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A comprehensive review on quality by design (QbD) in pharmaceuticals

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Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013; n° 37, 223-236 ISSN 0976 – 044X

Review Article

A Comprehensive Review on Quality by Design (QbD) in Pharmaceuticals

1 1 1
Hardik Patel* , Shraddha Parmar , Bhavna Patel
1
Post Graduate Department of Pharmaceutical Sciences, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India.
*Corresponding author’s E-mail: [email protected]

Accepted on: 22-04-2013; Finalized on: 30-06-2013.

ABSTRACT
Quality by Design (QbD) refers to a holistic approach towards drug development. Quality by design is a vital part of the modern
approach to pharmaceutical quality. There is much confusion among pharmaceutical scientists in generic drug industry about the
appropriate element and terminology of quality by design. The purpose of this paper is to discuss the pharmaceutical Quality by
Design (QbD) and illustrate how it can be used to ensure pharmaceutical quality. The QbD is a systemic approach to pharmaceutical
development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality.
Some of the QbD elements include: Defining Quality target product profile, Identifying critical quality attributes, link the drug
excipients attributes, establishing design space, control strategy, and product life cycle management. Using QbD, pharmaceutical
quality is assured by understanding and controlling formulation and manufacturing variables. A new approach to drug development
could increase efficiencies, provide regulatory support and flexibility, and offer important business benefits throughout the
product’s life cycle. This article explores the processes used in developing a market formulation and required supportive data,
particularly in light of the industry’s current movement toward submissions based on QbD. The work also facilitates the adoption
and implementation of QbD. principles in the development of pharmaceutical industries. Successful implementation of QbD
concepts requires cooperation across a multitude of company teams, from R&D to manufacturing to quality control and regulatory
affairs. This is necessary to ensure that QbD concepts are incorporated not only when the first activities are initiated around a
product’s design but also during the design of the process used to make the product and other activities associated with a product’s
life cycle. The application of the concept of quality by design (QbD) presented in this paper aligns with the principles of ICH Q8, Q9
and Q10 guidelines.
Keywords: control strategy, critical material attributes, critical process parameters, design space, Quality by design.

INTRODUCTION describes how it can be used to ensure pharmaceutical

quality with emphasis on solid oral dosage forms of small

Q uality by Design (QbD) was first described by

Joseph M. Juran1, and applied heavily, particularly
in the automotive industry. The fundamental
premise behind QbD is that quality can be “designed in”
molecules. The pharmaceutical industry works hard to
develop, manufacture, and bring to market new drugs—
and to comply with regulatory requirements to
demonstrate that the drugs are safe and effective. A new
to processes through systematic implementation of an
approach to drug development could increase
optimization strategy to establish a thorough
efficiencies, provide regulatory relief and flexibility, and
understanding of the response of the system quality to
offer important business benefits throughout the
given variables, and the use of control strategies to
product’s life cycle. This article explores the processes
continuously ensure quality. The FDA has recently begun
used in developing a market formulation and requisite
to advocate the QbD methodology for the pharmaceutical
supportive data, particularly in light of the industry’s
sector.2
current movement toward submissions based on quality
In order to describe quality by design, we must first by design (QbD). It outlines activities that should be
define what we mean by quality. In a 2004 paper, Janet performed early in the drug development process before
Woodcock (Director for the Centre for Drug Evaluation initiating manufacturing and attempting market entry.
and Research) defined pharmaceutical quality as a The article identifies the type of data needed to address
‘product that is free of contamination and reproducibly regulatory concerns and provides a pragmatic baseline for
delivers the therapeutic benefit promised in the label to manufacturing facility requirements. Finally, it introduces
the consumer’.3 new technologies that support the QbD approach. This
paper describes a concise, coherent, and universal
‘Quality in manufacturing is a measure of Excellence or a
approach for determining criticality for parameters,
state of being free from defects, deficiencies, and
material attributes, conditions, and quality attributes. The
significant variation’.
work also explains the risk based distinctions governing
This explanation focuses on the QbD for generic drugs. the assignment of criticality to provide consistency and
The concept of QbD was mentioned in the ICH Q8 facilitate the adoption and implementation of Quality by
guidance, which states that “quality cannot be tested into Design (QbD) principles in the development of
products, i.e., quality should be built in by design”. This pharmaceutical manufacturing processes. This paper
paper discusses the pharmaceutical quality by design and describes an approach and technical process for

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developing and implementing a Control Strategy, which is concentrated on acceptance limits or statistical aspects.
a planned set of controls, derived from current product FDA reviewers’ conservatism results from the fact that
and process understanding that assures process manufacturers may not understand how drug substance,
performance and product quality. Development of a excipients, and manufacturing processes affect the
Control Strategy requires a structured process, involving a quality of their products or they do not share this
multidisciplinary team of experts, linking pharmaceutical information with FDA reviewers. Under the traditional
development to the manufacturing process, and regulatory evaluation system, all products are treated
engineering controls of process equipment. This paper equally without regard to the risk to the consumer.12 This
concentrates on the techniques and principles involved in has the effect of placing too much review time on low-risk
developing the early Control Strategy rather than the products and more significantly, takes away needed
operational implementation of the strategy. This paper resources from the review of high-risk products. CMC
describes progress made by the Design Space within the review assessments of complex dosage forms (modified
Product Quality Lifecycle. Product quality attributes can release products, topicals and transdermals) as well as
be accurately and reliably predicted over the design space narrow therapeutic index (NTI) drugs differ only
established for materials used, process parameters, marginally from those of simple dosage forms (many
environmental and other conditions. The focus of this immediate release solid oral products). Further, all CMC
paper is on the technical elements of Design Space information in applications are sometimes evaluated
4, 5
development. equally, without differentiation of criticality, resulting in
the requirement of intensive resources for each
QUALITY
application.
“The degree to which a set of inherent properties of a
In summary, product quality and performance are, in the
product, system or process fulfils requirements” (ICH Q9)
traditional framework, achieved predominantly by
“Good pharmaceutical quality represents an acceptably restricting flexibility in the manufacturing process and by
low risk of failing to achieve the desired clinical end product testing. The present regulatory review
attributes.” system places little or no emphasis on how the design of
an effective and efficient manufacturing process can
Pharmaceutical Quality by Testing
ensure product quality. As a result, the complexities of
Product quality is ensured by raw material testing, drug process scale-up, particularly for complex dosage forms
substance manufacturing, a fixed drug product are often not recognized. Product specifications often are
manufacturing process, in-process material testing, and derived using test data from one or more batches (often
end product testing. If they meet the manufacturer’s not at production scale), and mechanistic understanding
proposed and FDA approved specifications or other does not play a significant role in this process. Finally, the
standards such as USP for drug substance or excipients, burdensome regulatory requirement of supplements
they can be used for the manufacturing of the products.6 imposed on manufacturers for executing minor and
Since a few tablets out of several million are tested, drug incremental changes to manufacturing processes and
manufacturers are usually expected to conduct extensive controls inhibits continuous improvement and strategies
in process tests, such as blend uniformity, tablet for the implementation of continuous “real time”
hardness, etc; to ensure the outcome of in-process assurance of quality.
testing also meets the FDA approved in-process testing
Pharmaceutical Quality by Design
specifications. Manufacturers are also not permitted to
make changes to the operating parameters specified in QbD is a systematic approach to development that begins
the batch record or other process changes without filing with predefined objectives and emphasizes product and
supplements with the FDA. As a result, the FDA has been process understanding and process control based on
overwhelmed by the number of Chemistry, sound science and quality risk management (ICH Q8(R))
Manufacturing, and Controls (CMC) supplements filed in
QbD means designing and developing formulations and
recent years. For example, in 2005 and 2006, the FDA
manufacturing processes to ensure predefined product
Office of Generic Drugs received over 3,000 CMC
quality. Thus, QbD requires an Understanding and
supplements annually.7-10 This combination of fixed
controlling formulation and manufacturing process
manufacturing steps and extensive testing is what
variables influence product quality.
ensures quality under the traditional system. Limited
characterization of variability, inadequate understanding Relevant documents from the International Conference
to identify and quantify critical process parameters, and on Harmonization of Technical Requirements for
caution on the part of regulators leads to a very rigid and Registration of Pharmaceuticals for Human Use (ICH), ICH
inflexible specifications that prohibit the release of Q8, Pharmaceutical Development, along with ICH Q9,
products that may have acceptable clinical performance Quality Risk Management, and ICH Q10, Pharmaceutical
11
.Significant industry and FDA resources are spent Quality Systems, indicate on an abstract level how quality
debating issues related to acceptable variability, need for by design acts to ensure drug product quality.
additional testing controls, and establishment of
specification acceptance criteria. Often these debates are
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ICH Q8 defines quality as “The suitability of either a drug  Control manufacturing processes to produce
substance or drug product for its intended use. This term consistent quality over time.
includes such attributes as the identity, strength, and
Under the QbD concept, pharmaceutical quality for
purity.” ICH Q6A emphasizes the role of specifications
stating that “Specifications are critical quality standards generic drugs is assured by understanding and controlling
that are proposed and justified by the manufacturer and formulation and manufacturing variables. End product
approved by regulatory authorities.”13 Pharmaceutical testing confirms the quality of the product and is not part
QbD is a systematic, scientific, risk-based, holistic and of the manufacturing consistency or process control.
proactive approach to pharmaceutical development that Under QbT a product specification is often set by
observing data from a small number of batches believed
begins with predefined objectives and emphases product
and processes understanding and process control.14 It to be acceptable and then setting acceptance criteria that
means designing and developing formulations and required future batches to be the same. Under QbD
manufacturing processes to ensure predefined product consistency comes from the design and control of the
quality objectives. QbD identifies characteristics that are manufacturing process and the specification of drug
critical to quality from the perspective of patients, product under QbD should be clinically relevant and
generally determined by product performance. QbD
translates them into the attributes that the drug product
should possess, and establishes how the critical process requires an understanding how formulation and process
variables influence product quality. These discussions
parameters can be varied to consistently produce a drug
product with the desired characteristics.15 In order to do have generally focused on the development of new drugs.
this the relationships between formulation and Drawing on these discussions and some specific aspects
manufacturing process variables (including drug of the development of generic products, a QbD
substance and excipient attributes and process development process may include & begin with a target
product profile that describes the use, safety and efficacy
parameters) and product characteristics are established
and sources of variability identified. This knowledge is of the product & Define a target product quality profile
that will be used by formulators and process engineers as
then used to implement a flexible and robust
manufacturing process that can adapt and produce a a quantitative surrogate for aspects of clinical safety and
consistent product over time. efficacy during product development & Gather relevant
prior knowledge about the drug substance, potential
excipients and process operations into a knowledge
space. Use risk assessment to prioritize knowledge gaps
for further investigation & Design a formulation and
identify the critical material (quality) attributes of the
final product that must be controlled to meet the target
product quality profile & Design a manufacturing process
to produce a final product having these critical material
attributes & identify the critical process parameters and
raw material attributes that must be controlled to achieve
these critical material attributes of the final product. Use
risk assessment to prioritize process parameters and
material attributes for experimental verification. Combine
prior knowledge with experiments to establish a design
space or other representation of process understanding &
establish a control strategy for the entire process that
may include raw material controls, process controls and
monitors, design spaces around individual or multiple unit
operations, and final product tests. The control strategy
Figure 1: Overview of QbD should include expected changes in scale and can be
Thus, some of the QbD elements may include, guided by a risk assessment & continually monitor and
update the process to assure consistent quality Design of
 Define quality target product profile that describes experiments (DOE), risk assessment, and process
the use, safety and efficacy of the product. analytical technology (PAT) are tools that may be used in
 Design and develop product and manufacturing the QbD process when appropriate. The difference
processes. between QbD for NDA and ANDA products is most
apparent at the first step of the process. For an NDA, the
 Identify critical quality attributes, process target product profile is under development while for the
parameters, and sources of variability. ANDA product the target product profile is well
established by the labelling and clinical studies conducted
 Establish a control strategy for the entire process. to support the approval of the reference product Table 1.

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Table 1: Current Vs QbD approach to pharmaceutical development

Conventional Product Development QbD Approach (Ideal)
Quality assured by end product testing and inspection and mainly Quality built into product & process by design, based on scientific
an empirical approach. understanding and a systematic approach.
Data intensive submission – disjointed information without “big Knowledge rich submission – showing
picture” product knowledge & process understanding
Specifications based on batch history Specifications based on product performance requirements
Flexible process within design space, allowing continuous
“Frozen process” disallowing changes
improvement
Focus on formulation and process robustness – understanding
Focus on reproducibility – often avoiding or ignoring variation
and controlling variation

“Quality is built in by design, not tested in”

“Quality by design is about doing things consciously.”
Key Aspects of Qbd

Figure 2: Flow diagram (Key Aspects of QbD)

TARGET PRODUCT PROFILE (TPP) For Reformulation, Changes to product characteristics or
performance that result from a reformulation may not
FDA published a recent guidance defining a Target
require that data.
Product Profile (TPP): “The TPP provides a statement of
the overall intent of the drug development program, and Many aspects of the TPP determine the actions of
gives information about the drug at a particular time in formulation and process development scientists. It is the
development. Usually, the TPP is organized according to role of a pharmaceutical scientist to translate the
the key sections in the drug labelling and links drug qualitative TPP into what we define as the target product
development activities to specific concepts intended for quality profile (QTPP) for further use in a quality by design
inclusion in the drug labelling.” When ICH Q8 says that process.
pharmaceutical development should include
Identifying Quality Target Product Profile (Qtpp)
“...identification of those attributes that are critical to the
quality of the drug product, taking into consideration “Begin with the end in mind”
intended usage and route of administration”, the
By Beginning with the end in the mind, the result of
consideration of the intended usage and route of
development is robust formulation and manufacturing
administration would be through the TPP.
process with an acceptable control strategy that ensures
The TPP is a patient and labelling centred concept, it can the performance of the drug product.
be thought of as the “user interface” of the drug product.
The quality target product profile (QTPP) is “a prospective
Thus a generic version and its reference product would be
summary of the quality characteristics of a drug product
expected to have the same TPP. A generic product may
that ideally will be achieved to ensure the desired quality,
use a different formulation or design to implement the
taking into account safety and efficacy of the drug
TPP. The characteristics and performance tests of a drug
product.”The QTPP is an essential element of a QbD
product would depended on the particular
approach and forms the basis of design of the generic
implementation and may differ between a generic and
product.
reference product.
The quality target product profile (QTPP) is a quantitative
For a new drug, changes to the TPP may require new
substitute for aspects of clinical safety and efficacy.
safety or efficacy data.

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International Society of Pharmaceutical Engineers (ISPE) many as five biorelevant dissolution conditions) to
Product Quality Lifecycle Implementation (PQLI) calls this evaluate formulations and processes before performing
the Pharmaceutical Target Product Profile. bioequivalence studies.
Quality target product profile (QTPP) Includes, but not QbD should rely on the relevance of individual studies
limited to: rather than the number of studies because one of the
objectives of QbD is to understand how the material
 Dosage form
attributes of the drug substance and excipients influence
 Route of administration product quality.18
 Strength In order to design and develop a robust generic product
that has the desirable QTPP, a product development
 Release or Delivery of the drug
scientist must give serious consideration to the
 Pharmacokinetic characteristics biopharmaceutical properties of the drug substance.
These biopharmaceutical properties include physical,
e.g., dissolution, aerodynamic performance
chemical, and biological properties. Physical properties
 Drug product quality characteristics for intended use include physical description (particle size, shape, and
e.g., sterility, purity. distribution), polymorphism, and aqueous solubility as
function of pH, hygroscopicity, and melting points.19-21
Generic products would include bioequivalence to the
RLD as part of the QTPP. The QTPP is not a specification A summary of formulations used in clinical safety and
because it includes tests such as bioequivalence or efficacy and in any relevant bioavailability or
stability that are not carried out in batch to batch release. bioequivalence studies should be provided.
The QTPP should only include patient relevant product
Any changes between the proposed commercial
performance. For example, if particle size is critical to the
formulation and those formulations used in pivotal
dissolution of a solid oral product, then the QTPP should
clinical batches and primary stability batches should be
include dissolution but not particle size. Particle size
clearly described and the rationale for the changes
would be a critical material attribute and thus included in
provided.
the process description and control strategy. The QTPP
should be performance based and not mechanism Overages
based.16-17
Use of an overage of a drug substance to compensate for
Drug Substance and Excipient Properties degradation during manufacture or a product’s shelf life,
or to extend shelf life, is discouraged.
Drug substance–physicochemical and biological
properties in relation to product performance and Any overages in the manufacture of the drug product
manufacturability. whether they appear in the final formulated product or
not, should be justified considering the safety and efficacy
Excipients - concentration, characteristics and
of the product.
functionality in relation to product performance and
manufacturability and functionality during shelf-life. Information should be provided on the-
It is well recognized that excipients could be a major  Amount of overage,
source of variability. Characterization and understanding
 Reason for the overage (e.g., to compensate for
of excipients' pharmaceutical properties depend on the
expected and documented manufacturing losses),
function and utility of excipients. Drug-excipient
and
compatibility knowledge and information are valuable in
the design of formulation and manufacturing processes.  Justification for the amount of overage.
Such information may be gained through theoretical
The overage should be included in the amount of drug
investigation and experimental studies. It is known to all 22
substance listed in the batch formula.
that mechanistic understanding of degradation kinetics
provides more value in predicting stability than Manufacturing Process Development
experimental data collected under artificial stress
Process development and formulation design cannot be
conditions.
separated because a formulation cannot become a
Formulation Design and Development product without a prescribed process. Process design is
the initial stage of process development, in which an
Not all prototype formulations can be evaluated in human
outline of the commercial manufacturing processes is
subjects, which mean that developing sensitive in vitro
documented, including the intended scales of
dissolution methods is crucial to an effective
manufacturing. The outline should include all the factors
development program. FDA's recommended in vitro
that need to be considered for the design of the process,
dissolution method is generally used for quality control.
including facility, equipment, material transfer, and
Generic-drug sponsors report using in-house methods for
manufacturing variables. Other factors to consider during
pharmaceutical development (some mentioned using as
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process development are the QTPP and CQAs. Depending as mixing, milling, granulation, drying, compression, or
upon the product being developed, type of process, and coating that involves physical or chemical changes. A
process knowledge the development scientists have, it physical, chemical, or microbiological property or
may be necessary to conduct preliminary feasibility characteristic of an input or output material is defined as
studies before completing the process development. The a material attribute. Process parameters include the type
selection of the type of process depends upon the of equipment and equipment settings, operating
formulation and the properties of the materials. conditions (e.g., time, temperature, pressure, pH, and
speed), and environmental conditions such as moisture.
A formulation without a process is, for example, a pile of
The output of a process depends on the process
powder. Process design is the initial stage of process
parameters and the input material attributes. Process
development where an outline of the commercial
robustness is the ability of a process to demonstrate
manufacturing processes is identified on paper, including
acceptable quality of the product and tolerate variability
the intended scales of manufacturing.
in inputs at the same time. The effects of variations in
The selection of type of process depends upon the process parameters and input material attributes are
product design and the properties of the materials. For evaluated in process-robustness studies. The analysis of
example, tablet manufacturing typically involves one of these experiments identifies CPPs and CMAs that could
two methods: direct compression or granulation. Direct affect product quality and establishes limits for these
compression is the most straightforward, easiest to CPPs and CMAs within which the quality of drug product
control, and least expensive tablet manufacturing is assured. When the limits on CPPs and CMAs are scale-
process. It uses two primary unit operations, mixing and independent, they may form the basis of a design space
compression, to produce the finished tablet. Direct as defined in ICH Q8 (R1). Even when a design space is not
compression is used when ingredients can be blended, established, multivariate experiments are valuable
positioned onto a tablet press, and made into a high because they identify CPPs and CMAs and support a
quality tablet without any of the ingredients having to be conclusion of process robustness.
changed. When powders are very fine, fluffy, will not stay
Process parameters and material attributes are critical
blended, or will not compress, then they may be
when a practical change can result in failure for the
granulated. Granulation is the process of collecting
product to meet the QTPP or a CQA that is outside an
particles together by creating bonds between them.
acceptable range. Process parameters are not critical
Bonds are formed by compression or by using a binding
when there is no trend to failure and there is no evidence
agent. Wet granulation, the process of adding a liquid
of significant interactions within the proven acceptable
solution to powders, is one of the most common ways to
range. It was necessary to conduct process robustness
granulate. The dry granulation process is used to form
studies for each unit operation; The primary reason for
granules without using a liquid solution. Forming granules
this claim was that some generic-drug sponsors have
without moisture requires compacting and densifying the
sufficient prior knowledge to determine whether a
powders. Dry granulation can be conducted on a tablet
process parameter or material attribute is critical or not
press using slugging tooling, or more typically on a roller
and to know when process operating conditions will be
compactor. Pharmaceutical development scientists have
robust. Process-robustness studies should be risk-based,
just begun making use of computer-aided process design
that is, more studies with complex products and fewer
(CAPD) and process simulation to support process
studies with simple low-risk dosage forms.
development and optimization of manufacturing. The
utility of CAPD and process simulation in drug product A pharmaceutical manufacturing process is usually
design is limited. This is largely because the comprised of a series of unit operations to produce the
pharmaceutical industry has traditionally put emphasis on desired product. A unit operation is a discrete activity
new drug discovery and development, and the complexity that involves physical changes, such as mixing, milling,
of drug product manufacturing operations are not well granulation, drying, compaction, and coating. A physical,
recognized. chemical or microbiological property or characteristic of
an input or output material is defined as an attribute.
The use of CAPD and process simulation should result in
Process parameters include the type of equipment and
more robust processes developed faster and at a lower
equipment settings, batch size, operating conditions (e.g.,
cost, resulting in higher quality products.23-25
time, temperature, pressure, pH, and speed), and
Identification of critical process parameters (CPPS) and environmental conditions such as moisture. The quality
critical material attributes (CMAS) and critical quality and quantity of drug substance and excipients are
attributes (CQAS) and relationship of critical quality considered as attributes of raw materials. During process
attribute (CQAS) to critical process parameters (CPPS) development, raw materials, process parameters and
and critical material attributes (CMAS) and source of quality attributes are investigated. The purpose of these
variability studies is to determine the critical raw material
attributes, process parameters and quality attributes for
A pharmaceutical manufacturing process usually consists
each process, and to establish any possible relationships
of a series of unit operations to produce the desired
among them. Critical quality attributes (CQA) are physical,
quality product. A unit operation is a discrete activity such
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chemical, biological, or microbiological property or 2. Measure: The critical product performance attributes
characteristic that must be controlled directly or should be measured to see if they are out of
indirectly to ensure the quality of the product. Critical specification. The out of specification data should be
process parameters (CPP) are process inputs that have a analyzed and used to the sigma level of the process.
direct and significant influence on critical quality
3. Analyze: When the sigma level is below the target,
attributes when they are varied within regular operation
steps should be taken to increase it, starting by
range. Lists typical tablet manufacturing unit operations,
identifying the most significant causes of the
process parameters, and quality attributes for solid
excessive variability.
dosage forms. It should be noted that the equipment
maintenance, operator training, standard operating 4. Improve: The process should be redesigned and/or
procedure (SOP) related to the specific product process controls should be incorporated to eliminate
manufacturing, and facility supporting systems may link or attenuate the significant root causes of variance.
to product quality directly or indirectly. Therefore, risk
5. Control: The improved manufacturing process should
assessment should be used to reduce variables to be
be evaluated and maintained.
investigated. Process robustness is defined as the ability
of a process to demonstrate acceptable quality and Design of experiments (DOE) is a structured and
performance and tolerate variability in inputs at the same organized method to determine the relationship among
time. In process robustness studies, effects of variations factors that influence outputs of a process. When DOE is
in process parameters for a candidate process are applied to pharmaceutical process, factors are the raw
evaluated. The analysis of these experiments identifies material attributes (e.g., particle size) and process
critical process parameters that could potentially affect parameters (e.g., speed and time), while outputs are the
product quality or performance, and establishes limits for critical quality attributes such as blend uniformity, tablet
the critical process parameters within which the quality of hardness, thickness, and friability. As each unit operation
drug product is assured. Ideally, data used to identify has many input and output variables as well as process
process parameters should be derived from commercial parameters, it is impossible to experimentally investigate
scale processes to avoid any potential impact of scale-up. all of them. Scientists have to use prior knowledge and
However, in reality, these studies are often conducted on risk management to identify key input and output
laboratory or pilot-scale batches. If results from the small variables and process parameters to be investigated by
scale batches have not been shown to be size DOE. DOE results can help identify optimal conditions, the
independent, any conclusion from small scale studies may critical factors that most influence CQAs and those that
need to be verified in the actual commercial production do not, as well as details such as the existence of
batches. At the end, the effect of raw material attributes interactions and synergies between factors. Based on the
and critical process parameters on product quality or acceptable range of CQAs, the design space of CPPs can
product variability is fully understood and established. be determined. When considering scale-up, however,
Ideally, the interactions between materials attributes and additional experimental work may be required to confirm
critical process parameters should be understood so that that the model generated at the small scale is predictive
critical process parameters can be varied to compensate at the large scale. This is because some critical process
for changes in raw materials. To demonstrate the parameters are scale dependent while others do not. The
reproducibility and consistency of a process, process operating range of scale dependent critical process
capability should be studied. Process capability is a parameters will have to change because of scale-up. Prior
statistical measure of the inherent process variability for a knowledge can play a very significant role in this regard as
given characteristic. The most widely accepted formula most pharmaceutical companies use the same
for process capability is a six sigma. Process capability technologies and excipients on a regular basis.
index is the value of the tolerance specified for a Pharmaceutical scientists can often take advantage of
particular characteristic divided by the process capability, past experience to define critical material properties,
which is defined as follows: processing parameters and their operating ranges. 26-29
Process capability index (CpK) = Upper limit of IDENTIFYING CRITICAL QUALITY ATTRIBUTES (CQA)
specification - lower limit of specification / (σ) standard
Definition ICH Q8 (R1) defines CQAs as physical, chemical,
deviation.
biological or microbiological properties or characteristics
If the CpK value is significantly greater than one, the that should be within an appropriate limit, range, or
process is deemed capable. If the process capability is distribution to ensure the desired product quality.
low, recommend an iterative five-step procedure to
The International Society of Pharmaceutical Engineers
progressively reduce the variability of the process. These
(ISPE) & Product Quality Lifecycle Implementation (PQLI)
five steps are:
defines critical quality attributes (CQAs) as physical,
1. Define: The intended improvement should be clearly chemical, biological or microbiological properties or
stated. characteristics that need to be controlled (directly or
indirectly) to ensure product quality.

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CQA has been used by some to describe elements of the aggregation, polymorphism, rheological properties, and
QTPP (such as dissolution) while others have used CQA to globule size of emulsions, biological activity or potency,
describe mechanistic factors (such as particle size and and/or immunological activity. The TPP would be the
hardness) that determine product performance. Thus labelling statement (supported by clinical data) that the
CQA is used to describe both aspects of product product does not dose-dump when taken with alcohol. A
performance and determinants of product performance. performance test in the QTPP would be an in vitro
dissolution test in alcohol. The critical material attributes
It was stated that the ICH working definition of CQA was:
(CMA) would be the thickness of a tablet coat. Defining
“A CQA is a quality attribute (a physical, chemical,
the CMAs on this mechanistic physical property level
biological or microbiological property or characteristic)
makes it the best link to the manufacturing process
that must be controlled (directly or indirectly) to ensure
variables.26-27
the product meets its intended safety, efficacy, stability
and performance”. This CQA definition implies that the CRITICAL PROCESS PARAMETERS
intended safety, efficacy, stability and performance are
What is a Process Parameter?
not CQAs. Safety and efficacy clearly fall under the
domain of the TPP. But if stability and performance are Critical process parameter (CPP) is defined as any
not CQA and not part of the TPP, then what are they? We measurable input (input material attribute or operating
are thus compelled to acknowledge that there is an parameter) or output (process state variable or output
intermediate category of product performance (or material attribute) of a process step that must be
surrogates for quality) that we have defined as the QTPP. controlled to achieve the desired product quality and
process uniformity. In this view, every item would be a
It seems more precise to consider the TPP, QTPP, and
process parameter.
material attributes as separate categories. The use of CQA
can be reserved for cases where there is a need to refer We propose that process parameter be understood as
collectively to the targets of a QbD approach. CQA is referring to the input operating parameters (mixing
generally assumed to be an attribute of the final product, speed, flow rate) and process state variables
but it is also possible to indicate a CQA of an intermediate (temperature, pressure) of a process or unit operation.
or a raw material. Under this definition, the state of a process depends on
its CPPs and the CMAs of the input materials. Monitoring
Although many people have identified dissolution as a
and controlling output material attributes can be a better
critical quality attribute, we consider that a set of critical
control strategy than monitoring operating parameters
material attributes (CMAs) that are independent of each
especially for scale up. For example, a material attribute,
other provide specific goals with which to evaluate a
such as moisture content, should have the same target
manufacturing process. For example a dissolution test
value in the pilot and commercial processes. An operating
may depend on particle size and hardness. Particle size
parameter, such as air flow rate, would be expected to
and hardness are CMAs which can be directly linked to
change as the process scale changes.
raw materials and manufacturing process parameters.
Independent CMAs are the best way to provide a For a given unit operation, there are four categories of
mechanistic link of the product quality to the critical parameters and attributes
process parameters in the manufacturing process. At the
 Input material attributes
2005 Drug Information Association meeting, Reed
discussed dissolution in detail and indicated the greater  Output material attributes
value of has very specific CQAs. Others have commented
 Input operating parameters
negatively that processing behaviour of materials is
usually evaluated in performance tests (flowability) rather  Output process state conditions.
than focusing on fundamental material properties.
What is an Unclassified Process Parameter
Differentiating between CMAs (properties) and multi-
There are many material attributes and process
faceted performance tests is part of the movement away
parameters that are important and even essential to
from quality by testing to quality by design.
product quality, but it is of little value to define all
The evolution of ICH Q8 is also consistent with making a parameters as critical.
distinction between CMA and performance tests. The
Thus we propose three categories for attributes or
2004 Q8 draft put CQA and performance tests into the
parameters:
same pile of physiochemical and biological properties:
1. Unclassified,
The physicochemical and biological properties relevant to
the performance or manufacturability of the drug product 2. Critical and
should be identified and discussed. These could include 3. Non-critical
formulation attributes such as pH, osmolarity, ionic
strength, lipophilicity, dissolution, redispersion, For example, in the granulation process, the impeller
reconstitution, particle size distribution, particle shape, speed should clearly be identified as an unclassified

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process parameter because if impeller speed were zero form of prior knowledge, process models or experimental
the process step would not be successful. However, this data) to cover the POS and the increased chance that a
does not mean that impeller speed is always a critical parameter will be found critical in the large POS. The only
parameter. If development studies demonstrated the constraint on the narrowness of the POS is that the POS
granulation was not affected by realistic changes in must encompass the variability of the process parameters
impeller speed, it would not be identified as critical. around their target values.
What is a Critical Process Parameter Our criteria for identifying critical and non-critical
parameters are that a parameter is Non-critical when
A parameter is Critical when a realistic change in that
there is no trend to failure within the POS and there is no
parameter can cause the product to fail to meet the
evidence of interactions within the proven acceptable
QTPP.
range (PAR)(see explanatory footnote on first page of
Thus, whether a parameter is critical or not depends on article), which is the range of experimental observations
how large of a change one is willing to consider. that lead to acceptable quality. A sponsor has the option
of conducting experimental observations over the entire
A simple example is that an impeller speed of zero will
POS; in this case the POS could be equivalent to the PAR.
always fail.
Alternatively a sponsor may use prior knowledge,
Thus the first step in classifying parameters is to define mechanistic models and trends from the PAR to draw
the range of interest which we call the potential conclusions about sensitivity over a POS that is larger
operating space (POS). The POS is the region between the than the PAR. If the lack of interaction part of the test
maximum and minimum value of interest to the sponsor cannot be met, then the parameter remains a UPP.
for each process parameter. The POS can also be
A parameter is critical when there is an observation of
considered as the extent of the sponsor’s quality system
failure or a trend to failure predicted within the POS. If
with respect to these parameters. This definition is at the
the interaction between two parameters is significant
discretion of the application that sponsor must balance
enough to predict a potential failure in the POS, then both
the trade-offs in its definition. The POS defines the scope
parameters should be considered as critical. The most
of the application and the sponsor’s quality system so
definitive way to identify critical and noncritical
that going outside of the POS must need an amendment
parameters is by scientific investigations involving
or supplement to the application. Thus sponsors benefit
controlled variations of the parameters.
from defining a large feasible POS. The cost of a large POS
is the need for the pharmaceutical development (in the
Table 2: Classification of Process Parameters
Parameter Type Definition Sensitivity
No failure in target product quality profile (TPQP) observed or predicted in the
Non-Critical Process
Not critical (non‐CPP) potential operating space (POS),
parameter (Non-CPP)
No interactions with other parameters in the proven acceptable range (PAR)
Unclassified Process Criticality Not established
parameter (UPP) unknown The default in the absence of pharmaceutical development
Critical Failure in target product quality profile (TPQP) observed or predicted in the
Critical Process parameter
(control needed to potential operating space (POS), or
(CPP)
ensure quality Interactions with other parameters in the proven acceptable range (PAR)

Uniqueness of Critical Process Parameters inlet air flow rate and inlet air temperature indicated as
Because of the broadness of the CPP definition it is operating parameters.
possible for two investigators to examine the same
Batch record for the first unit might indicate a fixed
process and come to a different set of CPP. The set of CPP
temperature, while the second unit would have a design
is not unique, but the chosen set must be sufficient to
space that indicated the combination of inlet air flow rate
ensure product quality. Different sets of CPP can have
and inlet air temperature that would insure the
several origins. One is that the definition of operating
appropriate product temperature.30
parameters depends on the engineering systems installed
on a piece of process equipment. RISK ASSESSMENT AND DESIGN SPACE
Example, one fluid bed dryer may define the product Quality Risk Management (ICH Q9) indicates that, the
temperature as an operating parameter and have an manufacturing and use of a drug product necessarily
internal control system (a thermostat) that maintains that entail some degree of risk.
temperature, while another fluid bed dryer may have
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Risk assessment is a valuable science based process used experience. The Design Space also contains the proven
in science-quality risk management that can aid in acceptable ranges (PAR) for CPPs and acceptable values
identifying which material attributes and process for their associated CQAs. Normal operating ranges are a
parameters potentially have an effect on product CQAs.
subset of the Design Space and are managed under the
Risk assessment is typically performed early in the company Pharmaceutical quality System. The Design
pharmaceutical development process and is repeated as Space may also contain operating ranges for process
more information becomes available and greater parameters classified in the intermediate criticality
knowledge is obtained. Risk assessment tools can be used
category discussed previously. Information regarding site
to identify and rank parameters (e.g., process,
equipment, input materials) with potential to have an and scale of manufacture may also be included,
impact on product quality, based on prior knowledge and depending on the quality of the process knowledge upon
initial experimental data. which the Design Space is based.
Use of a risk assessment tool: In the presence of interacting critical process parameters
A cross-functional team of experts could work together to a design space is one approach to ensure product quality
develop an Ishikawa (fishbone) diagram that identifies although it is not a check-box requirement.
potential variables which can have an impact on the
desired quality attribute The current definition of design space is “The
multidimensional combination and interaction of input
ICH Q8 (R1) defines Design space as, the variables (e.g., material attributes) and process
multidimensional combination and interaction of input parameters that have been demonstrated to provide
variables (e.g., material attributes) and process
assurance of quality.”
parameters that have been demonstrated to provide
assurance of quality. This definition evolved from early ICH Q8 drafts where
design space was defined as “the established range of
Working within the design space is not considered as a process parameters that has been demonstrated to
change. Movement out of the design space is considered
provide assurance of quality”. The change emphasizes the
to be a change and would normally initiate a regulatory multidimensional interaction of input variables and
post-approval change process.
closely binds the establishment of a design space to a
Many believe design space and QbD are interchangeable conduct of a DOE that includes interactions among the
terms. This is incorrect. For generic-drug applications, input variables.
design space is optional. QbD can be implemented
A design space may be constructed for a single unit
without a design space because product and process operation, multiple unit operations, or for the entire
understanding can be established without a formal design
process.
space. It should be pointed out that implementation of
QbD is strongly encouraged by FDA. For some complex Submission of a design space to FDA is a pathway
drug substances or drug products, implementation of obtaining the ability to operate within that design space
without further regulatory approval. 31-35
QbD is considered a required component of the
application. Scale-Up

The Design Space is linked to criticality through the results Currently, the mechanistic understanding of
pharmaceutical unit operations is limited. Scale-up is
of risk assessment, which determines the associated
largely based on general rule-of-thumb and trial-and-
CQAs and CPPs. It describes the multivariate functional error approaches. During scale-up, process parameters
relationships between CQAs and the CPPs that impact may vary while material attributes will not. QbD offers
them, and should include their linkage to or across unit many more advantages for complex products than for
operations. Such relationships are arrived at by iterative simple ones. It was noted that scale-up can be done
application of risk assessment and experimental design, without QbD, but with much higher risk.
modelling, as well as the use of literature and prior

Figure 3: Steps to Design Space

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DEFINING CONTROL STRATEGY Developing the control strategy

ICH Q8 (R1) defines control strategy as: Development of a Control Strategy requires a structured
process, involving a multi-disciplinary team of experts,
A planned set of controls, derived from current product
linking pharmaceutical development to the
and process understanding that ensures process
manufacturing process, and engineering controls of
performance and product quality.
process equipment.
The controls can include parameters and attributes
The PQLI Control Strategy Team has proposed a Control
related to:
Strategy Model that facilitates understanding and that
 Drug substance, may be used a cross-functional communication tool.
 Drug-product materials and components, Personnel at all levels should be able to understand the
way control strategy links from CQAs to operational
 Facility and equipment operating conditions,
aspects to ensure, for example that:
 In-process controls,
 Chemists understand in-process controls are
 Finished-product specifications, established to keep the process inside the design
space and seek opportunities for simplification of
 The associated methods and
controls, as knowledge is gained.
 Frequency of monitoring and control. (ICH Q10)
 Engineers know how equipment operating conditions
Specifically, the control strategy may include: impact product quality.
 Control of input material attributes (e.g., drug  Quality Assurance professionals know where the
substance, excipients, and primary packaging highest risks are in the process.
materials) based on an understanding of their impact
Although the primary driver for development of a control
on process-ability or product quality.
strategy will be assurance of product safety, efficacy and
 Product specifications quality, the Control Strategy may also ensure the meeting
of other business objectives such as operator health and
 Practical controls
safety, protection of the environment, manufacturability,
 Facility controls, such as utilities, environmental and supplies related issues, efficiency, and profitability.
systems and operating conditions Development of a Control Strategy for a product will
therefore be a structured activity involving a multi-
 Controls for unit operations that have an impact on
disciplinary team of experts. This team may include
downstream processing or end-product quality (e.g.
representatives from formulation development, drug
the impact of drying on degradation, particle size
distribution of the granulate on dissolution) substance development, process development, analytical
development, QC, QA, Regulatory Affairs, manufacturing,
 A monitoring program (e.g., full product testing at engineering, and specialists in Process Analytical
regular intervals) for verifying multivariate prediction Technology (PAT) and chemo-metrics.
models.
A Control Strategy and a product release strategy are not
The Control Strategy should establish the necessary the same, but demonstration of adherence to the Control
controls - based on patient requirements - to be applied Strategy would support the product or batch release
throughout the whole product lifecycle from product and strategy.
process design through to final product, including API and
Drug Product manufacture, packaging and distribution. Control of input material attributes

Minimal and enhanced approaches Variability in the manufacturing processes may be caused
by variability in the drug substance and raw materials and
As in ICH Q8(R), a distinction may be drawn between a their attributes, when linked to a CQA. The impact of not
minimal and an enhanced control strategy approach. only chemical but also physical material attributes and
their variability need to be understood. For example, for
In a Minimal Control Strategy, drug product quality is
an oral solid dosage product, impact of factors such as
controlled primarily by intermediate (in process material)
participle size distribution, particle shape distribution,
and end product testing.
density, surface area, surface energy, flow, cohesiveness,
In an Enhanced Control Strategy drug product quality friction, elastic modulus, amorphous content,
ensured by risk-based control strategy for well compactibility, hygroscopicity, solubility, and static charge
understood product and process, and quality controls are should be assessed. A linkage between the product CQAs
shifted upstream, with the possibility of real-time release and the input material attributes should enable
or reduced end-product testing. identification and understanding of the most critical
material attributes and their impact on the product CQAs.
Controlling the variability of input materials can be

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managed in different ways, e.g. by functional Other revisions to the Control Strategy may relate to
specifications (not necessary in concurrence with continual improvement, for example the introduction of
compendia specifications) or by managing the variability improved analyser or control technology.
directly in the process using closed loop controls. One
Periodic reviews of risk assessments and mitigation
example is raw materials affected by seasonal variations
should be conducted to determine the appropriateness of
in the moisture level and used in a moisture critical blend.
the Control Strategy based on product manufacturing
By applying PAT tools such as NIR (Near Infrared)
history.
spectroscopy, drying can be monitored on-line and the
drying process controlled to the end-point with a closed Failure or deviations should be investigated and the
feed-backward control loop in place. In many cases the effectiveness of the control system considered in relation
variability in a material input can be managed by to the identified root cause.
operating the process conditions differently within the
Corrective and preventive actions should be applied and
Design Space. Other input materials such as packaging
the Control Strategy updated as necessary (including any
material should be studied during development to
regulatory actions required) in the light of new product
identify and understand which material attributes impact
and process knowledge.
the manufacturing process and final product CQAs.
Implementing PAT in the Control Strategy will require the
Real‐time testing / In-process controls
application of process models (multivariate prediction
Real time testing is needed to base the release the models) that either predicts CQAs or CPPs or a
product on product and process understanding rather combination of both. These models may require frequent
than on end product testing alone or on result of batch updates, depending on the maturity of the model (e.g.,
analysis. the amount of data and their variability within the
model), as well as the kind of data that has been included
Real time testing include all controls that need to be
to reflect variability in scale, equipment, analytical set-up,
performed during processing, including control of Critical
sampling, and site.
Process Parameters, in-process material attributes and
components, as well as equipment and facility A monitoring program for verifying the validity of process
parameters that must be monitored or controlled to models should be established and be based on a risk
achieve the product CQAs. analysis of the model itself and include possible ways to
verify the model by other means. One example would be
Controlling the Critical Process Parameters during
to compare the predicted CQA value to a conventional
processing is important as they have a direct impact on
analytical method. The monitoring program should
the CQAs, but other parameters, that have an impact on
include requirements for when a model has to be
downstream processing or other end-product quality
updated (e.g. change of raw material supplier or
attributes not already covered by a CQA, should be
deviations resulting in increased knowledge).
monitored or controlled as well. Which parameters to
monitor or control is the outcome of Quality Risk Continuous Improvement
Management (QRM) activities aimed at mitigating the
“Continuous improvement is an essential element in a
risks arising during manufacturing.
modern quality system that aims at improving efficiency
In-process controls could include by optimizing a process and eliminating wasted efforts in
production. These efforts are primarily directed towards
 conventional sampling and
reducing variability in process and product quality
 At-line analysis or On-line or in-line univariate characteristics.”
sensors or multivariate probes (typical spectroscopy)
QbD focuses on building quality into the product and
They may be manual or automated, depending on the manufacturing processes, as well as continuous process
nature of the process itself, what needs to be measured improvement – reduction of variability.
and controlled, how often, scale, process time, and the
The backbone for Continuous Improvement is the
nature of the manufacturing equipment. 36-37
Pharmaceutical Quality System. PQS should facilitate
Control strategy and the product lifecycle continual improvement and help to: “Identify and
implement appropriate product quality improvements,
The Control Strategy is related to the level of process
process improvements, variability reduction, innovations
understanding at a given time, and evolves as
and pharmaceutical quality system enhancements,
manufacturing experience increases.
thereby increasing the ability to fulfil quality needs
The originally specified measures, controls or models may consistently.
be modified or even removed, or the need for additional
Quality risk management can be useful for identifying and
controls may be identified.
prioritizing areas for continual improvement. “Continuous
improvement is not the same as corrective actions
preventative actions (CAPA). CAPA’s occur when product

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quality characteristics are in question (e.g., out of 15. IBM Business Consulting Services Transforming
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Source of Support: Nil, Conflict of Interest: None.

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