Quality by Design - QbD Model for "Tablets" © by Shivang Chaudhary

QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION OF COMPRESSED SOLID ORAL DOSAGE FORM-TABLETs

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

Designed & Developed by

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

mailto:[email protected]


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Aim

• Stable & Therapeutic Equivalent (Pharmaceutical Equivalent + Bioequivalent) IR Generic Tablet 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


Quality Risk Assessment of CMAs & CPPs


PAT & Development of Feedback Controls

Implementation of Control Strategy



iNSIDES

Targeting

Bullets

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


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




CMAs & CPPs


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



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

QUALITY TARGET PRODUCT PROFILE (QTPP) A Prospective Summary of • the quality characteristics of a drug product • that IDEALLY will be achieved to ensure the desired quality,

• taking into account Safety & Efficacy of the drug product. Note: QTPP will be finalized - • On the basis of Therapeutic Equivalence for Pharmaceutical Abbreviated New Drug Application (ANDA- Generics)=

Pharmaceutical Equivalence (same dosage form, route of administration, strength & same quality) + Bio-Equivalence (same pharmacokinetics in terms of Cmax, AUC;

• On the basis of Therapeutic Safety & Efficacy for Pharmaceutical New Chemical Entities (NCE-Innovator) / New Drug Applications (NDA-Novel Drug Delivery Systems as compared to already approved & available conventional dosage forms)

What is QTPP?

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Pharmaco-KINETICS

Fasting Study and/or Fed BE Study 90 % confidence interval of the PK parameters, AUC0-t, ,

AUC0-∞ and Cmax, should fall within bioequivalence limits of 80-125 with reference product

Bioequivalence requirement needed

to meet required rate & extent of drug absorption

EASE OF STORAGE & DISTRIBUTION

Can be stored at real time storage condition as a normal practice with desired stability & can be distributed

from the manufacturer to end user same as per Reference Product.

Required to handle the product easily with suitable accessibility

STABILITY & SHELF LIFE Should be stable against hydrolysis, oxidation, photo degradation & microbial growth. At least 24-month

shelf-life is required at room temperature

Equivalent to or better than Reference Product shelf-life

PATIENT ACCEPTANCE & PATIENT COMPLIANCE

Should be suitably flavored & colored for possessing acceptable taste ( in case of soluble/ dispersible/

effervescent tablet) similar with Reference Product. Can be easily administered/used similar with

Reference Product labeling

Required to achieve the desired patient acceptability & suitable compliance

QTPP Element Target Justification

Dosage FORM Tablets Pharmaceutical equivalence requirement:

same dosage form

Dosage DESIGN Immediate Release / Modified Release

Formulation with/ without Coating 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 Tablets



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Critical Quality Attribute (CQA) A CQA is a • Physical, • Chemical, • Biological, or • Microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. Note: CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) & Finished drug product. On the basis of Quality [Assay, Uniformity of Dosage units, Redispersibility, Reconstitution time, Aerodynamic property], Safety [Impurities (Related substances), Residual Solvents, Osmolarity & Isotonicity, Microbiological limits, Sterility & Particulate matter], Efficacy [Diffusion, Dissolution & Permeation] & Multidisciplinary [Patient Acceptance & Compliance].

What is CQA?

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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 Score Configuration Similar to

reference product Yes*

To ensure PATIENT COMPLIANCE for half dosing & for comparable EASE OF SPLITTING

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 Tablets

EFFICACY SAFETY QUALITY MULTI DISCIPLINARY



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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?

SCREENING

DRY MIXING

COMPRESSION

Screen Type & Size Mill Type (cone mill)

Mill Speed

Blender Type & Fill level Order of Addition

Rotation speed & Time Number of Revolutions

Powder PSD Powder Flow ability Powder Bulk Density

Blend Assay Blend Uniformity

Blend BD/TD Blend Flow ability

Blend Compressibility

Powder PSD & Flow ability Powder Bulk Density


Filing speed (RPM/SPM) Feed Frame paddle speed

Feeder Fill depth Pre Compression Force

Main Compression Force Hopper Design & Run Time

Appearance, Dimensions, Weight variation,

Hardness, Friability, Assay, Impurities, CU

Disintegration, Dissolution

Processing Parameters

Input Materials’ Attributes

Manufacturing Process Steps

Quality Attributes of Output Materials

Drug PSD & Flow ability Excipient PSD & Flow ability Excipient BD TD Moisture

Excipient lot to lot variability

LUBRICATION Blender Type & Fill level

Order of Addition Rotation Speed & Time Number of Revolution

WET GRANULATION Impeller/ Chopper Speed Powder Dry Mixing time

Granulation Kneading time Solution Addition/ Spraying rate

Granulation Fluid Quantity


Granule PSD Granule Flow ability

DRYING Inlet air volume Inlet air temperature

Capacity utilized Filter type/ shake interval

Granule LOD Granule PSD

SIZING Mill type

Blade type/ orientation/ Oscillation degree / speed Screen type/ Screen size

Number of recycles


Granule Assay Granule Uniformity


Granule LOD Granule PSD

Granule PSD & Flow ability Granule Assay & Uniformity

Flow promoters PSD & Specific Surface area

Blend Assay, Blend Uniformity

Blend BD/TD & Flow ability Blend Compressibility

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

RISK ASSESSMENT

RISK EVALUATION

RISK ANALYSIS

RISK IDENTIFICATION

Identification of Factors involved in

High Shear Wet Granulation Process Map

Environment (Temperature & RH)

COATING

Spraying Rate, Atomization Pressure, No. of Guns, Nozzle

Diameter, Gun to Bed Distance, % Load, Coating Pan Speed,

Inlet Air Temperature

Appearance, Dimensions, Weight variation, Hardness, Friability, Assay, Impurities,

Content Uniformity, Disintegration, Dissolution

Appearance, Dimensions, Weight variation (individual/composite), Hardness, Friability, Assay, Impurities, CU

Disintegration ,Dissolution

RISK ASSESSMENT

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

RISK EVALUATION

RISK ANALYSIS

RISK IDENTIFICATION

Identification of Risk Factors by

Ishikawa Fishbone Diagram


MILLING SCREEN SIZE

BLENDER SPEED-RPM ATOMIZATION PRESSURE

INLET AIR TEMPERATURE

RAW MATERIAL

DILUENT PSD & WATER

BINDER TYPE & CONC.

DISINTEGRANT CONC.

LUBRICANT CONC.

SOLUTION SPRAYING RATE

COATING PAN SPEED

SOLUTION CONC/ VISCOSITY

GRANULATION & DRYING

LIQUID ADDITION RATE

ATOMIZATION AIR PRESSURE

INLET AIR TEMPERATURE

FLUIDIZATION AIR VELOCITY

IMPELLER/ MIXER SPEED

API PARTICLE SIZE

COMPRESSION FORCE

PRESS TURRET SPEED

FEEDER FILL DEPTH TEMPERATURE

RELATIVE HUMIDITY

COMPRESSION/ ENCAPSULATION

CHOPPER/GRANULATOR SPEED

TURRET & FEEDER SPEED

SIZING & BLENDING COATING

ENVIRONMENT

TOTAL GRANULATION TIME

MILLING SPEED

BLENDING TIME

BD/TD/ FLOW OF MATERIAL

TYPE OF TOOLING

FLOW PROMOTER CONC.

PRINCIPLE OF MILLING

PRINCIPLE OF BLENDING

API WATER CONTENT

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FP CQAs Solid state

/Polymorph Particle size

Flow Properties

Moisture content

Residual Solvent

Solubility Process

Impurity Chemical Stability

Physical High Low Low Low Low Low Low Low Assay Low Low Low Low Low Low High High

Uniformity Low High High Low Low Low Low Low Impurities Low Medium Low Medium Medium Low High High Dissolution High* High* 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


RISK IDENTIFICATION

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Physico- Chemical Property of Actives

Critical Material Attribute (CMAs)

Failure Mode (Critical Event)

Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode)

P S D RPN (=P*S*D)

Physical Property

Solid Sate Form

Different Polymorph/ form

Solubility of drug substance may get affected= >> Dissolution of drug product may get affected >> BIOAVAILABILITY-EFFICACY may get compromised

2 4 4 32

Particle Size Distribution (PSD)

Higher PSD BCS Class II/IV Low Solubility drug >> Dissolution of drug product may get affected >> BIOAVAILABILITY/EFFICACY may get compromised

4 4 3 48

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

Moisture content High water content

Rate of degradation may get affected >> Impurity profile may get affected >> SAFETY of the product may get compromised

2 3 2 12

Residual Solvents High residual solvent

Residual solvents are likely to interact with drug substance >> Impurities profile may get affected >> SAFETY may get compromised

2 3 2 12

Chemical Property

Solubility Different Salt/ Form

Dissolution of the drug product may get affected >> BIOAVAILABILITY-EFFICACY may got compromised

2 3 4 24

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 ASSESSMENT

RISK ANALYSIS

RISK EVALUATION

Quantitative Failure Mode Effect Analysis (FMEA) of Active Pharmaceutical Ingredient’s (API) Attributes


Probability of Risk can be Reduced through

DoE Optimization

Detectability of Risk can be increased through In Line PAT System

RISK IDENTIFICATION

RISK ANALYSIS

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

C

B

A SOLID STATE FORM

FLOW PROPERTY

PARTICLE SIZE

RISK EVALUATION

RISK ASSESSMENT

CMAs of

API


CRITICAL

Active Pharmaceutical Ingredient’s (API) Attributes Required to be Optimized &/Or Controlled

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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

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

Inactive Ingredients’ (Excipients’) Attributes


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Excipient (Inactive ingredient)

Critical Material Attribute (CMAs)



S P D RPN (=S*P*D)

Diluent

Particle Size Distribution

Uneven Flow properties of the blend may be affected (in dry mixing process) >> Uniformity of dosage units may be affected >> Quality/ Safety may got compromised

3 3 2 18

Moisture Content High Impurity profile may be affected (in case of moisture sensitive drugs) = Safety may got compromised

3 3 2 18

Amount of Binder

More than optimum

Produces hard granules= Produces tablet / capsule with greater disintegration time & retarded dissolution= Efficacy may got compromised

4 4 2 32 Binder/ Granulating agent Less than

optimum

Loose granules will be formed, which may produce friable Tablet = Patient acceptance/ Patient compliance got compromised

4 4 2 32

Disintegrant Amount of Disintegrant

Less than optimum

Desired Dissolution cannot be achieved (in case of immediate release product) = Efficacy may got compromised

4 4 2 32

Surfactant as a Wetting Agent

Amount of Surfactant

Less than optimum

Desired Dissolution cannot be achieved in case of hydrophobic drugs = Efficacy may got compromised

4 4 3 48

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

3 3 2 18

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

3 3 2 18

Lubricant Concentration of Lubricant

Less than optimum

Material get stuck to the surface of punches/toolings >> PICKING may be observed >> Patient acceptance/ compliance may got compromised

3 3 2 18

Higher than Optimum

Hydrophobic lubricant may surface coat the drug particle >> Dissolution may got retarded = Efficacy may got compromised

3 3 3 27

Coloring/ Flavor/ Sweetener agent

Concentration

Lower than optimal

Shade variation/ Mottling may be observed = Patient compliance may got compromised

3 3 1 9

Higher than optimum

Safety may got compromised 3 3 3 27

RISK ASSESSMENT

RISK IDENTIFICATION

RISK ANALYSIS

RISK EVALUATION

Quantitative Failure Mode Effect Analysis (FMEA) of Inactive Ingredients’ (Excipients’) Attributes


RISK IDENTIFICATION

RISK ANALYSIS

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

C

B

A BINDER (%w/w)

SURFACTANT (%w/w)

DISINTEGRANT (%w/w)

RISK EVALUATION

RISK ASSESSMENT

CMAs of

EXCIPIENTS


CRITICAL

Inactive Ingredients’ (Excipients’) Attributes Required to be Optimized &/Or Controlled


HIGH SHEAR WET GRANULATION

ROLLER COMPACTION DRY GRANULATION

FLUID BED GRANULATION

DRY MIXING-DIRECT COMPRESSION

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FP CQAs Co-sifting Blending Roller

Compaction Sizing

Blending & Lubrication

Compression Film Coating

Description Low Low Low High High High High Assay Medium High Low Medium High Low Low

Impurities Low Low Low Low Low Low Medium Uniformity Medium High Low Medium High High Low Dissolution Low Low High Low High High High

FP CQAs Co-sifting Blending Rapid Mixing Granulation

Fluid Bed Drying

Sizing Blending & Lubrication


Description Low Low Low Low High High High High Assay Medium High Medium Low Medium High Low Low

Impurities Low Low Low High Low Low Low Medium Uniformity Medium High Medium Low Medium High High Low Dissolution Low Low High Low Low High High High

FP CQAs Co-sifting Fluid Bed

Granulation Sizing

Blending & Lubrication


Description Low Low High High High High Assay Medium High Medium High Low Low

Impurities Low High Low Low Low Medium Uniformity Medium High Medium High High Low Dissolution Low High Low High High High

FP CQAs Co-sifting Blending Lubrication Compression Film Coating Description Low Low High High High

Assay Medium High Low Low Low Impurities Low Low Low Low Medium Uniformity Medium High Low High Low Dissolution Low Low High High High

RISK ASSESSMENT

RISK EVALUATION

RISK IDENTIFICATION

RISK ANALYSIS

Qualitative Risk based Matrix Analysis of Tablet Manufacturing Processes

RISK IDENTIFICATION

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Unit Operations

Critical Process Parameter (CPPs)



P S D RPN

(=P*S*D)

Screening Sifting Larger Sieve size.

Uneven Particle Size Distribution>> Uncertainty in Uniformity >> SAFETY may get compromised

2 3 3 18

Granulation in Rapid Mixer Granulator

Dry Mixing Rate (No of RPM *Time)

Lower RPM & Shorter Time

Lesser No. of total Revolutions >> Uncertainty in Uniformity >> SAFETY may get compromised

2 3 3 18

Rate of Impeller / Mixer

High RPM & Longer Time Produce Larger granules (forms

agglomerate/lumps)>> Dissolution of Tablet / Capsule can be increased >> BIOAVAILABILITY-EFFICACY may get compromised

4 4 3 48

Rate of Chopper/ Granulator

Low RPM & Shorter Time

4 4 3 48

Binder-Granulating agent spraying rate

High RPM 4 4 3 48

Drying in Fluid Bed Drier

Inlet Temperature

Lower than optimum

Physical Appearance may get affected >> STICKING/ PICKING may be observed >> Patient ACCEPTANCE may get compromised

3 3 2 18

High Product Temperature

Rate of degradation & Impurity profile may be affected >> SAFETY may get compromised

3 3 3 27

Fluidizing Air Flow rate

Higher CFM Increased attrition & evaporation produces fines >> Process EFFICIENCY may get compromised

3 3 2 18

Sizing (Milling & Screening)

Comil Speed Increase Speed Fines may be generated >> Poor flow leads to uncertainty in uniformity of dosage units

3 3 3 27

Comil Screen Larger # Size Uneven PSD leads to uncertainty in Uniformity Larger granules >> Dissolution may be increased >> EFFICACY may get compromised

3 3 3 27

Dry Mixing (Blending) & Lubrication

Blending Rate (No of RPM *Time)

High RPM & High Time

Dissolution may get retarded >> EFFICACY may get compromised

3 3 4 36

Compression / Filling

Turret/ Feeder Speed

High Speed Appearance (LAMINATION), WEIGHT VARIATION may be observed= Uniformity of dosage units may get affected >> SAFETY & EFFICACY may get affected

4 4 3 48

Compression Force /Tamping force

High Force Appearance (CAPPING), HARDNESs of Tablet/ Slug may get affected >> Disintegration/ Dissolution may get affected >> EFFICACY may get compromised

4 4 3 48

Film Coating

Spraying rate Higher Rate Physical Appearance may get affected >> STICKING/ PICKING may be observed >> Patient ACCEPTANCE may get compromised

3 4 3 36 Atomizing Pressure Lower pressure 3 4 3 36 Pan Speed Very Low 3 4 3 36

Bed Temperature

Lower 3 4 3 36

High Temp.

Physical Appearance (BLISTERING/ WRINKLING/ BRIDGING/ ORANGE PEEL DEFECTS), Impurity profile may get affected >> Patient ACCEPTANCE & SAFETY may get compromised

3 3 3 27

RISK ASSESSMENT

RISK ANALYSIS

RISK EVALUATION

Quantitative Failure Mode Effect Analysis (FMEA) of Processing Parameters


RISK IDENTIFICATION

RISK ANALYSIS

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

BINDER

DISINTEGRANT

KNEADING TIME C

B

A A

B BLENDING TIME

COMPRESSION FORCE

TURRET SPEED B

A

BLENDING SPEED

CMAs & CPPs of

WET GRANULATION CPPs of

DRY MIXING- BLENDING

CPPs of

TABLET COMPRESSION

RISK EVALUATION

RISK ASSESSMENT


CRITICAL

Processing Parameters Required to be Optimized &/Or Controlled

EXPOSURE TIME B

DRYING TEMPERATURE A

CPPs of

FLUID BED DRYING


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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




CMAs & CPPs


Definition of QTPP

IDENTIFICATION OF CMAs/CPPs

RISKS

LOWER HARDNESS INADEQUATE DISINTEGRATION

QUALITY COMPROMISED EFFICACY COMPROMISED

HIGH FRIABILITY INADEQUATE DISSOLUTION

SOFT GRANULES HARD GRANULES

BINDER

DISINTEGRANT

KNEADING TIME C

B

A

Optimization of CMAs & CPPs OF

HIGH SHEAR WET GRANULATION PROCESS

DoE For

WET GRANULATION (Contd…)


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





“High”

“Medium”

“Low”

C

NO. OF LEVELS

A BINDER

KN

EA

DIN

G T

IME

NO. OF FACTORS EXPERIMENTAL DESIGN SELECTED

TOTAL NO OF EXPERIMENTAL RUNS (TRIALS)

3

3

Face Centered CENTRAL COMPOSITE DESIGN

2f fp+ (2*f)sp + cp = (22 )+ (2*3) + (6) = 8+6+6 = 20

To Optimize CMAs & CPPs of HIGH SHEAR WET GRANULATION OBJECTIVE

• in wet granulation process binder, disintegrant & kneading time are 3 most critical parameters which are required to be optimized with respect to hardness, friability, disintegration & dissolution.

• Here, all three factors conveniently have only three levels with very narrow nearly same Region of Operability & Region of Interest.

• Thus, Face Centered central composite design with practical alpha value of ±1 has been selected for optimization of all three factors simultaneously having only three levels & nearly the same region of interest & region of operability with little co linearity, cuboidal rather than spherical., & missing data.

Factors (Variables) Levels of Factors Studied -α = -1 0 +α = +1

A Binder (%w/w) 4% 7% 10% B Disintegrant (%w/w) 1% 3% 5% C Kneading Time (min) 2 min 4 min 6 min

DoE For




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP




DoE For



CQAs CMAs CPP

PREDICTION EFFECT EQUATION OF EACH FACTOR BY QUADRATIC MODEL

HARDNESS =+75.16+25.00A-2.40B+8.00C-1.00AB-2.25AC-1.25BC-4.91A2+0.091B2-0.91C2

FRIABILITY=+0.11-0.071A+6.000E-003B-0.025C +0.000AB+ 7.500E-003AC+0.000BC+0.024A2-1.364E-003B2+3.636E-003C2

DISINTEGRATION TIME=+8.21+2.30A-2.90B+1.00C-0.62AB+0.13AC-0.37BC-0.27A2+3.73B2+0.23C2

DRUG DISSOLVED=+94.83-7.90A+3.70B-4.70C+ 0.88AB+2.38AC+0.38BC-6.82A2-1.82B2-3.82C2

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For



Responses (Effects) Goal for Individual Responses Y1 Hardness (n) To achieve tablet hardness in the range from 65 to 85N Y2 Friability (%) To achieve minimum friability i.e. NMT 0.15% Y3 Disintegration (min) To achieve tablet DT within 10 minutes Y4 Dissolution (%) To achieve maximum dissolution in 30 minutes i.e. NLT 90%

Factors (Variables) Knowledge Space Design Space Control Space A Binder (%) 4.00-10.00 5.75-7.75 6.00-7..50 B Disintegrant (%) 1.00-5.00 2.50-5.00 3.00-4.00 c Kneading Time (min) 2.00-6.00 2.50-5.50 2.50-4.50




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


DoE For

FLUID BED DRYING (Contd…)


INADEQUATE EXPOSURE HIGH TEMPERATURE

SAFETY COMPROMISED

MICROBIAL LOAD INPROCESS IMPURITIES

EXPOSURE TIME B

Optimization of CPPs of

FLUID BED DRYING PROCESS

DRYING TEMPERATURE A

RISKS

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


Factors (Variables) Levels of Factors studied 0 1 2

A Drying Temperature 0.70 1.00 1.30 B Exposure Time 0.30 1.05 1.80

NO. OF FACTORS

NO. OF LEVELS

EXPERIMENTAL DESIGN SELECTED

ADD. CENTER POINTS

TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)

2

3

32 FULL FACTORIAL DESIGN

0

32 FP =9

OBJECTIVE To Optimize Critical Processing Parameters of Fluid Bed Drying of HGC/Tablets.

A DRYING TEMPERATURE

B

EX

PO

SUR

E T

IME


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For


CQA CPPs

PREDICTION EFFECT EQUATION OF EACH FACTOR BY QUADRATIC MODEL

Loss on Drying =+1.12-0.32A-0.40B+0.000AB+0.22A2+0.17B2

Impurities=+1.42+0.28A+0.47B+1.000E-002AB +0.14A2+0.26B2

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


Factors (Variables) Knowledge Space Design Space Control Space A Drying TEMPERATURE (C) 40.0-80.0 45.0-75.0 50.0-70.0 B Drying TIME (minutes) 30.0-90.0 35.0-70.0 40.0-60.0

Responses (Effects) Goals for Individual Responses Y1 LOD (%) To achieve loss on drying NMT 1.5%

Y2 Impurities(%) To achieve minimum in process impurities i.e. NMT 1.5%

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




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP



DRY MIXING- BLENDING PROCESS

RISKS

INAPPROPRIATE BLENDING SPEED &/OR TIME

BLEND UNIFORMITY COMPROMISED

CONTENT UNIFORMITY COMPROMISED

BLENDING SPEED A

B BLENDING TIME

DoE For

DRY MIXING- BLENDING (Contd…)


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





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


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




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP




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



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





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






Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP



TABLET COMPRESSION PROCESS

LOWER HARDNESS INADEQUATE DISINTEGRATION

QUALITY COMPROMISED EFFICACY COMPROMISED

WEIGHT VARIATION

SAFETY COMPROMISED

HIGH FRIABILITY INADEQUATE DISSOLUTION CONTENT NONUNIFORMITY

RISKS

COMPRESSION FORCE

TURRET SPEED B

A

DoE For

TABLET COMPRESSION (Contd…)


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





Factors (Variables) Levels of Factors studied -α -1 0 +1 +α

A COMPRESSION FORCE (kN) 1.17 2.00 4.00 6.00 6.83 B TURRET SPEED (RPM) 3.79 10.00 25.00 40.00 46.21

NO. OF FACTORS

NO. OF LEVELS


TOTAL NO OF EXPERIMENTAL RUNS (TRIALS)

2

5

circumscribed CENTRAL COMPOSITE DESIGN (cCCD)

2fp + 2sp + cp = (22 )+ (2*2) + (5) = 4+4+5 = 13

To Optimize Critical Processing Parameters of Tablet Compression Process OBJECTIVE

A

B

• In Tablet Compression, 2 Processing Parameters were critical & required to be optimized

• Moreover, the region of operability should be greater than region of interest to achieve the maximum rate of productivity to get maximum daily output at commercial manufacturing scale

• Thus, 5 Level cCCD is a time & cost effective best alternative to 3 Level FFD for optimization.

• However in 5 level cCCD, region of operability was greater than region of interest to accommodate additional star points to study extreme levels (highest & lowest) of both factors.

“Highest”

“High”

“Medium”

“Low”

“Lowest”

TUR

RE

T SP

EE

D

COMPRESSON FORCE

DoE For




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP




CPPs

Prediction Effect Equation On Individual Response by QUADRATIC MODEL

CQAs

FRIABILITY =+0.15 -0.066A +0.026B

-7.500E-003AB +0.028A2

+0.021B2

DRUG DISSOLVED IN 30 MIN =+97.20 -8.37A +0.16B -1.75AB -5.73A2

-1.48B2

CONTENT UNIFORMITY =+4.15 -0.088A +1.45B

-0.08AB +0.13A2

+0.73B2

DoE For



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP




Factors (Variables) Knowledge Space Design Space Control Space A Compression Force (kn) 2.0-6.0 3.0-5.0 3.5-4.5 B Turret Speed (RPM) 10-40 10-30 15-25

Responses (Effects) Goal for Individual Responses Y1 Friability To achieve tablet friability NMT 0.2%w/w Y2 Dissolution Drug release should NLT 90% in 30 minutes Y3 Content uniformity Acceptance Value should in CU test should NMT 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 individual goals

DoE For





Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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




CMAs & CPPs


Definition of QTPP

CONTROLLING PHASE

ANALYZING PHASE

DESIGNING PHASE

IDENTIFICATION OF CRITICAL STEPs

SIFTING DRYING GRANULATION SIZING COMPRESSION BLENDING COATING

SIFTER FOR

DELUMPING

RAPID MIXER

GRANULATOR FLUID BED

DRYER

BIN

BLENDER

COMPRESSION

MACHINE

COATING

MACHINE SIFTER CUM

MULTI MILL

A B C D E F G

CRITICAL PROCESSING STEPS

PAT For

TABLET MANUFACTURING (Contd…)



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

SIFTER FOR

DELUMPING

RAPID MIXER


DRYER

BIN

BLENDER

COMPRESSION

MACHINE

COATING

MACHINE

TEMPERATURE &

RELATIVE HUMIDITY

At Line

Thermo-hygrometer

GRANULE SIZE DISTRIBUTION

At line Malvern

Particle Size Analyzer OR

On line Sieve Shaker Analysis,

BD-TD Apparatus &

Reposiography

API / EXCIPIENT PURITY

At line UV/ HPLC/ GC,

On line LOD/ HMB or W/KF

API / EXCIPIENT PARTICLE

SIZE DISTRIBUTION

At line Malvern Particle

Size Analyzer OR On Line

Sieve Shaker Analysis

RESIDUAL MOISTURE

CONTENT

On Line LOD

Halogen Moisture Balance or

At Line Water by KF/ GC

BLEND UNIFORMITY

At line UV/HPLC

system; LUBRICATION

analyzed by on line BD-

TD & Reposiography

COMPRESSION

On Line

Weight variation,

Hardness, Friability &

Disintegration Test

Content Uniformity &

Dissolution profiling

analyzed by At line

UV/ HPLC systems

COATING

On Line

Weight variation,

Disintegration test,

CU & Dissolution profiling

by At Line UV/ HPLC;

Color shade variation by

At line Raman Pectrometer

PARTICLE SIZE

DISTRIBUTION

At Line Malvern PSA or

On Line Sieve Shaking

SIFTER CUM

MULTI MILL

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


DESIGNING PHASE

PAT For




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

TEMPERATURE &

RELATIVE HUMIDITY

In Line

Thermo-hygrometer


In Line Lasentec FBRM (Focused

Beam Reflectance Measurement)

or

PVM (Particle Video Monitoring)

&

AES (Acoustic Emission

Spectroscopy)

API / EXCIPIENT PURITY

In Line FT-NIR

API / EXCIPIENT PARTICLE

SIZE DISTRIBUTION

In line FBRM

RESIDUAL MOISTURE

CONTENT

In Line Bruker FT-NIR

BLEND UNIFORMITY

In Line FT-NIR

COMPRESSION

In Line Compression Force

Sensor with Servo motor for

Automatic control of

Weight/ Hardness &

Content Uniformity by

In Line FT-NIR

COATING

Color measurement by In

Line UV-Visible spectro

Shade Variation by

In Line Raman Spectro;

Coating Integrity/

thickness by In Line

Terahertz spectroscopy

PARTICLE SIZE

DISTRIBUTION

In Line FBRM

Real Time Data Analysis at Scale UP-Exhibit Manufacturing Scale by IN LINE analyzers with auto-sensors & Real time data comparison with Raw scale data

for Finalization of Control Strategies at Commercial Scale

CONTROLLING PHASE

DESIGNING PHASE

ANALYZING PHASE

PAT For


SIFTER FOR

DELUMPING

RAPID MIXER


DRYER

BIN

BLENDER

COMPRESSION

MACHINE

COATING

MACHINE SIFTER CUM

MULTI MILL



DESIGNING PHASE

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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

Auto controlling of


by adjusting

Impeller Speed

Chopper Speed

Granulation time

Solution spraying rate

Auto controlling of

RESIDUAL MOISTURE CONTENT

by adjusting Inlet air volume

Inlet air temperature

Auto controlling of

BLEND UNIFORMITY

by adjusting

Rotation speed *

Rotation Time =

Number of Revolutions

Auto-controlling of

TABLET WEIGHT &

HARDNESS by Adjusting

Filing Turret speed,

Feed Frame paddle speed

Feeder Fill depth

Pre Compression Force

Main Compression Force

Auto-controlling of

%WEIGHT GAIN/

COATING INTEGRITY

By adjusting

Spray rate per nozzle,

Atomization air pressure,

Pan Rotation Speed,

Inlet air temperature

Auto controlling of

PARTICLE SIZE DISTRIBUTION

by adjusting Milling Speed &

Number of recycles

Auto-controlling of

TEMPERATURE &

RELATIVE HUMIDITY

Air Handling Unit

(AHU)

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

PAT For


SIFTER FOR

DELUMPING

RAPID MIXER


DRYER

BIN

BLENDER

COMPRESSION

MACHINE

COATING

MACHINE SIFTER CUM

MULTI MILL


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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 Thus, the control strategy is an integrated overview of how quality is assured based on current process and product knowledge.

What is Control Strategy?


CONTROL OF CPPs

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FACTOR(s) CMAs Ranges studied at

LAB scale Actual data

for EXHIBIT batches Proposed range for

COMMERCIAL batch PURPOSE of Control

Active Pharmaceutical Ingredient (API) Critical Material Attributes Polymorphic

Form 2Ө values x, y, z x, y, z x, y, z

To ensure batch to batch consistency in Dissolution

Particle Size Distribution

(PSD)

D10: NMT x um NMT x um NMT x um To ensure batch to batch consistency in Blend Uniformity (BU), Content Uniformity (CU) & Dissolution

D50: NMT y um NMT y um NMT y um

D90: NMT z um NMT z um NMT z um

EXCIPIENT Critical Material Attributes

Microcrystalline Cellulose

(Avicel PH 102)

Particle Size Distribution D10: NMT 100 um D50: NMT 100 um D90:NMT 100 um To ensure batch to batch consistency in BU & CU during dry mixing for wet granulation

Moisture Content NMT 5.0% NMT 5.0% NMT 5.0%

Crospovidone (Polyplasdone

XL 10)

Level in Formulation 1-5%w/w 3.5%w/w 3-4%w/w To ensure batch to batch consistency in disintegration & dissolution

Specific surface area 1.2-1.4 m2/g 1.2-1.4 m2/g 1.2-1.4 m2/g

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)

Level in Formulation 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

Magnesium Stearate

(Vegetable Grade)

Level in Formulation 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


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FACTOR(s) CPPs Ranges studied at

LAB scale Actual data

for EXHIBIT batches Proposed range for

COMMERCIAL batch PURPOSE of Control

Co-Sifting Screen Mesh # Size 30# 30# 30# To ensure PSD consistency to prevent segregation

High Shear Wet GRANULATION

Pre-mixing time 10-20 min 12-18 min 13-17 min To ensure batch to batch consistency Particle Size Distribution (PSD), Bulk Density (BD) & Tapped Density (TD) in order to warrant Uniform Flow property & Disintegration of Granules

Binder addition rate 1.0-2.0 min 1.0-2.0 min 1.5-2.0 min

Rate of Wet Mass Kneading & Granulation

2-6 min (Impeller Speed: (50-100 RPM; Chopper Speed: 1500 RPM)

3.5 min (Impeller Speed: 60-90 RPM; Chopper Speed: 1500 rpm)

2.5-4.5 min (Impeller Speed: 70-80 RPM; Chopper Speed: 1500 RPM)

Fill Level (%v/v) 30-70% 40-60% 45-55%

Fluid Bed DRYING

Inlet Air Temperature 40.0-80.0 45.0-75.0 50.0-70.0 To ensure Low Water content in granules in order to prevent In Process impurity, Microbial growth & Compression defects (Sticking/ Picking)

Total Drying Time 30.0-90.0 35.0-70.0 40.0-60.0 Fluidization Air Velocity 50-100 CFM 55-85 CFM 60-80 CFM

Water Content 0.5-5.0% 1.5-3.0% 1.5-3.0%

Fill Level (%v/v) 30-70% 40-60% 45-55%

Milling/ SIZING

Milling Speed 800-1200 rpm 900-1100 rpm 950-1050 rpm To ensure consistency in PSD of granules Mill Screen Size 1-2 mm 1.5 mm 1.5 mm

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%

Tablet COMPRESSION

Compression Force 2.0-6.0 kN 3.0-5.0 kN 3.5-4.5 kN To ensure batch to batch consistency in Hardness, Weight variation & Disintegration in order to ensure Friability, CU & Dissolution without any Compression defects (Capping/ Lamination)

Feeder Speed 2.5-10 RPM 2.5-7.5 RPM 3.5-6.5 RPM

Turret Speed 10-40 RPM 10-30 RPM 15-25 RPM

Film COATING

Liquid Spraying Rate X-Y gm/min X++

-Y++

gm/min X++

-Y++

gm/min To ensure batch to batch consistency in Physical Appearance, Weight variation & Disintegration

Atomization Pressure 1-4 bar 2-4 bar 2.5-3.5 bar

Pan Rotation Speed 3-10 RPM 3-8 RPM 4-7RPM

Bed Temperature 40-60°C 40-55°C 45-55°C

CONTROL OF CMAs

CONTROL OF CPPs

CONTROL STRATEGY For

Critical Processing Parameters


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?


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.


© 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]


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Quality by Design - QbD Model for "Tablets" © by Shivang Chaudhary

Healthcare

Transcript of Quality by Design - QbD Model for "Tablets" © by Shivang Chaudhary