affected 2 3 >> SAFETY of the product may get compromised Residual solvents are likely to interact with drug substance >> Impurities profile may get affected 2 3 >> SAFETY may get compromised Dissolution of the drug product may get affected 2 3 >> BIOAVAILABILITY-EFFICACY may got compromised Assay & Content Uniformity may be affected 2 3 >> EFFICACY may get compromised Assay & impurity profile of drug product may be affected = 2 3 >> Quality & SAFETY may got compromised Susceptible to dry heat/oxidative/hydrolytic/UV light degradation- impurity profile may get affected 2 3 >> Quality & SAFETY may got compromised MICROBIAL LOAD may get increased during transportation, shipping, storage & in-use 2 3 >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of patient may get compromised
Probability*
Severity**
Detect ability***
Very Unlikely Occasional Repeated Regular
Minor Moderate Major Extreme
Always Detected Regularly Detected Likely not Detected Normally not Detected
D
RPN (=P*S*D)
4
32
3
48
2
12
2
12
4
24
4
24
3
18
3
18
4
24
Score 01 02 03 04
Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.
Implementatn of
Control Strategy
Score based on
Score based on
Score based on
PROBABILITY FOR OCCURANCE OF FAILURE
LIKELY SEVERITY IMPACT ON DRUG
PROBABILITY OF FAILURE OF DETECTION.
PRODUCT CQA.
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION Definition of
QTPP
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Active Pharmaceutical Ingredient’s (API) Attributes Required to be Optimized &/Or Controlled
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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 © Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION Definition of
QTPP
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Active Pharmaceutical Ingredient’s (API) Attributes Required to be Optimized &/Or Controlled
Determination of
CQAs
CMAs of
API
Quality Risk Assessment of
CMAs & CPPs
A
SOLID STATE FORM
B
PARTICLE SIZE
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
Qualitative Risk based Matrix Analysis of
Definition of
Inactive Ingredients’ (Excipients’) Attributes
QTPP
Determination of
CQAs FP CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Appearance Assay Uniformity of Content** Uniformity of Weight*** Impurities pH of System Microbial Limits Antimicrobial content Antioxidant content Extractable Viscosity/specific gravity Particle Size Distribution** Dissolution** Redispersibility** Reconstitution time*** Low Medium High
Surfactants Solvents/ Hydrocolloid (Solubilizing Buffering Co-solvents/ (Suspending / Wetting agent Vehicles agent) agents)
Preservatives
Organoleptic Additives
Anti Microbial
Anti Oxidant
Colors
Flavors
Sweeteners
High High High Low High High Medium Low Low High High
High High High Low Medium Low Low Low Low High Low
High High High Low Low Low Medium Low Low Low High
Low Low Low Low High High Low High High Low Low
Low Low Low Low Medium Low High High Medium Low Low
Low Low Low Low Medium Low Low Medium High Low Low
High Low Low Low Medium Low Medium Low Low Low Low
Low Low Low Low Medium Low Medium Low Low Low Low
Low Low Low Low Medium Low Medium Low Low Low Low
Low
High
Low
Low
Low
Low
Low
Low
Low
Low High High
High High High
Low High High
High Low Low
Low Low Low
Low Low
Low Low Low
Low Low Low
Low Low Low
Broadly acceptable risk. No further investigation is needed Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk. Risk is unacceptable. Further investigation is needed to reduce the risk.
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
Excipient
Solvents/ Cosolvents/ Vehicles
CQAs
CMAs & CPPs
DoE
Surfactants (As a Solubilizing/ Wetting agents)
PAT
Electrolytes (As a Controlled Flocculating Agent)
Hydrocolloid (As a Supporting Structured Vehicle)
Control Strategy
Quantity of Vehicle/ Solvent
Failure Mode (Critical Event)
P
S
D
RPN (=P*S*D)
3
3
3
27
4
3
2
24
2
3
4
24
3
3
3
27
3
4
4
48
3
4
4
48
3
4
4
48
3
4
4
48
3
4
4
48
2
3
4
24
3
4
4
48
3
3
2
18
SOLUBILITY of the weak acidic / weak basic drugs may get affected >> EFFICACY may get compromised
3
3
3
27
CHEMICAL STABILITY of pH sensitive drugs/ preservatives may get affected >> SAFETY of patient may get compromised
3
3
3
27
Less than optimum
MICROBIAL LOAD may get increased during transportation, storage & inuse >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of patient may get compromised
3
3
4
36
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
Not optimum
Product TASTE may not be palatable & agree able >> Patient COMPLIANCE may get compromised
3
3
2
18
Not optimum
APPEARANCE of the product may not be pleasant >> Patient ACCEPTANCE may get compromised
3
3
2
18
Less than optimum More than optimum
Source of Vehicle/ Solvents/ Cosolvents
Natural without purification
Ionic Nature of Surfactant
Cationic/ Anionic in nature
Less than optimum Concentration of Surfactant
Less than optimum Concentration of Electrolytes More than optimum Source of Hydrocolloid Concentration of Hydrocolloid
Natural Less than optimum
More than optimum
Buffering Agent
Anti-Microbial Implementatn of
CMAs
More than optimum
& Development of Design Space
&Development of Feedback Control system
RISK ASSESSMENT
Inactive Ingredients’ (Excipients’) Attributes
QTPP
Quality Risk Assessment of
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of
Definition of
Determination of
RISK ANALYSIS
Anti-Oxidant Sweetener/ Flavoring agent Coloring agent
pH of the Buffer Concentration of Anti-Microbial Concentration of Anti-Oxidant Concentration of Sweetener/ Flavor Concentration of Coloring Agent
Within Neutral Range Within Acidic/ Basic Range
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode) Drug Substance may NOT get completely SOLUBILIZED or uniformly DISTRIBUTED >> CONTENT UNIFORMITY may get affected >> SAFETY & EFFICACY may get compromised Product may get BULKIER to handle >> Patient ACCEPTANCE & COMPLIANCE may get compromised 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 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 Drug Substance/ Preservatives may NOT getting effectively SOLUBILIZED/ DISTRIBUTED within system >>SAFETY & EFFICACY may get compromised 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 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 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 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 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 VISCOSITY of dispersion medium may be too low >> Rate of SEDIMENTATION will be high >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised VISCOSITY of dispersion medium may be too high >> POUR ABILITY of the product may get compromised >> PATIENT COMPLIANCE may get compromised
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION Definition of
QTPP
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Inactive Ingredients’ (Excipients’) Attributes Required to be Optimized &/Or Controlled
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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 © Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Definition of
Inactive Ingredients’ (Excipients’) Attributes
QTPP
Required to be Optimized &/Or Controlled
Determination of
CMAs of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
EXCIPIENTS A
SURFACTANT (%w/w)
B
HYDROCOLLOID (%w/w)
C
ANTI MICROBIAL (%w/w)
D
ANTI OXIDANT (%w/w)
E
SWEETENER (%w/w)
F
FLAVOR (%w/w)
G
COLOR (%w/w)
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
Qualitative Risk based Matrix Analysis of
Definition of
Processing Parameters
QTPP
Determination of
CQAs FP CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Physical attributes Assay Uniformity of Content** Uniformity of Weight*** Impurities pH of System Microbial Contents O2 in headspace/ dissolved O2 Antimicrobial content Antioxidant content Extractable Viscosity/specific gravity Particle Size Distribution** Dissolution** Redispersibility** Reconstitution time*** Low Medium High
Solubilizing*/ Solvent/ Wetting** of Controlled Final Volume Organoleptic pH Filtration*/ Vehicle Solids (API+ Flocculation Bodying with make up additives adjustment Milling** in Preparation Preservative) by Hydrocolloid with vehicle addition by buffering Colloid mill & storage by Electrolytes & mixing Surfactants
High Low Low Low High High High High Low Low Low High Low Low Low High
High High High Low High Medium Low High Medium Medium High Low Low High High High
High High High Low Low High Low Low High High Medium Low High Low Low Low
High High High Low Low Medium Medium Low Low Low Low High High Low Low Low
High Low Low Low Low Medium Medium Low Low Low Low Low Low Low Low Low
Low Medium Low Low High High Low Low High High High Low Low High Low High
High High High Low High High Medium High High High High High Low High Low High
High High High Low Low Low Low Low Low Low Low Low High High High High
Filling & Capping
Low Medium Low High High High High High High High High Low Low Low Low Low
Broadly acceptable risk. No further investigation is needed Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk. Risk is unacceptable. Further investigation is needed to reduce the risk.
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
Unit Operations
Critical Process Parameter (CPPs) Rate of Addition Filtration Rate
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Solvent/ Vehicle Preparation with organoleptics & storage
Wetting* of Solids (API+ Preservative) by Surfactants Controlled Flocculation by Surfactants / Electrolytes / Polymers
Heating Rate (Temp*Time)
Bodying with Hydrocolloid*
P
S
D
RPN (=P*S*D)
Higher than Optimum
Physical Attributes, Impurity profile & Microbial Load may get affected >> Safety may get compromised
2 2
3 3
4 4
24 24
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
3
3
3
27
2 2
3 3
4 4
24 24
3
3
4
36
3
3
4
36
2
3
4
24
3
4
4
48
2
3
4
24
2
3
4
24
Order of addition Impeller Design & Position
Incorrect Improper
Mixing Rate (Speed*Time)
Lower than Optimum
Heating Rate (Temp*Time) Order of Addition Mixing Rate (Speed*Time)
Rate of Addition
Rate of Addition Impeller Design & Position Mixing Rate (Speed*Time) Heating Rate (Temp*Time) Type & Principle of Mill Filter/ Mill Screen Size Rate of Milling
Implementatn of
Filling , Capping & Sealing with nitrogen purging
Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)
Lower than Optimum
Mixing Rate (Speed*Time) pH Adjustment with Buffer &Final Volume make up with vehicle & final mixing
Failure Mode (Critical Event)
Mixing Rate (Speed*Time) with Co-Solvents
Order of Addition
MicroMilling** in Colloid mill
Control Strategy
RISK ASSESSMENT
Processing Parameters
QTPP
CQAs
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of
Definition of
Determination of
RISK ANALYSIS
Filling rate (Speed*Time) Nitrogen purging rate Capping & Sealing rate
Higher than optimum Incorrect Lower than Optimum Incorrect Higher than optimum
Physical Attributes (Color, Odor, Taste) , Content Uniformity & ultimately Assay may get affected >> Safety & Efficacy may get compromised >> PATIENT COMPLIANCE may get compromised 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 Impurity profile & ultimately Assay may get affected >> CHEMICAL STABILITY may get compromised >> SAFETY may get compromised 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
Lower than Optimum
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
3
3
4
36
Higher than Optimum Improper Lower 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
2 3
3 3
4 4
24 36
Lower than Optimum
Microbiological Stability may get affected >> Safety may get compromised Impurity profile & Assay may get affected > CHEMICAL STABILITY may get compromised >> SAFETY may get compromised
3
3
4
36
3
3
4
36
2 2
3 3
4 4
24 24
3
3
3
27
3
2
2
12
3
3
4
36
3 3
3 3
4 4
36 36
Higher than Optimum Improper Incorrect Higher than Optimum
Physical Attributes, Impurity profile, Microbial Load, Content Uniformity & ultimately Assay may get affected >> PHYSICAL STABILITY may get compromised >> Quality, SAFETY & EFFICACY may get compromised
Not Optimum
Uniformity of Weight may get affected >> PATIENT ACCEPTANCE may get compromised
Higher than Optimum Lower than optimum Lower than Optimum
Dissolved / Headspace Oxygen may get increased >>Oxidation Impurity profile & Assay may get affected >> Safety may get compromised
© Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION Definition of
QTPP
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Processing Parameters Required to be Optimized &/Or Controlled
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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 © Created & Copyrighted by Shivang Chaudhary
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Definition of
Processing Parameters
QTPP
Required to be Optimized &/Or Controlled
CPPs of
Determination of
CQAs
CONTROLLED SOLUBILIZATION
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
A
%SURFACTANT
B
%HYDROCOLLOID
C
MIXING TIME
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
Definition of
QTPP
Determination of
CQAs
4 How to evaluate & optimize risks by
Quality Risk Assessment of
CMAs & CPPs
Designing of Experiments?
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
What is DoE & DS? Definition of
QTPP
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
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.
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 © Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
CONTROLLED FLOCCULATION(Contd…)
QTPP
Optimization of CMAs & CPPs OF
Suspension Homogenization Process
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
C
STIRRING TIME
B
HYDROCOLLOID
A
SURFACTANT
RISKS PAT
&Development of Feedback Control system
INADEQUATE VISCOSITY
INADEQUATE ZETA POTENTIAL
HIGH RATE OF SEDIMENTATION
CONTENT UNIFORMITY COMPROMISED Implementatn of
QUALITY COMPROMISED
SAFETY COMPROMISED
EFFICACY COMPROMISED
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
CONTROLLED FLOCCULATION(Contd…)
QTPP
To Optimize CMAs & CPPs of Liquid Suspension Dosage Form
OBJECTIVE Determination of
Quality Risk Assessment of
CMAs & CPPs
3
NO. OF FACTORS
NO. OF FACTORS
3
NO. OF LEVELS
3
EXPERIMENTAL DESIGN SELECTED
“High”
Medium
C
DoE
BOX BEHNKEN DESIGN STIRRING TIME
CQAs
& Development of Design Space
ADD. CENTER POINTS
2
TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
12MP + 3CP =15
“Low” A
SURFACTANT
PAT
&Development of Feedback Control system
3
NO. OF LEVELS
Factors (Variables) Implementatn of
Control Strategy
A B C
SURFACTANT (%) HYDROCOLLOID (%) STIRRING TIME (min)
-1 0.50%w/w 20%w/w 30min
Levels of Factors Studied 0 1.00%w/w 30%w/w 45min
+1 1.50%w/w 40%w/w 60min © Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs Definition of
QTPP
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
CONTROLLED FLOCCULATION(Contd…) CMAs
CPP
CQAs
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
PREDICTION EFFECT EQUATION OF INDIVIDUAL RESPONSE BY QUADRATIC MODEL Sedimentation Volume Ratio = +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
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs Definition of
QTPP
Determination of
CQAs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
CONTROLLED FLOCCULATION(Contd…) Responses (Effects) Y1 Sedimentation Volume Ratio Y2 Zeta Potential (mV) Y3 Viscosity (cps) Y4 Content Uniformity (AV)
Goal for Individual Responses To achieve the minimum SVR i.e. NMT 0.1 To achieve zeta potential of suspension in the range of -40 to -50 mv To achieve viscosity in the range of 40 to 50 cps To achieve minimum acceptance value in CU i.e. NMT 2.0
By Overlaying contour maps from each responses on top of each other, RSM was used to find the IDEAL “WINDOW” of Operability-Design Space per proven acceptable ranges & Edges of Failure with respect to individual goals
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
Factors (Variables) A SURFACTANT (%) B HYDROCOLLOID (%) C STIRRING TIME (min)
Knowledge Space 0.50-1.50 20.0-40.0 30-60
Design Space 0.75-1.25 27.5-37.5 37-53
Control Space 0.85-1.15 30.0-35.0 40-50
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
SWEETENER : FLAVOR : COLOR(Contd…)
QTPP
Optimization of
Sweetener Flavor & Color Ratio in liquid oral mixtures
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
3
COLORANT
2
FLAVOR
1
SWEETENER
RISK UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE
Implementatn of
Control Strategy
PATIENT ACCEPTANCE COMPROMISED
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
SWEETENER : FLAVOR : COLOR(Contd…)
QTPP
OBJECTIVE
To Optimize Sweetener : Flavor : Color ratio of Liquid Orals
Determination of
CQAs
EXPERIMENTAL DESIGN SELECTED D-OPTIMAL MIXTURE DESIGN
CMAs & CPPs
SWEETENER
Quality Risk Assessment of
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
• 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. TOTAL NO OF EXP RUNS (TRIALS)
Factors (Variables) A SWEETENER (%w/w) B FLAVOR (%w/w) C COLOR (%w/w)
Lower Levels 1.00% 0.50% 0.00%
16
Higher Levels 1.50% 1.00% 0.50%
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs Definition of
QTPP
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
SWEETENER : FLAVOR : COLOR(Contd…) CMAs
CQAs
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
PREDICTION EFFECT EQUATION OF EACH FACTOR BY SPECIAL
CUBIC MODEL
Implementatn of
Control Strategy
Patient Acceptability Score= +3.79A+3.19B+2.67C+2.57AB+4.73AC+1.94BC+15.05ABC
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DEVELOPMENT OF DESIGN SPACE
SWEETENER : FLAVOR : COLOR(Contd…)
QTPP
CQAs
ANALYSIS OF RESPONSES
DoE For
Definition of
Determination of
DESIGN OF EXPERIMMENTS
Responses (Effects) Y1 PATIENT ACCEPTANCE SCORE
Goal for Individual Responses To achieve maximum Patient Acceptance Score as maximum as possible out of 10. & NLT 4.5 out of 5.0
By Overlaying contour maps from each responses on top of each other, RSM was used to find out the IDEAL “WINDOW” of operability-Design Space per proven acceptable ranges & Edges of Failure with respect to ultimate goals
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
Factors (Variables) A SWEETENER (%w/w) B FLAVOR (%w/w) C COLOR (%w/w)
Knowledge Space 1.00-1.50% 0.50-1.00% 0.00-0.50%
Design Space 1.10-1.35% 0.52-0.76% 0.05-0.25%
Control Space 1.15-1.30% 0.60-0.70% 0.10-0.20%
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
PRESERVATIVE SYSTEM(Contd…)
QTPP
Optimization of
Preservative system for In use Stability of Multidose Liquid Orals
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
C
BUFFERING AGENT
B
ANTIOXIDANT
A
ANTIMICROBIAL
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
RISKS INADEQUATE ANTIMICROBIAL CONC.
INADEQUATE ANTIOXIDANT CONC
MICROBIAL LOAD
IN-USE OXIDATION IMPURITIES SAFETY COMPROMISED
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
PRESERVATIVE SYSTEM(Contd…)
QTPP OBJECTIVE
To Optimize Preservative System for In Use Stability Of Multi-dose Sterile Product (Injection, Eye/Ear Drops)
Determination of
CQAs
Quality Risk Assessment of
PAT
&Development of Feedback Control system
A
Control Strategy
2
A B C
ADD. CENTER POINTS
3
TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
23 + 3 = 11
ANTIMICROBIAL
Factors (Variables) Implementatn of
NO. OF LEVELS
23 FULL FACTORIAL DESIGN WITH ADD. CENTER POINTS
BUFFERING AGENT
DoE
& Development of Design Space
3
EXPERIMENTAL DESIGN SELECTED
C
CMAs & CPPs
NO. OF FACTORS
Antimicrobial (%W/W) Antioxidant (%W/W) Buffering Agent (%W/W)
-1 0.005 0.050 0.800
Levels of Factors studied Center point (0) 0.010 0.100 1.400
+1 0.015 0.150 2.000
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs Definition of
QTPP
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
DoE For
PRESERVATIVE SYSTEM(Contd…) CMAs
CQAs
Determination of
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
PREDICTION EFFECT EQUATION OF EACH FACTOR BY
Implementatn of
Control Strategy
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
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
PRESERVATIVE SYSTEM(Contd…)
QTPP
CQAs
DEVELOPMENT OF DESIGN SPACE
DoE For
Definition of
Determination of
ANALYSIS OF RESPONSES
Responses (Effects) 5 Reduction in Microbial Load after 14D in use Y1 %Oxidized Impurities after 14D in use Y2
Goals for Individual Responses To achieve NLT 99.5% reduction in microbial load To minimize the level of oxidized impurities NMT 0.5%
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
Factors (Variables) A Antimicrobial (%W/W) B Antioxidant (%W/W) C Buffering Agent (%W/W)
Knowledge Space 0.005-0.015 0.050-0.150 0.800-2.000
Design Space 0.010-0.015 0.080-0.150 0.800-2.000
Control Space 0.012-0.015 0.100-0.150 1.000-1.500
© Created & Copyrighted by Shivang Chaudhary
Definition of
QTPP
Determination of
CQAs
How to Identify & Optimize CMAs & CPPs of Primary Packaging Process by Stability Studies?
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
ANALYSIS OF STABILITY DATA
DEFINING OF PACK CONTROLS
DEFINING OF PACK CONTROLS
PDbD
Definition of
PACKAGING DEVELOPMENT bY DESIGN
QTPP
SELECTION & OPTIMIZATION OF CMAs & CPPs OF
LIQUID ORAL PACKAGING PROCESS
Determination of
FOR LIQUID ORAL SUPENSION DOSAGE FORM DEVELOPMENT AS PER QbD
CQAs
Quality Risk Assessment of
CMAs & CPPs
DoE
& Development of Design Space
C
CAP
B
CAP LINER
A
LINER SEALING & CAPPING
F
POST-GASSING
E
BOTTLE FILLING
D
BOTTLE
RISKS PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
COMPROMISE IN MECHANICAL STRENGTH
COMPROMISE IN PHYSICAL BARRIER
COMPROMISE IN CHEMICAL COMPATABILITY
FAILURE IN BUBBLE TEST, VACUUM / PRESSURE DECAY
OOT / OOS IN WVTR, OTR, LTR OR MICROBIAL LOAD TESTS
OOS IN IMPURITY LIMITDURING SHELF LIFE
CHANCES OF DRUG PRODUCT INTEGRITY LOSS
PRODUCT EXPOSURE TO MOISTURE, OXYGEN, LIGHT, MICROORGANISMS
COMPROMISE IN DRUG PRODUCT SHELF LIFE
COMPROMISE IN QUALITY, SAFETY & EFFICACY © 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
PDbD
Definition of
PACKAGING DEVELOPMENT bY DESIGN (Contd)
QTPP
Available Options of Primary Packaging Material A
B
Plastic HDPE
C
Plastic PP
Plastic PET
Determination of
CQAs
PP CAP
PP CAP
PvDC Liner 75 gauge
Quality Risk Assessment of
CMAs & CPPs
PP CAP
PvDC Liner 75 gauge
Plastic HDPE Bottle
Plastic PP Bottle
D
Plastic PET Bottle
F
Glass USP IV
Glass USP II
Al CAP
Al CAP
DoE
PvDC Liner 75 gauge
PvDC Liner 75 gauge
PvDC Liner 75 gauge
& Development of Design Space
Glass USP II Bottle
Glass USP IV Bottle
PAT
&Development of Feedback Control system
G
Glass USP I
Al CAP PvDC Liner 75 gauge
Implementatn of
Control Strategy
Glass USP I Bottle
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
Selection of Primary Packaging Material Positive Control (Plastic HDPE)
Tests Determination of
CMAs & CPPs
DoE
& Development of Design Space
PAT
Barrier Properties Oxygen Permeation Water Vapor Permeation Resistance to Acids Resistance to Alkalis Resistance to Alcohols Resistance to Mineral oils Resistance to Solvents Resistance to Heat Resistance to Cold Resistance to Sunlight Resistance to High Humidity Processing / Storage Parameters Clarity / Translucency Toughness / Impact Resistance Autoclavable / Sterilizable Extractable / Leachable Weathering- Flaking –Alkalinity Breathing – Permeation – O2/CO2
Moderate Low Good Very Good Good Fair Good Good Fair Fair Excellent
Low Very Low Fair Good Good Good Fair Fair Good Fair Excellent
Very Low Very Low Fair Good Good Good Good Good Good Fair Excellent
Colorless, Translucent Good Yes Low Low High
Transparent, Clear Fair to Good Yes Low Low Moderate
Transparent, Clear Good Yes Moderate Moderate Low
Transparent, Clear Very Good Yes Moderate Moderate Low
None None Fair Very Poor Poor Fair Poor Good Good Fair Good
None None Excellent Excellent Excellent Excellent Excellent Excellent Excellent Fair Excellent
Translucent Fair Yes Very High Very High None
Negative Control (Glass USP Type I)
Optically Clear, Transparent Good Yes Low Low None
SELECTION CRITERIAS MECHANICAL STRENGTH
Control Strategy
Test Pack (For Selection of Packaging material with PVdC Cap liner & PP Cap) Plastic Plastic Plastic Glass O-PP A-PET C-PET USP Type IV
High Low Fair Good Good Fair Good Fair Excellent Fair Good
&Development of Feedback Control system
Implementatn of
DEFINING OF PACK CONTROLS
PACKAGING DEVELOPMENT bY DESIGN (Contd)
QTPP
Quality Risk Assessment of
VERIFICATION OF PACK CONTROLS
PDbD
Definition of
CQAs
ANALYSIS OF STABILITY DATA
-Strong enough to withstand handling -should fit in packaging line -long life
PHYSICAL BARRIER
CHEMICAL COMPATABILITY
BIOLOGICAL SAFETY
ECONOMICAL ACCEPTABLE
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
Extract able/ Leachable Should be -absent / within limits -biological safe -nontoxic
Total Cost, Unit Price acceptable with comparable Advantages
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF PACK CQAs
DESIGN OF $TABILITY STUDY
Comparative Accelerated Stability Study with different Packaging Material – Scale Up Batch Specification-CQAs (Acceptance Criteria)
Tests Determination of
CQAs Physical Description
DoE
& Development of Design Space
PAT
&Development of Feedback Control system
Implementatn of
Control Strategy
DEFINING OF PACK CONTROLS
PACKAGING DEVELOPMENT bY DESIGN (Contd)
QTPP
CMAs & CPPs
VERIFICATION OF PACK CONTROLS
PDbD
Definition of
Quality Risk Assessment of
ANALYSIS OF STABILITY DATA
Related Substance (Impurity) / HPLC
Assay (API) Assay (Antimicrobial) Assay (Antioxidant) pH of system Microbial Contents Viscosity Specific Gravity Extractable / Leachable Constituents 1Impurity
Clear, Transparent
Initial Analysis (0 Days)
40°±2°C /75±5%RH for 3 Months Positive Control (Plastic HDPE)
Test Pack (For Selection of Packaging material Negative for optimized formula with PVdC Cap liner & PP Cap) Control Plastic Plastic Plastic Glass (Glass PP A-PET C-PET USP Type IV USP Type I) Weathering Complies Complies Complies Complies Flaking 0.35 0.30 0.24 0.29 0.20 0.34 0.28 0.22 0.30 0.28 0.22 0.17 0.14 0.17 0.13 0.20 0.18 0.18 0.19 0.18 0.31 0.30 0.27 0.33 0.23 1.44 1.29 1.11 1.31 1.06
Complies
Complies
Imp A1: NMT 0.5% Imp B2: NMT 0.5% Imp C3: NMT 0.5% Imp D4: NMT 0.5% Max UNK:NMT 0.5% Total : NMT 3.0%
0.15 0.18 0.10 0.07 0.14 0.66
0.39 0.37 0.25 0.19 0.35 1.59
95% to 105%
98.8
96.7
97.1
97.6
98.1
97.5
98.4
90% to 110%
99.7
89.6
91.6
93.9
97.4
94.1
98.9
90% to 110%
98.6
84.4
90.5
92.3
96.5
96.1
97.8
6.5-7.5 Absent 40-50 cps 0.9-1.2 g/ml
7.1 Absent 46 cps 1.1 g/ml
6.8 Absent 44 cps 1.0 g/ml
6.6 Absent 44 cps 1.1 g/ml
6.9 Absent 42 cps 1.1 g/ml
7.1 Absent 42 cps 1.1 g/ml
7.2 Absent 45 cps 1.1 g/ml
Within Limits / Nontoxic-safe
Absent
Absent
Absent
DMT, EG
Absent
8.4 Absent 46 cps 1.1 g/ml Na2O, CaO, K2O, BaO, Al2O3, B2O3
generated due to oxidation
2Impurity
generated due to temperature effect
3Impurity
B2O3, Na2O (
