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

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

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

facebook.com/QbD.PAT.Pharmaceutical.Development

Designed & Developed by

mailto:[email protected]


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



Aim

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

• Robust & Rugged Reproducible Manufacturing Process

• with a Control Strategy that ensures the quality & performance of the drug product

as per Quality by Design

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


What is the meaning of

Quality by Design?

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

How to define

Target Product Profile?

1


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: • For Pharmaceutical Abbreviated New Drug Application (ANDA- Generics) QTPP will be finalized -on the basis of

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

• Thus QTPP of Generics will be defined based on the properties of the drug substance, characterization of the RLD product, and consideration of the RLD label and intended patient population.

• For Pharmaceutical New Chemical Entities (NCE-Innovator) QTPP will be finalized on the basis of Therapeutic Safety & Efficacy / New Drug Applications (NDA-Novel Drug Delivery Systems as compared to already approved & available

conventional dosage forms)

What is QTPP?

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Pharmaco-KINETICS

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

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

Bioequivalence requirement needed

to meet required rate & extent of drug absorption

EASE OF STORAGE & DISTRIBUTION

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

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

Required to handle the product easily with suitable accessibility

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

shelf-life is required at room temperature

Equivalent to or better than Reference Product shelf-life

PATIENT ACCEPTANCE & PATIENT COMPLIANCE

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

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

Reference Product labeling

Required to achieve the desired patient acceptability & suitable compliance

PATIENT’S POINT OF VIEW

PHYSICIAN”s POINT OF VIEW

PHARMACIST’s POINT OF VIEW

Quality Target Product Profile (QTPP) of Suspension


Similar Dosage FORM : Suspension

Dosage DESIGN : IR

ROUTE of Administration : Oral

Dosage STRENGTH : x mg/ml

Drug Product QUALITY : Assay, Uniformity, Impurities, Dissolution, Microbiological Limits, Antioxidant content, Antimicrobial content, PSD, pH, Viscosity/ Sp. Gravity, Leachable/ Extractable within acceptable limits of specification

Therapeutic Equivalence = Pharmaceutical Equivalence + Bio-Equivalence Of Generic Suspension with Patient Compliance

PHARMACEUTICAL Equivalence

BIO- Equivalence

PATIENT Compliance

Similar Pharmacokinetics: Rate of Absorption AUC0-t, , AUC0-∞

Extent of Absorption: Cmax

90 % CI of these PK Parameters should fall within bioequivalence limits of 80-125 with reference product

Primary PACKAGING: Container : (Glass/Plastic/Metal) & Closure : (Plastic/Metal/Rubber)

Ease of Storage & Distribution Should be stable against sedimentation, caking, hydrolysis, oxidation, photo degradation & microbial growth with at least 12 months stability at normal room temperature & 28 Days of in-Use Shelf Life

Patient Acceptance Should possess acceptable flavor, taste & odor

Patient Compliance re-dispersible upon shaking/administered (pourable & palatable)/used/ applied similarly with Reference Product labeling Note: Plastic/ Rubber should not allow permeation, leaching, extraction or sorption


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

How to determine

Critical Attributes of Quality?

2


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]. Identification of critical quality attributes (CQAs) was based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute of the drug product.

What is CQA?

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Critical Quality Attributes (CQA) of Suspension

EFFICACY SAFETY QUALITY MULTI DISCIPLINARY


PSD & Dissolution

Assay Physical Attributes

Identification

Content Uniformity

Assay of Preservative

Extractable & Leachable

Microbiological Limits

!

!

!

Formulation & Process variables have direct impact on this CQA. This will remain as a target element of the drug product profile and should be investigated and discussed in detail in subsequent risk assessment and pharmaceutical development

Formulation and process variables are unlikely to impact this CQA. Therefore, the CQA will not be investigated and discussed in detail in subsequent risk assessment and pharmaceutical development.

Formulation & Process variables does not have any impact on this CQA. No need for any further investigation & discussion.

pH & Impurities

Should be between 90.0 to 110.0 % of labeled claim to ensure safety & efficacy

Should Conform to USP <905> Uniformity of Dosage Units: 85.0-115.0 % of labeled claim with AV:

NMT 15.0 to ensure patient Safety & product Efficacy

As per USP <51> Should maintain the microbial quality of the product & to prevent oxidation throughout

shelf life & proposed in-use shelf life to ensure patient safety.

Should be within limits as per ICH Q3A & Q3B OR Reference Product Characterization to ensure chemical stability of

formulation & patient Safety

Stability data should show evidence that extractable &

leachable from the container/closure systems

are consistently below acceptable levels to ensure

patient safety.

Should Conform to USP <61 & 62> But controlled at Drug Substance & Excipient Release stage itself to ensure microbiological stability & patient safety

NLT 85 % (Q) of labeled amount of drug / single dose should be dissolved within 30 mins. in pH 1.2- 0.1N HCl (500 ml), USP Apparatus II paddle),

50 rpm to ensure desired bioavailability & efficacy

Positive for Drug Substance But controlled at Drug Substance Release stage itself

Color, Flavor, Taste , Viscosity USP <911> / Sp. Gravity USP <841> & Re-dispersibility should be mostly

similar to reference product to ensure physical stability & Patient

Acceptance & Compliance


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

How to assess Risks associated with

Materials & Process?

3


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 Flocculation Process Map

Vehicle Preparation & Storage Organoleptic addition

Controlled Flocculation 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 & SEALING

COLLOID MILL MESH SIZE

FILTER SCREEN SIZE

EXTRACTABLE/LEACHABLE

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

pH ADJUSTMENT & ADDITION OF

ORGANOLEPTICS

FILRATION RATE

STIRRING RATE (SPEED *TIME)

CO-SOLVENT QUANTITY

STIRRING RATE

RATE OF FILLING & SEALING

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

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 Medium Low Low Low Low Low Low Low

Impurities Medium Medium Low Low High High Low Medium 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 Medium 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 High 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.

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 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 may get affected >> BIOAVAILABILITY-EFFICACY may got compromised

2 3 4 24

Volatility High Assay & Content Uniformity may 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

API Attributes which got RPN more than 30 were get highest priority among all the risks, they should be taken into consideration as most

Critical Material Attributes of API , which were required to be optimized &/or controlled

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 High High Low Low Low Low Low Low

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

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

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

Extractable High High Low 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 CMAs Failure Mode (Critical Event)


P S D RPN

(=P*S*D)

Solvents/ Co-solvents/ Vehicles

Quantity of Vehicle/ Solvent

Less than optimum Drug Substance may NOT get completely SOLUBILIZED or uniformly DISTRIBUTED >> CONTENT 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 Vehicle/ Solvents/ Co-solvents

Natural without purification

Source of VEHICLE is natural i.e. PLANT OR ANIMAL BASED ORIGIN >> Potential for microbial attack & growth >> MICROBIOLOGICAL STABILITY may get compromised >> SAFETY of the patient may get compromised

2 3 4 24

Surfactants (As a Solubilizing/ Wetting 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 3 4 4 48 ZETA POTENTIAL of the system may be too low >> Particles COALESCE & flocculated suspension forms >> Suspension start to form REDISPERSIBLE SEDIMENT >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

3 4 4 48

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

3 4 4 48

Electrolytes (As a Controlled Flocculating Agent)

Concentration of Electrolytes

Less than optimum

VERY LOOSE FLOCS will be formed through reducing forces of repulsion >> Particles repel each other & forms deflocculated suspension which upon settled down invariably leads to form HARD CAKE >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

3 4 4 48

More than optimum

HARD BOUND FLOCS will be formed by increasing forces of coalescence >> Particles COALESCE & flocculated suspension forms >> Suspension start to form REDISPERSIBLE SEDIMENT >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

3 4 4 48

Hydrocolloid (As a Supporting Structured Vehicle)

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

2 3 4 24

Concentration of Hydrocolloid

Less than optimum

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

3 4 4 48

More than optimum VISCOSITY of dispersion medium may be too high >> POUR ABILITY of the product may get compromised >> PATIENT COMPLIANCE may get compromised

3 3 2 18

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

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

3 3 4 36

Sweetener/ Flavoring agent

Concentration of Sweetener/ Flavor

Not optimum Product TASTE may not be palatable & agree able >> Patient COMPLIANCE may get compromised 3 3 2 18

Coloring agent Concentration of Coloring Agent

Not optimum APPEARANCE of the product may not be pleasant >> Patient ACCEPTANCE may get compromised 3 3 2 18

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

RISK EVALUATION

RISK ASSESSMENT

CRITICAL

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

Excipients’ Attributes which got RPN more than 30 were get highest priority among all the risks, they should be taken into consideration as most

Critical Material Attributes of Excipients, which were required to be optimized &/or controlled

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*/ Wetting** of Solids (API+ Preservative)

by Surfactants

Controlled Flocculation

by Electrolytes

Bodying with Hydrocolloid

Organoleptic additives addition

pH adjustment by buffering

Final Volume make up

with vehicle & mixing

Filtration*/ Milling** in Colloid mill

Filling & Capping

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

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

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

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

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

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

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

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

Failure Mode (Critical Event)


P S D RPN

(=P*S*D)

Solvent/ Vehicle Preparation with organoleptics & storage

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 Physical Attributes may get affected

>> Safety may get compromised 3 3 3 27

Higher than Optimum

Impurity profile & Assay may get affected >> Safety may get compromised 3 3 3 27

Mixing Rate (Speed*Time) with Co-Solvents

Lower than Optimum

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

Wetting* 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

Controlled Flocculation by Surfactants / Electrolytes / Polymers

Order of Addition Incorrect Physical Attributes, Particle Size Distribution (flocks) Content Uniformity & ultimately Assay may get affected >> Sedimentation/Caking may be observed >> PHYSICAL STABILITY may get compromised >> SAFETY & EFFICACY may get compromised

2 3 4 24


Bodying with Hydrocolloid*

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


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

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

MicroMilling** in Colloid mill

Type & Principle of Mill 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/ Mill Screen Size Incorrect 2 3 4 24

Rate of Milling Higher than Optimum 3 3 3 27

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

RISK EVALUATION

RISK ASSESSMENT

CRITICAL

Processing Parameters Required to be Optimized &/Or Controlled

Process Parameters which got RPN more than 30 were get highest priority among all the risks, they should be taken into consideration as most

Critical Process Parameters , which were required to be optimized &/or controlled

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

How to evaluate & optimize risks by

Designing of Experiments?

4


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 FLOCCULATION(Contd…)

Optimization of CMAs & CPPs OF

Suspension 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






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

DoE For



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP





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

DoE For


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP






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

DoE For





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

How to Identify & Optimize CMAs & CPPs of Primary Packaging Process by Stability Studies?

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

RISKS

COMPROMISE IN MECHANICAL STRENGTH

COMPROMISE IN PHYSICAL BARRIER

COMPROMISE IN CHEMICAL COMPATABILITY

A

C

PACKAGING DEVELOPMENT bY DESIGN


DEFINING OF PACK CONTROLS


ANALYSIS OF STABILITY DATA

DESIGN OF $TABILITY STUDY

IDENTIFICATION OF PACK CQAs

FOR LIQUID ORAL SUPENSION DOSAGE FORM DEVELOPMENT AS PER QbD

SELECTION & OPTIMIZATION OF CMAs & CPPs OF LIQUID ORAL PACKAGING PROCESS

F

E

D BOTTLE FILLING

LINER SEALING & CAPPING

POST-GASSING

CHANCES OF DRUG PRODUCT INTEGRITY LOSS

PRODUCT EXPOSURE TO MOISTURE, OXYGEN, LIGHT, MICROORGANISMS

COMPROMISE IN DRUG PRODUCT SHELF LIFE

COMPROMISE IN QUALITY, SAFETY & EFFICACY

OOT / OOS IN WVTR, OTR, LTR OR MICROBIAL LOAD TESTS

OOS IN IMPURITY LIMITDURING SHELF LIFE

FAILURE IN BUBBLE TEST, VACUUM / PRESSURE DECAY

PDbD

BOTTLE

CAP

B CAP LINER

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP


Al CAP

Glass USP IV Bottle

A Plastic HDPE C Plastic PET B Plastic PP

D Glass USP IV


VERIFICATION OF PACK CONTROLS




PDbD

Available Options of Primary Packaging Material

PACKAGING DEVELOPMENT bY DESIGN (Contd)

F Glass USP II

G Glass USP I

Al CAP

Glass USP II Bottle

Al CAP

Glass USP I Bottle

PP CAP

Plastic HDPE Bottle

PvDC Liner 75 gauge

PP CAP

Plastic PP Bottle

PP CAP

Plastic PET Bottle

PvDC Liner 75 gauge PvDC Liner 75 gauge

PvDC Liner 75 gauge PvDC Liner 75 gauge

PvDC Liner 75 gauge

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP







Tests Positive Control

(Plastic HDPE)

Test Pack (For Selection of Packaging material with PVdC Cap liner & PP Cap)

Negative Control (Glass

USP Type I) Plastic O-PP

Plastic A-PET

Plastic C-PET

Glass USP Type IV

Barrier Properties Oxygen Permeation High Moderate Low Very Low None None Water Vapor Permeation Low Low Very Low Very Low None None Resistance to Acids Fair Good Fair Fair Fair Excellent Resistance to Alkalis Good Very Good Good Good Very Poor Excellent Resistance to Alcohols Good Good Good Good Poor Excellent Resistance to Mineral oils Fair Fair Good Good Fair Excellent Resistance to Solvents Good Good Fair Good Poor Excellent Resistance to Heat Fair Good Fair Good Good Excellent Resistance to Cold Excellent Fair Good Good Good Excellent Resistance to Sunlight Fair Fair Fair Fair Fair Fair Resistance to High Humidity Good Excellent Excellent Excellent Good Excellent Processing / Storage Parameters

Clarity / Translucency Colorless,

Translucent Transparent,

Clear Transparent,

Clear Transparent,

Clear Translucent

Optically Clear, Transparent

Toughness / Impact Resistance Good Fair to Good Good Very Good Fair Good Autoclavable / Sterilizable Yes Yes Yes Yes Yes Yes Extractable / Leachable Low Low Moderate Moderate Very High Low Weathering- Flaking –Alkalinity Low Low Moderate Moderate Very High Low Breathing – Permeation – O2/CO2 High Moderate Low Low None None

ECONOMICAL ACCEPTABLE

MECHANICAL STRENGTH

SELECTION CRITERIAS

CHEMICAL COMPATABILITY

PHYSICAL BARRIER

Protection from -heat & moisture -oxygen /any gas / vapor -UV / Visible light -microorganism

Does not react with -Product Contents -Packing Ingredients -not impart its color odor taste to drug product

-Strong enough to withstand handling -should fit in packaging line -long life

Total Cost, Unit Price acceptable with comparable Advantages

PDbD

Selection of Primary Packaging Material


BIOLOGICAL SAFETY

Extract able/ Leachable Should be -absent / within limits -biological safe -nontoxic

Here , Drug Substance in Liquid formulation is susceptible to oxidation, hydrolysis, temperature, light, pH Change & Microbial Growth. (A) Plastic containers possess potential problems of high permeability of gases & vapors & sorption of preservatives & flavors by packaging material itself. (B) Moisture condenses on the surface of General Purpose Soda Lime Glass container in moist atmosphere & extracts weekly bonded alkali ions. When the surface becomes dry in high temperate atmosphere, white deposit of alkali carbonate is produced by reaction with CO2 from the air. If the film is allowed to remain, further condensation dissolves away some of the silica with a loss of surface brilliance or clarity, known as “weathering”. This silica rich layer on the surface of the glass container fall away & can be seen as glistering flakes in the contents. Known as “Flaking”. Thus, with respect to (i) Physical Appearance (ii) Assay of API & Preservatives (iii) impurities generated upon storage (iv) pH Change (iv) extractable & leachable profiling ; Crystalline Poly Ethylene Terephthalate (C-PET) [due to least permeability, sorption & extractable] with PVdC Liner & PP Cap was selected as primary pack

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP







1Impurity generated due to oxidation 2Impurity generated due to temperature effect 3Impurity generated due to moisture effect 4 Impurity generated due to light exposure

Tests Specification-CQAs (Acceptance Criteria)

Initial Analysis

(0 Days)

40°±2°C /75±5%RH for 3 Months Positive Control (Plastic HDPE)

Test Pack (For Selection of Packaging material for optimized formula with PVdC Cap liner & PP Cap)

Negative Control (Glass

USP Type I) Plastic

PP Plastic A-PET

Plastic C-PET

Glass USP Type IV

Physical Description Clear, Transparent Complies Complies Complies Complies Complies Weathering

Flaking Complies

Related Substance (Impurity) / HPLC

Imp A1: NMT 0.5% 0.15 0.39 0.35 0.30 0.24 0.29 0.20 Imp B2: NMT 0.5% 0.18 0.37 0.34 0.28 0.22 0.30 0.28 Imp C3: NMT 0.5% 0.10 0.25 0.22 0.17 0.14 0.17 0.13 Imp D4: NMT 0.5% 0.07 0.19 0.20 0.18 0.18 0.19 0.18 Max UNK:NMT 0.5% 0.14 0.35 0.31 0.30 0.27 0.33 0.23 Total : NMT 3.0% 0.66 1.59 1.44 1.29 1.11 1.31 1.06

Assay (API)

95% to 105% 98.8 96.7 97.1 97.6 98.1 97.5 98.4

Assay (Antimicrobial)

90% to 110% 99.7 89.6 91.6 93.9 97.4 94.1 98.9

Assay (Antioxidant)

90% to 110% 98.6 84.4 90.5 92.3 96.5 96.1 97.8

pH of system 6.5-7.5 7.1 6.8 6.6 6.9 7.1 8.4 7.2 Microbial Contents Absent Absent Absent Absent Absent Absent Absent Absent Viscosity 40-50 cps 46 cps 44 cps 44 cps 42 cps 42 cps 46 cps 45 cps Specific Gravity 0.9-1.2 g/ml 1.1 g/ml 1.0 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml Extractable / Leachable Constituents

Within Limits / Nontoxic-safe

Absent Absent Absent DMT, EG Absent Na2O, CaO, K2O, BaO, Al2O3, B2O3

B2O3, Na2O (<5 ppm)

PDbD

Comparative Accelerated Stability Study with different Packaging Material – Scale Up Batch


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP







Tests Specification-CQAs (Acceptance Criteria)

Initial Analysis

(0 Days)

40°±2°C /75±5%RH up to 6 Months: in C-PET Bottle-PP Cap-PVdC Liner

1 Month 2 Months 3 Months 6 Months

Description Clear, Transparent Complies Complies Complies Complies Complies

Related Substance (Impurity) / HPLC

Imp A1: NMT 0.5% 0.14 0.19 0.22 0.26 0.28

Imp B2: NMT 0.5% 0.17 0.20 0.21 0.22 0.24

Imp C3: NMT 0.5% 0.10 0.12 0.12 0.14 0.15

Imp D4: NMT 0.5% 0.08 0.13 0.15 0.18 0.20

Max Unk :NMT 0.5% 0.15 0.21 0.25 0.28 0.30

Total : NMT 3.0% 0.68 0.90 1.02 1.14 1.25

Assay (API) 95% to 105% 98.9 98.6 98.2 97.9 97.4

Assay (Anti Microbial) 90% to 110% 99.5 99.1 98.6 97.9 97.6

Assay (Anti Oxidant) 90% to 110% 98.7 98.3 97.2 96.5 96.2

pH of system 6.5-7.5 7.1 7.1 6.9 7.0 6.8

Microbial Contents Absent Absent Absent Absent Absent Absent

Viscosity / Rheology 40-50 cps 46 cps 44 cps 44 cps 43 cps 47 cps

Density / Sp. Gravity 0.9-1.2 gm/cc 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml

Extractable / Leachable Absent Absent Absent Absent Absent Absent

PDbD PACKAGING DEVELOPMENT bY DESIGN (Contd)

Accelerated Stability Study with Finalized Primary Pack : C-PET Bottle-PP Cap-PVdC Liner– Exhibit Batch

1Impurity generated due to oxidation 2Impurity generated due to temperature effect 3Impurity generated due to moisture effect 4 Impurity generated due to light exposure

Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP







CPAs / CPPs Ranges studied at

LAB scale Actual data

for EXHIBIT batches Proposed range for

COMMERCIAL batch PURPOSE of Control

Container

Material C-PET

Crystalline Poly Ethylene Teraphthalate

C-PET Crystalline Poly Ethylene

Teraphthalate

C-PET Crystalline Poly Ethylene

Teraphthalate

To ensure Mechanical Strength, Physical Barrier & Chemical Compatibility for target shelf life of drug product during transportation, storage or routine-use

Capacity 250 ml 250 ml 250 ml

Closure

Cap Polypropylene PP Cap

22 mm Polypropylene PP Cap

22 mm Polypropylene PP Cap

22 mm To ensure Physical Barrier & Chemical Compatibility for target shelf life of drug product during transportation, storage or routine-use

Cap Liner Two Piece Re-sealable

PVdC Cap Liner 75 gauge

Two Piece Re-sealable PVdC Cap Liner

75 gauge

Two Piece Re-sealable Aluminum Cap Liner

75 gauge

Processing Parameters

Method of Filling with Mechanism

Volumetric Filling by Positive

Displacement Piston Action





To ensure batch to batch consistency in bottle pack without any Mechanical damage, Physical Leakage or Chemical Incompatibility to achieve target shelf life of drug product during transportation, storage or routine-use

Rate of Filling 30-50 bottles / min to prevent Foaming

30-50 bottles / min to prevent Foaming

30-50 bottles / min to prevent Foaming

Post-gassing With N2 purging With N2 purging With N2 purging

Cap Liner Sealing Induction Sealing

(20-60 bottles/min) Induction Sealing

(20-60 bottles/min) Induction Sealing

(20-60 bottles/min) Environmental Conditions

Temperature 21-25°C 21-25°C 21-25°C To ensure batch to batch uniformity in surrounding environmental factors during on line processing of packaging to provide protection from temperature, moisture, light & oxidation

Humidity 20-40 % RH 20-30 % RH 20-30 % RH

O2 or N2 Under Nitrogen Laminar Flow

Under Nitrogen Laminar Flow

Under Nitrogen Laminar Flow

UV- Visible Light Packaging Under

Sodium Vapor Lamp Packaging Under

Sodium Vapor Lamp Packaging Under

Sodium Vapor Lamp

PDbD PACKAGING DEVELOPMENT bY DESIGN (Contd) Implementation of Controls for Packaging of– Commercial Batches


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

How to control risks by

Process Analytical Technology?

5


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 FLOCCULATION WITH HEATING & MIXING

A B C

CRITICAL PROCESSING STEPS

PAT For

SUSPENSION 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

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

CONTROLLED FLOCCULATION

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

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

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

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

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

How to

Implement Controls

6

for Commercial Manufacturing?


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




Active Pharmaceutical Ingredient (API) Critical Material Attributes

Polymorphic Form

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

Particle Size Distribution

(PSD)

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

D50: NMT y um NMT y um NMT y um

D90: NMT z um NMT z um NMT z um

EXCIPIENT Critical Material Attributes

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




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 warrent 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



Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Surfactant Electrolyte Hydrocolloid Anti Microbial

Anti Oxidant

Buffer Controlled Flocculation

Temperature

Controlled Flocculation Stirring Time

0.8%

1.0%

0.20 %

30%

35%

0.015%

0.10%

0.15%

1.0%

1.5%

65˚C

40 min

45 min

0.25 %

0.012%

0

1

0

20

30

40

5

0

60

7

0

80

9

0

10

0

0

0

.5

1.0

1

.5

2.0

2

.5

3.0

3

.5

4.0

4

.5

5.0

0

0

.1

0.2

0

.3

0.4

0

.5

0.6

0.7

0

.8

0.9

1

.0

0.0

00

0

.00

5

0

.01

0.0

15

0.0

20

0

.02

5

0.0

30

0.0

35

0

.04

0

0.0

45

0

.05

0

0.0

0. 5

1

.0

1.5

2

.0

2.5

3

.0

3.5

4

.0

4.5

5

.0

Controls for Critical Material Attributes


0

1

0

20

30

40

5

0

60

7

0

80

9

0

10

0

0.0

0

0

.05

0.1

0

0.1

5

0

.20

0.2

5

0

.30

0.3

5

0

.40

0.4

5

0

.50

0

1

0

20

30

40

5

0

60

7

0

80

9

0

10

0

75˚C


Implementatn of

Control Strategy

PAT &Development




CMAs & CPPs


Definition of QTPP

Viscosity Assay Impurities pH Content Uniformity

PSD D90 Dissolution in 30 min

1.0 cP

90%

110%

1%

6.5

7.5

0 AV

10 AV

25 um

0 um

85%

100%

1.2 cP

0%

0

1

0

20

30

40

5

0

60

7

0

80

9

0

10

0

0.5

0

.6

0

.7

0.8

0

.9

1.0

1

.1

1.2

1

.3

1.4

1

.5

50

6

0

7

0

80

90

1

00

11

0

12

0

13

0

14

0

1

50

0

0

.2

0.4

0

.6

0.8

1

.0

1.2

1

.4

1.6

1

.8

2.0

Controls for Critical Quality Attributes of

In Process Intermediates & Finished Product

0

1

2

3

4

5

6

7

8

9

1

0

Preservative Content

90%

110%

50

6

0

7

0

80

90

1

00

11

0

12

0

13

0

14

0

1

50

0

1

0

20

30

40

5

0

60

7

0

80

9

0

10

0

0

1

0

20

30

40

5

0

60

7

0

80

9

0

10

0

Management of

Product Life

Cycle


How to manage quality throughout

Product Life Cycle

7

By continual improvement?

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.


-4

-3

-2

-1

0

1

2

3

4

0 1 2 3 4 5 6

Mea

n o

r R

ange

of

Ch

arac

teri

stic

Qu

alit

y

Sample Number

WECO Rules for signaling "Out of Control"

2 Out of the 3 Consecutive Points above +2 Sigma & below +3 sigma

4 Out of the 5 Consecutive Points above +1 Sigma & below +2 sigma

8 Consecutive Points or 10 out of 11 points or 12 out of 14 points or 14 out of 17 points or 16 out of 20 points fall on same Side of Control Line

2 Out of the 3 Consecutive Points below -2 Sigma & above -3 sigma

4 Out of the 5 Consecutive Points below -1 Sigma & above -2 sigma

8 Consecutive Points or 10 out of 11 points or 12 out of 14 points or 14 out of 17 points or 16 out of 20 points fall on same Side of Control Line

+3σ Limit

+1σ Limit

0

-1σ Limit

-2σ Limit

-3σ Limit

Management of

Product Life

Cycle

Any Point bove +3 Sigma

Any Point below -3 Sigma

+2σ Limit

Upper Control Limit

Lower Control Limit

Central Line

Other Trend Rules: 6 consecutive points in a row trending up OR down (same side) 14 consecutive points in a row alternating up & down (same side) 8 consecutive points in a row more than 1σ from center line (either side) 15 consecutive points in a row within 1σ of center line (either side)

“Continual Trend Analysis” in Process Control Charts Assessment of Common (Chance) Cause Vs. Special (Assignable) Cause

Special Cause

Special Cause

Co

mm

on

Cau

ses

Type of variation Synonyms

Common cause

Chance cause Non-assignable cause Noise Natural pattern

Special cause Assignable cause Signal Unnatural pattern

Management of

Product Life

Cycle

Process Variations Common (Chance) Cause Vs. Special (Assignable) Cause

Common Cause Chance cause/ Non-Assignable

cause (NOISE) Special Cause / Assignable cause

(Signal)

Operator absent

Poor adjustment of equipment

Operator falls asleep

Faulty controllers

Machine malfunction

Fall of ground

Computer crash

Poor batch of raw material

Power surges

Unnatural unpredictable pattern of variation, outside historic

experiment base.

New, surprise, unanticipated, emergent or previously neglected

phenomena within the system

Inappropriate procedures/ SOP Poor design &

Poor maintenance of machines Poor working conditions

Substandard raw materials Measurement error

Vibration in industrial processes Ambient temperature / humidity

Insufficient training Normal wear and tear Variability in settings

Computer response time

Natural Predictable Pattern of variation, within a historic

experience base

Phenomena constantly active within the system;



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


Conclusion

Justification for

Risk Reduction

BEF

OR

E A

FTER

Detectability of Solid State form was increased by

including pXRD test at drug substance release stage itself

Detectability of content uniformity was increased by implementing in line FT-NIR

during mixing stage

Detectability of desired PSD was increased by

implementing Malvern & FBRM at release

Risk Reduction For Critical Material Attributes of API

Probability of undesired PSD was reduced by implementing

IVIVC during development


Conclusion

Justification for

Risk Reduction

BEF

OR

E A

FTER

Probabilities of Poor Wetting of API & Preservatives was

reduced by optimizing ranges of Surfactant via DoE

generated Design Space (DS)

Probability of Flocculation & Caking was reduced by

optimizing ranges of surfactant / electrolyte via DoE / DS

Probabilities of increased Sedimentation rate was

reduced by optimizing ranges of Hydrocolloid via DoE


Risk Reduction For Critical Material Attributes of Excipients

Probability of Microbial Spoilage upon storage was

reduced by optimizing ranges of Anti-microbial via DoE / DS

Probability of Oxidation upon storage was reduced by

optimizing ranges of Anti-Oxidant via DoE / DS


Conclusion

Justification for

Risk Reduction

BEF

OR

E A

FTER

Probability of poor wetting, flocculation, sedimentation &

caking were reduced by optimizing ranges of

Surfactant, Electrolyte & Hydrocolloid via DoE


Detectability of Desired Particle Size Distribution was increased by utilizing FBRM/

PVM Sensors as PAT Tool

Detectability of Content Uniformity was increased by

utilizing inline FT-NIR PAT

Detectability of online impurity during filling &

packaging was increased by utilizing in line FT-NIR & DO meter & pH meter as PAT

Detectability of Solvent/ Vehicle Purity was increased by utilizing inline FT-NIR PAT

Risk Reduction For Critical Processing Parameters of Tableting

Detectability of pH was increased by inline pH Meter


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

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 in-process 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.

QTPP was defined based upon the Voice of the Customers [Requirements of Pharmacist (Pharmaceutical Equivalence), Physician (Bioequivalence) & Patient Acceptance & Compliance]

From the targets defined in QTPP, required in-process & finished product specifications were determined in the form of in process

& finished product CQAs

With respect to CQAs, Risk associated with

each CMAs & CPPs were extensively

analyzed out by FMEA, which decided “which risk should get first priority?” based upon Severity * Probability * Detectability of individual risk.

Severity of Risks could not be reduced. Probability of Risk occurrence was reduced by

systematic series of experiments through DoE & Stability Studies; while Detectability of Risk was increased by online/ inline/ at line

PAT tools

During Commercial Manufacturing, Continual Risk Review & Communication was done between Stakeholders of R&D & Production for

Continual Improvement by Trend Analysis in Control Charts with Cp, Cpk for Product Lifecycle Management

Target Quality

A planned set of controls for CMAs & CPPs were derived from Lab Scale Developmental batch & Scaled Up Exhibit batches, which were verified by Process Performance indices (Pp, Ppk)


© 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]


facebook.com/QbD.PAT.Pharmaceutical.Development

Created & Copyrighted by

“Quality doesn’t costs, it always pays”

mailto:[email protected]




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

Healthcare