J Pharm Innov (2008) 3:23–29
DOI 10.1007/s12247-008-9025-3
PERSPECTIVE
Risk-based Quality by Design (QbD): A Taguchi Perspective
on the Assessment of Product Quality, and the Quantitative
Linkage of Drug Product Parameters and Clinical
Performance
Robert P. Cogdill & James K. Drennen
Published online: 6 March 2008
# International Society for Pharmaceutical Engineering 2008
Abstract For good reason, quality by design (QbD) has
become a topic of significant interest within the pharmaceu-
tical industry. Whereas regulatory agencies and standard-
setting organizations are moving swiftly to establish QbD
guidance relevant to the needs of pharmaceutical manufac-
turing, much of the core science of QbD was established long
ago by Dr. Genichi Taguchi and other leaders in the field of
quality management. In order for the pharmaceutical
industry to fully capitalize on QbD, new methods for
quantitatively assessing product quality need to be estab-
lished. This perspective article presents a risk-based strategy
for quality assessment which uses model-based simulation to
link variation in drug product parameters and clinical
performance. This work is intended to provide background
and introduction for a series of manuscripts dealing with
QbD based on probabilistic risk assessment.
Keywords Quality by design (QbD) .
Taguchi methods . Design space . PAT . Specifications .
Pharmaceutical development . Quality loss function (QLF)
Introduction
Quality by Design
Quality by design (QbD), which has become a topic of
significant interest within the pharmaceutical industry, is
described by Food and Drug Administration (FDA)
R. P. Cogdill : J. K. Drennen (*)
Duquesne University Center for Pharmaceutical Technology,
Pittsburgh, PA, USA
e-mail: drennen@duq.edu
guidance [1] as “building in quality from the development
phase and throughout a product’s life cycle.” According to
the same guidance, (implementing) 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.” Another
definition of QbD is given by FDA’s report on Critical Path
Opportunities for Generic Drugs, which states that “under
the QbD paradigm, quality is built into the final product by
understanding and controlling formulation and manufactur-
ing variables: testing is used to confirm the quality of the
product” [2]. The recent revision (R1) of the ICH Q8
guideline defines QbD as 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 manage-
ment [3]. The differences between the current and desired
states of pharmaceutical manufacturing (regarding QbD)
are summarized in [3].
Incorporating QbD into development activities is strate-
gically important because it is the prerequisite for the
establishment of an operating design space, and it is
perhaps the most direct means of communicating process
understanding. The establishment of an extensive design
space can be an important driver of efficiency because an
operational adjustment within the (approved) design space
is not considered a change; therefore, reducing the need to
submit a post approval supplemental filing. Furthermore,
the capability to operate flexibly within an established
design space is essential to achieving true continuous
improvement [4–6].
The pharmaceutical industry has moved very quickly
to begin working to incorporate QbD into development
24
protocols and, in some respects, is accelerating regulatory
changes because of the demand for guidance. For example,
the 2005 Step 4 version of the International Conference on
Harmonization (ICH) Q8 Guideline on Pharmaceutical
Development [7], which is often cited in reference to
QbD by FDA guidance, does not specifically mention QbD.
Rather, the guideline states that “it is important to recognize
that quality cannot be tested into products; i.e., quality
should be built in by design.” This is substantially
addressed by the R1 revision of the Q8 Guideline, however,
which provides significant clarification of aspects related to
QbD, including harmonized definitions for critical quality
attributes, critical process parameters, real-time release, and
methods which can be used to define a design space [3].
In 2005, FDA began a pilot program which enables
participating firms to submit chemistry, manufacturing,
and controls (CMC) information demonstrating applica-
tion of QbD using the quality overall summary (QOS)
format [8]. The CMC pilot project provides a mechanism
for FDA and industry to cooperate on strategies for the
implementation of the ICH Q8 and Q9 guidelines, and
FDA’s PAT guidance. According to a recent interview with
Dr. Chi-wan Chen [8], deputy director of the Office of New
Drug Quality Assessment (ONDQA), considerable diversity
was observed in the way QbD and the concept of design
space is approached by industry participants.
Chen described FDA’s view of QbD as a “systematic
approach to product and process design and development”
involving seven key elements:
& Identification of target product profile
& Determination of product critical quality attributes (CQAs)
& Linkage of raw material attributes and process param-
eters to CQAs
& Risk assessment
& Design space
& Design and implementation of a control strategy
& Product lifecycle management and continuous improvement
Whereas the main elements and specific techniques of
QbD, such as design of experiments (DOE) or failure mode
effect analysis (FMEA), have been described in detail,
much less discussion has been devoted on how to define the
target product profile, which is perhaps the most unique and
challenging aspect of QbD applied to pharmaceutical
manufacturing. In other words, before QbD can be achieved
for a particular product or process, the true meaning of what
defines quality, i.e., the voice of the consumer, must be
known.
In a 2004 perspective article [9], Janet Woodcock
described the problems and limitations of the current
definition (or lack thereof) of pharmaceutical quality and
suggested that the concept of pharmaceutical quality should
be recast in terms of risk. She observed (and recently
J Pharm Innov (2008) 3:23–29
reiterated [10]) that the lack of observable connection
between critical product attributes and clinical performance
is a persistent roadblock to establishing an effective, risk-
based definition of pharmaceutical quality. The objectives
of this manuscript are to (1) describe the connections
between Taguchi’s concepts of quality loss, pharmaceutical
quality, and risk, and (2) propose a simulation framework
for the assessment of pharmaceutical quality based on
probabilistic risk assessment.
Taguchi Methods and QbD
Quality by design is not a new concept [11–16]. Indeed, Dr.
Genichi Taguchi, who has been credited by some as the
father of QbD, began using designed experiments based on
orthogonal arrays while working as a consultant for
Morinaga Pharmaceuticals Company of Japan from 1947
to 1949. While at Morinaga, Taguchi was taught DOE and
statistical methods by Motosaburo Masuyama, who was
leading an effort to improve the quality and yield of the
industrial production of penicillin.
Whereas Dr. Taguchi’s earliest professional work was
concerned with statistical sampling theory [11], his greatest
contributions to industrial technology are associated with
his lifelong work to advance the science of robust design.
The Japanese quality revolution began with the prolifera-
tion of Dr. Walter Shewhart’s techniques for statistical
process control (SPC), which were taught to Japanese
engineers and scientists beginning in the late 1940s by a
Shewhart disciple, W. Edward Deming [16]. Taguchi recog-
nized that, whereas online methods of quality improvement,
such as SPC, are highly effective in bringing existing
processes into control, thereby reducing waste and the need
for end-of-process inspection, the most efficient point
during the product lifecycle to achieve high quality is not
during production, but during design.
Taguchi defines the development of a product or process
as a three-stage operation: system design, parameter design,
and tolerance design [12, 13]. In relation to pharmaceutical
development, system design includes, for example, select-
ing the active ingredient and drug delivery platform to
achieve a specific pharmacodynamic target (defined by
efficacy and lack of toxicity). The concept of system design
is conveyed in the ICH Q8 guideline for pharmaceutical
development, which defines quality as “the suitability of
either a drug substance or drug product for its intended use”
[7]. Effective system design begins with a quantitative
understanding of target quality, followed by identification
of a product or process capable of reliably achieving the
target.
Tolerance design corresponds to setting the specifica-
tions for raw and in-process materials necessary to achieve
finished product quality targets. When variations in certain
J Pharm Innov (2008) 3:23–29
raw material attributes are observed to have a critical effect
on finished product quality or when the true range or effect
of variability is unknown, the typical engineering response
is to tighten the corresponding raw material acceptance
specifications.
Taguchi’s approach to development is unique, however,
because of his focus on parameter design. During parameter
design, the engineer seeks to optimize the system design
through simple, offline experiments to identify configura-
tions which minimize performance variation in the presence
of uncontrollable variance factors or noise. The objective of
parameter design is to reduce the need to rely on restrictive
tolerance specifications to achieve quality, which is the
essence of ‘building quality into’ a design. Taguchi adapted
concepts from fields such as statistics and signal processing
to assemble a toolbox of simple techniques an engineer
could use to quickly perform parameter design using
limited resources. Taguchi’s methods include linear graphs,
orthogonal arrays, and the signal-to-noise (S/N) ratio for the
identification of the control parameters.
Taguchi’s Continuous Quality Loss Function
An essential component of Taguchi’s methods is his
concept of the continuous quality loss function (QLF),
which provides the numerical basis for his S/N technique.
Before the widespread use of Taguchi’s methods within
Japanese industry, the prevailing quality assessment method
was pass/fail testing to determine conformance with speci-
Fig. 1 Graphical comparison of pass/fail specifications and (Taguchi’s)
continuous QLF. Whereas systems based on pass/fail specification testing
do not distinguish between quality levels within acceptance limits,
25
fications. Process capability, which is currently used as a
target metric for process improvement and benchmarking
studies, is based on the concept of conformance with
specifications. The problem with pass/fail specifications, as
Taguchi observed, is that no distinction is made between
the quality of an item produced exactly on target and an
item which just meets specifications (Figs. 1 and 2).
Taguchi defines the quality of a product as “the (minimum)
loss imparted by the product to the society from the time
the product is shipped” [11]. Accordingly, any product
deviation from the target design results in greater loss and,
hence, lower quality. Taguchi sought to incorporate not
only direct costs, such as material waste, but also indirect
costs, such as restocking fees, loss of brand image, or losses
experienced by the customer. Mathematically, Taguchi’s
QLF is essentially a calculation of the mean squared
deviation or error (MSE) between observed and target
attribute values. Whereas Taguchi’s QLF is admittedly
simplistic, some empirical studies have demonstrated that
the formula is often accurate within reasonable limits [11].
The continuous QLF is an important metric for design
because it provides the engineer with a simple formula for
estimating the cost of variability and, hence, a means of
determining the value of investments in quality improve-
ment. Taguchi intended that practitioners would ‘calibrate’
the QLF for a particular product or process by estimating
the actual loss related to one or more levels of deviation,
thereby transforming units of product attribute variability
into a single measurement system based on cost. For many
systems based on Taguchi’s QLF only achieve minimum quality loss
when the target value is achieved. In a risk-based system, the shape of the
QLF could be determined by risk assessment simulation
26
Fig. 2 Schematic representation of the limitations of measuring
product quality using multiple criteria without considering their
interaction. Whereas both tablets A and B are very close to product
quality acceptance limits (perhaps within the limit of measurement
precision), only tablet A would be graded as acceptable, despite the
fact that it likely poses greater pharmaceutical risk than tablet B
products, the use of economic loss as a basis for quality
measurement facilitates accurate prioritization of variance
factors and financial optimization of both product and
process without sacrificing consideration of quality.
Risk as a Basis for Measurement of Drug Quality
Whereas the concept of a continuous QLF is important for
the implementation of QbD during drug development,
financial cost is not an appropriate basis for the measure-
ment of quality loss associated with pharmaceutical
products. In an efficient market, the point of optimal
economic operation is where the marginal cost and
marginal benefit of incremental investment in quality
improvement are equal. In the traditional economic sense,
Fig. 3 Sources of risk from
medicine. FDA-CDER 2005
Report to the Nation
J Pharm Innov (2008) 3:23–29
however, the markets for pharmaceutical drugs (and health-
care in general) are not efficient.
Patients are generally unable to directly determine the
quality of an individual drug product before consumption
and often assume that quality is uniform (i.e., assured by
industrial and regulatory oversight) [9]. Consider, for
example, the persistent willingness of consumers to
purchase prescription drugs via the Internet, which offers
scant assurance of product condition or pedigree [17]. In
addition, purchase decisions are often driven by external
factors, such as physician recommendation, insurance
coverage, or lack of alternative treatments rather than
perception of superior quality. In other words, the con-
sumer’s response to quality is inefficient relative to the
manufacturer’s response to production cost. Therefore, the
economic value of quality is less determined by consumer
demand than by regulatory oversight for which product cost
has not always been a concern (as costs are borne by the
manufacturer, consumer, and society, not the regulator).
Rather than economic cost, risk provides a more
appropriate basis for the measurement and valuation of
drug product quality as manufacturers, patients, and
regulators are uniformly aligned in their desire to minimize
the sources of risk associated with drug therapy (Fig. 3). At
the most basic level, patients seek safe, effective, and
affordable drug therapy; all other considerations (e.g., taste
or appearance) are essentially subordinate. Within a risk-
based quality measurement system, the mean and variance
of product attributes, such as API content and the rate of
drug release, are transformed into estimates of risk because
of toxicity (e.g., superpotency) and inefficacy (e.g., incom-
plete release). Therefore, the objectives of product, process,
and specification design would uniformly be to minimize
risk.
An advantage of risk-based quality measurement is that
it provides an ethical way of weighing the value of
additional quality assurance expenditures. Consider that,
whereas we have assumed nearly inelastic demand sensi-
tivity to quality variation, many healthcare economists have
demonstrated that patients do exhibit price elasticity in their
purchase decisions, even when a third party payer (e.g.,
J Pharm Innov (2008) 3:23–29
Fig. 4 Schematic view of the models and their connections as part of
a Monte Carlo probabilistic risk assessment system
prescription insurance) is involved [18–20]. Thus, if the
price elasticity of demand for a given product can be
estimated, incremental price increases might be transformed
into a measure of risk analogous to the risk of inefficacy (or
lack of availability). This would create an ethical incentive
to optimize the alignment of regulatory and financial
priorities.
Whereas the relationship of cost to risk is obviously
indirect, the concept of indirect risk is similar to Taguchi’s
use of indirect costs in determining quality loss. Further-
Fig. 5 Example of the effect of product quality variability (content
uniformity) on chronic dosing of a model drug (theophylline)
generated by Monte Carlo simulation. Risk might be measured as
the probability of excursion out of the therapeutic range after
27
more, risk related to product cost would only impact design
decisions once additional investment in quality assurance
no longer provided meaningful risk reduction. Taguchi,
who was notoriously cost-conscious, is noted as saying that
“it’s just as unethical to add tremendous cost to ensure
products are of good quality as it is to ship defective goods”
[11]. Furthermore, in addition to protecting public health by
assuring the safety, efficacy, and security of drug products,
the FDA is (also) responsible for advancing public health
by helping to speed innovations that make medicines more
effective, safer, and more affordable [21]. As stated at the
end of FDA’s 2004 Critical Path Initiative report, (industry,
academia, and FDA) must work together to find…less
costly ways to turn good biomedical ideas into safe and
effective treatments, (otherwise) “the hoped-for benefits of
the biomedical century may not come to pass, or may not
be affordable” [21]. Finally, when asked about the critical
success factors for the industry and regulatory agencies
over the next 5 to 10 years, Dr. Moheb Nasr, Director of the
Office of New Drug Quality Assessment, stated that the
“ultimate success (for industry and regulators) is having
affordable medicines for the patient” [4].
Simulation for Quality Risk Assessment
Consider the potential risk consequences related to the
specification of product quality acceptance criteria. Insuffi-
achieving steady state, for example, or the average deviation from
target concentration. Process sigma, σ, is defined such that 3σ is equal
to 1.0 Cpk or 2,700 defects per million opportunities (DPMO)
28
Fig. 6 Example of how a risk-based system of product quality
assessment might be implemented. Depending on the nature of the
product (and how it will be prescribed) the region of acceptable risk
might be similar to or significantly more or less extensive than an
acceptance region based on (univariate) specifications
cient quantitative understanding of how product variability
affects the safety and efficacy risks of treatment can result in
the specification of product quality acceptance criteria which
do not sufficiently mitigate risks to patient harm; in such a
case, a risk-based quality design system should indicate
that a net risk reduction could be achieved by tightening
specifications. Alternatively, however, it is plausible that
insufficient understanding more frequently leads to the
imposition of excessively strict tolerances as a way of
mitigating the unknown level of risk [9, 21]. Comprehensive
risk analysis would show that the amount of risk mitigated
by unrealistically restrictive design tolerances (or standards)
does not offset the negative effects on patients because of
reduced affordability (or availability) of treatment.
Whereas appropriate dosing guidelines are routinely
determined by carefully balancing the relationship between
dose, efficacy, and toxicity for a given population of
patients, it is considerably more difficult to determine the
quality cost imposed by variation in drug product attributes.
First, the criticality of variation in factors, such as API
content and rate of drug release, are interrelated and often
patient-specific. For example, the probability of ineffective
treatment posed by a subpotent tablet will be magnified if
the rate or extent of drug release is low and will be further
exacerbated if the patient’s rate of drug elimination is high.
Second, the dynamics of repeated dosing and patient
compliance complicate the relationship between variation
in the attributes of individual doses and the overall safety
J Pharm Innov (2008) 3:23–29
and effectiveness of treatment. Finally, the limitations (lag
time, sampling, precision) of systems for measuring both
product characteristics and patient response can mask subtle
(yet relevant) correlations. These and other limiting factors
have been described previously by Woodcock [9].
Mathematical models form the language used to com-
municate the connections between fundamentals and
observed phenomena. Models are advantageous because
they allow greater understanding of processes and systems,
yet provide users a platform to easily manipulate the inputs
to examine the outputs [22]. To the extent that a fun-
damentally relevant model can be identified, model
coefficients provide an efficient means of separating signal
from noise. Model-based representations of patient, phar-
maceutical, pharmacokinetic (PK), and pharmacodynamic
(PD) systems are the key to overcoming the finite limits of
sampling when trying to assess the clinical relevance of
quality. Models have long been used successfully to
describe the dynamics of drug release, absorption, distribu-
tion, metabolism, and elimination (ADME), and patient
response.
Monte Carlo simulation is a stochastic modeling tech-
nique often used for probabilistic risk assessment, which
offers a flexible mathematical framework to harness the
various models (and probability density functions) neces-
sary to link product quality and clinical risk. Monte Carlo
simulation differs from traditional simulation in that the
model parameters are treated as stochastic or random
variables, rather than fixed values [22]. Figure 4 illustrates
how the various models representing drug products and
Fig. 7 Example of how product quality variability, measured as
process sigma, might be correlated to clinical performance. The
synthetic data used for this example did not include variability in
factors other than drug content uniformity. Because there are 2 df in
process capability measurement and, hence, some ambiguity in the
data, clinical risk based on simulation may be a more effective
measure of quality to guide operational or design changes
J Pharm Innov (2008) 3:23–29
patients could be linked for the purpose of simulating the
clinical effect of changes in drug product design or quality.
If repeated dosing is assumed, for example, the pharma-
cokinetic concept of superposition could be used to
estimate the relationship between content uniformity and
the probability of exceeding the therapeutic window of
target plasma drug concentration (Fig. 5). The model-based
system could, therefore, be used to set “realistic” target
values for drug quality attributes (Fig. 6) or manufacturing
performance (Fig. 7). Ultimately, the goals of risk modeling
would be to (1) optimize the product and process design for
minimum risk, (2) develop for each product a system for
optimizing patient-specific dosing guidelines, and (3)
generate a risk-based QLF or design space which could
be paired with PAT and process control systems so that
production could be maintained in a low risk state.
Summary
Quality by design is an important current topic in
pharmaceutical manufacturing because it is the logical next
step in the path toward the desired state that began with the
FDA’s PAT guidance and twenty-first century cGMPs
initiative. As was the case with PAT, the pharmaceutical
industry benefits from many years of pioneering work in
QbD by Taguchi and others. As has also been observed
with the introduction of PAT, however, the unique aspects
of pharmaceutical product design and manufacturing are
leading the industry to push the development of new
concepts and strategies for QbD.
The objectives of this work were to (1) describe the
connections between Taguchi’s concepts of quality loss,
pharmaceutical quality, and risk, and (2) propose a
simulation framework for the assessment of pharmaceutical
quality based on probabilistic risk assessment. This manu-
script is intended to precede a series of future articles which
will provide a more detailed demonstration of how risk-
based QbD can be achieved and integrated with PAT
systems to enhance the development, production, and
quality assessment of pharmaceutical products.
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