quality by design - qbd model for "hard gelatin capsule" dosage form - fluid bed...
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QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION OF ENCAPSULETED SOLID ORAL DOSAGE FORM-HARD GELATIN CAPSULE
A MODEL
© 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 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
Designed & Developed by
© Created & Copyrighted by Shivang Chaudhary
Aim
• Stable & Therapeutic Equivalent (Pharmaceutical Equivalent + Bioequivalent) IR Generic HG Capsule Formulation
• 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?
Note: “Quality doesn’t costs, it always pays” & “Quality does not happen accidently, Quality must be designed in by planning, not tested in afterwards.“
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?
© 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
Pharmaco-KINETICS
Fasting Study and/or Fed BE Study 90 % confidence interval of the PK parameters, AUC0-t, ,
AUC0-∞ and Cmax, should fall within bioequivalence limits of 80-125 with reference product
Bioequivalence requirement needed to meet required rate & extent of
drug absorption
EASE OF STORAGE & DISTRIBUTION
Can be stored at real time storage condition as a normal practice with desired stability & can be distributed
from the manufacturer to end user same as per Reference Product.
Required to handle the product easily with suitable accessibility
STABILITY & SHELF LIFE Should be stable against hydrolysis, oxidation, photo degradation & microbial growth. At least 24-month
shelf-life is required at room temperature
Equivalent to or better than Reference Product shelf-life
PATIENT ACCEPTANCE & PATIENT COMPLIANCE
Should be suitably colored for possessing acceptableshade similar with Reference Product.
Can be easily administered/used similar with Reference Product labeling
Required to achieve the desired patient acceptability & suitable compliance
QTPP Element Target Justification
Dosage FORM Hard Gelatin Capsule Pharmaceutical equivalence requirement:
same dosage form
Dosage DESIGN Immediate Release / Modified Release Formulation Immediate release design needed to meet
label claims
ROUTE of Administration Oral Pharmaceutical equivalence requirement:
same route of administration
Dosage STRENGTH x mg Pharmaceutical equivalence requirement:
same strength
Drug Product QUALITY
ATTRIBUTES
Description
Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable reference standards (i.e., identity, assay, purity & quality).
Assay Uniformity Impurities Dissolution Microbiological Limits Water Content Residual Solvents
PRIMARY PACKAGING
Plastic Container & Closure/ Metal Blister system should be qualified as suitable for drug product with desired
appropriate compatibility & stability. Should protect product from heat, moisture,
oxygen, light & microbial attack.
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 HGC
© 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?
© 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
Assay 90.0 to 110.0 % of
labeled claim. Yes
Assay variability will affect SAFETY AND EFFICACY. Process variables may affect the assay of the drug product. Thus, assay will be evaluated
throughout formulation and process development.
Weight Variation/ Content Uniformity
Conforms to USP <905> Uniformity of Dosage Units: 90.0-110.0 % of
labeled claim with AV: NMT 15.0; RSD : NMT 5.0%
Yes Variability in content uniformity will affect SAFETY AND EFFICACY.
Both formulation and process variables may impact content uniformity, so this CQA will be evaluated throughout formulation and process development.
Water Content As per In house specification according to stability data
Yes If drug is sensitive to moisture, it will impact stability & ultimately SAFETY &
EFFICACY. If drug is not sensitive to moisture, it will not impact stability
Impurities As per
ICH Q3A& Q3B
Yes
Degradation products can impact SAFETY and must be controlled based on compendia/ICH requirements or reference product characterization to limit patient exposure. Formulation and process variables may impact degradation products. Therefore, degradation products will be assessed
during product and process development.
Residual Solvents
Conforms to USP <467> option 1
Yes* Residual solvents can impact SAFETY, but as it will be primarily
controlled during drug substance & drug product manufacturing by drying, Therefore, Formulation and Process variables are unlikely to impact this CQA.
Microbiological Limits
Conforms to USP <61 & 62>
Yes* Microbial Load will impact patient SAFETY, but as it will be primarily
controlled during drug substance & drug product manufacturing, Therefore, Formulation and Process variables are unlikely to impact this CQA.
Dissolution
NLT X % (Q) of labeled amount of drug is dissolved in y Minutes in
pH Z buffer, 900 ml, Apparatus I/II, 50/100 rpm.
Yes Failure to meet the dissolution specification can impact bioavailability
(EFFICACY). Both formulation and process variables affect the dissolution profile. This CQA will be investigated throughout formulation and process development.
Quality Attributes of Drug Product
Target Is this a CQA?
Justification
Physical Attributes
Color and shape should acceptable to the patient. No visual tablet
defects should be observed. Yes To ensure PATIENT ACCEPTABILITY comparable to reference product
Size Similar to reference product No To ensure PATIENT COMPLIANCE with treatment regimens &
for comparable EASE OF SWALLOWING
Identification Positive for Drug Substance Yes* Though identification is critical for SAFETY AND EFFICACY, this CQA can be
effectively controlled & monitored at drug substance release.
Critical Quality Attributes (CQA) of HGC
EFFICACY SAFETY QUALITY MULTI DISCIPLINARY
© 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?
© Created & Copyrighted by Shivang Chaudhary
Screening (Co-Sifting/ Co-Milling)
Capsule Filling
Screen Type & Screen Size Mill Type (cone mill)
Mill Speed
Powder PSD Powder Flow ability Powder Bulk Density
Blend Assay Blend Uniformity
Blend BD/TD Blend Compressibility
Filing speed (RPM/SPM) Feed Frame paddle speed
Feeder Fill depth Taping Force
Filling principle (Dosator/Tamping)
Hopper Design & Fill level Total Run Time
Appearance, Dimensions, Weight variation
(individual/composite), Hardness, Friability,
Assay, Content Uniformity Impurities- Related
Substances(RS) Disintegration Time,
Dissolution (% Drug Release)
Critical Processing Parameters
Critical Attributes of Input Materials
Manufacturing Process Steps
Quality Attributes of Output Materials
Drug PSD & Flow ability Excipient PSD & Flow ability
Excipient BD TD Excipient Moisture Content
Excipient lot to lot variability
Lubrication Blender Type & Fill Level
Order of Addition Rotation speed & Time Number of Revolution
Drum to hopper transfer
Blend Assay & Uniformity Blend BD/TD
Blend Compressibility
Fluid Bed Mixing, Fluid Bed Granulation &
Fluid Bed Drying
Inlet air Volume, Inlet Air temperature, Spray Rate per nozzle,
Nozzle diameter and numbers, Atomization air pressure,,
Capacity utilized, Filter type & shake interval/duration
Powder PSD Powder Flow ability Powder Bulk Density
Granule PSD Granule Flow ability
Granule LOD
Sizing (Milling / Sifting)
Mill type Blade configuration orientation
Oscillation degree / speed Screen type/ Screen size
Number of recycles
Granule PSD Granule Flow ability
Granule Assay
Granule PSD & Flow ability Granule Assay
Lubricant/ Glidant specific surface area Anti-adherant PSD
Granule4 PSD Granule Flow ability
Granule LOD
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
RISK ASSESSMENT
RISK EVALUATION
RISK ANALYSIS
RISK IDENTIFICATION
Identification of Factors involved in
Fluid Bed Granulation Process Map
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
MILLING SCREEN SIZE
BLENDER SPEED-RPM INLET AIR VOLUME/ FLOW
INLET AIR TEMPERATURE
RAW MATERIAL
DILUENT PSD & WATER
BINDER TYPE & CONC.
GLIDANT CONC.
GELATIN: WATER RATIO.
SOLUTION SPRAYING RATE
COATING PAN SPEED
SOLUTION CONC/ VISCOSITY
LIQUID ADDITION RATE
ATOMIZATION AIR PRESSURE
INLET AIR TEMPERATURE
FLUIDIZATION AIR VELOCITY
API PSD & WATER CONTENT
TAMPING FORCE
DOSING DISK SPEED
TEMPERATURE
RELATIVE HUMIDITY
ENCAPSULATION
SIZING & BLENDING
DEDUSTING &
POLISHING
ENVIRONMENT
PRINCIPLE OF MILLING
BLENDING TIME
DOSING DISK SIZE
GELATIN: GLYCERINE RATIO.
GELATIN: TYPE & CONC.
COLOR SOURCE & CONC.
PRESERVATIVE TYPE & CONC.
FILLING PRINCIPLE (DOSATOR/ TAMPING)
BD/TD/ FLOW OF MATERIAL
MOISTURE OF GELATIN SHELL
MILLING SPEED
PRINCIPLE OF BLENDING
RISK ASSESSMENT
RISK EVALUATION
RISK ANALYSIS
RISK IDENTIFICATION
Identification of Risk Factors by
Ishikawa Fishbone Diagram
© Created & Copyrighted by Shivang Chaudhary
FLUID BED GRANULATION
PRODUCT TEMPERATURE
OUTLET AIR TEMPERATURE
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 Solid state
/Polymorph Particle Size Distribution
Flow Properties
Hygro- Scopicity
Moisture content
Residual Solvent
Solubility Process
Impurity Chemical Stability
Physical High Low Low High Low Low Low Low Low Assay Low Low Low Low Low Low Low High High
Uniformity Low High High Low Low Low Low Low Low Impurities Low Medium Low High Medium Medium Low High High Dissolution High* High* Low Low Low Low High* 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.
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of Active Pharmaceutical Ingredient’s (API) Attributes
© Created & Copyrighted by Shivang Chaudhary
© 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
Property 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
Flow Properties
Poor flow Poor blend uniformity in simple dry mixing process= uncertainty in uniformity of dosage units due to possible segregation = Quality may got compromised
4 4 3 48
Hygroscopicity High water content
Rate of degradation may be affected = Impurity profile may be affected = Safety may got compromised
3 4 2 36
Moisture content High water content
Rate of degradation may get affected >> Impurity profile may get affected >> SAFETY of the product may get compromised
3 4 2 36
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 3 18
Chemical Property
Solubility Different Salt/ Form
Dissolution of the drug product may get affected >> BIOAVAILABILITY-EFFICACY may got 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
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.
RISK IDENTIFICATION
RISK ASSESSMENT
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Active Pharmaceutical Ingredient’s (API) 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
C
B
A SOLID STATE FORM
FLOW PROPERTY
PARTICLE SIZE
D HYGROSCOPICITY
E MOISTURE CONTENT
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Active Pharmaceutical Ingredient’s (API) Attributes Required to be Optimized &/Or Controlled
CMAs of
API
© 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
FP CQAs Gelatin Plasticizers Water Preservative Colorant Opacifier Physical High High High Low High High
Assay Low Low Low Low Low Low Uniformity Low Low Low Low Low Low Impurities High Medium High Medium Low Low Dissolution High High High 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.
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of
Shell-Inactive Ingredients’ (Excipients’) Attributes
© 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
Excipient (Inactive ingredient)
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)
Gelatin
Bloom or Gel Strength
Lower than optimum< 150g
Low cohesive strength of cross linking of shell >> PHYSICAL STABILITY may get affected >> Patient Acceptance may get compromised
4 4 2 32
Viscosity of Gelatin Solution
Higher than Optimum <25mp
Capsule shell may get brittle & hard >> Disintegration/Dissolution of the shell may get affected >> Bioavailability-EFFICACY may get compromised
4 4 2 32
Moisture Content
Less than optimum
Capsule shell may get BRITTLE & HARD >> Physical Properties of Shell may get altered >> Disintegration/Dissolution of the shell may get affected >> Bioavailability-EFFICACY may get compromised
4 4 3 48
Higher than optimum
LEVEL OF IMPURITIES of the Hygroscopic/ Moisture sensitive product may get increased >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
3 4 3 36
Plasticizers
Ratio of Dry Plasticizer to Dry Gelatin (0.4/1, 0.6/1.0, 0.8/1.0)
Less than optimum
Capsule shell may get BRITTLE & HARD >> Physical Properties of Shell may get altered >> Disintegration/Dissolution of the shell may get affected >> Bioavailability-EFFICACY may get compromised
4 4 3 48
Higher than optimum
LEVEL OF IMPURITIES of the product may get increased >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
3 3 3 27
Water Ratio of Water to Dry Gelatin (0.7, 1.0, 1.3)
Less than optimum
Capsule shell may get BRITTLE & HARD >> Physical Properties of Shell may get altered >> Disintegration/Dissolution of the shell may get affected >> Bioavailability-EFFICACY may get compromised
4 4 3 48
Higher than optimum
LEVEL OF IMPURITIES of the Hygroscopic/ Moisture sensitive product may get increased >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
3 4 3 36
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
2 3 4 24
Anti-Oxidant Concentration of Anti-Oxidant
Less than optimum
LEVEL OF OXIDIZED IMPURITIES of the product may get increased >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised
2 3 3 18
Colorant Concentration of Colorant
Lower than optimal
Shade variation/ Mottling may be observed >> Patient ACCEPTNCE/ COMPLIANCE nay get compromised 3 3 2 18
Fe >15 ppm Probability of impurity formation with FD&C Certified Dyes get increased due to REDOX Potential of Iron Itself >> Safety may got compromised
3 3 3 27
Opacifier Concentration of Opacifier
Lower than optimal
Shine variation/ Mottling may be observed >> Patient ACCEPTNCE/ COMPLIANCE nay get compromised 3 3 2 18
Higher than optimum
Safety may got compromised 2 3 3 18
RISK ASSESSMENT
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Shell-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
C
B
A BLOOM/GEL STRENGTH
MOISTURE CONTENT
VISCOSITY OF GELATIN
D GLYCERINE: DRY GELATIN
E WATER : DRY GELATIN
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Shell-Inactive Ingredients’ (Excipients’) Attributes Required to be Optimized &/Or Controlled
CMAs of
SHELL EXCIPIENTS
© 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
FP CQAs Diluent Binder Granulating
Agent Disintegrant
Wetting Agent
Glidant Anti-
adherant Lubricant
Physical Low Low Low Low Low Low High High Assay Medium Low Low Low Low Low Low Low
Uniformity High Low Low Low Low High Low Low Impurities Medium Low Low Low Medium Medium Low Low Dissolution Low High High High High Low High High
Risk Based MATRIX ANALYSIS for CMAs of
INACTIVE FILL MATERIAL
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.
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of
Fill-Inactive Ingredients’ (Excipients’) Attributes
© 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
Excipient (Inactive ingredient)
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)
Diluent/ Filler
Particle Size Distribution
Not Optimum Flow properties of the blend may be affected (in dry mixing process) >> Uniformity of dosage units may be affected >> Safety may got compromised
3 4 3 36
Moisture Content High Impurity profile may be affected (in case of moisture sensitive drugs) >> Safety may got compromised
3 4 3 36
Amount of Binder
More than optimum
Produces hard granules/pellets >> Greater disintegration time & retarded dissolution >> Efficacy may got compromised
3 3 3 27
Binder/ Granulating agent Less than
optimum
Flow properties of the blend may be affected (in dry mixing process)>> Uniformity of dosage units may be affected >> Safety may got compromised
3 3 3 27
Disintegrant Amount of Disintegrant
Less than optimum
Desired disintegration-Dissolution cannot be achieved (in case of immediate release product) >> Efficacy may got compromised
3 3 3 27
Wetting Agent/ surfactant
Amount of Surfactant
Less than optimum
Desired Dissolution cannot be achieved in case of hydrophobic drugs >> Efficacy may got compromised
3 3 3 27
Glidant Concentration of Glidant
Less than optimum
Flow of granules or powder from hopper to die by reducing friction between particles may be affected >> Uniformity of dosage units may affected >> Quality may got compromised
4 4 2 32
Anti-adherant Concentration of Anti-adherant
Less than optimum
Ejection of finished product from tooling may be difficult= Material get stuck to the surface of filling die >> STICKING may be observed = patient acceptance/ compliance may got compromised
4 4 2 32
Higher than Optimum
Hydrophobic anti-adherant may surface coat the drug particle >> DISSOLUTION may got retarded = Efficacy may got compromised
4 4 2 32
RISK ASSESSMENT
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Fill-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
C
B
A DILUENT PSD
GLIDANT CONC.
DILUENT MOISTURE
D ANTI-ADHERANT CONC.
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Fill-Inactive Ingredients’ (Excipients’) Attributes Required to be Optimized &/Or Controlled
CMAs of
FILL EXCIPIENTS
© Created & Copyrighted by Shivang Chaudhary
HARD GELATIN CAPSULE SHELL PREPARATION (MOLD PIN DIPPING TECHNIQUE)
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 Loading of Empty
Capsule Shell Separation of Cap
from Body
Filling of Capsules by Tamping/
Dosator
Locking of Capsules
Cleaning/ DE dusting
Polishing & brushing
Description Low Low High High High High Assay Low Low Low Low Low Low
Impurities Low Low Low Low High Low Uniformity Low Low High Low Low Low Dissolution Low Low High High Low Low
HARD GELATIN CAPSULE FILLING (ENCAPSULATION PROCESS)
FP CQAs Co-sifting Blending Lubrication Description Low Low High
Assay Medium High Low Impurities Low Low Low Uniformity Medium High Low Dissolution Low Low High
DRY MIXING BLENDING- LUBRICATION FOR FILL MATERIAL PREPARATION
FP CQAs Dipping Spinning Drying Striping Trimming Joining Description Low Low High Medium High Low
Assay Low Low Low Low Low Low Impurities Low Low High Low Low Low Uniformity Low Low Low Low Low Low Dissolution Medium High Low Low Low Low
RISK ASSESSMENT
RISK EVALUATION
RISK IDENTIFICATION
RISK ANALYSIS
Qualitative Risk based Matrix Analysis of Processing Parameters
© 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
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)
FILL MATERIAL PREPARATION (DRY MIXING-BLENDING)
Screening Co-Sifting Larger Sieve size
Uneven PSD = Uncertainty in CONTENT Uniformity >> SAFETY may get compromised
2 3 3 18
Fluid Bed Granulation
Spraying rate Higher Agglomerates may be produced >> Dissolution profiling may get affected >> BA-EFFICACY may get compromised
3 4 4 48 Atomizing pressure Lower 3 3 4 36
Fluidization velocity Higher Fines may get produced >> Chances of Segregation >> CU may get affected >> SAFETY may get compromised 3 3 4 36
Dry Mixing Blending Rate (No of RPM * Time)
Low RPM & Low Time
Lesser No. of total Revolutions >> Uncertainty in Uniformity >> SAFETY may get compromised
3 3 4 36
Lubrication Blending Rate (No of RPM *Time)
High RPM & High Time
Dissolution profiling may get retarded >> BIOAVAILABILITY/ EFFICACY may get compromised
3 3 4 36
SHELL MATERIAL PREPARATION (MOLD PIN DIPPING TECHNIQUE)
Dipping & Spinning
Rotation Speed Not Optimum Appearance (Gelatin Shell Thickness Uniformity), Disintegration - Dissolution profiling may get affected >> EFFICACY & Patient ACCEPTANCE may get affected
3 3 3 27
Drying
Inlet Temperature of Heating & Cooling Air
Lower than Optimum
Moisture content in shell may be higher & DEFORM >> PHYSICAL & CHEMICAL STABILITY may get affected
3 3 4 36
Higher than optimum
Capsule Shell may get BRITTLE & HARD >> Disintegration-Dissolution may get retarded >> BIO AVAILABILITY-EFFICACY may get compromised
3 3 4 36
Stripping & Trimming
Striping Force Higher than optimum
Chances of Shell damage during striping by jaws >> Patient ACCEPTANCE may get compromised
2 3 3 18
Trimming Length Higher than optimum
Disintegration time & pattern may get affected >> BIO AVAILABILITY-EFFICACY may get compromised
2 3 3 18
Joining of Cap from Body
Pressing Force Higher than optimum
Chances of Shell damage by tamping pins >> Patient ACCEPTANCE may get compromised
2 3 2 12
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.
RISK IDENTIFICATION
RISK ASSESSMENT
RISK ANALYSIS
RISK EVALUATION
Quantitative Failure Mode Effect Analysis (FMEA) of Processing Parameters
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
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)
HARD GELATIN CAPSULE FILLING PROCESS (ENCAPSULATION)
Loading & Separation
Vacuum pressure in separation of cap-body
Higher than optimum
PINHOLES & CRACKS occurs when the dome of the capsule body fractures due to excessive vacuum during separation.
2 3 2 12
Filling of Capsules (Encapsulation)
Filling Principle
DOSATOR & Piston System
Not Suitable for powder having low BD & TD (COHESIVE BULK POWDERS)
3 3 3 27
TAMPING & Dosing Disc
Not suitable for material having high BD & TD (FREE FLOWING GRANULES / PELLETS)
3 3 3 27
Dosing Disk Size Incorrect Hardness of PLUG, Weight Variation may get affected >> Disintegration/ Dissolution & Uniformity may get affected >> SAFETY &EFFICACY may get compromised
3 3 4 36
Feeder / Dosing Disk Speed
Higher than optimum Appearance (CRACKS), Weight Variation may be observed >> Uniformity of dosage units may get affected >> SAFETY & EFFICACY may get compromised
3 4 4 48
Tamping Force Higher than optimum
Appearance (BENT) , Hardness of Slug / PLUG may get affected >> Disintegration/ Dissolution may get affected >> BIOAVAILABILITY/ EFFICACY may get compromised
3 4 4 48
Locking of Capsules
Body Joining Pins Incorrect setting Physical LOCKING LENGTH may get affected >> DENTS/ TELESCOPE/ SPILT may be observed portion >> Patient ACCEPTANCE may get compromised
3 3 3 27 Pin Size/ Configuration
Incorrect
Bushings Misalignment
Cleaning & Polishing
Spraying Rate Higher than optimum Physical Appearance (Foreign particles/ dirt) may get
affected >> Patient ACCEPTANCE may get compromised 3 3 3 27
Rotational Speed Lower than optimum
Environmental Factors
Temperature Higher (>25°C) Impurity profiling may get affected >> CHEMICAL STABILITY may get compromised >> SAFETY may get compromised
3 4 4 48
Relative Humidity Higher (>40%RH) 3 4 4 48
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.
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
C
B
A SPRAYING RATE
FLUIDIZATION VELOCITY
ATOMIZATION PRESSURE
A
B BLENDING TIME
BLENDING SPEED
A GLIDANT CONCENTRATION
B ANTI ADHERANT CONC.
C FILLING RATE
RISK IDENTIFICATION
RISK ANALYSIS
RISK EVALUATION
RISK ASSESSMENT
CRITICAL
Processing Parameters Required to be Optimized &/Or Controlled
CPPs of
FLUID BED GRANULATION CPPs of
DRY MIXING-LUBRICATION
CPPs of
HARD GELATIN ENCAPSULATION
© 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
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
FLUID BED GRANULATION (Contd…)
Optimization of CPPs of
FLUID BED TOP SPRAY GRANULATION PROCESS
RISKS
LOWER HARDNESS INADEQUATE DISINTEGRATION
QUALITY COMPROMISED EFFICACY COMPROMISED
HIGH FRIABILITY INADEQUATE DISSOLUTION
SOFT GRANULES HARD GRANULES
HIGHER %FINES HIGHER %AGGLOMERATES
C
B
A BINDER SPRAYING RATE
FLUIDIZATION AIR VELOCITY
ATOMIZATION AIR PRESSURE
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
DoE For
FLUID BED GRANULATION(Contd…)
© Created & Copyrighted by Shivang Chaudhary
Factors (Variables) Levels of Factors studied -α -1 0 +1 +α
A Binder Spraying Rate (gm/min) 1.64gm/min 3 gm/min 5 gm/min 7 gm/min 8.36gm/min B Atomization Pressure (bar) 0.32bar 1 bar 2 bar 3 bar 3.68bar C Fluidization Air Velocity (cfm) 32.96cfm 50 cfm 75 cfm 100 cfm 117.04cfm
NO. OF FACTORS
NO. OF LEVELS
EXPERIMENTAL DESIGN SELECTED
ADD. CENTER POINTS
TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
3
5
CIRCUMSCRIBED CENTRAL COMPOSITE RSM for 3 factors
5
8 fp +6 sp +6 cp =20
OBJECTIVE To Optimize CPPs of Fluid Bed Granulation Process
A BINDER SPRAYING RATE
C
FLU
IDIZ
ATI
ON
AIR
VE
LOC
ITY
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
FLUID BED GRANULATION(Contd…)
CQAs CPPs
PREDICTION EFFECT EQUATION OF EACH FACTOR BY QUADRATIC MODEL
Agglomerates (%w/w) = +2.21+1.61A-0.34B-0.20C-0.16AB-0.14AC +0.038BC+0.65A2 +0.14B2+0.082C2
Fines (%w/w) = +2.00-0.25A+1.78B+0.35C-0.012AB+0.013AC+0.16BC+0.22A2+0.59B2+0.22C2
%Process Efficiency (%) = +97.18+1.76A+0.52B-5.83C+0.50AB+0.50AC-0.50BC-1.92A2-1.39B2-3.69C2
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
FLUID BED GRANULATION(Contd…)
Factors (Variables) Knowledge Space Design Space Control Space A Spraying Rate (gm/min) 3-7 3.50-5.50 4.00-5.00 B Atomization Pressure (bar) 1-3 1.25-2.25 1.50-2.00 C Fluidization Air Velocity (cfm) 50-100 55-75 60-70
Responses (Effects) Goal for Individual Responses Y1 Agglomerates (%w/w) Agglomerates should NMT 2.5%w/w Y2 Fines (%w/w) Fines should NMT 2.5%w/w Y3 Process Efficiency (%) To achieve the maximum process efficiency (%yield) NLT 95%w/w
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
Optimization of CPPs of
DRY MIXING- BLENDING PROCESS
RISKS
INAPPROPRIATE BLENDING SPEED &/OR TIME
BLEND UNIFORMITY COMPROMISED
CONTENT UNIFORMITY COMPROMISED
BLENDING SPEED 1
2 BLENDING TIME
DoE For
DRY MIXING- BLENDING (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
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
Factors (Variables) Levels of Factors studied 0 1 2
A Blending Speed (in RPM) 8 10 12 B Blending Time (in minutes) 5 10 15
NO. OF FACTORS
NO. OF LEVELS
EXPERIMENTAL DESIGN SELECTED
TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)
2
3
32 FULL FACTORIAL DESIGN
Lf = 32 FP = 9
To Optimize Critical Processing Parameters of Dry Mixing Process OBJECTIVE
A BLENDING SPEED
B
BLE
ND
ING
TIM
E
“High”
“Medium”
“Low”
• In Dry Mixing Process, 2 Processing Parameters were critical & required to be optimized
• Moreover, It was required to investigate interactive & quadratic relationship between factors & response to find out optimum ranges
• Thus, 3 Level FFD is a time & cost effective best option for optimization of 2 factors.
• However 3 Level FFD facilitates investigation of interactive & quadratic relationship of factors & response in the terms of multiplied 2FI & squared main effects in the quadratic model equation
DoE For
DRY MIXING- BLENDING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
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
CPPs CQAs
Prediction Effect Equation On Individual Response by QUADRATIC MODEL
Average Assay of Blend Uniformity =+99.61 +0.78A+2.32B-0.95AB-1.52A2-2.22B2
RSD Of Blend Uniformity=+1.94-0.47A-1.45B+0.53AB+1.13A2+1.98B2
DoE For
DRY MIXING- BLENDING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
DESIGN OF EXPERIMMENTS
ANALYSIS OF RESPONSES
DEVELOPMENT OF DESIGN SPACE
Factors (Variables) Knowledge Space Design Space Control Space A Blending Speed (RPM) 8.0-12.0 9.15-11.35 9.5-11.0 B Blending Time (minutes) 5.0-15.0 10.0-13.5 10.0-12.0
Responses (Effects) Goals for Individual Responses Y1 Avg. Assay of BU (%) To achieve average assay of BU in the range from 98 to 102%
Y2 RSD of BU(%) To achieve minimum variability in BU i.e. NMT2.0%
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 individual goals
DoE For
DRY MIXING- BLENDING (Contd…)
DEVELOPMENT OF DESIGN SPACE
ANALYSIS OF RESPONSES
DESIGN OF EXPERIMMENTS
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
IDENTIFICATION OF CMAs/CPPs
© Created & Copyrighted by Shivang Chaudhary
DoE For
HARD GELATIN CAPSULE ENCAPSULATION (Contd…)
Optimization of CMAs & CPPs of
HARD GELATIN CAPSULE ENCAPSULATION PROCESS
INADEQUATE DISINTEGRATION
QUALITY COMPROMISED EFFICACY COMPROMISED SAFETY COMPROMISED
RISKS
WEIGHT VARIATION & CONTENT NON UNIFORMITY
INAPPROPRIATE FLOW PROPERTY & FILLING RATE
INADEQUATE DISSOLUTION
A GLIDANT
B ANTIADHERANT
C FILLING RATE
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
HARD GELATIN CAPSULE ENCAPSULATION (Contd…)
Factors (Variables) Levels of Factors Studied -1 0 +1
A Glidant (%w/w) 0.10%w/w 0.25%w/w 0.40%w/w B Lubricant (%w/w) 0.50%w/w 1.25%w/w 2.00%w/w C Filling Rate (SPM) 50SPM 65SPM 80SPM
NO. OF FACTORS
NO. OF LEVELS
EXPERIMENTAL DESIGN SELECTED
TOTAL NO OF EXPERIMENTAL RUNS (TRIALS) $
3
3
BOX BEHNKEN DESIGN
12MP + 3CP =15
To Optimize CMAs & CPPs of Hard Gelatin Capsule Encapsulation. OBJECTIVE
A GLIDANT
C
FIL
LIN
G R
ATE
“High”
Medium
“Low”
• In Hard Gelatin Encapsulation, 2 different CMAs & 1 CPP required to be optimized. Due to 3 factors, more no. of runs were required for optimization in the case of CCD.
• Moreover, Here Region of Interest & Region of Operability was nearly the same
• Thus, BBD is an economic alternative to CCD for optimization of 3 factors simultaneously at 3 levels providing strong coefficient estimates near the center of design space, where presumed optimum with nearly same region of interest & region of operability.
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
HARD GELATIN CAPSULE ENCAPSULATION (Contd…)
PREDICTION EFFECT EQUATION OF EACH FACTOR BY QUADRATIC MODEL
Weight Variation =+1.53-0.21A-0.11B+0.37C-0.025AC-0.025BC+0.28A2+0.18B2+0.91C2
Content Uniformity=+3.03-0.35A-0.16B+0.74C-0.025AB-0.075AC+0.61A2+0.43B2+1.83C2
Disintegration Time =+3.23-0.21A+0.82B-0.16C-0.17AB-0.050AC-0.075BC+0.66A2+1.03B2+0.058C2
CMAs CPP
%Drug Dissolved in 30 minutes =+95.67+2.00A-4.25B+1.50C+1.00AB-0.50AC+0.50BC-4.58A2-7.08B2-0.083C2
CQAs
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
HARD GELATIN CAPSULE ENCAPSULATION (Contd…)
Factors (Variables) Knowledge Space Design Space Control Space A Glidant (%) 0.10-0.50 0.18-0.36 0.20-0.30 B Anti-adheant (%) 0.50-2.00 0.70-1.30 0.80-1.20 C Filling Rate (SPM) 50-80 58-72 60-70
Responses (Effects) Goal for Individual Responses Y1 Weight Variation Relative Standard Deviation in WV test should NMT 2.0% Y2 Content Uniformity Acceptance Value in CU test should NMT 4.0 Y3 Disintegration To achieve complete disintegration (no residue) within 5 minutes Y Dissolution To achieve at least 95% drug release within 30 minutes
© 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
PAT For
HARD GELATIN CAPSULE MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
EMPTY CAPSULE
SHELL ELEVATOR
AUTOMATIC CAPSULE
SHELL CONVEYING
SYSTEM
INLINE WEIGH
CHECKING SYSTEM
INLINE METAL
DETECTOR SYSTEM
MINI CAPSULE
SORTER
EMPTY CAPSULE
ELIMINATOR by
VACCUM
FILLING STATION
BY TAMPING /
DOSATOR SYSTEM
BIN BLENDER
FOR PRODUCT
MIXING
AUTOMATIC
PRODUCT
ELEVATOR SYSTEM
CAPSULE ORIENTS &
CAP/ BODY SEPARATES
BY VACUUM SYSTEM
CAPSULE READY
FOR PACKING
DEDUSTING &
POLISHING
SYSTEM
AUTOMATIC
PRODUCT
CONVEYING SYSTEM
AUTOMATIC
CAPSULE FILLING
MACHINE
AIR DISPLACEMENT
UNIT
DRY MIXING
SEPARATION OF CAP FROM BODY
LOADING OF EMPTY CAPSULES
FILLING OF CAPSULES
DE DUSTING
CLOSING OF CAPSULES
CLEANING & POLISHING
A B C D E F G
CRITICAL PROCESSING STEPS
SORTING
H
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Risk Analysis of CMAs & CPPs with respect to CQAs at Raw Scale Developmental level by ON LINE / AT LINE Analyzers for Prediction of Real Time Data &
Designing of Control Strategies at Commercial Scale
CONTROLLING PHASE
ANALYZING PHASE
IDENTIFICATION OF CRITICAL STEPs
DESIGNING PHASE
TEMPERATURE &
RELATIVE HUMIDITY
by At Line Thermo-
hygrometer
API / EXCIPIENT PURITY
analyzed by
At line UV/ HPLC/ GC,
On line LOD/ HMB or W/KF
API / EXCIPIENT PARTICLE
SIZE DISTRIBUTION
analyzed by At line Malvern
Particle Size Analyzer
OR On Line
Sieve Shaker Analysis
BLENDING &
LUBRICATION
Blend Uniformity
analyzed by At line
UV/HPLC system
CAPSULE FILLING
On Line Weight Variation &
Disintegration Testing
ONLINE METAL
DETECTOR SYSTEM
ONLINE VISUAL INSPECTION
FOR DEDUSTING, POLISHING
& SORTING OF UNFILLED/
DEFECTIVE CAPSULES
ONLINE GROUP
WEIGHT
CHECKING of
Filled Capsules
CAPSULE READY
FOR PACKING
ONLINE GROUP
WEIGHT
CHECKING of
Empty Capsules
MOISTURE CONTENT of
EMPTY CAPSULE SHELLS by
On line Halogen Moisture
Balance or At line
Water by KF
PAT For
HARD GELATIN CAPSULE MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CRITICAL STEPs
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Real Time Data Analysis at Scale UP-Exhibit Manufacturing Scale by IN LINE analyzers with auto-sensors & Real time data comparison with Raw scale data
for Finalization of Control Strategies at Commercial Scale
CONTROLLING PHASE
DESIGNING PHASE
ANALYZING PHASE
WEIGHT VARIATION
of Filled Capsules
by In line
Check Weigher
based on Gravimetric
EMFR System
INLINE METAL
DETECTOR SYSTEM
IN LINE MINI
CAPSULE
SORTER
IN LINE
EMPTY CAPSULE
ELIMINATOR by
VACCUM
TEMPERATURE &
RELATIVE HUMIDITY
by In Line Thermo-
hygrometer
IN LINE
DEDUSTING &
POLISHING
SYSTEM
API / EXCIPIENT PURITY
analyzed by In line
Bruker FT NIR
API / EXCIPIENT PARTICLE
SIZE DISTRIBUTION
by In Line Lasentec
Focused Beam Reflectance
Measurement (FBRM)
CONTENT UNIFORMITY
analyzed by In Line Bruker FT-NIR BLEND UNIFORMITY
analyzed by In line
Bruker FT-NIR
WEIGHT VARIATION
of Empty Capsules
Shells by In line
Check Weigher
based on Gravimetric
EMFR System
MOISTURE CONTENT
OF EMPTY CAPSULE SHELLS
by Inline Bruker/ MT
FT_NIR System
CAPSULE READY
FOR PACKING
PAT For
HARD GELATIN CAPSULE MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
IDENTIFICATION OF CRITICAL STEPs
DESIGNING PHASE
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Application of Auto-controllers at real time Manufacturing scale For Continuously attaining Acceptable ranges of CMAs & CPPs with respect to desired CQAs
A DEVELOPED PAT SYSTEM FOR CONTINUOS AUTOMATIC ANALYSING & CONTROLLING MANUFACTURING THROUGH TIMELY MEASUREMENTS OF CQA & CPPs WITH THE ULTIMATE GOAL OF CONSISTANTLY ENSURING FINISHED PRODUCT QUALITY AT REAL TIME COMMERCIAL SCALE
ANALYZING PHASE
CONTROLLING PHASE
INLINE WEIGHT
CHECKING SYSTEM
auto controlling
Turret Speed of
Filled Capsules
IN LINE MINI
CAPSULE
SORTER
IN LINE EMPTY
CAPSULE
ELIMINATOR
by VACCUM
CAPSULE READY
FOR PACKING
Auto-controlling of
TEMPERATURE &
RELATIVE HUMIDITY
Air Handling Unit
(AHU)
IN LINE
DEDUSTING &
POLISHING
SYSTEM
Auto controlling of
BLEND UNIFORMITY
by adjusting
Rotation Speed *
Rotation Time =
Number of Revolutions
Auto-controlling of
FILLED CAPSULE WEIGHT &
PLUG HARDNESS by adjusting
Filing Turret Speed,
Feed Frame Paddle speed
Tamping Force, Dosator
Piston Stroke Volume
INLINE METAL
DETECTOR SYSTEM
Auto controlling
ON/OFF System of
Machine
Auto Controlling of
EMPTY CAPSULE
SHELL WEIGHT by
adjusting Feeder
Speed for Empty
Capsule shells
PAT For
HARD GELATIN CAPSULE MANUFACTURING (Contd…)
© Created & Copyrighted by Shivang Chaudhary
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
Control Strategy A planned set of controls for CMAs & CPPs- derived from current product and process understanding • During Lab Scale Developmental Stage • Scaled Up Exhibit-Submission Stage that ensures process performance and product quality • During Commercial Stage
Note: For finalizing & implementation of Control Strategy for each & individual CMAs &/or CPPs; ranges studied at lab scale developmental stage will be compared with pilot plant scale up & pivotal scale exhibit batches to ensure consistent quality of finished product
What is Control Strategy?
© Created & Copyrighted by Shivang Chaudhary
CONTROL OF CPPs
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
FACTOR(s) CMAs Ranges studied at
LAB scale Actual data
for EXHIBIT batches Proposed range for
COMMERCIAL batch PURPOSE of Control
API- Critical Material Attributes Polymorphic
Form 2Ө values x, y, z x, y, z x, y, z
To ensure batch to batch consistency in Dissolution
Particle Size Distribution
(PSD)
D10: NMT x um NMT x um NMT x um To ensure batch to batch consistency in Blend Uniformity (BU), Content Uniformity (CU) & Dissolution
D50: NMT y um NMT y um NMT y um
D90: NMT z um NMT z um NMT z um
Density or Flow Property
Bulk Density (BD) & Tapped Density (TD)
BD: NLT 0.35gm/cc TD: NLT 0.45gm/cc
BD: NLT 0.40gm/cc TD: NLT 0.50gm/cc
BD: NLT 0.40gm/cc TD: NLT 0.50gm/cc
To ensure batch to batch consistency good Flow Property in order to ensure BU & CU.
Water Moisture Content NMT 3%w/w NMT 2.5%w/w NMT 2%w/w To prevent physical or chemical reaction of API with capsule shell.
FILL-EXCIPIENT Critical Material Attributes
Microcrystalline Cellulose
(Avicel PH 200)
Particle Size Distribution 60#: ≥ 10%w/w 100#: ≥ 50%w/w
60#: ≥ 10%w/w 100#: ≥ 50%w/w
60#: ≥ 10%w/w 100#: ≥ 50%w/w
To ensure batch to batch consistency in BU & CU during dry mixing for wet granulation Moisture Content NMT 5.0% NMT 3.0% NMT 2.0%
Polyvinylpyrolidone (Pladone
K 29/32)
Level in Formulation 4-10%w/w 7.5%w/w 6-8%w/w To give consistent binding functionality to granules to warrant hardness & friability
K Value 29-32 29-32 29-32
Colloidal Silicone Dioxide
(Aerosil 200 Pharma)
Concentration (%w/w) 0.10-0.50 0.18-0.36 0.20-0.30 To promote consistent flow property of granules from hopper to die.
Specific surface area 175-225 m2/g 180-220 m2/g 185-215 m2/g
Purified Talc (Vegetable
Grade)
Concentration (%w/w) 0.50-2.00 0.70-1.30 0.80-1.20 To ensure consistent lubrication & smooth ejection of compressed tablet from die.
Specific surface area 10-20 m2/g 10-20 m2/g 10-20 m2/g
CONTROL OF CMAs
CONTROL STRATEGY For
Critical Material Attributes
© Created & Copyrighted by Shivang Chaudhary
CONTROL OF CPPs
Implementatn of
Control Strategy
PAT &Development
of Feedback Control system
DoE & Development of Design Space
Quality Risk Assessment of
CMAs & CPPs
Determination of CQAs
Definition of QTPP
FACTOR(s) CMAs Ranges studied at
LAB scale Actual data
for EXHIBIT batches Proposed range for
COMMERCIAL batch PURPOSE of Control
SHELL-EXCIPIENT Critical Material Attributes
GELATIN as a base
Type of Gelatin Type A (Acid bone) Type A (Acid bone) Type A (Acid bone)
To ensure batch to batch consistency in Cohesive strength of Cross linking that occurs between gelatin molecules in empty gelatin shell in order to ensure physical strength
pH 3.8–5.5 4.0–5.0 4.0-5.0
Isoelectric point 6.0-9.5 7.0-9.0 7.0-9.0
Bloom or Gel Strength (weight in gms required to move a plastic plunger i.e. 0.5 inches in diameter 4 mm into 62/3% gelatin gel that has been held at 10°C for 17 hours)
150-250 gm 170-240 gm 180-230 gm
Concentration (%w/w) 35-45% 36-44% 38-42%
Viscosity of 62/3% Gelatin Solution at 60°C
2.7-3.7 mPa 2.7-3.2 mPa 2.7-3.0 mPa
To ensure batch to batch consistency of Molecular Chain length for Mfg. consistency
Moisture Content 10-15%w/w 12-15%w/w 12-15%w/w To prevent physical or chemical reaction of API with empty capsule shell
Glycerin as a PLASTICIZER
Dry Glycerine to Dry Gelatin Ratio
0.25-0.55 0.30-0.50 0.35-0.45 To prevent softening (tacky) or hardening (brittleness) of shell retarded dissolution & handling problems during processing/ packaging
WATER as solvent
Water to Dry Gelatin Ratio
0.70-1.30 0.90-1.10 0.90-1.10
Concentration (%w/w) 30-50% 35-45% 38-42%
IRON Iron Content in raw gelatin
NMT 15 ppm NMT 12 ppm NMT 10ppm
To prevent chemical reaction with certain FD&C dyes & organic compound
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
FILL MATERIAL PREPARATION (DRY MIXING-BLENDING)
Co-Sifting Screen Mesh # Size 30# (NMT 5% ≥ 600um
30# (NMT 3% ≥ 600um
30# (NMT 1% ≥ 600um
To ensure PSD consistency to prevent segregation
Fluid Bed GRANULATION
Inlet Air Temperature 25-40°C 28-37°C 30-35°C To ensure batch to batch consistency in PSD, BD & TD in order to warrant Uniform Flow property, BU, CU & Desired Dissolution
Binder Spraying Rate 3-7 gm/min 3.50-5.50 gm/min 4.0-5.0 gm/min Atomization Pressure 1-3 bar 1.25-2.25 bar 1.50-2.00 bar Fluidization Velocity 50-100 cfm 55-75 cfm 60-70 cfm Fill Level (%v/v) 30-70% 40-60% 45-55%
Blending & Lubrication
Blending Speed 8.0-12.0 RPM 9.5-11.5 RPM 9.5-11.0 RPM To ensure batch to batch consistency in Blend Uniformity & Dissolution
Blending Time 5.0-15.0 Min 11.0 Min 10.0-12.0 Min
Fill Level (%v/v) 30-70% 40-60% 45-55% SHELL MATERIAL PREPARATION (MOLD PIN DIPPING TECHNIQUE)
SPINNING Rotation Speed X-Y RPM (X+3) – (Y-3) RPM (X+5) – (Y-5) RPM To prevent softening (tacky) or hardening (brittleness) of shell & handling problems .
DRYING Inlet Air Temperature 20°-30°C 23°-28°C 23°C-28°C
HARD GELATIN CAPSULE FILLING PROCESS (ENCAPSULATION)
Hard Gelatin Capsule FILLING
& LOCKING
Filling Principle TAMPING & Dosing Disc
TAMPING & Dosing Disc
TAMPING & Dosing Disc
To ensure batch to batch consistency in Weight variation in order to ensure Content Uniformity without any crack
Dosing Disk Size Size “1” Size “1” Size “1”
Filling Rate 50-80 58-72 60-70 Turret Speed 10-40 RPM 10-30 RPM 15-25 RPM
Tamping Force 0.5-3.0 kN 1.0-2.0 kN 1.0-1.5 kN
To ensure batch to batch consistency in Hardness of plug & Dissolution in order to Dissolution without any defects (Bent/ Dents/ Telescope/ Spilt )
De-dusting & POLISHING
Liquid Spraying Rate X-Y gm/min X++
-Y++
gm/min X++
-Y++
gm/min To ensure batch to batch consistency in Appearance Pan Rotation Speed 3-10 RPM 3-8 RPM 4-7RPM
ENVIRONMENTAL Factors
Temperature 21°C-25°C 21°C-25°C 21°C-25°C To ensure batch to batch Physical & Chemical Stability
Relative Humidity <40%RH <30 %RH <30 %RH
CONTROL OF CMAs
CONTROL OF CPPs
CONTROL STRATEGY For
Critical Processing Parameters
© Created & Copyrighted by Shivang Chaudhary
Conclusion
Detectability of Risk was increased by implementation of automatic inline
Process Analytical Technology (PAT)
RPN = Severity * Probability * Detectability
Severity of Risks could Not be reduced
Through QbD, Risk associated with each & every CMAs & CPPs with respect to CQAs identified from QTPP were effectively & extensively assessed
out by FMEA (Failure Mode Effective Analysis), which decided “which risk should get first priority?” based upon Severity * Probability * Detectability of individual risk.
Probability of Risk occurrence was reduced by systematic series of experiments through
Designing of Experiments (DoE)
which ensured timely measurement of critical quality and performance attributes of raw and
in-process materials or parameters to control the quality of finished product.
which generated safe & optimized ranges of CMAs & CPPs with respect to desired CQAs par overlaid DESIGN SPACE, where all the desired
in process & finished product CQAs are met simultaneously.
Justification for
Risk Reduction
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”