International Journal of Pharmaceutics 528 (2017) 354–359

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

The future of pharmaceutical quality and the path to get there

Lawrence X. Yu* , Michael Kopcha
Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD 20993, United States

A R T I C L E I N F O A B S T R A C T

Article history:
Received 11 March 2017 While six sigma quality has long been achieved in other industries, it is rarely seen in the pharmaceutical
Received in revised form 3 June 2017 sector. However, consumers and patients deserve six sigma quality pharmaceuticals with minimal risks
Accepted 12 June 2017 of shortages or recalls. We propose that the future of pharmaceutical quality is six sigma, meaning that no
Available online 12 June 2017 more than 3.4 defects occur per million opportunities. We discuss the path to get there, including
economic drivers, performance-based regulation, Quality by Design, advanced manufacturing
Keywords: technologies, and continuous improvement and operational excellence. This article outlines an
Pharmaceutical quality ambitious goal and is intended to be thought-provoking in spite of the challenging path to get there. This
Six sigma
goal is envisioned because it is in the best interest of patients and consumers and is realizable with
Quality by Design
continued advances and investments in science and technology. The fundamental destination of
Performance-based regulation
Advanced pharmaceutical manufacturing pharmaceutical quality has been long envisioned: a maximally efficient, agile, flexible pharmaceutical
Process capability manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.
Published by Elsevier B.V.

1. Introduction that we still have a long way to go in improving quality in the

pharmaceutical industry to better serve these patients and
The U.S. Food and Drug Administration (FDA) Pharmaceutical consumers.
Quality for the 21 st Century Initiative aims to promote a maximally Therefore, to realize the FDA’s vision for the pharmaceutical
efficient, agile, flexible pharmaceutical manufacturing sector that manufacturing sector, we must continue to improve the overall
reliably produces high quality drugs without extensive regulatory quality of pharmaceuticals. Manufacturing capability in many
oversight (FDA, 2004a). Over the years, substantial progress has diverse industries is analyzed using sigma, the number of standard
been made toward this vision, including process analytical deviations between the process mean and the nearest specification
technology (PAT) (FDA, 2004b), Current Good Manufacturing limit (Nunnally and McConnell, 2007). We propose that the future
Practices (CGMPs) for the 21 st century (FDA, 2004a), Quality by of pharmaceutical quality is six sigma, meaning that no more than
Design (QbD) (FDA, 2009a), and Emerging Technology (FDA, 3.4 defects occur per million opportunities. This is a dramatic
2015a) initiatives. Overall product/process understanding and improvement from the current two to three sigma quality seen in
manufacturing quality have improved in the industry as a whole. pharmaceutical manufacturing. Two sigma quality represents
While the quality of newly introduced products has been 308,537 defects per million opportunities. The six sigma vision of
significantly higher, concerns over pharmaceutical product quality the future of pharmaceutical quality requires the reduction of
have continued due to unacceptably high product recalls and drug defects from
30% to 0.0003%. While six sigma has long been the
shortages. Largely driven by legacy products, the number of target for quality in the electronic, communication, and automo-
product recalls has actually increased over recent years (FDA, bile industries (Harry and Schroeder, 2005), it is rarely seen in the
2015b) (Fig. 1). Alarming drug shortages have also persisted as pharmaceutical industry where six sigma quality is, in many cases,
product quality remains a primary driver (ISPE, 2017). The drive to far from reality. However, consumers and patients deserve six
improve quality and address shortages and recalls is motivated by sigma quality products with minimal risks of shortages or recalls.
the patient and consumer. These recent trends serve as a reminder Here we discuss the path to achieve six sigma quality for
pharmaceuticals, including economic drivers, performance-based
regulation, QbD, advanced manufacturing technologies, and
continuous improvement and operational excellence.
* Corresponding author.
E-mail address: lawrence.yu@fda.hhs.gov (L.X. Yu).

http://dx.doi.org/10.1016/j.ijpharm.2017.06.039
0378-5173/Published by Elsevier B.V.
 L.X. Yu, M. Kopcha / International Journal of Pharmaceutics 528 (2017) 354–359 355

Fig. 1. Number of Class I Drug Product recalls per year (FDA, 2015b). A Class I recall denotes a situation in which there is a reasonable probability that the use of, or exposure to,
the violative product will cause serious adverse health consequences or death. Recalls for misbranding (i.e. product marketed without an approved NDA/ANDA) were removed
from the data set to focus on recalls initiated due to quality issues.

2. Economic drivers promised in the label to the consumer (Woodcock, 2004). Product
quality is therefore fundamentally linked to safety and efficacy. In
The pharmaceutical industry is highly regulated because other words, quality can be defined as the safety and efficacy of the
patients and consumers are generally unable to discern quality next dose a patient or consumer takes. In current practice, we
problems unless they cause severe adverse events or death. Public ensure that a drug product meets appropriate quality standards or
perception is that all products approved by the FDA are safe and specifications. However, the frequency or degree of meeting the
effective. The public also expects approved products to be of quality standard in manufacturing is not often measured, reported,
equally high quality. Unlike electronics or automobiles, patients or made publicly available. The FDA’s recent initiative of quality
and consumers do not typically distinguish quality in the metrics (FDA, 2016) is intended to fill some of this gap so that we
manufacture of pharmaceuticals. They expect every drug to have have better understanding and knowledge of the state of product
the requisite quality to address their medical condition regardless quality. These quality metrics are self-reported measures that
of how or by whom the drug was manufactured. Consequently, provide quantitative and objective insight into the state of quality
manufacturers have little economic incentive to leverage quality. It for product and facility. They can improve inspections, identify
is easier to simply comply with FDA requirements. Woodcock and factors leading to supply disruption, and provide reliable
Wosinska (Woodcock and Wosinska, 2013) used economic theory information on quality that is readily understood by consumers.
to frame the drug-shortage problem as the inability of the market As a result, quality information can be a factor for consideration in
to observe and reward quality. Moving forward, we need to the marketplace.
introduce incentives to the drug industry that enable the market to
recognize and reward quality. 3. Performance-based regulation
This lack of reward for quality reinforces price competition and
encourages manufacturers to minimize costs. As a result, low cost Regulation may intervene at any of three stages of any
manufacturers can maintain a market share based largely on price organization’s activities: the planning, acting, or output stages
competition. Although not always the case, these manufacturers (Coglianese and Lazer, 2003). Potential outputs include both
have high vulnerability to product quality issues, including product private and social goods (i.e., saleable products or services) as well
recalls and supply disruption. For many consumer products, recalls as positive and negative externalities that affect society. Regulation
and supply disruption cause some inconvenience to the consumer is often needed when competitive economics drive private
and economic loss to the manufacturer. For pharmaceuticals, organizations to produce unhealthy social goods. In our case, this
recalls and supply disruption can be life threatening, in addition to manifests in unsafe, ineffective, or low quality pharmaceuticals.
causing economic loss. Therefore, we believe quality drugs are a Regulations exist because companies failed to adequately
must, with reliability and sustainability taken into consideration. ensure quality which resulted in tragic consequences. Indeed,
A high quality drug product is defined as a product free of the death of more than 100 people in 1937 across the United States
contamination that reproducibly delivers the therapeutic benefit from Elixir Sulfanilamide, a drug used to treat streptococcal

Fig. 2. Stages of organizational production and types of regulation.

356 L.X. Yu, M. Kopcha / International Journal of Pharmaceutics 528 (2017) 354–359

infections, led to the passage of the 1938 Food, Drug, and Cosmetic product development and manufacturing. We recognize that
(FD&C) Act (Ballentine, 1981). Prior to the FD&C Act, safety studies industry and regulatory authorities have used risk-based
were not required for new drugs. In the early 19600 s, women approaches to product development and control strategy estab-
around the globe gave birth to children with severe birth defects as lishment during marketing review to ensure in vivo performance.
result of the sedative drug thalidomide. This drug was never According to ICH Q8 (FDA, 2009c), a control strategy can include,
approved in the United States, but the response to the global outcry but is not limited to, the following:
led to the 1962 Kefauver-Harris amendments to the FD&C Act,
which required drug manufacturers to prove that drugs were not  Control of input material attributes (e.g., drug substance,
only safe, but also effective (Hamburg, 2012). Each of these excipients, primary packaging materials) based on an under-
historical events, in its own way, shows how regulation responded standing of their impact on processability or product quality
to the needs of the market to eliminate unhealthy social goods and  Product specification(s)
not vice versa. More recently, the global heparin crisis led to a  Controls for unit operations that have an impact on downstream
sudden spike in serious adverse events after a contaminant, processing or product quality (e.g., the impact of drying on
oversulfated chrondroitin sulfate, was introduced into the heparin degradation, particle size distribution of the granulate on
manufacturing process which went undetected by quality control dissolution)
methods (Szajek et al., 2016). In light of this and other events  In-process or real-time release testing in lieu of end-product
surrounding pharmaceutical quality, the FDA established a testing (e.g., measurement and control of critical quality
systemic focus on quality in a new Office of Pharmaceutical attributes during processing)
Quality to integrate review, inspection, surveillance, and research  A monitoring program (e.g., full product testing at regular
across the drug product lifecycle (Yu and Woodcock, 2015). intervals) for verifying multivariate prediction models
The ultimate goal of all regulation is to change outcomes by
targeting regulatory intervention at any of the three stages: The management-based approach brings burdensome regula-
planning, acting, outputs (Fig. 2). Management-based approaches tory requirements imposed on manufacturers for executing minor
intervene at the planning stages, compelling regulated organiza- and incremental changes to manufacturing processes and controls,
tions to improve their internal management in an attempt to inhibiting continuous improvement and strategies for the imple-
increase the achievement of public goals without negative mentation of continuous “real time” assurance of quality.
consequences. Means-based approaches intervene in the acting For drug substance and product manufacturing of small
stage, specifying technologies to be used or steps to be followed. molecules, the capacity to assess output is high. Therefore, we
Performance-based approaches intervene at the output stage, can consider a move from management-based to performance-
specifying or proscribing social outputs. based regulation, meaning that regulatory authorities establish
Two major variables that determine the effective use of a product specifications and encourage industry to improve the
regulatory approach are (Coglianese, 2016): (i) the capacity to probability of meeting the product specifications. This may give the
measure the output and (ii) the degree of homogeneity of the pharmaceutical industry flexibility to make changes, adopt new
regulated entities across both location and time (Fig. 3). For technology, and improve quality. However, for complex biophar-
industries in which there is a low capacity to measure output and maceuticals the capacity to assess output is lower than in small
low homogeneity of the regulated entities, management-based molecule manufacturing and there could be challenges with a
regulation is the preferred approach. On the other hand, for performance-based regulatory approach. As such, the most
regulated entities with a high capacity to measure output, effective form of pharmaceutical regulation is the combination
performance-based regulation is preferred. of management- and performance-based regulation in the near
For the regulation of pharmaceutical quality, we have term, with the eventual goal of performance-based regulation only.
traditionally used the management-based approach, meaning that In many ways, the drive toward both six sigma quality and
regulatory authority is heavily involved in the planning stage of performance-based regulation of pharmaceutical manufacturing is
predicated upon specifications that are soundly established based
on clinical relevance. We recognized that manufacturers set
specification limits based on several risk-based factors including:
(i) the extent to which a critical quality attribute will have an
impact on safety and efficacy of the product, (ii) an understanding
of first principles associated with the drug substance and
formulation, (iii) pharmacodynamics and pharmacokinetics of
the drug, (iv) in vitro data corroborated by clinical results, and (v)
variability of analytics, process manufacturing, and patient
responses. Of course the connection between specification limits
and product performance is more direct for some attributes (e.g.,
assay, impurities, dissolution) than others. These readily measur-
able attributes with a link to clinical performance form the
foundation of performance-based regulation.

4. Pharmaceutical Quality by Design (QbD)

Pharmaceutical QbD is a systematic approach to development

that begins with predefined objectives and emphasizes product
and process understanding and process control, based on sound
Fig. 3. Conditions for effective use of performance-, means-, and management-
science and quality risk management (FDA, 2009a). The key
based regulations. elements of QbD include: (i) a quality target product profile (QTPP)
that identifies the critical quality attributes (CQAs) of the drug
 L.X. Yu, M. Kopcha / International Journal of Pharmaceutics 528 (2017) 354–359 357

product; (ii) product design and understanding including identifi- parameters within the established design space. Level 1 employs
cation of critical material attributes (CMAs); (iii) process design automatic engineering control to monitor the CQAs of the output
and understanding including identification of critical process materials in real time. Input material attributes are monitored and
parameters (CPPs) and linking CMAs and CPPs to CQAs; and (iv) a process parameters are automatically adjusted to assure that CQAs
control strategy that includes specifications for the drug substance of an output material conform to the established acceptance
(s), excipient(s) and drug product as well as controls for each step criteria. When the control strategy moves from Level 3 to Level 1,
of the manufacturing process (Yu, 2008). greater assurance of product quality is achieved. Following QbD
QTPP is a prospective summary of the quality characteristics of principles, process understanding coupled with a high level of
a drug product that ideally will be achieved to ensure the desired process control can provide sufficient evidence that batches will
quality, taking into account safety and efficacy of the drug product. meet specifications, allowing for potential real time release of
QTPP typically includes administration, dosage form, route of batches. The direct outcome of using QbD for product development
administration, dosage strength, container closure system, phar- is the potential to increase process capability from 2 to 3 sigma to
macokinetic characteristics, stability expectation, and drug prod- the goal of six sigma (Migliaccio, 2011) (Fig. 4). A genuine QbD may
uct CQAs. The drug product CQAs are physical, chemical, biological, play the most important role in assuring consistently high product
or microbiological properties or characteristics of a finished drug quality and robust manufacturing, as quality differences can often
product that should be within an appropriate limit, range, or be directly attributed to the difference in product and process
distribution to ensure the desired product quality. Attributes can design and development.
be critical or not critical based on severity of harm to the patient
should the product fall outside the acceptable range for that
attribute. 5. Pharmaceutical emerging technology
The overall goal of product design is to develop a robust product
that can deliver the desired QTPP over the product shelf life. FDA analysis of data collected from manufacturers indicates
Product understanding is defined as the ability to link input CMAs that production disruptions cause 66% of drug shortages (FDA,
and CPPs to output CQAs. Strictly speaking, process and product 2013). These production disruptions are often due to the use of
design and development cannot be split since a formulation cannot outdated manufacturing technologies and equipment for drug
become a product without a process. Process design is the initial substance and drug product production. Though the type of
stage of process development where an outline of the commercial equipment/technology and the reasons for being outdated may
manufacturing processes is identified on paper, including the vary, new technology is generally important for improving
intended scales of manufacturing. This should include all the consistency and efficiency in manufacturing. Accelerating the
factors that need to be considered for the design of the process, development and adoption of pharmaceutical manufacturing
including facility, equipment, material transfer, and manufacturing innovations, so-called “emerging technology,” is needed to realize
variables. Steps to establish process understanding are very similar the vision of six sigma quality. The FDA defined emerging
to those of product understanding (Yu et al., 2014). While technology as technology: (i) with the potential to modernize
developing a strategy for investigating both product and process the body of knowledge associated with pharmaceutical develop-
design and understanding, studies can be designed in such a way ment to support robust, predictable, and/or cost-effective process-
that both the objectives of product and process understanding are es or novel products and (ii) with which the FDA has limited review
achieved simultaneously. In addition, an interactive (or interde- or inspection experience. Some relevant examples of emerging
pendent) relationship among material attributes, process param- technology include continuous manufacturing of drug substance
eters, and product attributes can be more easily developed in and drug product, “on-demand” manufacturing of drug products,
carefully planned and designed experimental studies. use of robots in pharmaceutical manufacturing, 3D printed tablets,
The knowledge gained through product and process under- and new container and closure systems for injectable products.
standing forms the basis for establishing a control strategy. There Emerging technology can lead to robust manufacturing
are three levels of control strategy (Yu et al., 2014). Level 3 is the processes with fewer interruptions, fewer product failures, and
level of control traditionally used in the pharmaceutical industry. greater assurance of product quality. Pharmaceutical manufactur-
This control strategy relies on extensive end product testing and ing is still largely batch in nature and relatively inefficient, poorly
tightly constrained material attributes and process parameters. understood, and poorly controlled as compared to other industries.
Level 2 consists of pharmaceutical control with reduced end A batch process is defined as one in which materials are charged
product testing and flexible material attributes and process into the system at the beginning of the process and the product is

Fig. 4. Process capability using a QbD approach to product development.

358 L.X. Yu, M. Kopcha / International Journal of Pharmaceutics 528 (2017) 354–359

been successful as the quality of newly introduced products is

generally much higher (as illustrated in Fig. 4). However, the FDA
has still been confronted with unprecedented drug shortages and
product recalls, largely for legacy products, limiting patient access
to critical drug products and undermining healthcare (FDA, 2015b;
ISPE, 2017). Therefore, continuous improvement is a part of our
overall effort to improve product quality, particularly for legacy
products. Regulatory authorities need to create an environment
and provide incentives for manufacturers to continually improve
their manufacturing processes.
Continuous improvement is defined as recurring activity to
increase the ability to fulfill requirements, which can be measured
by process capability (FDA, 2009b). The process capability (Cp and
Cpk) indices are obtained when calculations are based on the
inherent variability, due to common causes, of a stable process (i.e.,
in a state of statistical control). A state of statistical control is
demonstrated when the process exhibits no detectable patterns or
Fig. 5. Understanding the effect of passive and active PAT control on the quality of
output materials.
trends, such that the variation seen in the data is believed to be
random and inherent to the process (Yu et al., 2015; Peng et al.,
2015). If the process is not in a state of statistical control, the
discharged at once sometime later. In a true batch process, no calculations are based on standard deviation of all individual
material crosses the system boundaries between the time the raw samples taken over a longer period of time. The result is the
materials are charged and the time the product is discharged. On process performance index (Pp and Ppk).
the other hand, a continuous process is one in which materials are A continuous improvement effort seeks to remove sources of
continuously charged into the system while the product is inherent variability from the process operation conditions and raw
continuously discharged (Lee et al., 2015). Adopted by other material quality, resulting in higher process capability. Continuous
industries, continuous manufacturing is one innovation that can improvement typically has five phases: (i) defining the problem
lead to more efficient, better understood, and better controlled and the project goals, (ii) measuring key aspects of the current
processes (Yu, 2016). process and collecting relevant data, (iii) analyzing the data to
The process analytical technology (PAT) initiative from the turn investigate and verify cause-and-effect relationships, (iv) improv-
of the 21st century provides the foundation of continuous ing or optimizing the current process based on data analysis (e.g.,
manufacturing while the QbD effort of the past decade further design of experiments), and (v) controlling the new process to
fostered the development and adoption of continuous manufactur- ensure that any deviations are corrected.
ing for pharmaceuticals. A typical batch process employs a passive Process variability can be common cause/inherent or special
control strategy. After manufacturing, the output material is tested cause/intermittent. While continuous improvement reduces com-
to determine if it meets the expected quality. If not, the material is mon causes, operational excellence directly controls special cause
reprocessed or discarded. In continuous manufacturing, an active variability. On this front, special cause variability can be disastrous,
control strategy controls the quality of output materials by resulting in significant financial loss and drug shortage. ICH Q10
adjusting process parameters (Fig. 5). In the theoretical ideal describes a comprehensive model for an effective pharmaceutical
situation, the quality of output material is assured during quality system to direct and control a manufacturer’s ability to
manufacture. manage quality (FDA, 2009b). An operative quality management
The FDA has recently approved: (i) OrkambiTM (lumacaftor/ system (QMS) includes four elements: (i) a process performance
ivacaftor), the first new drug application approved using a and product quality monitoring system, (ii) a corrective action and
continuous manufacturing technology, and (ii) PrezistaTM (dar- preventive action (CAPA) system, (iii) a change management
unavir), the first new drug application supplement approved for system, and (iv) management review of process performance and
switching from an existing batch process to a continuous one. product quality. Knowledge and quality risk management enable a
Continuous manufacturing offers numerous potential benefits, manufacturer to implement these four QMS elements.
including reduced variability and increased reliability through the Implementing these four QMS elements provides the founda-
development and adoption of precise analytical technology and tion of product quality. The other critical enhancer is the culture of
less reliance on labor-intense manual activities. Costs can be quality, an environment in which employees not only follow
reduced due to reduction in equipment footprints and labor needs, quality guidelines but also consistently see others taking quality-
and increased process efficiency. Less processing time is required focused actions and hear others talking about quality (Srinivasan
per unit dose (minutes vs. days). Scale-up bottlenecks can be and Kurey, 2014). A true culture of quality exhibits a range of easily
eliminated leading to more agile and responsive supply chains. recognizable attributes, including clearly visible, engaged, and
Importantly, increased capability enables rapid response to drug unwavering senior management support for quality and clearly
shortages, emergencies, and patient demand to ensure a consistent articulated vision, values, and quality goals. Active and ongoing
supply of high quality drug products (Yu et al., 2016). For many engagement with customers continually identifies and addresses
pharmaceuticals, continuous manufacturing is a necessity for current and evolving needs. Performance expectations for all
realizing the six sigma vision. individuals throughout the company clearly link to quality goals
and incentives (ForbesInsights, 2014).
According to some reports, world-class organizations are much
6. Continuous improvement and operational excellence more likely than others to exhibit the above attributes (ForbesIn-
sights, 2014). They are also more likely to regard their quality
Over the past 15 years, the FDA had a number of initiatives capabilities as a means of creating and sustaining competitive
intended to improve product quality, including PAT, QbD, and advantage, leading to stronger profitability. As a result of their
Emerging Technology initiatives. These initiatives have largely greater investment in and commitment to quality, these
 L.X. Yu, M. Kopcha / International Journal of Pharmaceutics 528 (2017) 354–359 359

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