Quality by Design - QbD Model for "HARD GELATIN CAPSULE" Dosage Form - Fluid Bed Granulation Process

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

mailto:[email protected]


https://www.facebook.com/QbD.PAT.Pharmaceutical.Development



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


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 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


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

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


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 (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




CMAs & CPPs


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




CMAs & CPPs


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


FLUID BED GRANULATION

PRODUCT TEMPERATURE

OUTLET AIR TEMPERATURE

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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




CMAs & CPPs


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


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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




RISK ASSESSMENT

RISK EVALUATION

RISK IDENTIFICATION

RISK ANALYSIS

Qualitative Risk based Matrix Analysis of

Shell-Inactive Ingredients’ (Excipients’) Attributes



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Excipient (Inactive ingredient)

Critical Material Attribute (CMAs)



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


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


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




CMAs & CPPs


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


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

Risk Based MATRIX ANALYSIS for CMAs of

INACTIVE FILL MATERIAL




RISK ASSESSMENT

RISK EVALUATION

RISK IDENTIFICATION

RISK ANALYSIS

Qualitative Risk based Matrix Analysis of

Fill-Inactive Ingredients’ (Excipients’) Attributes



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Excipient (Inactive ingredient)

Critical Material Attribute (CMAs)



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




CMAs & CPPs


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


HARD GELATIN CAPSULE SHELL PREPARATION (MOLD PIN DIPPING TECHNIQUE)

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Unit Operations

Critical Process Parameter (CPPs)



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



RISK IDENTIFICATION

RISK ASSESSMENT

RISK ANALYSIS

RISK EVALUATION

Quantitative Failure Mode Effect Analysis (FMEA) of Processing Parameters


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Unit Operations

Critical Process Parameter (CPPs)



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



RISK IDENTIFICATION

RISK ASSESSMENT

RISK ANALYSIS

RISK EVALUATION

Quantitative Failure Mode Effect Analysis (FMEA) of Processing Parameters

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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



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


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




CMAs & CPPs


Definition of QTPP





DoE For

FLUID BED GRANULATION(Contd…)


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


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For


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




CMAs & CPPs


Definition of QTPP






DoE For


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




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


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…)



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



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




CMAs & CPPs


Definition of QTPP






DoE For


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


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.


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For


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




CMAs & CPPs


Definition of QTPP






DoE For


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


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

PAT For

HARD GELATIN CAPSULE MANUFACTURING (Contd…)


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


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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


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




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


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




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

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



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

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

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



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


CONTROL OF CPPs

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FACTOR(s) CMAs Ranges studied at




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


Critical Material Attributes


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FACTOR(s) CPPs Ranges studied at




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



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


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 doesn’t costs, it always pays”

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Healthcare

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