QbD for Pharma Products Development

QbD for Pharma Products Development
Dr. Basavaraj K. Nanjwade
Principal Scientist
Trroy Life Sciences Pvt Ltd
C-14, New Town Yelhanka
Bangalore-560064, Karnataka, India
1Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

Content
• Components of the Drug Product
• Drug Product
• Manufacturing Process Development
• Container Closure System
• Microbiological Attributes
• Compatibility
• Quality Target Product Profile
• Critical Quality Attributes
• Risk Assessment: Linking Material Attributes and Process Parameters
to Drug Products CQAs
• Design Space
• Control Strategy
• Product Lifecycle management and Continual Improvement
• Submission of Pharmaceutical Development and Related Information
in Common Technical Document (CTD) Format (3)

Quality by Design
A Systematic approach
• To development
• That begins with predefined objectives
• Emphasizes product and process understanding
• Process control
• Based on sound sciences and quality risk
management

Quality by Design
• Pharmaceutical quality refers to product free of
contamination and reproducibly delivers the therapeutic
benefit promised in the label to the consumer.
• The Quality of the pharmaceutical product can be
evaluated by in vivo or in vitro performance tests.
• Quality by design assures in vitro product performance
and In vitro product performance provides assurance of
in vivo product performance.

QbD Approach

QbD Tools
• Design of experiments (DoE)
• Risk assessment
• Process analytical technology (PAT)

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 and responses
to evaluate all the potential factors simultaneously,
systematically and speedily.
• With complete understanding of the process to assist in
better product development and subsequent process scale-up
with pretending the finished product quality and
performance.

Risk assessment
• Basic Risk Management Facilitation Methods
• Failure Mode Effects Analysis (FMEA)
• Failure Mode, Effects and Criticality Analysis (FMECA)
• Fault Tree Analysis (FTA)
• Hazard Analysis and Critical Control Points (HACCP)
• Hazard Operability Analysis (HAZOP)
• Preliminary Hazard Analysis (PHA)
• Risk Ranking and Filtering
• Supporting Statistical Tools

Process analytical technology (PAT)
• Multivariate tools for design, data acquisition
and analysis
• Process analyzers
• Process control tools
• Continuous improvement and knowledge
management tools

Quality by End Product Testing

Quality by Design

Traditional approach & Enhanced QbD approach
Aspects Non-QbD QbD
Pharmaceutical
Development
Empirical, Random,
Focus on optimization
Systematic, Multivariate
experiments, Focus on control
strategy and robustness
Manufacturing
Process
Fixed Adjustable within design space,
managed by company’s quality
systems
Process Control Some in-process testing PAT utilized, Process operations
tracked and trended
Product Specification Primary means of quality
control, based on batch
data
Part of the overall quality control
strategy, based on desired product
performance
Control Strategy By testing and inspection Risk-based control strategy , real-
time release possible

Components of the Drug Product
• Drug Substance: The physicochemical and biological
properties of the drug substance that can influence the
performance of the drug product and its
manufacturability, or were specifically designed into
the drug substance (e.g., solid state properties), should
be identified and discussed.
• Excipients: The excipients chosen, their concentration,
and the characteristics that can influence the drug
product performance (e.g., stability, bioavailability) or
manufacturability should be discussed relative to the
respective function of each excipient.

Drug Product
• Formulation Development: Any excipient
ranges included in the batch formula
• Overages: Amount of drug substance listed in
the batch formula.
• Physicochemical and Biological Properties:
Selection of dissolution vs. disintegration
testing

Manufacturing Process Development
• The manufacturing processes used to produce
batches for pivotal clinical trials (safety,
efficacy, bioavailability, bioequivalence) or
primary stability studies.
• Process robustness can be useful in risk
assessment and risk reduction

Container Closure System
• The choice and rationale for selection of the container
closure system for the commercial product (described
in 3.2.P.7) should be discussed.
• The choice of materials for primary packaging should
be justified.
• Justification for secondary packaging materials
should be included, when relevant.

Microbiological Attributes
• The selection and effectiveness of preservative
systems in products containing antimicrobial
preservative
• For sterile products, the integrity of the container
closure system as it relates to preventing
microbial contamination
• Antimicrobial preservative effectiveness should
be demonstrated during development.

Compatibility
• The compatibility of the drug product with
reconstitution diluents (e.g., precipitation,
stability) should be addressed to provide
appropriate and supportive information for the
labeling.
• This information should cover the recommended
in-use shelf life, at the recommended storage
temperature and at the likely extremes of
concentration.

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 and Efficacy of the
drug product.
Aditya Bangalore Institute of Pharmacy Education and Research 1910/03/2018

QTPP of Solution
QTPP Element Target Justification
Dosage Form Solution Same dosage form
Dosage Design IR Formulation Label claims
Route of Administration Oral/External
Dosage Strength
Drug Product Quality Attributes
Appearance
Assay
Content Uniformity
Impurities
pH of system
Microbial limits
Antimicrobial content
Antioxidant content
Extractable
Viscosity/Specification
Primary and Secondary Packaging
Pharmaco-Kinetics
Ease of Storage and Distribution
Stability and Self Life
Patient Acceptance and Patient Compliance

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.
• CQAs are generally associated with the drug substance,
excipients, intermediates (in-process materials), and
drug product.

CQA of Solution
Quality Attributes of Drug Product Target In this a
CQA?
Physical Appearances Colour, Odor & taste etc Yes
Identification Monograph Yes
Rheological properties (viscosity/specific
gravity
As Per Pharmacopoeia Yes
Assay 90.0 to 110.0% Yes
Weight variation/Content Uniformity Labelled claim (NMT 15.0%) Yes
Antimicrobial Preservative content As per Pharmacopoeia Yes
Antioxidant preservative content As per specification Yes
pH of System As per Pharmacopoeia Yes
Impurities/Degradation Product As per ICH Q3A&Q3B Yes
Microbiological Limits Conforms to USP, BP, IP Yes
Extractable Conforms to USP, BP, IP Yes
Dissolution As per specification Yes

Risk Assessment: Linking Material Attributes
and Process Parameters to Drug Products CQAs
• Risk assessment tools can be used to identify
and rank parameters (e.g., process, equipment,
input materials) with potential to have an
impact on product quality, based on prior
knowledge and initial experimental data.

Risk Assessment

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 parameter
• Most likely to affect the CQAs of an
intermediate or finished drug product and
therefore should be monitored or controlled.
• To ensure the process produces the desired
quality product.

Critical Material Attribute (CMAs)
Physico-Chemical
Properties
Critical Material Attribute
(CMAs)
Failure Mode Effect
Analysis (FMEA)
(Critical Event)
Physical Properties
Solid State Form Different Polymorph/form
Particle Size Distribution
(PSD)
High PSD
Moisture content High water content
Residual solvents High residual solvent
Chemical Properties
Solubility Different salt/Form
Volatility High
Process Impurities Less Purity
Chemical Stability Poor
Biological Properties Microbial Content High

Critical Material Attribute (CMAs)
Excipient (Inactive Ingredient) Critical Material Attribute Failure Mode (Critical Event)
Vehicles/Solvents Quantity of Vehicle/Solvent Less than optimum
More than optimum
Hydrocolloid (Suspending agent as
a structured vehicle)
Source of Hydrocolloid Natural
Concentration of Hydrocolloid
Less than optimum
More than optimum
Surfactants (As
Solubilizing/agents)
Ionic Nature of surfactant Cationic/Anionic in nature
Concentration of Surfactant
Less than optimum
More than optimum
Buffering Agent
pH of the Buffer
Within Neutral Range
Within Acidic/Basic Range
Anti-Microbial Concentration of Anti-Microbial Less than optimum
Anti-Oxidant Concentration of Anti-oxidant Less than optimum
Sweetener/Flavouring agent Concentration of sweetener/Flavour Not Optimum
Coloring agent Concentration of Coloring Agent Not Optimum

Critical Process Parameters (CPP)
Aditya Bangalore Institute of Pharmacy Education and Research 29
Unit Operations Critical Process Parameters (CPPs) Failure Mode (Critical Event)
Vehicle/Solvent Preparation Storage & Distribution
Rate of Addition Higher than Optimum
Filtration Rate
Heating Rate (Temp Time) Lower than Optimum
Higher than Optimum
Mixing Rate (Speed Time)
With Co-Solvents
Lower than Optimum
Solubilization of solid (API+Presevative) by surfactants Order of addition Incorrect
Impeller Design & Position Improper
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Higher than Optimum
Supporting by structured Vehicles Order of Addition Incorrect
Organoleptic addition with mixing Order of Addition Incorrect
Heating Rate (Temp Time) Higher than Optimum
pH Adjustment with Buffer & Final Volume make up with vehicle &
final mixing
Impeller Design & Position Improper
Heating Rate (Temp Time) Lower than Optimum
Higher than Optimum
Ultrafiltration in Colloidal mill
Type & Principle of Filter Improper
Filter Screen size Incorrect
Rate of Filtration Higher than Optimum
Filling, Capping & Sealling with nitrogen purging
Filling rate (Speed Time) Not Optimum
Higher than Optimum
Nitrogen purging rate Lower than Optimum
Capping & sealing rate Lower than Optimum
10/03/2018

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 and responses to
evaluate all the potential factors simultaneously, systematically
and speedily;
• With complete understanding of the process to assist in better
product development and subsequent process scale-up with
pretending the finished product quality and performance.

Design Space
The Multidimensional Combination and
Interaction of
• Critical Material Attributes and
• Critical Process Parameters that have been
demonstrated to provide assurance of quality.

Design Space
1. Selection of Variables
2. Describing a Design Space in a Submission
3. Unit Operation Design Space(s)
4. Relationship of Design Space to Scale and
Equipment
5. Design Space Versus Proven Acceptable
Ranges
6. Design Space and Edge of Failure

Design Space
33Aditya Bangalore Institute of Pharmacy Education and Research
Temperature
Pressure
Large square shows the ranges tested in the DOE
Red area shows points of failure
Green area shows points of success.
10/03/2018

1. Selection of Variables
• A description should be provided in the application of
the process parameters and material attributes
considered for the design space, those that were
included, and their effect on product quality.
• The rationale for inclusion in the design space should
be presented.
• In some cases, it is helpful to provide also the
rationale as to why some parameters were excluded.
• Knowledge gained from studies should be described
in the submission.

2. Describing a Design Space in a
Submission
• A design space can be described in terms of ranges of
material attributes and process parameters, or through
more complex mathematical relationships.
• It is possible to describe a design space as a time
dependent function (e.g., temperature and pressure
cycle of a lyophilisation cycle), or as a combination of
variables such as components of a multivariate model.
• Scaling factors can also be included if the design space
is intended to span multiple operational scales.
• Analysis of historical data can contribute to the
establishment of a design space.

3. Unit Operation Design Space(s)
• The applicant can choose to establish
independent design spaces for one or more unit
operations, or to establish a single design
space that spans multiple operations.
• While a separate design space for each unit
operation is often simpler to develop, a design
space that spans the entire process can provide
more operational flexibility.

4. Relationship of Design Space to
Scale and Equipment
• When describing a design space, the applicant should consider
the type of operational flexibility desired.
• A design space can be developed at any scale.
• The applicant should justify the relevance of a design space
developed at small or pilot scale to the proposed production
scale manufacturing process and discuss the potential risks in
the scale-up operation.
• If the applicant proposes the design space to be applicable to
multiple operational scales, the design space should be
described in terms of relevant scale-independent parameters.
• Dimensionless numbers and/or models for scaling can be
included as part of the design space description.

5. Design Space Versus Proven
Acceptable Ranges
• A combination of proven acceptable ranges
does not constitute a design space.
• However, proven acceptable ranges based on
univariate experimentation can provide useful
knowledge about the process.

6. Design Space and Edge of Failure
• It can be helpful to determine the edge of failure for
process parameters or material attributes, beyond
which the relevant quality attributes cannot be met.
• However, determining the edge of failure or
demonstrating failure modes are not essential parts of
establishing a design space.

Design Space for drying

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.

Control Strategy
• A planned set of controls for CMAs and 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

Control Strategy for CMA
Factors CMA’s Purpose of Control
Active Pharmaceutical Ingredient (API) CMA
Polymorphic Form 2 values To ensure batch to batch consistency in Dissolution
Excipient CMA
Vehicle Grade To ensure consistence compatibility, purity & Micro. Stab.
Surfactant Type (Tween 80) To ensure batch to batch consistency in solubility, pour
ability, Physical Stability & Compatibility
Concentration (%w/w)
Hydrocolloids Source (CMA)
Concentration (%w/w)
Sweetener Concentration (%w/w) To ensure batch to batch consistent Patient Acceptance &
Compliance
Flavor Concentration (%w/w)
Color Concentration (%w/w)
Anti-Microbial Concentration (%w/w) To ensure batch to batch consistency Chemical &
Microbiological stability
Anti-Oxidant Concentration (%w/w)
Buffer Concentration (%w/w)

Control Strategy for CPP
Factors (s) CPPs Purpose of Control
Vehicle/Solvent Preparation with
Sweetener, Flavor, Color
Heating Temperature To ensure consistance
compatibility, acceptability, purity
& Micro. Stability
Mixing Time
Controlled Solubilization by
surfactant & hydrocolloids
Heating Temperature To ensure batch to batch consiste
cy in Solubility, Pour ability,
Physical Stability & Compatibility
Mixing Time
pH Adjustment with Buffer &
Final Volume make up with
vehicle & final Mixing
Heating Temperature To ensure batch to batch
consistency Chemical &
Microbiological stability
Mixing Time
Ultrafiltration Particulate Matter Screen
Size
To ensure batch to batch purity to
warrant Safety
Microbial Filter Screen Size
Filling, Capping & Sealing Temperature To ensure Chemical Stability
Vacuum Pressure with
Nitrogen Purging

Product Lifecycle Management and
Continual Improvement
• Throughout the product lifecycle, companies have
opportunities to evaluate innovative approaches to
improve product quality
• Process performance can be monitored to ensure that it is
working as anticipated to deliver product quality
attributes as predicted by the design space.
• Expansion, reduction, or redefinition of the design space
could be desired upon gaining additional process
knowledge.
• Change of design space is subject to regional
requirements.

Continual Improvement
Risk Review and Risk Communication
Lifecycle
Management
Formulation
R&D
Analytical
R&D
Regulatory
Affairs
Manufacturing
Plant
Quality
Assurance
Quality
Control

SUBMISSION OF PHARMACEUTICAL
DEVELOPMENT (3)
• Quality Risk Management and Product and Process
Development
• Design Space
• Control Strategy
• Drug Substance Related Information

Quality Risk Management and Product
and Process Development (3.1)
• Quality risk management can be used at different stages
during product and process development and
manufacturing implementation.
• The assessments used to guide and justify development
decisions can be included in the relevant sections of P.2.
• For example, risk analyses and functional relationships
linking material attributes and process parameters to
product CQAs can be included in P.2.1, P.2.2, and P.2.3.
• Risk analyses linking the design of the manufacturing
process to product quality can be included in P.2.3.

Design Space (3.2)
• As an element of the proposed manufacturing process, the design space(s)
can be described in the section of the application that includes the
description of the manufacturing process and process controls (P.3.3).
• If appropriate, additional information can be provided in the section of the
application that addresses the controls of critical steps and intermediates
(P.3.4).
• The product and manufacturing process development sections of the
application (P.2.1, P.2.2, and P.2.3) are appropriate places to summarize and
describe product and process development studies that provide the basis for
the design space(s).
• The relationship of the design space(s) to the overall control strategy can be
discussed in the section of the application that includes the justification of
the drug product specification (P.5.6).

Control Strategy (3.3)
• The section of the application that includes the
justification of the drug product specification
(P.5.6) is a good place to summarize the overall
drug product control strategy.
• However, detailed information about input
material controls and process controls should still
be provided in the appropriate CTD format
sections (e.g., drug substance section (S), control
of excipients (P.4), description of manufacturing
process and process controls (P.3.3), controls of
critical steps and intermediates (P.3.4)).

Drug Substance Related Information (3.4)
• If drug substance CQAs have the potential to affect
the CQAs or manufacturing process of the drug
product, some discussion of drug substance CQAs
can be appropriate in the pharmaceutical development
section of the application (e.g., P.2.1).

Benefits of QbD
• Better understanding of the process.
• Less batch failure.
• More efficient and effective control of change.
• Return on investment / cost savings.
• An enhance QbD approach to pharmaceutical
development provides opportunities for more flexible
regulatory approaches.

Benefits of QbD
• Consistent product quality
• Reduced risk of recalls
• Real-time release
• Cost Reduction
• Reduced inventories
• Less waste
• Higher yields
• Increased process understanding resulting in more efficient production
processes
• Faster process development, upscaling and tech transfer
• Regulatory flexibility, relief and easier regulatory approach
• Improved clinical outcome quality
• Easy Technology Transfer

Manufacturing changes within the approved design space
• Reduction of post-approval submissions.
• Better innovation due to the ability to improve processes without
resubmission to the FDA when remaining in the Design Space.
• More efficient technology transfer to manufacturing.
• Greater regulator confidence of robust products.
• Risk-based approach and identification.
• Innovative process validation approaches.
• Less intense regulatory oversight and less post-approval
submissions.
• For the consumer, greater drug consistency.
• More drug availability and less recall.

Manufacturing changes within the approved design space
• Improved yields, lower cost, less investigations, reduced testing, etc.
• Time to market reductions: from 12 to 6 years realized by amongst
others.
• First time right: lean assets management.
• Continuous improvement over the total product life cycle (i.e.
controlled, patient guided variability).
• Absence of design freeze (no variation issues).
• Less validation burden.
• Real time controls (less batch controls).
• Realistic risk perceptions.
• Contributes substantially to realize the better, cheaper and safer
mandate.

QbD activities within FDA
• In FDA’s Office of New Drug Quality Assessment
(ONDQA), a new risk-based pharmaceutical quality
assessment system (PQAS) was established based on the
application of product and process understanding.
• Implementation of a Question-based Review (QbR)
Process has occurred in CDER’s Office of Generic Drugs.
• Implementation of QbD for a Biologic License
Application (BLA) is progressing.

International Conference on
Harmonization (ICH)
• Pharmaceutical Development Q8 (R2)
• Quality Risk Management Q9
• Pharmaceutical Quality System Q10 (Science-
based and risk- based approaches)

International Conference on
Harmonization (ICH)
• The difference between QbD for NDA and
ANDA products is most apparent at the first
step of the process.
• For an NDA, the target product profile is under
development while for the ANDA product the
target product profile is well established by the
labelling and clinical studies conducted to
support the approval of the reference product.

RPN = Probability* Severity* Detectability
Probability Severity Detectability
Probability of Risk occurrence
can reduced by systematic
series of experiments through
Designing of Experiments
(DoE)
Severity of Risks
could not be reduced
Detectability of Risk can
increased by implementation of
automatic inline
Process Analytic Technology
(PAT)
Which generated safe and
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
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.
RPN (Risk Priority Number) more than 30 seek critical attention for DoE for possible failure
10/03/2018

Total Risk Priority Number (RPN)
Probability Severity Delectability Score
Very Unlikely Minor Always Detected 01
Occasional Moderate Regular Detected 02
Repeated Major Likely Detected 03
Regular Extreme Normally not Detected 04
Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure
10/03/2018

Quality Target product Profile (QTPP)
-Therapeutic Equivalence for Generic Drug Product
-Pharmaceutical Equivalence (same dosage form, route of administration, strength and same quality)
-Bio-Equivalence (same pharmacokinetics in terms of Cmax, AUC to reference product)
Critical Quality Attributes (CQAs)
-Quality: Assay, Uniformity of Dosage units
-Safety: Impurities (Related substances), Residual Solvents, Microbiological limits
-Efficacy: Dissolution & Absorption &
-Multidisciplinary: Patient Acceptance & Compliance
Quality Risk Assessment of CMAs & CPPs with CQAs
-Risk Identification by Ishikawa Fishbone
-Risk Analysis by Relative Risk Based Matrix Analysis
-Risk Evaluation by Failure Mode Effective Analysis (FMEA)
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.
10/03/2018

62Aditya Bangalore Institute of Pharmacy Education and Research
THANK YOU
10/03/2018

QbD for Pharma Products Development

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