KEY COMPONENTS OF PHARMACEUTICAL QUALITY BY DESIGN (QBD) – AN INTRODUCTION

By Dr. Saurabh Arora

Managing DirectorAuriga Research Limited

CONTENTS

Introduction Current approach vs QbD Why QbD is Win-Win Implications of QbD Overview of QbD Key Components Conclusion

HOW DO WE ESTABLISH PRODUCT QUALITY?Then and Now

HISTORICAL APPROACH TO QUALITY

No testing required Testing of final products Testing of ingredients and final product Extensive testing of ingredients, final

products and control of process parameters Testing and control based on process

validation and strict adherence to process

JUST GET FROM A TO B

Traditional approach focused on achieving compliance to product specifications

Only minor variations studied to established that the product is reproducible

Not necessarily the best way to get from A to B

A BETTER WAY TO CROSS THE RIVER?

QBD

What is the best way to get from A to B? What are the other routes can I take to safely

get from A to B? It is like having a GPS navigation system for

your product and process!

NEW LEVEL OF QUALITY

Systematic development process Moving away from “hit and trial” Quality is built into the product not only

controlled by testing

CURRENT VS. QBD APPROACH TO PHARMACEUTICAL DEVELOPMENT

Current Approach QbD Approach

Quality assured by testing and inspection

Quality built into the product & process by design, based on scientific understanding

Data intensive submission – disjoined information without “big picture”

Knowledge rich submission – showing product knowledge & process understanding

Specifications based on batch history

Specifications based on product performance requirements

“Frozen Process” discouraging changes

Flexible process within design space, allowing continuous improvement

Focus on reproducibility – often avoiding or ignoring variations

Focus on robustness – understanding and controlling variations

THINK WIN-WINQbD is good for both the manufacturers and the regulators

QBD IS WIN-WIN

Wins for the regulatorMore pharmaceutical products approved in shorter timelineBetter quality products reaching the marketLower-cost products available to the consumerReduced audit frequency

QBD IS WIN-WIN

Wins for the manufacturer

Reduced time to market

Space and flexibility for more innovation

Reduced documentation

Better communication between authorities and industry

Guaranteed quality for every unit produced

Decreased cost of production by improved productivity

Competitive advantage in the market

Image improvement

Creating value using existing data and resources

Better knowledge management

IMPLICATIONS ON THE ORGANISATIONImplications on of QbD

QBD IMPLICATIONS

QbD

Organization Process

Management

Personnel

QA/QC

IT

Technology

Understanding

IMPLICATIONS ON PERSONNEL

Employees need new skills Scientific data analysis Statistics Process control Very similar to 6 Sigma training structure

Master black belts Black belts Green belts

IMPLICATIONS ON PERSONNEL

Structural changes might be required There might be need for new Department There is a need for increased collaboration

between departments and functions Increased contact with regulatory authorities Clearly defined to accountability roles and

responsibility Interdisciplinary project team, QA, R&D, IT,

manufacturing

IMPLICATIONS ON MANAGEMENT

Commitment of management Initial phase will require more investment,

though there will be saving in the long run. Define the QbD development strategy, team,

goals, objectives, commit to resources, expected benefits

Might be risky to ignore QbD Regular review of the progress Choice of outsourcing partner Ensuring proper communication

IMPLICATIONS ON QA

Must be aware of changes in the regulatory process

The structure of audits will changeScrutiny will challenge scientific

understanding of quality factors and risk mitigation

More focus on the development Department

Comparison between real design space and documented design space

Documentation of improvements, changes and deviations

IMPLICATIONS ON QA

Validation Validation to focus on management of critical

to quality parameters Could be, real-time using PAT instead of three

batch Better process understanding Reduced

validation effort Software validation

Documentation Better process understanding may change

specifications Submissions would need to include design

space and control space

LINKING 4 AREAS OF PROCESS UNDERSTANDING

Risk managemen

t

QA/QC

Technology

IT

QbD

BASIC TERMINOLOGYDefinitions and acronyms

WHAT IS PQ?

What is Pharmaceutical Quality (PQ)? According to USFDA – a product should be called as of

pharmaceutical quality when it is - Free of Contamination Reproducibly delivers the therapeutic benefits

promised in the label to the consumer

Pharmaceutical Quality = f (Properties of Drug Substance, excipients, Mfg. Process, Packaging)

WHAT IS PHARMACEUTICAL QBD ?

It is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

OVERVIEW OF QBD

Labeled Use

Safety & Efficacy

Identify

Critical Material Attributes (CMA) &

Critical Process Parameters (CPP)

Design Formulation

Design Process

Define

Target Product Quality Profile (TPQP)

Knowledge Space

Establish

Control Strategy

Monitor & Update Process

Target --------------------------- Design ----------------------- Implementation

KEY COMPONENTS OF QBD

Target Product Profile (TPP) It is patient & labeling centered concept It includes

Route of administration Dosage form and size Max. & Min. Doses Pharmaceutical elegance (appearance) Target patient population

KEY COMPONENTS OF QBD

Target Product Quality Profile (TPQP) It is quantitative surrogate for aspects

of clinical safety & efficacy It includes quantitative targets for

Impurities & stabilityDissolution release profile & Other product specific performance

requirements e.g. Bioequivalence to the RLD for generic products Resuspendability for an oral suspension Adhesion for a transdermal system Viscosity for a topical cream etc.

KEY COMPONENTS OF QBD

Critical Quality Attributes (CQAs) These are Physical, chemical, biological or

microbiological properties or characteristics of final product that need to be controlled (directly or indirectly) to ensure product quality e.g. Dissolution test

CQAs include both Aspects of product performance Determinants of product performance

KEY COMPONENTS OF QBD

Critical Material Attributes (CMAs) These are Physical, chemical, biological

or microbiological properties or characteristics of raw materials & mfg. process parameters that need to be controlled to ensure product quality

These are independent of each other e.g. Particle Size & Hardness areCMAs

CQA of RM & Mfg. Process Parameters = CMA

KEY COMPONENTS OF QBD

Process Parameters (PP) It is any input operating parameter (mixing

speed, flow rate) and process state variable (temperature, pressure) of a process or unit operation

Classification of PP for a Unit Operation Unclassified Process Parameters (UPP) Critical Process Parameters (CPP) Non-critical Parameters (non-CPP)

CLASSIFICATION OF PROCESS PARAMETERS

Parameter Type Definition Sensitivity

non-CPP Not critical • No failure in target product quality profile (TPQP) observed or predicted in the potential operating space (POS), and• No interactions with other parameters in the proven acceptable range (PAR)

UPP Criticality Unknown

• Not established• The default in the absence of pharmaceuticalDevelopment

CPP Critical (control needed to ensure quality)

• Failure in target product quality profile (TPQP) observed or predicted in the potential operating space (POS), or• Interactions with other parameters in the proven acceptable range (PAR)

IDENTIFICATION OF PROCESS PARAMETERS

Wet Granulation

Material AttributesDrug Substance

DS AmountDS Form

DS Particle SizeDS Moisture Content

DS Bulk Density

Material AttributesExcipients

Exp. AmountExp. Particle SizeExp. Bulk Density

GranulationOperating ParametersChopper Configuration

Impeller SpeedGranulation TimeOrder of Addition

TemperatureSpray Nozzle Type

Binder Addition Rate

GranulationState Conditions

Power ConsumptionTemperature

Material AttributesAfter GranulationBlend Uniformity

Granule Size DistributionAgglomerate Size

MoistureBulk Density

Flow Properties

KEY COMPONENTS OF QBD

Design Space The multidimensional combination and

interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

A design space may be constructed for a single unit operation, multiple unit operations, or for the entire process

TOOLS TO IMPLEMENT QBD

Design of experiments (DOE) Risk assessment Process analytical technology (PAT)

DESIGN OF EXPERIMENT (DOE)

Structured, organized method for determining the relationship between factors affecting a process and the response of that process

DOE Methodology1. Choose Experimental Design (e.g. Full

Factorial design)2. Conduct randomized experiments3. Analyze data4. Create multidimensional surface model

RISK ASSESSMENT

Risk It is defined as the combination of the

probability of occurrence of harm and the severity of that harm

Risk assessmentA systematic process of organizing

information to support a risk decision to be made within a risk mgmt process.

It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards

PROCESS ANALYTICAL TECHNOLOGY (PAT) A system for designing, analyzing and

controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw & in process materials and processes with the goal of ensuring final product quality.

The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical and risk analysis conducted in an integrated manner.

CONCLUSIONThe End

CONCLUSION

Quality by design is an essential part of the modern approach to pharmaceutical quality

QbD is Win-Win

PAT, DOE and Risk Assessments are tools to facilitate the implementation of QbD.

THANK YOU!

Dr. Saurabh AroraPresentation will be available for download @

WWW.Lab-Training.Com