quality by design - qbd model for "liquid oral solution"

QUALITY BY DESIGN FOR FORMULATON DEVELOPMENT & PROCESS OPTIMIZATION OF A MONOPHASIC LIQUID ORAL DOSAGE FORM-SOLUTIONS

A MODEL

© Created & Copyrighted by Shivang Chaudhary

Implementatn of

Control Strategy

PAT &Development

of Feedback Control system

DoE & Development of Design Space

Quality Risk Assessment of

CMAs & CPPs

Determination of CQAs

Definition of QTPP

© Copyrighted by Shivang Chaudhary

Formulation Engineer (QbD/PAT System Developer & Implementer) MS (Pharmaceutics)- National Institute of Pharmaceutical Education & Research (NIPER), INDIA

PGD (Patents Law)- National academy of Legal Studies & Research (NALSAR), INDIA

+91 -9904474045, +91-7567297579 [email protected]

https://in.linkedin.com/in/shivangchaudhary

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Designed & Developed by

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Aim

• Stable & Therapeutic Equivalent (Pharmaceutical Equivalent + Bioequivalent) IR Generic Liquid Oral Solution

• Robust & Rugged Reproducible Manufacturing Process

• with a Control Strategy that ensures the quality & performance of the drug product as per Quality by Design

To Develop :

Project

Goal

QbD & Its Elements

Definition of QTPP


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?

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 BE study is not required in Solution as drug is already available in the solution form at the site of absorption

Bioequivalence study is not required to meet required rate & extent of drug absorption

EASE OF STORAGE & DISTRIBUTION

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

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

Required to handle the product easily with suitable accessibility

STABILITY & SHELF LIFE

Should be stable Hydrolysis, Oxidation, Photodegradation & Microbial Growth. At least 12-months shelf-life is required at room temperature. At least 28 Days of in-Use Shelf Life is

required during routine use of multidose product

Equivalent to or better than Reference Product shelf-life

PATIENT ACCEPTANCE & PATIENT COMPLIANCE

Should possess acceptable taste, flavor, odour & attractable pleasant color most probably as similar with Reference Product. Can be easily administered (pourable & palatable)/ used/

applied similarly with Reference Product labelling

Required to achieve the desired patient acceptability & suitable compliance

QTPP Element Target Justification

Dosage FORM Solution Pharmaceutical equivalence requirement:

same dosage form

Dosage DESIGN Immediate Release Formulation Immediate release design needed to meet

label claims

ROUTE of Administration Oral/ External Pharmaceutical equivalence requirement:

same route of administration

Dosage STRENGTH x mg Pharmaceutical equivalence requirement:

same strength

Drug Product

QUALITY ATTRIBUTES

Appearance

Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable reference standards (i.e., identity, assay of drug, assay of preservatives, microbial load, purity & quality)

Assay Content Uniformity Impurities pH of System Microbial Limits Antimicrobial content Antioxidant content Extractables Viscosity/Specific Gravity

PRIMARY & SECONDARY PACKAGING

Container (Glass/Plastic/Metal) & Closure (Plastic/Metal/Rubber) system should be qualified as suitable for drug product with

desired Compatibility & Stability. Should product from heat, moisture, oxygen, carbon dioxide, light & microbial attack.

Plastic should not allow permeation, leaching, sorption, or any other chemical or physical deformation.

Required to achieve the target shelf-life and to ensure product integrity during transportation, storage

& during routine-use

PATIENT’S POINT OF VIEW

PHYSICIAN”s POINT OF VIEW

PHARMACIST’s POINT OF VIEW

Quality Target Product Profile (QTPP) of Solution



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 Quality Attributes of

Drug Product Target

Is this a CQA?

Justification

Physical Appearances

Color, Odor and taste should acceptable to the patient.

Yes Color, Odor & Taste are not directly linked to safety and efficacy. Therefore, they are not critical. But to ensure patient acceptability it should be similar with reference product

Identification Positive for drug as per USP Monograph

of Drug Substance Yes*

Though identification is critical for safety, it can be effectively controlled at drug substance release stage. Formulation and process variables do not impact identity.

Therefore, this CQA will not be discussed during development.

Rheological properties (viscosity /specific gravity)

As per USP <911> for viscosity; conforms to USP <841> for specific gravity

Yes

Viscosity/ Specific gravity of the suspension should be balanced to make it possible to pour easily from container or to apply on the skin or to maintain optimum consistency to hold globules in emulsion to ensure PHYSICAL STABILITY. Formulation variables may have impact on viscosity. Therefore, this CQA will be discussed during formulation development

Assay 90.0 to 110.0 % of labeled claim. Yes Assay variability will affect SAFETY AND EFFICACY. Formulation & Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout development.

Weight Variation/ Content Uniformity

Conforms to USP <905> Uniformity of Dosage Units: 90.0-110.0 % of labeled

claim with Acceptance Value: NMT 15.0; Yes

Variability in content uniformity will affect SAFETY AND EFFICACY. Both formulation and process variables may have impact on weight variation & content uniformity,

so this CQA will be evaluated throughout development.

Antimicrobial preservative content

As per USP <51> & As per In house specification according to

developmental & stability data Yes

Liquid dosage forms are very liable to microbial attack as it contains mostly aqueous vehicle /solvent. Formulation, compounding, packaging variables & environmental factors

may impact on antimicrobial content. Thus to maintain the microbial quality of the product throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus,

this CQA will be discussed throughout formulation & process development.

Antioxidant preservative content

As per In house specification according to developmental & stability data

Yes

Liquid dosage forms are more prone to oxidation. Formulation, Compounding, Packaging Process variables & Environmental factors may impact on antioxidant content. Thus to

maintain the levels of oxidized impurities throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus, this CQA will be discussed throughout development.

pH of System Conforms to USP <791> Yes Formulation & Processing variables may affect the pH of the drug product having

impact on SOLUBILITY & CHEMICAL STABILITY. Thus, pH of the formulation will be evaluated throughout formulation & development .

Impurities / Degradation

Products

As per ICH Q3A& Q3B & USP <1086>

Yes

Degradation products can impact safety and must be controlled based on compendia / ICH requirements or reference product characterization to ensure patient SAFETY.

Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development.

Microbiological Limits

Conforms to USP <61 & 62> Yes

Microbial Load will impact patient SAFETY. Formulation, compounding, packaging variables & environmental factors may impact microbial limits. Thus to

maintain the microbial quality of the product throughout shelf life & proposed in-use shelf life to ensure patient SAFETY. Thus, this CQA will be discussed

throughout formulation & process development.

Extracta/,ble Conforms to USP <660> for glass, <661> for plastic & comparable to

reference product Yes*

Generally, development and stability data should show evidence that extractable from the container/closure systems are consistently below levels that are demonstrated to be

acceptable and safe, elimination of this test can normally be accepted to ensure SAFETY This should be reinvestigated if the container/closure system or formulation changes.

Dissolution As per In house specification according

to developmental & stability data Yes*

For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE Can be waived. Generally, in vivo BE studies are waived for solutions on the assumption

that release of the drug substance from the drug product is self-evident and that the solutions do not contain any excipient that significantly affects drug absorption

Critical Quality Attributes (CQA) of Solution

EFFICACY SAFETY QUALITY MULTI DISCIPLINARY



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?

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK ASSESSMENT

RISK EVALUATION

RISK ANALYSIS

RISK IDENTIFICATION

Identification of Factors involved in

Controlled Solubilization Process Map

Vehicle Preparation & Storage Organoleptic addition

Controlled Solubilization by Surfactants & Hydrocolloid

pH adjustment & Final Volume make up with vehicle & final mixing

Type of purification system (ion exchange/reverse osmosis)

Rate of filtration Heating temperature & time Type & Position of Impeller

Mixing Speed & Time

Order of addition Heating temperature & Time Type & Position of Impeller

Mixing Speed & Mixing Time

Physical Attributes (color, odor, taste) Vehicle purity, Vehicle polarity

Vehicle pH, Vehicle Viscosity/sp. Gravity Vehicle Volatility, Vehicle Microbial content

Physical Attributes (color, flavor. taste), Assay, Impurity, Uniformity of Dosage units,

Viscosity/Rheology, Specific Gravity/Density & Extractable volume of system,

pH & Preservative content of system, Dissolution*, Reconstitution time**,

Dissolved Oxygen of system Microbial content of system

Critical Processing Parameters

Critical Attributes of Input Materials

Manufacturing Process Steps

Quality Attributes of Output Materials

Solvent source, purity, polarity, pH, Viscosity/sp. Gravity, Volatility, Microbial content

Type & Source of color/ flavor/ sweetener (natural/ semisynthetic/ synthetic),

Microbial content of color, flavor & sweetener

Order of addition Heating temperature & Time Type & Position of Impeller

Mixing Speed & Mixing Time

pH of buffer/salts, Concentration of buffers/salts

Purity, Solubility, Compatibility, Stability & Toxicity of Buffers/Salts

Vehicle purity, polarity, pH, Viscosity, Sp. Gravity, Volatility, Microbial

Physical Attributes , Assay, Impurity, pH & Preservative content of system

Dissolution*, Reconstitution time**

Filtration in Colloid mill Type & Principle of milling

Milling speed Screen size of mill

Type & Size of Filter Rate of filtration

Physical Attributes (clarity#/ Homogeneity*) Assay, Impurity, Uniformity of Dosage units, Viscosity/Rheology, Specific Gravity/Density

Microbial content of system

Filling , Capping & Sealing with nitrogen purging

Filling rate Capping & Sealing rate

Nitrogen purging &/or sparging rate Sealing rate after closure fitting

Physical Attributes, Assay, Impurity, Uniformity of dosage units*,

Uniformity of Weight**, Viscosity/Rheology, Specific Gravity/Density &

Extractable volume of system, pH & Preservative content of system,

Dissolved / Headspace Oxygen content of system

Microbial content of system Patient Acceptance & Compliance

Physical Attributes (Clarity#, Homogeneity*), Assay, Impurity, Uniformity of Dosage units,

Viscosity/Rheology, Specific Gravity/Density of system, pH & Preservative content of system

Dissolved Oxygen of system Microbial content of system

Material of container (Glass/Metal/ Plastic) Material of closure (Metal/Plastic/Rubber)

Design & Size of container/closure

Drug substance PSD/SSA, Contact angle, Vehicle purity, polarity, pH,

Viscosity, Rheology, Sp. Gravity/ Density, Volatility & Microbial content

Type & Concentration of Surfactant Concentration of preservative

Source ,Concentration, Viscosity, pH & Microbial contents of hydrocolloids

# Applicable to Solution only; * Applicable to Suspension only; ** Applicable to reconstituted powder only

Physical Attributes (Clarity#, Homogeneity*), Assay, Uniformity of Dosage units*, pH,

Impurity, Assay of Preservative content of system, Particle Size distribution*, Zeta

potential*, Redispersibility*, Dissolution*, Reconstitution time**

Physical Attributes (Homogeneity#/Sedimentation*/Caking*)

Assay, Uniformity of Dosage units, pH & Preservative content of system

Viscosity/Rheology, Specific Gravity/Density & Extractable volume of system,

Particle Size distribution*, Zeta Potential*, Redispersibility*,Microbial content of system

Environment (Temperature and RH)

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK ASSESSMENT

RISK EVALUATION

RISK ANALYSIS

RISK IDENTIFICATION

Identification of Risk Factors by

Ishikawa Fishbone Diagram

RAW MATERIAL

API STABILITY

HYDROCOLLOID SOURCE

SURFACTANT SOURCE

SOLUBILIZATION BY SURFACTATNT

BODYING BY HYDROCOLLOID&/OR

VOLUME MAKE UP

MATERIAL OF 1° PACKAGING

FILTRATION, FILLING & CAPPING

COLLOID MILL MESH SIZE

FILTER SCREEN SIZE

TARGET EXTRACTABLE VOL.

NITROGEN PURGING RATE BUFFER CONCENTRATION

COLOR SOURCE & CONC.

STIRRING RATE

FLAVORS SOURCE & CONC

SWEETENERS SOURCE & CONC

VEHICLE QUANTITY

HYDROCOLLOID CONC.

TYPE OF HYDROCOLLOID TYPE & CONC. OF SURFACTANT

TYPE & CONC. OF PRESERVATIVE

STIRRING RATE

API PSD & SURFACE AREA

ADDITION OF ORGANOLEPTICS & pH ADJUSTMENT

FILRATION RATE

STIRRING RATE (SPEED *TIME)

CO-SOLVENT QUANTITY

STIRRING RATE

RATE OF FILLING

VISCOSITY OF SYSTEM API AQUEOUS SOLUBILITY

INTERFACIAL TENSION OF SYSTEM

BIOBURDEN

OXYGEN EXPOSURE

ENVIRONMENTAL FACTORS

LIGHT EXPOSURE

RELATIVE HUMIDITY

TEMPERATURE

CONC. OF COMPLEXING AGENTS

API PURITY

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

FP CQAs Physical

Form Particle

size** Solubility* Volatility Purity Stability

Microbial Content

Moisture content***

Residual Solvent***

Appearance High Low Low Low Low Low Low Low Low Assay Low Low Low Low High High Low Low Low

Uniformity of Content** Medium High High High Low Low Low Low Low Uniformity of Weight*** Low Low Low Low Low Low Low Low Low

Impurities Medium MEdium Low Low High High Low Low Medium pH of System Low Low Low Low Low Medium Medium Low Low

Microbial Limits Low Low Low Low Low Low High Medium Low Antimicrobial content Low Low Low Low Low Low High Low Low Antioxidant content Low Low Low Low Low Low Low Low Low

Extractable Low Low High High Low Low Low Low Low Viscosity/specific gravity Low Low Low High Low Low Low Low Low

Particle Size Distribution** Low Medium Low Low Low Low Low Low Low

Dissolution* High High High Medium Low Medium Low Low Low Redispersibility** Low High Low Low Low Low Low Low Low

Reconstitution time*** Low High High Low Low Low Low Low Low

Low Broadly acceptable risk. No further investigation is needed

Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.

High Risk is unacceptable. Further investigation is needed to reduce the risk.


RISK ASSESSMENT

RISK EVALUATION

RISK IDENTIFICATION

RISK ANALYSIS

Qualitative Risk based Matrix Analysis of Active Pharmaceutical Ingredient’s (API) Attributes

Physico- Chemical Property of Actives

Critical Material Attribute (CMAs)

Failure Mode (Critical Event)

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

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

Physical Property

Solid Sate Form

Different Polymorph/ form

Solubility of drug substance may get affected= Dissolution of drug product may get affected= Bioavailability/Efficacy may get compromised

2 4 4 32

Particle Size Distribution (PSD)

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

4 4 3 48

Moisture content High water content

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

2 3 2 12

Residual Solvents High residual solvent

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

2 3 2 12

Chemical Property

Solubility Different Salt/ Form

Dissolution of the drug product can be affected >> Bioavailability/Efficacy may got compromised 2 3 4 24

Volatility High Assay & Content Uniformity can be affected >> Efficacy may get compromised 2 3 4 24

Process Impurities

Less Purity Assay & impurity profile of drug product may be affected = Quality & Safety may got compromised 2 3 3 18

Chemical Stability

poor Susceptible to dry heat/oxidative/hydrolytic/UV light degradation- impurity profile may get affected Quality & Safety may got compromised

2 3 3 18

Biological Property

Microbial Content High

MICROBIAL LOAD may get increased during transportation, shipping, storage & in-use >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of patient may get compromised

2 3 4 24

Probability* Severity** Detect ability*** Score Very Unlikely Minor Always Detected 01 Occasional Moderate Regularly Detected 02 Repeated Major Likely not Detected 03 Regular Extreme Normally not Detected 04

Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure.

Score based on

LIKELY SEVERITY IMPACT ON DRUG

PRODUCT CQA.

Score based on

PROBABILITY FOR OCCURANCE

OF FAILURE

Score based on

PROBABILITY OF FAILURE OF DETECTION.

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK IDENTIFICATION

RISK ASSESSMENT

RISK ANALYSIS

RISK EVALUATION

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

Probability of Risk can be Reduced through

DoE Optimization

Detectability of Risk can be increased through In Line PAT System

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK IDENTIFICATION

RISK ANALYSIS

RISK EVALUATION

RISK ASSESSMENT

CRITICAL

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

B

A SOLID STATE FORM

PARTICLE SIZE

CMAs of

API

FP CQAs Solvents/

Co-solvents/ Vehicles

Surfactants (Solubilizing/

Wetting agents)

Hydrocolloid (Suspending

agent)

Buffering agent

Preservatives Organoleptic Additives

Anti Microbial

Anti Oxidant

Colors Flavors Sweeteners

Appearance High High High Low Low Low High Low Low Assay High Low Low Low Low Low Low Low Low

Uniformity of Content** High High High Low Low Low Low Low Low Uniformity of Weight*** High Low Low Low Low Low Low Low Low

Impurities High Medium Low Medium Medium High Low Medium Low pH of System High Low Low High Low Low Low Low Low

Microbial Limits High Low Medium Medium High Medium Medium Medium Medium Antimicrobial content High Low Low High High Low Low Low Low Antioxidant content High Low Low High Low High Low Low Low

Extractable High High High Low Low Low Low Low Low Viscosity/specific gravity High Low High Low Low Low Low Low Low

Particle Size Distribution** Low High Low Low Low Low Low Low Low

Dissolution** Low High Low High Low Low Low Low Low Redispersibility** High High High Low Low Low Low Low Low

Reconstitution time*** High High High Low Low Low Low Low




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK ASSESSMENT

RISK EVALUATION

RISK IDENTIFICATION

RISK ANALYSIS

Qualitative Risk based Matrix Analysis of

Inactive Ingredients’ (Excipients’) Attributes

Excipient (Inactive ingredient)

Critical Material Attribute



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

Vehicles/ Solvents Quantity of Vehicle/ Solvent

Less than optimum

Drug Substance may NOT get completely SOLUBILIZED or uniformly DISTRIBUTED >> UNIFORMITY may get affected >> SAFETY & EFFICACY may get compromised

3 3 3 27

More than optimum

Product may get BULKIER to handle >> Patient ACCEPTANCE & COMPLIANCE may get compromised 4 3 2 24

Source of Hydrocolloid

Natural

Source of hydrocolloid is natural i.e. plant or animal based origin >> potential for microbial attack & growth >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of the patient may get compromised

3 3 4 36 Hydrocolloid (Suspending agent as a structured vehicle)

Concentration of Hydrocolloid

Less than optimum

VISCOSITY of dispersion medium may be too lower >> Rate of SEDIMENTATION will be high >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

4 4 2 32

More than optimum

VISCOSITY of dispersion medium may be too higher >> POUR ABILITY of the product may get compromised >> PATIENT COMPLIANCE may get compromised

4 4 2 32

Surfactants (As a Solubilizing/ agents)

Ionic Nature of Surfactant

Cationic/ Anionic in nature

If surfactant is positively/ negatively CHARGED >> INCOMPATIBLE with anionic/cationic drugs /preservatives / primary packaging material >> CHEMICAL / MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of the patient may get compromised

3 3 3 27

Concentration of Surfactant

Less than optimum

Drug Substance/ Preservatives may NOT getting effectively SOLUBILIZED/ DISTRIBUTED within system >>SAFETY & EFFICACY may get compromised

4 4 3 48 ZETA POTENTIAL of the system may be too low >> Particles coalesce & flocculated suspension forms >> Suspension start to form SEDIMENT >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

4 4 2 32

More than optimum

ZETA POTENTIAL of the system may be too high >> Particles repel each other & forms deflocculated suspension which upon settled down invariably leads to form HARD CAKE >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

4 4 2 32

Buffering Agent pH of the Buffer

Within Neutral Range

SOLUBILITY of the weak acidic / weak basic drugs may get affected >> EFFICACY may get compromised 3 3 3 27

Within Acidic/ Basic Range

STABILITY of pH sensitive drugs/ preservatives may get affected >> CHEMICAL STABILITY may get compromised >> SAFETY of patient may get compromised

3 3 3 27

Anti-Microbial Concentration of Anti-Microbial

Less than optimum

MICROBIAL LOAD may get increased during transportation, storage & in-use >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of patient may get compromised

3 3 4 36

Anti-Oxidant Concentration of Anti-Oxidant

Less than optimum

LEVEL OF OXIDIZED IMPURITIES of the product may get increased during transportation, storage & routine use >> CHEMICAL STABILITY may get compromised >> SAFETY of the patient may get compromised

4 4 3 36

Sweetener/ Flavoring agent

Concentration of Sweetener/ Flavor

Not optimum Product TASTE may not be palatable & agree able >> Patient COMPLIANCE may get compromised 4 4 2 32

Coloring agent Concentration of Coloring Agent

Not optimum APPEARANCE of the product may not be pleasant >> Patient ACCEPTANCE may get compromised 4 4 2 32

Probability* Severity** Detect ability*** Score Very Unlikely Minor Always Detected 01 Occasional Moderate Regularly Detected 02 Repeated Major Likely not Detected 03 Regular Extreme Normally not Detected 04

Total Risk Priority Number (RPN) MORE THAN 30 seek critical attention for DoE for possible failure.

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK ASSESSMENT

RISK IDENTIFICATION

RISK ANALYSIS

RISK EVALUATION

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

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK IDENTIFICATION

RISK ANALYSIS

B

A

HYDROCOLLOID (%w/w)

SURFACTANT (%w/w)

RISK EVALUATION

RISK ASSESSMENT

CMAs of

EXCIPIENTS

CRITICAL

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

D

C ANTI MICROBIAL (%w/w)

ANTI OXIDANT (%w/w)

F

E SWEETENER (%w/w)

FLAVOR (%w/w)

G COLOR (%w/w)

FP CQAs

Solvent/ Vehicle

Preparation & storage

Solubilizing of Solids (API+

Preservative) by Surfactants

Supporting in Structured

Vehicle

Organoleptic additives addition

pH adjustment by buffering

Final Volume make up with

vehicle & mixing

Filtration in Colloid mill

Filling, Capping &

Sealing

Physical attributes High Medium High High Low High High Low Assay Low High High Low Medium High High Medium

Uniformity of Content** Low High High Low Low High High Low Uniformity of Weight*** Low Low Low Low Low Low Low High

Impurities High High Low Low High High Low High pH of System High Medium Medium Medium High High Low High

Microbial Contents High Low High High Low High Low High O2 in headspace/ dissolved O2 High High Low Low Low High Low High

Antimicrobial content Low Medium Low Low High High Low High Antioxidant content Low Medium Low Low High High Low High

Extractable Low High High Low Low High Low High Viscosity/specific gravity High Low High Low Low High Low Low

Particle Size Distribution** Low Low High Low Low Low High Low Dissolution** Low High Low Low High High High Low

Redispersibility** Low High Low Low Low Low High Low Reconstitution time*** High High Low Low High High High Low




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


RISK ASSESSMENT

RISK EVALUATION

RISK IDENTIFICATION

RISK ANALYSIS

Qualitative Risk based Matrix Analysis of Processing Parameters

Unit Operations

Critical Process Parameter (CPPs)



P S D RPN

(=P*S*D)

Vehicle/ Solvent Preparation Storage& distribution

Rate of Addition Higher than Optimum Physical Attributes, Impurity profile & Microbial Load

may get affected >> Safety may get compromised 2 3 4 24

Filtration Rate 2 3 4 24

Heating Rate (Temp*Time) Lower than Optimum Microbiological Stability may get affected

>> Safety may get compromised 3 3 4 36

Higher than Optimum Impurity profile & Assay may get affected >> Safety may get compromised 3 3 4 36

Mixing Rate (Speed*Time) with Co-Solvents

Lower than Optimum Content Uniformity & Assay may get affected >> Efficacy may get compromised 3 3 4 36

Solubilization of Solids (API+ Preservative) by Surfactants

Order of addition Incorrect Physical Attributes, Zeta Potential, Content Uniformity & ultimately Assay may get affected >> Sedimentation/Caking may be observed >> Physical Stability may get compromised >> Safety & Efficacy may get compromised

2 3 4 24 Impeller Design & Position Improper 2 3 4 24

Mixing Rate (Speed*Time) Lower than Optimum 3 3 4 36

Heating Rate (Temp*Time) Higher than optimum Impurity profile & ultimately Assay may get affected > Chemical Stability may get compromised >> Safety may get compromised

3 3 4 36

Supporting by Structured Vehicles

Order of Addition Incorrect Physical Attributes, Viscosity, SVR/SHR. Content Uniformity & Ultimately Assay may get affected >> Sedimentation/Caking may be observed >> Physical Stability may get compromised >> Safety & Efficacy may get compromised

2 3 4 24 Rate of Addition Higher than optimum 2 3 4 24


Organoleptic addition With mixing

Order of Addition Incorrect Physical Attributes (Color, Odor, Taste) , Content Uniformity & ultimately Assay may get affected >> Safety & Efficacy may get compromised >> Patient Compliance may get compromised

3 3 3 27


Heating Rate (Temp*Time) Higher than optimum Impurity profile & Assay may get affected >> Safety may get compromised 3 3 3 27

pH Adjustment with Buffer &Final Volume make up with vehicle & final mixing

Rate of Addition Higher than Optimum Physical Attributes, Particle Size Distribution, pH/ Solubility, Content Uniformity & Assay may get affected >> Sedimentation/Caking may be observed >> Physical & Chemical Stability may get compromised >> Safety & Efficacy may get compromised

2 3 4 24 Impeller Design & Position Improper 2 3 4 24


Heating Rate (Temp*Time)

Lower than Optimum Microbiological Stability may get affected >> Safety may get compromised 3 3 4 36

Higher than Optimum Impurity profile & Assay may get affected > Chemical Stability may get compromised >> Safety may get compromised

3 3 4 36

Ultrafiltration in Colloid mill

Type & Principle of Filter Improper Physical Attributes, Impurity profile, Microbial Load, Content Uniformity & ultimately Assay may get affected >> Physical Stability may get compromised >> Quality, Safety & Efficacy may get compromised

2 3 4 24 Filter Screen Size Incorrect 2 3 4 24 Rate of Filtration Higher than Optimum 3 3 4 36

Filling , Capping & Sealing with nitrogen purging

Filling rate (Speed*Time) Not Optimum Uniformity of Weight may get affected

>> Patient Acceptance may get compromised 3 2 2 12

Higher than Optimum Dissolved / Headspace Oxygen may get increased >>Oxidation Impurity profile & Assay may get affected >> Safety may get compromised

3 3 4 36 Nitrogen purging rate Lower than optimum 3 3 4 36

Capping & Sealing rate Lower than Optimum 3 3 4 36

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


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


RISK IDENTIFICATION

RISK ANALYSIS

%HYDROCOLLOID

%SURFACTANT

MIXING TIME C

B

A

CPPs of

CONTROLLED SOLUBILIZATION

RISK EVALUATION

RISK ASSESSMENT

CRITICAL

Processing Parameters Required to be Optimized &/Or Controlled


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

CONTROLLED SOLUBILIZATION(Contd…)

Optimization of CMAs & CPPs OF

Solution Homogenization Process

QUALITY COMPROMISED EFFICACY COMPROMISED SAFETY COMPROMISED

INADEQUATE ZETA POTENTIAL

RISKS

INADEQUATE VISCOSITY HIGH RATE OF SEDIMENTATION

CONTENT UNIFORMITY COMPROMISED

A

B

C STIRRING TIME

HYDROCOLLOID

SURFACTANT

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


NO. OF FACTORS

NO. OF LEVELS

EXPERIMENTAL DESIGN SELECTED

ADD. CENTER POINTS

TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)

3

3

BOX BEHNKEN DESIGN

2

12MP + 3CP

=15

To Optimize CMAs & CPPs of Liquid Suspension Dosage Form OBJECTIVE

NO. OF FACTORS

NO. OF LEVELS

3

3

A SURFACTANT

C

STIR

RIN

G T

IME

“High”

Medium

“Low”

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

A SURFACTANT (%) 0.50%w/w 1.00%w/w 1.50%w/w B HYDROCOLLOID (%) 20%w/w 30%w/w 40%w/w C STIRRING TIME (min) 30min 45min 60min


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For


PREDICTION EFFECT EQUATION OF INDIVIDUAL RESPONSE BY QUADRATIC MODEL

CMAs CPP CQAs

Sedimentation Volume Ratio = +0.030-0.024A-0.089B-0.020C

+0.010AB+2.500E-003AC+2.500E-003BC+0.067A2+0.11B2+0.030C2

Zeta potential= -44.67+12.00A+5.62B+0.38C-2.25 AB-0.25AC+1.00BC

-6.92A2-2.67B2-1.17C2

Viscosity = +44.67+3.25A+8.38B+1.13C

-0.75AB-0.25AC+0.000BC-1.08A2-3.83B2+0.17C2

Content Uniformity= +1.73-0.20A-0.50B-0.15C

+0.000AB+0.050AC+0.000BC+0.41A2+0.76B2+0.26C2

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


Responses (Effects) Goal for Individual Responses Y1 Sedimentation Volume Ratio To achieve the minimum SVR i.e. NMT 0.1 Y2 Zeta Potential (mV) To achieve zeta potential of suspension in the range of -40 to -50 mv Y3 Viscosity (cps) To achieve viscosity in the range of 40 to 50 cps Y4 Content Uniformity (AV) To achieve minimum acceptance value in CU i.e. NMT 2.0

Factors (Variables) Knowledge Space Design Space Control Space

A SURFACTANT (%) 0.50-1.50 0.75-1.25 0.85-1.15 B HYDROCOLLOID (%) 20.0-40.0 27.5-37.5 30.0-35.0 C STIRRING TIME (min) 30-60 37-53 40-50

By Overlaying contour maps from each responses on top of each other, RSM was used to find the IDEAL “WINDOW” of Operability-Design Space per proven acceptable ranges & Edges of Failure with respect to individual goals




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP



DoE For

SWEETENER : FLAVOR : COLOR(Contd…)

Optimization of

Sweetener Flavor & Color Ratio in liquid oral mixtures

RISK

UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE

PATIENT ACCEPTANCE COMPROMISED

FLAVOR

SWEETENER 1

2

3 COLORANT

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


16

OBJECTIVE To Optimize Sweetener : Flavor : Color ratio of Liquid Orals


D-OPTIMAL MIXTURE DESIGN

TOTAL NO OF EXP RUNS (TRIALS)

Factors (Variables) Lower Levels Higher Levels A SWEETENER (%w/w) 1.00% 1.50% B FLAVOR (%w/w) 0.50% 1.00% C COLOR (%w/w) 0.00% 0.50%

• During Optimization of sweetener, flavor & color in liquid orals; ultimate response to be measured was Patient Acceptability Score which was a function of proportion of all 3 components in combination

• All 3 factors were components of a mixture, their operating ranges were not same but their total must be 2.0 %w/w of formulation & there were upper bound constraints on the component proportions in the formulation mixture

• Thus, Constrained Mixture Design is selected, in opposite to Simplex Mixture, as a special class of RSM for optimization of proportions especially applicable when there are upper or lower bound constraints on the component proportions.

SWE

ETE

NE

R


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For


PREDICTION EFFECT EQUATION OF EACH FACTOR BY SPECIAL CUBIC MODEL

CQAs CMAs

Patient Acceptability Score= +3.79A+3.19B+2.67C+2.57AB+4.73AC+1.94BC+15.05ABC

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


By Overlaying contour maps from each responses on top of each other, RSM was used to find out the IDEAL “WINDOW” of operability-Design Space per proven acceptable ranges & Edges of Failure with respect to ultimate goals

Responses (Effects) Goal for Individual Responses Y1 PATIENT ACCEPTANCE

SCORE To achieve maximum Patient Acceptance Score as maximum as possible out of 10. & NLT 4.5 out of 5.0

Factors (Variables) Knowledge Space Design Space Control Space A SWEETENER (%w/w) 1.00-1.50% 1.10-1.35% 1.15-1.30% B FLAVOR (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70% C COLOR (%w/w) 0.00-0.50% 0.05-0.25% 0.10-0.20%




Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP



DoE For

PRESERVATIVE SYSTEM(Contd…)

Optimization of

Preservative system for In use Stability of Multidose Liquid Orals

INADEQUATE ANTIMICROBIAL CONC. INADEQUATE ANTIOXIDANT CONC

MICROBIAL LOAD IN-USE OXIDATION IMPURITIES

ANTIMICROBIAL A

B ANTIOXIDANT

C BUFFERING AGENT

RISKS

SAFETY COMPROMISED

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


Factors (Variables) Levels of Factors studied -1 Center point (0) +1

A Antimicrobial (%W/W) 0.005 0.010 0.015 B Antioxidant (%W/W) 0.050 0.100 0.150 C Buffering Agent (%W/W) 0.800 1.400 2.000

NO. OF FACTORS

NO. OF LEVELS


ADD. CENTER POINTS

TOTAL NO OF EXPERIMENTAL RUNS (NO OF TRIALS)

3

2

23 FULL FACTORIAL DESIGN WITH ADD. CENTER POINTS

3

23 + 3 = 11

OBJECTIVE To Optimize Preservative System for In Use Stability Of Multi-dose Sterile Product (Injection, Eye/Ear Drops)

A ANTIMICROBIAL

C

BU

FF

ER

ING

AG

EN

T


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





DoE For


CQAs CMAs

PREDICTION EFFECT EQUATION OF EACH FACTOR BY LINEAR MODEL

REDUCTION in Microbial Load after 14 days =+99.42 +0.35A +0.075B +0.15C -0.050AB -0.075AC +0.025ABC

OXIDIZED Impurities after 14 days=+0.46 -0.035A -0.18B -0.052C +7.50E-003AB +5.00E-003AC + 0.010BC -2.50E-003ABC

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






DoE For


Responses (Effects) 5 Goals for Individual Responses Y1 Reduction in Microbial Load after 14D in use To achieve NLT 99.5% reduction in microbial load

Y2 %Oxidized Impurities after 14D in use To minimize the level of oxidized impurities NMT 0.5%

Factors (Variables) Knowledge Space Design Space Control Space A Antimicrobial (%W/W) 0.005-0.015 0.010-0.015 0.012-0.015 B Antioxidant (%W/W) 0.050-0.150 0.080-0.150 0.100-0.150 C Buffering Agent (%W/W) 0.800-2.000 0.800-2.000 1.000-1.500


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

VEHICLE PREPARATION WITH SWEETENER, FLAVOR & COLOR

pH & VOLUME MAKE UP WITH VEHICLE & STORAGE

CONTROLLED SOLUBILIZATION WITH HEATING & MIXING

A B C

CRITICAL PROCESSING STEPS

PAT For

SOLUTION MANUFACTURING (Contd…)



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

PAT For


TEMPERATURE &

RELATIVE HUMIDITY

At Line

Thermo-hygrometer

API / EXCIPIENT PURITY

At line UV/ HPLC/ GC,

On line LOD/ HMB or W/KF

API / EXCIPIENT PARTICLE

SIZE DISTRIBUTION

At line Malvern Particle Size

Analyzer OR On Line

Sieve Shaker Analysis

RATE OF CONTROLLED FLOCCULATION OR EFFECTIVE PRECIPITATION by In Line Lasentec FBRM or PVM FOR SUSPENSIONS /

EMULSIONS OR At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests

RATE OF SEDIMENTATION FOR PHYSICAL STABILITY by

In Line Lasentec FBRM or PVM OR

At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests

RATE OF STIRRING FOR COMPLETE HOMOGENIZED STATE by In Line BRUKER FT-NIR FOR HOMOGENIZED

STATE OF SOLUTION

VEHICLE PREPARATION

Bulk Uniformity by At line

UV-VISIBLE/ IR,-RAMAN

HPLC/ GC Spectroscopy


Bulk Uniformity by At line

UV-VISIBLE/ IR,-RAMAN

HPLC/ GC Spectroscopy

pH & VOLUME MAKE & STORAGE

Precipitation analyzed by

At Line Malvern PSA or

Online SVR/ SHR/ DF

On Line

pH Meter

On Line

Viscometer



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

PAT For


TEMPERATURE &

RELATIVE HUMIDITY

In Line

Thermo-hygrometer

API / EXCIPIENT PURITY

In Line FT-NIR

API / EXCIPIENT PARTICLE

SIZE DISTRIBUTION

In line FBRM

RATE OF CONTROLLED FLOCCULATION OR EFFECTIVE PRECIPITATION by In Line Lasentec FBRM or PVM FOR SUSPENSIONS /

EMULSIONS OR At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests

RATE OF SEDIMENTATION FOR PHYSICAL STABILITY by

In Line Lasentec FBRM or PVM OR

At Line Malvern PSA OR On Line SVR/SHR/ DF physical tests

RATE OF STIRRING FOR COMPLETE HOMOGENIZED STATE by In Line BRUKER FT-NIR FOR HOMOGENIZED

STATE OF SOLUTION

VEHICLE PREPARATION

Bulk Uniformity by In line Bruker

FT-NIR Spectroscopy for

homogenized state of solution


Bulk Uniformity by In line Bruker

FT-NIR Spectroscopy for

homogenized state of solution

pH & VOLUME MAKE & STORAGE

Precipitation analyzed by

In Line Lasentec FBRM or

Particle Video Monitoring

In Line

pH Meter

In Line

Viscometer



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

Auto-controlling of

TEMPERATURE &

RELATIVE HUMIDITY

Air Handling Unit

(AHU)

Auto controlling of

VEHICLE PREPARATION

Bulk Uniformity by adjusting

Heating Temperature

Heating Time

Mixing Speed

Mixing Time

Auto controlling of


Bulk Uniformity by adjusting

Heating Temperature

Heating Time

Mixing Speed

Mixing Time

Auto Maintaining of

PHYSICAL & CHEMICAL STABILITY

By adjusting

Stirring Speed

Stirring Time

Storage Temperature

Dissolved & Headspace Oxygen

Auto-controlling of

DISSOLVED OXYGEN

by adjusting Vacuum

Pressure & Stirring Time

Auto-controlling of

HEADSPACE OXYGEN

by adjusting Vacuum

Pressure & N2 Purging

PAT For



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

Active Pharmaceutical Ingredient (API) Critical Material Attributes

Polymorphic Form

2Ө values x, y, z x, y, z x, y, z To ensure batch to batch consistency in Dissolution

EXCIPIENT Critical Material Attributes

Vehicle Grade UV/RO Filtered Purified Water

UV/RO Filtered Purified Water

UV/RO Filtered Purified Water

To ensure consistence compatibility, purity & Microbial Stability

Surfactant Type (Tween 80) Non-ionic Non-ionic Non-ionic

To ensure batch to batch consistency in solubility, pour ability, Physical Stability & Compatibility

Concentration (%w/w) 0.50-1.50 0.75-1.25 0.85-1.15

Hydrocolloid Source (CMA) Semisynthetic Semisynthetic Semisynthetic

Concentration (%w/w) 20.0-40.0 27.5-37.5 30.0-35.0

Sweetener Concentration (%w/w) 1.00-1.50% 1.10-1.35% 1.15-1.30% To ensure batch to batch consistent Patient Acceptance & Compliance

Flavor Concentration (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70%

Color Concentration (%w/w) 0.00-0.50% 0.05-0.25% 0.10-0.20%

Anti-Microbial Concentration (%w/w) 0.005-0.015 0.010-0.015 0.012-0.015

To ensure batch to batch consistency Chemical & Microbiological stability

Anti-Oxidant Concentration (%w/w) 0.050-0.150 0.080-0.150 0.100-0.150

Buffer Concentration (%w/w) 0.800-2.000 0.800-2.000 1.000-1.500

CONTROL OF CMAs

CONTROL STRATEGY For

Critical Material Attributes


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

Vehicle/ Solvent Preparation

with Sweetener, Flavor, Color

Heating Temperature 60-80°C 63-77°C 65-75°C To ensure consistence compatibility, acceptability, purity & Microbial Stability Mixing Time 30-60 min 35-55 min 45 min

Controlled Solubilization by

Surfactant & hydrocolloids

Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch consistency in Solubility, Pour ability, Physical Stability & Compatibility Mixing Time 30-60 min 37-53 min 40-45 min

pH Adjustment with Buffer

&Final Volume make up

with vehicle & final Mixing

Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch consistency Chemical & Microbiological stability

Mixing Time 30-60 min 37-53 min 40-45 min

Ultrafiltration

Particulate Matter Screen Size

5 micron with vacuum



To ensure batch to batch purity to warrant Safety

Microbial Filter Screen Size

0.3 micron vacuum filter



Filling, Capping &

Sealing

Temperature 21-25°C 21-25°C 21-25°C

To ensure Chemical Stability Vacuum Pressure

with Nitrogen Purging

NLT 29.5” NLT 29.5” NLT 29.5”

CONTROL OF CMAs

CONTROL OF CPPs

CONTROL STRATEGY For

Critical Processing Parameters


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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