Understanding
Quality by design (QbD)
in Pharmaceuticals
Dr. Khushwant Yadav
SPP SPTM
SVKM’s NMIMS
Quality by design (QbD) is a
concept first developed by the
quality pioneer
Dr. Joseph M. Juran.
Dr. Juran believed that quality
should be designed into a
product, and that most quality
crises and problems relate to
the way in which a product was
designed in the first place.
“Quality Cannot Be
Tested Into Products; It
Has To Be Built In By
Design”
“Continuous improvement is a hallmark of quality
by design”
Taguchi on Robust Design:
Design changes during manufacture can result in the last
product produced being different from the first product
Quality:
The degree to which a set of inherent
properties of a product, system or process
fulfills requirements. (ICH Q9)
What is Quality by Design (QbD) ?:
QbD is defined as “a systematic approach to development that
begins with predefined objectives and emphasises product and
process understanding based on sound science and quality risk
management”.
According to FDA, QbD means Designing and developing a product and
associated manufacturing processes that will be used during product
development to ensure that the product consistently attains a predefined
quality at the end of the manufacturing process
Quality: The suitability of either a drug substance or a drug
product for its intended use. This term includes such
attributes as the identity, strength, and purity (ICH Q6A).
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 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.
Control Strategy: A planned set of controls, derived from current
product and process understanding that ensures process performance
and product quality. The controls can include parameters and attributes
related to drug substance and drug product materials and components,
facility and equipment operating conditions, in-process controls, finished
product specifications, and the associated methods and frequency of
monitoring and control. (ICH Q10)
Critical Process Parameter (CPP): A process parameter whose variability
has an impact on a critical quality attribute and therefore should be
monitored or controlled to ensure the process produces the desired
quality.
Critical Quality Attribute (CQA): 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.
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. Working within the design space is not considered as a change.
Movement out of the design space is considered to be a change and would normally
initiate a regulatory post approval change process. Design space is proposed by the
applicant and is subject to regulatory assessment and approval (ICH Q8).
According to Woodcock
A high- Quality drug product is defined as a product free of
contamination and reliably delivering the therapeutic benefit promised
in the label to the consumer.
The US Food and Drug Administration (FDA) encourages risk-based
approaches and the adoption of QbD principles in drug product
development, manufacturing, and regulation.
FDA’s emphasis on QbD began with the recognition that increased
testing does not necessarily improve product quality. Quality must be
built into the product.
Quality-By-Design documents providing high level directions with respect
to the scope and definition of QbD as it applies to the pharmaceutical
industry
Over the years, pharmaceutical QbD has evolved with the
issuance of:
ICH Q8 (R2) (Pharmaceutical Development),
ICH Q9 (Quality RiskManagement), and
ICH Q10 (Pharmaceutical Quality System)
In addition, the ICH Q1WG on Q8, Q9,andQ10 Questions and
Answers;
the ICHQ8/Q9/Q10 Points to Consider document; and
ICH Q11 (Development and Manufacture of Drug Substance)
QbD Elements include the following:
(1) a quality target product profile (QTPP) that identifies the critical quality
attributes (CQAs) of the drug product;
(2) product design and understanding including identification of critical material
attributes (CMAs);
(3) process design and understanding including identification of critical process
parameters (CPPs), linking CMAs and CPPs to CQAs;
(4) a Control Strategy that includes specifications for the drug substance(s),
excipient(s), and drug product as well as controls for each step of the
manufacturing process; and
(5) Process Capability and Continual improvement
QbD Tools and studies include:
Prior knowledge,
Risk assessment,
Mechanistic models,
Design of Experiments (DoE) and Data Analysis, and
Process Analytical Technology (PAT).
QbD Elements
QbD uses a science and risk-based approach that emphasizes the importance
of developing scientific knowledge and thorough understanding of both the
product and the process
A successful QbD approach:
- Better Understanding of products
- More Robust manufacturing processes
- Potential for timely and flexible regulatory approval
The US Food and Drug Administration (FDA) and other health authorities
are also engaged in applying QbD to pharmaceutical development and
manufacturing.
The Foundation for pharmaceutical companies to implement QbD in their
operations and product development has been by
Several International Conferences on Harmonization (ICH)
guidance documents (ICH Q8, ICH Q9, ICH Q10, and ICH Q11), and the
FDA Process Analytical Technology (PAT) guidance.
1. Quality Target Product Profile
The QbD approach begins with the Target Product Profile (TPP)
establishment of quality target product profile The establishment of a good
(QTPP). understanding of the target product
Definition profile (TPP) is an important step in
The QTPP is a prospective summary of the determining QTPP. The TPP provides a
quality characteristics of a Drug Product that statement of the overall intent of the drug
ideally will be achieved to ensure the desired development program and gives
quality, taking into account safety and efficacy information about the drug at a particular
of the product. (ICH 2009) time in its development lifecycle.
All important information from the TPP
(or equivalent source) that describes the use,
safety and efficacy of the product is utilizes
in developing QTPP.
In addition, it also includes the understanding
of scientific knowledge, health authority
requirements and in case of the Drug Product
intrinsic Active Product Ingredient
(API) properties.
The QTPP is derived from an understanding of the mode of action of the
product, patient profile, clinical indication, desired safety profile, and where
appropriate, includes Quality characteristics related to:
➢ Route of administration
➢ Intended Use
➢ Dosage Form
➢ Delivery system
➢ Dosage strength
➢ Container closure system
• Drug Product dosage form being developed
Therapeutic moiety release or delivery and attributes affecting
pharmacokinetic characteristics (e.g., dissolution, aerodynamic
performance) appropriate to the
• Drug Product quality criteria (e.g., sterility, purity, stability, and drug
release) appropriate for the intended marketed product
Inputs to and outputs from the
Quality Target Product Profile
(QTPP)
Clinical Control Strategy Commercial Control Strategy
Scientific Increasing Product Knowledge &
Knowledge Clinical Experience
Intrinsic API
Properties
Final
pCQAs CQAs
Target QTPP New CQAs
Control
Product Strategy
Profile (TPP)
Regulatory
Requirements
Establishment of the QTPP is a critical step for a QbD approach.
The QTPP includes not only the relevant information from the product
specification but also
patient relevant product performance.
For example, if the viscosity of a high concentration product is critical to the
reconstitution or delivery of the Drug Product, then the QTPP should
include viscosity information.
The QTPP is a living document that can change as more information
become available.
-When changes are made to the TPP or other key elements, a reevaluation
must be performed to assess
impact to the QTPP.
-The QTPP may be updated to reflect new knowledge about the product
and changes in the clinical development program.
Table: QTPP for A-MAb1
2. Critical Quality Attributes
Definition
ICH Q8 defines a CQA as a physical, A CQA is a
chemical, biological, or microbiological Product
property or characteristic that should be attribute and
within an appropriate limit, range, or
not an
distribution to ensure the desired product
quality (ICH 2009). Analytical Test
Safety and efficacy clearly fall under the
domain of the TPP
potential CQAs (pCQAs)
Obligatory CQA During product development, potential
An obligatory CQA is an attribute CQAs (pCQAs) are identified based on an
required by a health authority to be iterative applicationof risk-based tools.
either monitored or controlled as part
of the product’s control strategy. The list of pCQAs and their risk scores
will be further modified as product
knowledge increases through the various
stages of product development.
✓ At the time of filing for approval, the potential CQAs
become CQAs and should reflect the current knowledge
and understanding of the impact on patient safety and
product efficacy.
✓ When there is a change in a CQA, the impact on the design
space and control strategy should be assessed and updated
if necessary
Identifying CQAs
CQAs are generally linked with the drug substance, excipients, intermediates
(in process materials) and drug product.
For example
CQAs of solid oral dosage forms are typically those aspects affecting product
purity, strength, drug release and stability.
Whereas, for parentrals they are Sterility and clarity.
The CQAs can additionally include properties like
▪ particle size distribution
▪ bulk density that affect drug product.
Mostly CQAs are derived from the QTPP
and/or
Prior knowledge is used to guide the product & process development
and Subsequently
CQAs are accessed for risk management
3. Critical Process Parameters (CPPs)
& Design Space
Once pCQAs are identified, the next important step in the QbD process is to Define
CPPs and Design Space.
This work is usually done in parallel with the Identification and Characterization of
CQAs.
Definition Definition
Critical Process Parameters Design Space
(CPPs) The concept of design space has been
A CPP is defined as a process defined as “The multidimensional
parameter whose variability has combination and interaction of input
an impact on a critical quality variables (e.g., material attributes and
attribute and therefore should be process parameters) that have been
monitored demonstrated to provide assurance of
and controlled to ensure the quality within an acceptable range.”
process produces the desired ICH Q8 (R2)
quality (ICH, 2006).
➢ A design space can be applied to a single unit operation, multiple
unit operations, or the entire process.
➢ The establishment of a design space for a manufacturing process is
based on a good understanding of how the process impacts the
CQAs.
➢ The limits of the design space should correspond to the acceptable
ranges for the CQAs.
➢ In general, “a change within the established design space for a
manufacturing process is not considered as a significant change,”
while moving beyond the established design space is considered to
be a significant change and would require pre-approval by the
health authorities. In addition, more extensive preclinical or clinical
data may also be required to support such a change.
QbD ROADMAP and INTERLINKING of KEY-ELEMENTS
CQA Analytical Testing
Identification Strategy
Process
Development Increasing Product Knowledge
Knowledge Final
from Potential Control
Similar
CQAs Strategy
CQAs
Molecules Lifecycle
Management
Product
Plan
Understanding Process Design Space &
Multi-Step DoE or
Characterization & CPP Identification
Scientific Linkage Studies
Validation
Literature
Increasing Process Knowledge
Process
Characterization CPP & Design Space
Study Design Identification
Knowledge Management
4. Control Strategy and Control System
The control strategy is a key element of the QbD process. The
control strategy refers to a set of planned controls, derived from
current product and process understanding that ensures process
performance and product quality. One of the important parts of
control strategy is to establish a control system. A control system
is a set of defined controls and their established acceptance
criteria (or limit) based on product understanding that assures
product quality.
The control strategy comprises several elements including
• Raw material controls
• Process control via procedural & process parameter control
• In-process, lot release, and stability testing
• Testing to demonstrate comparability
• Testing done as part of process monitoring.
Raw material controls are controls relating to raw materials, excipients,
buffer components, etc. used in the formulation and manufacturing
processes, including supplier quality management, raw material
qualification, and raw material specifications.
Procedural controls are a comprehensive set of facility, equipment, and
quality system controls that result in robust and reproducible operations
and product quality.
Process parameter controls are linked to CPPs that must be controlled
within the limits of the design space to ensure product quality.
In-process testing is conducted using analytical test methods or
functionality test to ensure that selected manufacturing operations
are performing satisfactorily to achieve the intended
product quality.
Lot release testing is related to the testing at final lot release on a
set of quality attributes to confirm quality of the Drug Substance
or Drug Product.
Some of the attributes will also be tested as part of the stability
testing.
Characterization and comparability testing are often used to test certain
attributes beyond lot release testing for the purpose of intermittent
process monitoring or demonstration of comparability when a change is
being implemented (e.g., licensing a new production facility or modified
manufacturing process).
Process monitoring is the testing or evaluation of selected attributes or
parameters to trend product quality or process performance within the
design space and/or enhance confidence in an attribute’s normal
distribution.
Explain with suitable example how the different elements of control
strategy are determined using a risk-based assessment
The focus of the control strategy for a pharmaceutical is typically the
testing strategy for each attribute.
It should be determined using a risk-based assessment related to
the understanding of the potential impact of the quality attribute on
the safety and efficacy of the product
The testing strategy for each
attribute is typically developed using Interrelationship
a risk assessment tool and is also between
often confirmed using a separate risk Control strategy
assessment to determine the robustness and Design space
of the resulting testing strategy.
Establishing the control strategy
One approach for determining the testing strategy for each identified attribute is
to use a risk assessment tool that incorporates that quality attribute criticality and the
risk that an attribute will exceed the acceptable range for the CQA when the process
is operated within its design space or during with Drug Substance and Drug Product
storage in the recommended conditions.
The assessment would be performed for each quality attribute during Drug Substance
manufacturing, Drug Product manufacturing, Drug Substance stability, and Drug
Product stability.
From this evaluation, one of three possible outcomes is identified
for each quality attribute
1. Control system testing is required (in-process, lot release,
and/or stability testing)
2. Testing is required as part of process monitoring or to
support comparability
3. No testing is required.
Control System Testing
Control system testing includes:
in-process testing (e.g., bioburden, endotoxin),
product release testing (e.g., product attributes, adventitious agents,
impurities) and
stability testing (e.g., stability indicating product attributes).
Process Monitoring
Process monitoring programs should be designed to provide ongoing assurance
and verification that product quality is appropriately controlled during routine
commercial manufacturing.
The process-monitoring program is designed to meet the following criteria:
• Provide assurance that the process is operating in a validated state
• Provide knowledge to enhance process understanding
• Identify adverse trends and opportunities for process improvements
The comparability assessment considers product quality (physicochemical
characterization of the product), stability (degradation), and process
performance (key performance indicators and removal of process-related
impurities).
Quality Risk Management (QRM)
➢ Quality risk management (QRM) helps to identify and control potential
quality issues from early stages of development to marketing and large-
scale manufacturing for biopharmaceutical drug products.
➢ It gives a higher level of product quality assurance.
➢ It increases cost saving and efficiency for industry as well as regulators.
➢ For sponsors, it facilitates innovation, increases manufacturing
efficiency, reduces cost and product rejections, minimizes or eliminates
potential compliance actions, enhances opportunities for first cycle
approval, and streamlines post-approval changes and regulatory
processes.
➢ It also offers opportunities for continuous improvement.
➢ For regulators, it helps in more focused inspections and reduces burden
of post-approval supplements.
risk priority number (RPN) score
A risk priority number (RPN) score is calculated based on the
➢ Severity of operational parameter excursion ( S),
➢ Frequency Of Occurrence of the excursion ( O), and
➢ ease or difficulty of Detection of the excursion ( D).
These three aspects are each given a numeric value, usually between 1 and 10 (with
10 being highest risk).
An RPN score (= S × O × D) has been used in prioritizing activities and plans for
risk management and has been applied in various process development studies
Once the initial risk assessment is performed, all the factors can be identified
that could impact the CQAs. However, in order to manage and/control those
that pose a significant risk, risk analysis at times is often performed.
This process assigns a score depending upon the severity (impact) and
occurrence (frequency) as well as ease of detectability in case of an
excursion. Risk priority number (RPN) scores are calculated as shown below.
Risk priority number = Severity X Occurrence X Detectability
It is often challenging to assign a rating for severity,
occurrence, and detectability, especially if there is little
institutional knowledge regarding the product or process.
A consistent scale should be used each time to prevent bias or
variable results Often times, low scoring can be justified based
on experience, literature, or expert knowledge. However, since
this exercise is done without any prior experiments, it is often
times semi-quantitative
Lifecycle and Knowledge Management
Definition
➢ A post-approval lifecycle management (PALM) plan is a formal
document that explains:
how a product is managed within the QbD framework post
regulatory licensure.
➢ Health authorities expect that a product developed using QbD
has a formalized lifecycle management plan.
➢ The health authorities also expect that there is a formal
knowledge management program that archives and updates
documents associated with product and process knowledge, as
well as the documents summarizing the outputs of the QbD
strategy.
Components of the lifecycle management plan
(PALM)
• The lifecycle management plan explains how changes to the
critical process parameter (CPP) operating targets are
managed within and outside of design space.
• For a change to a CPP target within the design space, the level
of pre- and post-implementation testing is determined by the
level of risk and the potential for the change to impact a
CQA.
➢ The risk is assessed based on considerations such as CPP criticality, the
product quality attributes affected, and the classification of those
product quality attributes.
➢ There is pre-implementation and post implementation/ verification
testing.
➢ The post-change assessment testing is meant to verify that the change
had the desired result and that the design space continues to be valid for
the manufacturing process.
➢ The PALM also explains how changes to a non-CPP (operating
target and/or ranges) are managed as well. Since non-CPPs do not
impact CQAs, the assessment of these changes typically focus on key
performance indicators.
The lifecycle management plan may
also be included in the product
registration documentation
and, if so, then
the PALM becomes a regulatory
agreement between the health
authority and the company
The PALM is a key facilitator of knowledge
management as it requires the outputs
of the QbD strategy to be re-evaluated as new
process and product knowledge
is gained and requires that information and any
changes to CQAs, CPPs, design
space, and control strategy to be documented
and justified.
