The AAPS Journal (2025) 27:96

[Link]

REVIEW ARTICLE

Rethinking Pharmaceutical Industry with Quality by Design:

Application in Research, Development, Manufacturing, and Quality
Assurance
Joana Galvão Duarte1 · Maria Galvão Duarte2 · Ana Paula Piedade3 · Filipa Mascarenhas-Melo4,5

Received: 23 January 2025 / Accepted: 25 April 2025 / Published online: 20 May 2025
© The Author(s) 2025

Abstract
Quality by Design (QbD) is a transformative and systematic approach to developing top-tier pharmaceutical products, usher-
ing in a departure from traditional trial-and-error methods toward a more science-based, risk-oriented, and holistic strategy.
Central to QbD implementation is the meticulous development of formulations and manufacturing processes, consistently
fulfilling predefined quality objectives. The core objective of QbD remains unwavering — to guarantee the steadfast alignment
of the final pharmaceutical product with predetermined quality attributes, thereby mitigating batch-to-batch variations and
potential recalls. This article succinctly explores the multifaceted application of QbD methodology within the pharmaceutical
industry. Emphasizing its pivotal role in research and development, manufacturing, quality control, and quality assurance,
the discussion navigates through the strategic deployment of QbD elements and tools. Amidst the evident advantages of
QbD, challenges persist in its widespread adoption within the pharmaceutical sector and regulatory frameworks. This article
sheds light on the regulatory landscape that currently governs the implementation of QbD in these crucial stages of phar-
maceutical processes. For that reason, this review article aims to provide researchers, scientists, and industry professionals
with a thorough introduction to QbD so they may adopt this methodical approach to developing and producing high-quality
pharmaceutical products, always in compliance with the underlying regulations.

Keywords pharmaceutical manufacturing · pharmaceutical quality by design · quality assurance · quality control · research
and development

Abbreviations
AQbD Analytical Quality by Design
CCD Central composite design
CDR Cumulative Drug Release
* Filipa Mascarenhas-Melo CMAs Critical Material Attributes
filipamelo@".[Link]
CPPs Critical Process Parameters
1
Doctoral Program in Biomedical Sciences, School CQAs Critical Quality Attributes
of Medicine & Biomedical Sciences, University DOE Design of Experiments
of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, DS Design Space
4050-513 Porto, Portugal
EMA European Medicines Agency
2
Faculty of Pharmacy, University of Coimbra, Azinhaga FDA U.S. Food and Drug Administration
Sta. Comba, 3000-548 Coimbra, Portugal FDTs Fast-Dissolving Tablets
3
University of Coimbra, CEMMPRE, Department FMEA Failure mode and e"ect analysis
of Mechanical Engineering, 3030-788 Coimbra, Portugal FMECA Failure Mode, E"ects, and Criticality Analysis
4
Higher School of Health, Polytechnic Institute of Guarda, HACCP Hazard Analysis and Critical Control Points
Av. Dr. Francisco Sá Carneiro 50, 6300-559 Guarda, Guarda, ICH International Conference on Harmonization
Portugal
5
MAs Material Attributes
BRIDGES - Biotechnology Research, Innovation MDIs Metered Dose Inhalers
and Design for Health Products, Polytechnic University
of Guarda, Avenida Dr. Francisco Sá Carneiro, N.º 50, MODR Method Operable Design Region
6300-559 Guarda, Portugal MVDA Multivariate data analysis

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NIR Near-infrared spectroscopy method that could reliably and consistently produce high-
ODFs Orodispersible films quality products (7–9). Since then, QbD has gained impor-
PAT Process Analytical Technologies tance in the pharmaceutical industry, with global regula-
PCA Principal Component Analysis tory agencies advocating for its adoption (6, 7). Nowadays,
PHA Hazard analysis QbD is considered an integral component of pharmaceuti-
PLS Partial least squares cal development, and even more, a strategy that should be
PPs Process Parameters included in all new drug applications (2, 6, 8).
PSD Particle size distribution When compared to traditional quality control methods,
QAs Quality Attributes which mostly rely on end-product testing, where quality is
QbD Quality by Design assessed at the end of production, often resulting in waste,
QbT Quality by Testing inefficiencies, and costly regulatory setbacks when speci-
QRA Quality Risk Assessment fications are not met, QbD represents a paradigm change.
QTPP Quality Target Product Profile Instead, QbD places a strong emphasis on integrating qual-
RA Risk assessment ity into all phases of the product lifecycle, with an emphasis
REM Risk Estimation Matrix on proactive design and control. It understands that quality
RPN Risk priority number must be incorporated into a product from the start, based on
RSM Response Surface Methodology sound scientific concepts, rather than examined or tested at
RTR Real-Time Release the end (5).
SPC Statistical process control Studies indicate that QbD can reduce development time
w/o/w Water-in-oil-in-water by up to 40% by optimizing formulation parameters before
full-scale manufacturing. Additionally, its ability to define
and control a robust design space has led to fewer batch
Introduction failures, reducing material wastage by up to 50% in some
reported cases.
Ensuring pharmaceutical product quality is a top priority At the core of QbD lies the systematic identification and
for industries, driven by the need to safeguard patient safety management of critical quality attributes (CQAs) and criti-
and ensure the efficacy of products. As a result, the pharma- cal process parameters (CPPs) (5, 10) (Fig. 1). CQAs are the
ceutical sector stands as one of the most highly regulated fundamental features of a product that must be incorporated
industries worldwide (1). Traditional drug development has to guarantee its performance, e"ectiveness, and safety. These
historically relied on trial-and-error procedures focused on characteristics are closely related to the final pharmaceutical
creating a product that satisfies all regulatory requirements, product's therapeutic advantages, stability, and manufactur-
rather than simplifying and improving the development pro- ability (5). CPPs, on the other hand, are the process fac-
cess (Fig. 1). This method is often labor-intensive, costly, tors that have a big impact on CQAs. For the manufacturing
and prone to batch failures due to process variability (2). process to be optimized and consistent product quality to be
While it has enabled the commercialization of numerous attained, it is essential to comprehend the cause-and-e"ect
drugs, this method’s inefficiencies call for a more systematic relationship between CPPs and CQAs (5, 11).
approach to quality assurance (3, 4). QbD uses Design of Experiments (DOE), a powerful tool
The concept of Quality by Design (QbD) emerged in the for process optimization. By planning and executing experi-
manufacturing industry over 25 years ago, and it started to ments, collecting data, and analysing results statistically,
receive significant attention from the pharmaceutical industry DOE allows for the systematic evaluation of process param-
in the early 2000 s due to its potential to improve the efficacy, eters (12). This structured approach helps experts identify
quality, and safety of pharmaceutical products (2, 5). The U.S. key sources of variability and determine the optimal condi-
Food and Drug Administration (FDA) first introduced QbD tions needed to achieve the desired product quality features.
notions between 2001 and 2004, and described it as a proac- Controlling these critical variables within clearly defined
tive tool designed to introduce quality into the pharmaceuti- limits reduces the risk of product failures, inconsistencies,
cal product from the start, while improving the processes of and batch rejections.
development, manufacturing, and regulation (6) (Fig. 1). Another key element of QbD is the development of a
The pharmaceutical sector was first formally exposed to Quality Target Product Profile (QTPP) (2, 13), which out-
the notion of QbD in 2005 with the publication of the Inter- lines the therapeutic goals, safety requirements, and intended
national Conference on Harmonization (ICH) Q8 guideline product characteristics (14). It guides all phases of prod-
(Pharmaceutical Development) (5, 7). The guideline empha- uct development, enabling a comprehensive and scientifi-
sized the importance of understanding both the product and cally informed approach to formulation and process design.
the manufacturing process to establish a solid manufacturing QTPP streamlines decision-making processes and assures
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Fig. 1 Comparative Overview of Traditional vs. QbD-Based Pharmaceutical Development Methodologies. CPAs – Critical Quality Attributes;
CPPs – Critical Process Parameters

consistency and quality across the product lifecycle by align- submissions, its long-term advantages in process efficiency,
ing all stakeholders around a unified quality target (5, 14). regulatory flexibility, and patient safety outweigh the initial
Recognizing QbD's potential to improve the quality of phar- implementation challenges (20).
maceutical products, regulatory bodies have o"ered recom- In this comprehensive review, the objective is to thor-
mendations to support its use (9). The European Medicines oughly explore the significant role played by QbD in the
Agency (EMA) and the U.S. FDA have both released regula- pharmaceutical industry, focusing on its application across
tory frameworks that stress the significance of a methodi- fundamental domains — research and development, manu-
cal and scientific approach to pharmaceutical research and facturing, quality control, and quality assurance. By examin-
manufacture (7, 15, 16). ing the integration of scientific principles, risk assessment
In recent years, Analytical Quality by Design (AQbD) (RA), statistical methodologies, and DOE, the aim is to
has gained prominence as an extension of QbD principles provide a nuanced understanding of these and other foun-
into analytical method development. AQbD aligns with the dational concepts.
principles outlined in ICH Q14, ensuring that analytical Drawing on diverse case studies and real-world scenarios,
methods are robust, reproducible, and regulatory-compliant this work illustrates how QbD emerges as a transformative
throughout the product lifecycle. This approach establishes strategy within the pharmaceutical industry, leveraging
a Method Operable Design Region (MODR) to improve meticulous scientific analysis and a holistic, science-based
method performance while minimizing method variabil- overview of the entire pharmaceutical process. Ultimately,
ity, an essential factor for regulatory approval (15, 17–19). QbD stands as a revolutionary framework poised to elevate
Despite these benefits, QbD requires extensive upfront pharmaceutical products by ensuring patient safety, enhanc-
investment in experimental design, data collection, and ing product quality, and aligning seamlessly with regulatory
regulatory documentation, which can be challenging. How- standards. This review highlights how QbD principles refine
ever, as regulatory agencies increasingly favor QbD-based and advance the pharmaceutical development processes.
96 Page 4 of 23 The AAPS Journal (2025) 27:96

Quality by Design Although QbT has advantages and is still a crucial part of
quality assurance, it can be resource-intensive and inef-
To better understand how specific procedures or materi- fective at resolving possible problems that can occur dur-
als might a"ect the quality profile of a pharmaceutical ing production. QbD, on the other hand, is grounded on
product, the initial establishment of certain fundamental the ideas of risk management, knowledge of science, and
QbD aspects is a must (2, 5). Dr. Joseph M. Juran, a world- process improvement (6).
renowned pioneer in the field of quality, was the one who At its core, QbD focuses on designing both the prod-
initially developed the idea of Quality by Design, and also uct and its manufacturing process so that quality is built
contributed greatly to the advancement of quality control in rather than tested at the end (5). It is a systematic and
methodologies. Dr. Juran emphasized that quality was science-based approach that enhances the quality of pharma-
a fundamental requirement for achieving success in any ceutical products through the integration of scientific prin-
business endeavor and, therefore, advocated that quality ciples, risk assessment, and statistical methodologies (2, 5,
should be ingrained into the product from the very begin- 9). It emphasizes the proactive design and control of product
ning of its development, rather than as opposed to being and manufacturing processes to ensure consistent quality
inspected or corrected afterward. According to Dr. Juran’s and regulatory compliance (24). With QTPP, CQAs, CPPs,
teaching, many quality crises and issues can be traced back and DOE serving as its core values and concepts.
to the way a product was originally designed and devel- QTPP o"ers an extensive description of the target prod-
oped. Unlike the conventional Quality By Testing (QbT) uct quality attributes and serves as the foundation of the
method, which focuses on post-production testing and QbD methodology. It includes qualities that are essential to
inspection, QbD adopts a more proactive and systematic addressing patients'demands, such as safety, e"ectiveness,
approach to assure product quality throughout the whole performance criteria, and others (6). By outlining these goals
development and manufacturing process (Fig. 2) (21–23). early in the product development process, pharmaceutical

Fig. 2 Comprehensive breakdown of Pharmaceutical Quality by Quality Attributes; PAT—Process Analytical Technologies; QTPP –
Design (QbD) implementation steps. CMAs – Critical Material Quality Target Product Profile
Attributes; CPPs – Critical Process Parameters; CQAs – Critical
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teams can align their e"orts throughout the product’s life- a methodical and scientific approach, which ultimately
cycle. The QTPP guides all development stages—from improves patient safety, product efficiency, and quality (24).
formulation to manufacturing—by acting as a roadmap for The QTPP, considered the initial and pivotal component,
decision-making (5, 14, 25). establishes the scene by carefully describing the target
The specific product characteristics that are closely performance and quality attributes of the finished product
related to safety, e"ectiveness, and overall quality are known (Fig. 3). This comprehensive profile guides each phase of
as CQAs. A risk-based strategy is used to identify CQAs the development process. The QTPP unites stakeholders,
while taking into account their e"ect on the patient and from researchers to manufacturers and regulatory authori-
regulatory compliance. Drug potency, stability, dissolving ties, towards a single quality aim by explicitly express-
rate, and impurity levels are a few examples of CQAs. To ing the product's intended purpose, dosage form, mode of
guarantee that the finished product continually satisfies its administration, strength, and other essential quality factors.
quality requirements, these factors are meticulously moni- It is crucial in managing expectations among partners and
tored and controlled. expressing them, ensuring clarity and openness throughout
The critical manufacturing parameters known as CPPs the development process. Pharmaceutical businesses may
strongly influence the product's CQAs. CPPs are identified easily navigate the complexity of development using the
by carefully analyzing the correlation between the product QTPP as their compass, making informed decisions and
and the process. CPPs comprise variables such as mixing utilizing scientific knowledge to reach their quality targets
time, temperature, and pressure that have an e"ect on the (2, 5, 8).
product's quality during the manufacturing and formulation Following this methodical, science-based approach,
processes. Controlling CPPs within defined limits is critical QbD allows for pharmaceutical products that consistently
for consistent product performance. satisfy the highest quality standards, ensuring that patients
DOE is a powerful statistical tool within QbD that helps all over the world receive safe and e"ective products and
to systematically examine how process variables affect therapies. A critical stage in the QbD methodology, which
CQAs. It enables scientists to create mathematical models supports the creation of safe, efficient, and high-quality
that explain the link between CPPs and CQAs, organize trial pharmaceutical products, is the identification and control
sequences, gather pertinent data, and assess the outcomes. of CQAs (Fig. 3). CQAs are the particular characteristics
This makes it possible to pinpoint the ideal process variables that directly and significantly a"ect a product's safety, e"ec-
that result in the desired product quality. DOE also makes tiveness, and general quality. Considering their importance
it possible to modify and optimize processes e"ectively by to the patient, regulatory requirements, and the intended
helping to understand how di"erent components interact (2, application of the medicine, these essential characteristics
5, 8, 23). are carefully chosen. Following its identification, thorough
The pharmaceutical industry has seen notable advance- control procedures are developed and applied throughout
ments in efficiency, product uniformity, and patient safety the whole development and production process. During each
due to the implementation of QbD concepts (Fig. 2). The stage of manufacturing, stringent monitoring, testing, and
creation of more reliable pharmaceutical products that con- analysis are used to make sure that these CQAs stay within
sistently fulfill set quality targets has been made possible by predetermined limits, reducing the possibility of variances
the emphasis on understanding CQAs and CPPs. Ultimately, or flaws, and ensuring the uniformity and dependability of
the integration of QbD into pharmaceutical development has the final output. Additionally, by comprehending and man-
resulted in a more scientifically based and patient-focused aging CQAs, pharmaceutical businesses are better able to
approach, ensuring that medications are safer, more efficient, optimize their operations and choose wisely when it comes
and of greater quality for the benefit of patients all around to formulation, manufacturing, and packaging (5). Making
the world (6, 13). As QbD gains global momentum, collabo- use of this information, manufacturers may adjust their pro-
ration between industry stakeholders and regulatory agen- cesses to increase product quality and adhere to regulatory
cies is essential to furthering standardization and harmoniza- requirements, lowering the possibility of expensive recalls
tion across global marketplaces as QbD gains prominence. and assuring compliance with stringent quality laws. By
focusing on aspects that directly a"ect a product's thera-
peutic efficacy, CQAs additionally advocate patient safety.
Quality by Design Elements Keeping these characteristics under strict monitoring not
only improves the product's e"ectiveness but also reduces
The QbD methodology is a unique and paradigm-shifting the risk of unwanted responses and side e"ects, further
approach in the pharmaceutical industry, underpinned by enhancing patient happiness and well-being. CPPs, which
its foundational elements that guide the development, pro- complement CQAs, provide yet another essential basis
duction, and management of pharmaceutical goods through for attaining consistent and better product quality in the
96 Page 6 of 23 The AAPS Journal (2025) 27:96

Fig. 3 Integrated components in Pharmaceutical QbD implementation. CPPs – Critical Process Parameters; CQAs – Critical Quality Attributes;
DOE – Design of Experiments; PAT—Process Analytical Technologies; RA – Risk assessment

pharmaceutical manufacturing industry by determining the the continuous monitoring and real-time analysis of these
important characteristics of the finished product during the crucial factors (26). The pharmaceutical industry may create
manufacturing process (Fig. 3). Finding the CPPs requires a consistent and dependable production process by carefully
a multidisciplinary approach and a thorough understanding monitoring and adjusting CPPs, which lowers the possibil-
of the process, the product, and the way they interact (5, ity of batch failures, product recalls, and customer com-
25). Manufacturers can identify the elements that influence plaints (5, 27). Additionally, by comprehending and man-
a product's quality, efficacy, and safety by using scientific aging CPPs, companies may increase their process expertise
knowledge, data analysis, and testing. These crucial aspects, and obtain important insights into the causal connections
which might include formulation, raw material, equipment, between process variables and product quality. Using this
operational circumstances, and environmental considera- information as the foundation, businesses may improve effi-
tions, are unique to each product and production process. ciency, productivity, and cost-e"ectiveness while maintain-
A strong control system is put in place once the CPPs have ing quality. Also, industries may produce a more streamlined
been defined to guarantee that they are strictly adhered to and e"ective procedure that satisfies regulatory criteria and
within the ideal limits. The likelihood of out-of-specification patient expectations by improving the CPPs (2, 5, 13).
products is reduced, and process consistency is ensured by
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The Design Space (DS) is another dynamic and key com- fluctuations in product quality, it is intended to preserve the
ponent of QbD (Fig. 3). It refers to the multidimensional product's CQAs within the established parameters of the DS
combination and interplay of input variables and process (5, 13). Companies may develop a complete set of process
parameters that can be varied without negatively a"ecting controls, ensuring that every key process parameter is rig-
product quality. This defined range gives manufacturers the orously monitored and maintained through the integration
benefit of having flexibility within predetermined limits, of cutting-edge technology and powerful analytical tools.
empowering them to make strategic changes to the produc- Control Strategy also serves as a proactive risk manage-
tion process without sacrificing the final product quality. The ment tool by methodically identifying possible weak spots
DS is fundamentally an in-depth understanding of the inter- in the production process and putting in place the necessary
actions between di"erent process variables and CQAs that safeguards to stop quality deviations (5, 15). By enabling
a"ect the performance of the end product. It encompasses an businesses to identify and manage possible quality concerns
extensive understanding of the complex links between input early in the manufacturing cycle, the possibility of product
variables and output features rather than just being a range recalls and regulatory non-compliance is reduced. It also
of acceptable values. Process scientists plot the route for the promotes a culture of continuous improvement, where manu-
most e"ective and efficient process development by using facturers continuously review and improve their procedures
advanced techniques like the DoE. With the Design Space based on data and insights obtained in real-time. The Control
firmly established, producers are allowed to experiment with Strategy also covers every stage of the product's lifespan,
various process variables within its limits, thus promoting from formulation and manufacture through distribution and
a culture of innovation and ongoing improvement. Locat- post-marketing surveillance, going beyond the production
ing the most advantageous set of process parameters that line (32, 33). Pharmaceutical companies may confidently
consistently produce improved product quality enables the provide goods that continuously meet the highest quality
production process to be optimized. To find the best combi- standards, successfully meeting patient demands and regula-
nation that increases productivity, reduces unpredictability, tory requirements, by coordinating the Control Strategy with
and guarantees product quality at every stage of the manu- the Design Space (34).
facturing process, manufacturers might experiment with a Risk Assessment is another essential and proactive aspect
variety of inputs. As a risk management tool, the DS also that is crucial to the success of pharmaceutical research and
gives users a clear grasp of the possible repercussions of production in terms of product quality, patient safety, and
process variations and deviations. Establishing a strong DS overall business outcomes (Fig. 3). RA is a methodical and
enables industries to proactively evaluate and manage risks, thorough process that involves locating, assessing, and lim-
reducing the possibility of unforeseen quality problems iting any hazards that might have an impact on a product's
and departures from predetermined quality targets. Design quality, e"ectiveness, or patient safety (2, 5, 15). The phar-
Space's versatility is what makes it so appealing, as it may be maceutical industry may foresee and manage possible dif-
continually improved upon and enlarged as scientific knowl- ficulties and vulnerabilities by utilizing RA approaches early
edge develops and fresh insights are gained. This encourages in the development process. By using a proactive approach,
a proactive approach to process development, where manu- companies are better able to identify hazards and take action
facturers stay at the cutting edge of innovation and quality before they develop into serious problems, which lowers the
management, always keen to improve their processes and possibility of expensive quality concerns and product recalls
provide patients with even more trustworthy and e"ective (35). Manufacturers may better produce safe and e"ective
solutions (1, 5, 6, 28–31) medications that inspire trust in patients, healthcare profes-
The Control Strategy, which is based on current knowl- sionals, and regulatory authorities by addressing risks dur-
edge of the product and its production process, serves as the ing product development. Various risk variables are thor-
core principle of the QbD methodology (Fig. 3). A culture oughly considered throughout the RA process, ranging from
of accuracy, dependability, and steadfast dedication to prod- internal elements like raw material variability and process
uct quality is fostered by this strategic framework, which complexity to external factors like environmental conditions
has been designed to guarantee that the product qualities and regulatory requirements. Each risk that has been discov-
continually fit with the predetermined DS. Pharmaceutical ered is thoroughly examined, taking into account both the
companies may proactively reduce risks, stop quality devia- likelihood that it will occur and the gravity of its possible
tions, and improve both the robustness of their processes e"ects. By improving their risk mitigation methods, firms
and the general dependability of their goods by adopting an can prioritize and deploy resources to efficiently manage
efficient control strategy. The Control Strategy is a thorough the most severe risks. The proactive nature of risk assess-
and flexible strategy that includes several controls, moni- ment is one of its key features. Manufacturers can reduce the
toring, and measurement tools used throughout the prod- likelihood of quality deviations or safety issues by doing a
uct's lifespan. To protect against unanticipated changes or thorough study early in the product development lifecycle
96 Page 8 of 23 The AAPS Journal (2025) 27:96

and implementing risk controls and preventative measures controls and monitoring procedures. The robustness of the
from the start. As new information becomes available, pos- process is increased, variability is minimized, and the risk of
sible risks are continually recognized and handled through non-compliance or unforeseen quality problems is decreased
continuous risk monitoring and evaluation throughout the as a result of these controls acting as sentinels, monitoring
product's lifetime. against deviations and variations. DoE is not only a core
Additionally, RA promotes an organizational culture of tool in QbD but also encourages a culture of data-driven
ongoing learning and development. Companies may improve decision-making and continuous improvement. Through
their scientific understanding of their goods and processes by methodical experimentation and data analysis, DoE helps
detecting and comprehending possible weak points. This will identify optimal process configurations that improve prod-
help them make defensible judgments to optimize their pro- uct quality. Manufacturers can efficiently and quickly assess
duction processes. Pharmaceutical products become more various situations, improving their workflows to increase
dependable and secure as a result of this iterative process work efficiency, save costs, and expedite time-to-market (8,
of risk assessment and mitigation, which also encourages 36, 37).
innovation, efficiency improvements, and quality improve- In the QbD strategy, Knowledge Management emerges
ment. Insights from RA also enhance regulatory compliance as an important tool that plays a crucial role in capturing,
and show authorities that quality control and patient safety sharing, and implementing information gathered over the
are prioritized (7, 15, 16). This degree of care and openness whole product lifetime. Utilizing knowledge gained from
in risk management may speed up the regulatory approval prior experiences and research may be a strong tool in this
procedure and foster confidence with regulatory bodies, fast-paced and constantly changing pharmaceutical indus-
making it easier for innovative goods to reach the market. try for improving procedures and raising product quality to
Risk assessment plays a pivotal role in both QbD and AQbD previously unheard-of levels. A culture of continuous learn-
methodologies, particularly in optimizing analytical proce- ing and innovation is built on the foundation of knowledge
dures to ensure method robustness and regulatory flexibility. management, which fosters an atmosphere where expertise
The ICH Q14 guidelines highlight the importance of a sys- thrives and data-driven changes are welcomed. The system-
tematic, knowledge-driven approach to analytical method atic gathering and organizing of information, knowledge
development, where factors such as method sensitivity, pre- acquired, and best practices across the course of the product
cision, and linearity are defined within a design space. Incor- lifecycle is at the core of knowledge management (7, 15, 16).
porating AQbD principles allows for a risk-based approach For scientists, engineers, and industry experts involved in the
that ensures analytical methods remain adaptive and repro- creation and production of pharmaceuticals, this data reposi-
ducible throughout a product’s lifecycle (18, 19). tory becomes valuable, giving them access to a variety of
DoE has a complex function in the QbD methodology, important knowledge. Individuals may use this resource to
successfully acting as both a fundamental element and a their advantage to make educated decisions, streamline pro-
potent statistical tool. DoE is a key component of the QbD cedures, and take on difficult problems more successfully by
architecture and smoothly interacts with it, helping to real- drawing on real-world experiences, historical performance
ize its basic goals. DoE acts as a crucial catalyst for reveal- data, and industry insights. Knowledge management pro-
ing deeper insights into the connections between CPPs motes collaboration, allowing teams to share expertise and
and CQAs by enabling systematic testing and data analy- build integrated solutions across departments. Researchers,
sis (Fig. 3). In the QbD approach, DoE is utilized to build engineers, and quality assurance sta" share ideas through
strong and thorough mathematical models that illuminate collaboration, which promotes cross-functional learning and
the complex interplay between process factors and the eventually results in a thorough grasp of the final product
final product properties. These models serve as vital road and the production process. By overcoming barriers and
maps, directing manufacturers and researchers to an optimal gaining a comprehensive understanding of the full lifecy-
Design Space where constant product quality is achieved. cle, companies may more easily make decisions and share
Companies may use this expertise to create a flexible yet data between departments. Industries may begin on a road
clearly defined Design Space by developing a thorough of continual development by utilizing the colleDdge man-
grasp of the connections between processes and products. agement. Employing lessons from the past and data-driven
This range of options gives manufacturers the flexibility to insights enables businesses to pinpoint opportunities, reduce
adjust CPPs while keeping product characteristics within procedures, and optimize production processes. A culture
the acceptable limits. An e"ective Control Strategy, sup- of innovation and efficiency is fostered by this pursuit of
ported by insights from DoE, plays a key role in maintaining perfection, which guarantees that each iteration of product
consistent product quality during manufacturing (36, 37). development builds upon the accomplishments of the pre-
With a clear understanding of the factors a"ecting CQAs, vious iterations. Additionally, proactive risk management
manufacturers can proactively implement e"ective process is supported by knowledge management. Companies may
The AAPS Journal (2025) 27:96 Page 9 of 23 96

identify possible problems and put preventative measures demanding, particularly when dealing with a large number
in place to successfully manage risks by studying previous of variables (5, 12, 36, 37).
data and results. The possibility of unanticipated quality The QbD methodology also places a high priority on Risk
problems is decreased because of this proactive strategy, Assessment and Management, ensuring that possible threats
which also assures patient safety and inspires confidence in to product quality and patient safety are rigorously assessed,
regulatory authorities and medical experts. addressed, and eliminated.
The crucial role of these fundamental QbD components in Risk Assessment is most frequently used in regulatory
pharmaceutical research and production makes it clear why submissions, manufacturing risk analysis, and quality assur-
this strategy has attracted so much attention in ever-evolv- ance. Risk Assessment techniques, including Failure Mode
ing and exigent field (1, 5, 6, 9, 38). The benefits of QbD and E"ects Analysis (FMEA) and Hazard Analysis and Crit-
are clear, and it has the potential to completely alter how ical Control Points (HACCP), are essential for identifying
drugs are developed, manufactured, and given to patients. and mitigating risks throughout the product lifecycle. These
Theoretically, this methodical, scientific approach results in tools allow manufacturers to proactively address potential
greater comprehension of both products and manufacturing failures before they compromise product quality and patient
procedures, resulting in products that are not only safer but safety. These essential tools give industries a solid founda-
also more reliable, consistent, and tailored to patient needs. tion to evaluate risk at di"erent product development and
manufacturing phases, encouraging a culture of awareness,
readiness, and continuous improvement. The systematic
Quality by Design Tools assessment of potential risks that might have an impact on
a product's quality, e"ectiveness, and safety is at the core
To support pharmaceutical scientists and researchers in of risk assessment. Companies may comprehensively iden-
achieving high standards, QbD o"ers a wide range of spe- tify possible vulnerabilities and rate them based on their
cialized tools. These include specialized techniques, proce- severity and likelihood by using a variety of risk assess-
dures, and statistical approaches. The QbD methodology is ment approaches, such as risk matrices. These risk matrices
built upon these tools, allowing professionals to collect, ana- are useful decision-support tools that enable stakeholders to
lyze, and interpret data with purpose and accuracy. By using e"ectively allocate resources and prioritize risk reduction
these instruments, the industry can improve the production actions (5, 6, 10).
process and proactively regulate product quality, ensuring A crucial aspect of risk assessment is FMEA, which
that patients receive the best possible pharmaceuticals (5). focuses on identifying potential failure modes in the manu-
The DoE is one of the most widely used tools in QbD, facturing process. FMEA enables researchers and engineers
allowing for the systematic investigation of multiple formu- to examine each stage of the process, evaluating the possible
lation and process variables. It is most frequently used in impacts of failures and the underlying core causes using a
early-stage research and development, formulation optimiza- methodical and structured manner. Individuals may prior-
tion, and process scale-up. itize concerns and take preventive measures to enhance the
Using statistical modeling, DoE enables researchers to process and lower the chance of faults by evaluating the
define optimal design spaces, reduce variability, and predict severity, incidence, and detectability of possible failures (39,
the impact of CPPs on CQAs. The QbD methodology's cor- 40). In biologics manufacturing, FMEA has been applied
nerstone tool, DoE, has revolutionized how pharmaceutical to assess sterility risks in monoclonal antibody production,
researchers organize, carry out, and analyze experiments by leading to the implementation of enhanced aseptic process-
revealing the complex relationships between process vari- ing controls that significantly lowered contamination rates.
ables and product quality characteristics. HACCP is another e"ective method in risk assessment
Unlike traditional trial-and-error methods, DoE o"ers and management. It is particularly common in the food and
a structured and data-driven way to explore these links. pharmaceutical sectors. HACCP involves analysing every
Researchers can test di"erent CPP combinations and pin- step of the production process, from raw materials sourcing
point the ones that have the biggest e"ects on product quality through the distribution of the finished product. By identify-
by carefully arranging their trials. ing crucial control points and putting preventative measures in
This in-depth approach uncovers insights that might oth- place, companies may confidently handle possible threats and
erwise be missed. For instance, in the optimization of inhala- guarantee the safety and integrity of their products (39, 41).
tion drug delivery systems, DoE has been used to fine-tune Risk assessment and management are iterative proce-
particle size distribution and aerodynamic performance, dures that change over time as more data and information
ensuring consistent efficacy in metered-dose inhalers. become accessible. As the product lifecycle develops and
While DoE is powerful in experimental design, it requires new difficulties appear, businesses continuously monitor and
extensive statistical knowledge and can be computationally evaluate their operations and update risk assessments. The
96 Page 10 of 23 The AAPS Journal (2025) 27:96

risk management tactics are kept current and efficient in a 32). The pharmaceutical sector has included MVDA, which
constantly changing environment, thanks to this dynamic has raised the level of complexity in data interpretation and
approach (15, 42). However, both FMEA and HACCP rely decision-making. Researchers may negotiate the complexity
heavily on expert judgment to identify risks, rank their of process variables and quality features by utilizing these
severity, and propose mitigation strategies, making them statistical tools, going beyond the constraints of conventional
subjective. More so, these use qualitative assessments, such approaches. The MVDA enables researchers to make data-
as risk matrices, which are useful for identifying hazards driven choices that improve the quality of products, stream-
and prioritizing risks. However, they sometimes lack the line pharmaceutical processes, and guarantee the safety and
statistical rigor of other QbD tools, such as DoE, which rely e"ectiveness of medications for patients all over the world
on quantitative modeling and data-driven validation. (42, 43, 45).
A robust collection of statistical methods known as Mul- The QbD approach's Quality Risk Assessment (QRA) is
tivariate data analysis (MVDA) enables researchers to navi- an important aspect since it o"ers a systematic and data-
gate the tangled web of complex data sets with unmatched driven framework for assessing and managing risks that
accuracy and insight. MVDA is a crucial tool in the e"ort might influence product quality (15). When it comes to pro-
to optimize pharmaceutical research and production since actively identifying possible problems and prioritizing risk
it reveals patterns, correlations, and trends that are often mitigation tactics in the unpredictable and ever-changing
concealed when using conventional univariate approaches. pharmaceutical industry, QRA tools are crucial peers. The
Scientists can overcome the limits of conventional analy- main objective of QRA is to evaluate the possible e"ects of
sis by utilizing the capability of MVDA to comprehend the uncertainties and variations on the performance of products
multidimensional interactions between process factors and and their key quality attributes. Researchers and quality spe-
product quality parameters (43, 44). cialists examine the intricate nature of the production pro-
Principal Component Analysis (PCA), a transformational cess through a thorough study, closely examining the impact
method that enables researchers to condense and reduce of various process factors and raw materials on the quality of
huge datasets into more manageable dimensions while main- the finished product. Companies can identify the elements
taining essential information, is at the core of MVDA. PCA that represent the biggest dangers to product quality by
enables researchers to understand complicated data linkages, assessing the risks associated with each step in the process.
spot prevailing patterns, and find underlying structures that Industries are given the ability to spend their time, energy,
have the greatest impact on total variability by turning origi- and resources more e"ectively thanks to this risk-ranking
nal variables into fundamental components. This compre- approach. Stakeholders may focus on adopting strong con-
hensive method supports data-driven decision-making by trol measures and preventative activities to address the most
pointing scientists in the direction of the variables that have pressing concerns by identifying high-priority risks, thereby
the most influence on product quality and allowing them reducing the chance of quality deviations and assuring the
to concentrate their e"orts on the vital elements that drive safety and efficacy of products. Manufacturers may adopt
process optimization. An additional important component a proactive rather than a reactive approach to risk manage-
of MVDA is partial least squares (PLS), a dynamic tool ment thanks to QRA solutions. These manufacturers may
for examining multivariate correlations between response also make educated decisions that avoid quality issues by
variables and explanatory factors. PLS goes beyond typi- detecting possible risks in the initial phases of product devel-
cal regression analysis by taking into account numerous opment and throughout the production process. This proac-
response variables at once, enabling researchers to analyze tive approach not only protects the quality of the product but
complicated connections. PLS is a useful tool in the phar- also improves compliance with legal standards, resulting in
maceutical industry for pinpointing crucial process variables quicker approvals and easier market access. Furthermore,
and their e"ects on several key CQAs, enabling researchers QRA promotes a culture of ongoing learning and growth
to optimize procedures and produce goods that adhere to within the pharmaceutical sector. Companies get important
exacting quality standards. insights that guide their future choices as they continuously
Another e"ective MVDA method is cluster analysis, collect data and improve their awareness of risks. Research-
which is crucial in dividing data points into discrete groups ers can iteratively improve product quality by optimizing
based on similarities and di"erences. Scientists can identify procedures, improving control systems, and applying the
patterns and subgroups within a dataset by grouping the data information learned from prior evaluations. The industry's
into clusters. This process also reveals underlying structures commitment to providing goods that consistently satisfy the
that may not be seen using univariate methods, showing strictest quality standards is reinforced by the inclusion of
commonalities between observations. With the use of cluster QRA in the QbD framework. Companies reduce the chance
analysis, researchers may pinpoint subpopulations and traits of costly recalls, production delays, and compliance prob-
that may a"ect the e"ectiveness and quality of a product (8, lems by addressing risks at their source (5, 8, 17, 24, 46).
The AAPS Journal (2025) 27:96 Page 11 of 23 96

Within the QbD framework, Six Sigma is a well-known spot trends or patterns that may suggest deviations from the
and time-tested approach that promotes a structured and norm by putting individual data points on the chart together
data-driven process to enhance product quality. Origi- with control boundaries. These graphs provide early cues
nally developed in industrial settings, Six Sigma has been that allow for quick action before quality problems worsen.
adopted by the pharmaceutical sector in the quest for ongo- Companies may reliably guarantee that the process remains
ing improvement and client satisfaction. At its core, Six under control and that deviations are promptly addressed
Sigma aims to improve quality standards above average by by continuously monitoring the process and comparing it
minimizing process variability and flaws. Six Sigma seeks to to past data.
reduce process deviations and remove sources of waste and On the other hand, X-bar and R charts provide a more
inefficiency to provide a product that consistently meets or in-depth perspective of process variability, particularly
exceeds customer expectations. It does this by using rigor- when the process calls for repeatedly collected samples or
ous statistical analysis and strong problem-solving meth- measurements. The R chart measures the range within each
odologies. The methodology follows the DMAIC cycle— sample, whereas the X-bar chart tracks the average of each
Define, Measure, Analyze, Improve, and Control—which sample. Businesses can identify possible causes of incon-
guides organizations in optimizing their processes. During sistency and take targeted remedial action by assessing the
the"Define"phase, companies define the project's scope, variation between and within samples. Control charts ena-
lay out its objectives, and create distinct success measures. ble industries to adopt a proactive strategy for quality con-
Comprehensive data gathering and analysis take center stage trol. Manufacturers may use control charts to spot possible
in the"Measure"phase, establishing a baseline for assessing problems in real-time rather than responding to deviations
current performance and identifying crucial process param- after they happen, allowing them to take corrective steps
eters. The"Analyze"step dives into the data to find the under- before quality slips outside of the acceptable range. This
lying reasons for variation and flaws that might a"ect the data-driven decision-making reduces waste and expensive
quality of the final result. With this information, research- recalls while also assisting in maintaining a dependable and
ers and quality specialists can spot problems and provide consistent production process. They are also essential for
viable remedies. The"Improve"phase is where new ideas advancing attempts at continuous improvement. Companies
and process changes are put into practice to improve the can find chances for innovation and optimization by continu-
performance and quality of the final product. For improved ously reviewing process data and utilizing control charts to
efficiency and consistency, this phase may entail restructur- track performance. Control chart insights may guide process
ing actions, improving control techniques, or using cutting- improvements and alterations, promoting an efficient work
edge technology. environment and ongoing quality improvement (21, 51, 52).
Six Sigma focuses on maintaining the improve- Within QbD approach, Failure Mode, E"ects and Criti-
ments achieved in the earlier phases throughout the cality Analysis (FMECA) is another important tool that
final"Control"phase. Strong control measures are put into enables companies to proactively identify expected failure
place to continually monitor the process, ensuring that devi- modes and their e"ects. FMECA is key to risk management
ations are identified early and corrected as soon as possible. since it allows researchers and quality professionals to pin-
A crucial tool employed at this stage is statistical process point crucial failure modes, determine how they a"ect prod-
control (SPC), which enables businesses to monitor process uct quality and safety, and strategically allocate resources
performance in real-time and make data-driven choices to for focused process enhancements. FMECA is fundamen-
keep the process within the specified bounds. Intending to tally an established and methodical technique for assessing
attain the elusive Six Sigma level of performance, or deliver failure mechanisms and associated impacts on product per-
fewer than 3.4 faults per million chances, Six Sigma fosters formance. Companies may comprehend the many potential
a culture of data-based decision-making (8, 47–50). failure modes of a process or system, from slight variations
Control charts serve as diligent monitors, meticulously to serious quality issues, by performing a thorough examina-
tracking process performance over time to preserve consist- tion. Finding vulnerabilities and possible weak spots in the
ency and guarantee product quality. Producers can identify production process requires a comprehensive study. FMECA
trends, changes, or deviations from predetermined baselines, o"ers a data-driven method to prioritize risks by calculat-
o"ering dynamic and real-time insights into process vari- ing the criticality of each failure scenario. Manufacturers
ances. Utilizing control charts gives businesses a powerful may e"ectively spend their resources and e"orts by con-
tool to maintain process stability and quickly address any centrating on mitigating high-priority failure modes that
indications of deviation, thereby protecting the integrity of have the greatest impact on the quality of their products and
their goods and the confidence of their consumers. Shewhart the safety of their consumers. With the help of this focused
charts provide an easy-to-understand method to track pro- risk mitigation method, the total risk management proce-
cess changes over time. By using it, industries can quickly dure is optimized as the resources are directed toward the
96 Page 12 of 23 The AAPS Journal (2025) 27:96

most important areas. FMECA dives further than just listing production process, shortening cycle times, and increasing
probable failure modes to comprehend the underlying causes productivity. Additionally, the use of PAT tools promotes
and e"ects of each failure mode. Investigators can evaluate an innovative and constant improvement mentality. Inves-
probable failures'relevance by looking at how they a"ect tigators can find a likelihood for process optimization and
the result, considering both their immediate consequences efficiency improvement by continually evaluating real-time
and any e"ects across the whole process. Companies may information. Iteratively improving product quality is made
develop e"ective methods for preventing, identifying, and possible by researchers using the insights from PAT to assist
fixing probable problems thanks to this exhaustive examina- evidence-based decision-making.
tion. FMECA also promotes a culture of ongoing learning Pharmaceutical companies could drastically change
and growth within the pharmaceutical industry. Companies their approach to product development and production by
obtain important information from FMECA evaluations that utilizing these QbD techniques. The industry can keep its
help make more informed choices in the future and opti- promise to provide safe, efficient, and high-quality products
mize their processes. Industries may continually improve that contribute to patient well-being globally because of the
their risk management strategies using this iterative method, integration of data-driven decision-making, proactive risk
adjusting to new problems and changing industry norms (8, management, and continuous improvement. The pharmaceu-
53, 54). tical industry's ability for innovation and quality will only
Within the QbD system, PAT cutting-edge techniques and increase as QbD tools continue to advance, advancing medi-
technologies represent a paradigm shift in manufacturing cal knowledge and patient care to new levels.
and quality control, providing real-time data and insights. In conclusion, the QbD components o"er the theoreti-
This enables businesses to make rapid adjustments and data- cal foundation for a methodical approach to pharmaceutical
driven decisions, ultimately enhancing product quality and development, while the QbD tools are the particular proce-
process efficiency. Revolutionary tools and methods, such as dures and statistical approaches used to put these ideas into
spectroscopy, near-infrared spectroscopy (NIR) analysis, and practice and improve the manufacturing process to generate
real-time monitoring, are at the core of PAT. Scientists may products of consistently high quality. Together, they improve
examine the way matter interacts with light using the flexible the pharmaceutical industry's drug research and production
analytical instrument known as spectroscopy. This analysis operations'e"ectiveness, dependability, and safety (55).
can provide important details about a product's chemical
composition, purity, and uniformity. Real-time information
on CQAs during production processes is provided by NIR Application of Quality by Design Elements
analysis, a non-destructive and quick technology that probes and Tools in the Pharmaceutical Industry
into the molecular vibrations of materials. Companies may
continually monitor product qualities, spot any deviations, As stated by Rathore and Winkle, the implementation of
and quickly remedy problems by utilizing these cutting-edge QbD principles in process and product development follows
analytical approaches. a sequential progression of five distinct stages: definition,
The foundation of PAT is real-time monitoring tech- design, characterization, validation, and ongoing monitor-
niques, which give a responsive and dynamic perspective of ing and control of the processes involved (49, 56). In the
the manufacturing process. CPPs are continuously monitored pharmaceutical industry, the application of QbD has proved
to ensure that process changes are identified early, enabling fundamental in determining the e"ectiveness of the main
immediate action to preserve process stability and product processes that support the production of pharmaceutical
quality. Businesses may develop closed-loop control sys- products. This review article will therefore take a more
tems, automating modifications depending on the observed detailed look at the processes of research and development,
variances, by integrating real-time data with the overall qual- manufacturing, quality control, and quality assurance.
ity control plan. Increased process efficiency, less waste,
and better product consistency result from this degree of Research and Development
automation and reactivity. Pharmaceutical manufacturing
has become a proactive undertaking thanks to PAT. Tradi- Pharmaceutical Quality by Design is an innovative devel-
tional methods frequently entail offline analysis and sam- opment approach that begins with predefined objectives
pling, which causes delays in finding process variations and and emphasizes understanding and controlling both the
quality problems. PAT, on the other hand, gives a thorough product and process. It is a methodology that underscores
understanding of the process in real-time, enabling quick the importance of quality risk management in ensuring
detection and correction of any deviations from the speci- robust outcomes (49). Fahmy and colleagues employed a
fied quality requirements. This proactive approach reduces RA approach, integrating FMEA followed by a quantita-
the possibility of product faults while also streamlining the tive Plackett–Burman analysis. This method was applied
The AAPS Journal (2025) 27:96 Page 13 of 23 96

to identify CQA for immediate-release ciprofloxacin tab- RA, a fishbone diagram was constructed using the Mate-
lets, streamlining the formulation development process by rial Attributes (MAs) and Process Parameters (PPs) more
prioritizing experiments while maintaining an acceptable likely to influence the product Quality Attributes (QAs)
risk profile. In line with the ICH Q8 (R2), the identification (Fig. 4(D)). From this, the medium and high-risk PPs and
of CQAs is pivotal in dosage form development. Given the MAs were identified as CPPs and CMAs, respectively
vast array of formulation and processing factors influencing (Fig. 4(B)). A central composite design (CCD) was then
pharmaceutical manufacturing, a formal study of all possible employed to optimize key factors, including lecithin and
parameters and interactions is impractical. Therefore, by sys- drug concentrations, to define a design space. Using DoE,
tematically incorporating prior knowledge through FMEA the experiments were planned, and the design point with the
and utilizing a Plackett–Burman screening design, this team highest desirability yielded a nanosized, stable, and opti-
efficiently reduced the number of experiments, demonstrat- mum drug-entrapped formulation (Fig. 4(C)). Therefore, this
ing a practical approach to CQA identification (57). approach successfully led to the development of resveratrol-
Csóka et al. expanded the early QbD methodology by loaded mucoadhesive lecithin/chitosan nanoparticles, meet-
conducting an initial RA and developing a preformulation ing the predefined QTPP targets (45, 63).
design space (“zero phase”) for the drug substance before Another example of QbD application in Research and
defining a control strategy. Their approach integrated exist- Development is the study conducted by Arroyo-Urea et
ing tools to extend QbD into the early stages of pharma- al., which focused on the formulation optimization of pal-
ceutical research. This extension facilitated, as the authors mitoyl-L-carnitine-loaded nanoemulsions for drug delivery.
stated, a streamlined and cost-efficient transition from the The study demonstrated that applying DoE enables a system-
research phase to market approval and large-scale industrial atic and rational design of drug delivery platforms, leading
manufacturing (58). This strategy was also successfully to formulations with simple compositions that are easy to
implemented by other authors across various dosage form prepare. Furthermore, the optimized nanoemulsion showed
design processes, including the development of an intranasal promising properties for delivering hydrophobic drugs, with
nanosized formulation, a meloxicam-containing dry powder a formulation adaptable to di"erent active compounds with
inhalation formulation, a microparticle-based dry powder minimal modifications. These findings reinforce the role of
inhalation formulation of ciprofloxacin hydrochloride, and QbD in enhancing formulation robustness, ultimately con-
in stable water-in-oil-in-water (w/o/w) cosmetic multiple tributing to the development of more e"ective and stable
emulsions (36, 59–61). drug delivery systems (64). Similarly, Jadhav et al. used
The application of QbD principles is also transferable QbD in the development of imiquimod-loaded nanoemulsion
to orodispersible films (ODFs) manufacturing, addressing to define the CQAs, such as particle size, drug release pro-
inherent challenges in the development process. Thabet and files, and stability. These parameters were optimized using
colleagues used an Ishikawa diagram to connect CPPs such DoE to establish the desired formulation that met specific
as viscosity and drying temperature, and CMAs to CQAs. drug delivery goals and to ensure robustness during subse-
Based on such observations, this investigation highlighted quent scale-up (65).
the adverse e"ects of incorrectly selecting these parame- In another study, to optimize the formulation of a trans-
ters, resulting in bubble formation and mechanical instabil- dermal dexibuprofen patch (DXIBN), Akhlaq et al. pursued
ity in the films. In a broader context, the determination of a QbD approach using a Box–Behnken (three-factor-three-
CQAs originates from a prospective summary of the com- level) design. The physicochemical properties and the
prehensive understanding of customer requirements and influence of patch components on both the resultant tensile
preferences. The process initiates with an impact analysis strength and in vitro permeation were employed to predict
on varying product/process parameters, leading to further an ideal patch formulation. Significantly, the anticipated
studies for patient safety assessment. If a changed parameter characteristics (specifically, tensile strength and DXIBN
significantly poses harm, it is considered a critical quality steady-state flux) for the QbD-optimized formulation closely
attribute. Therefore, assessing high-risk variables impacting matched the experimental results. Thus, this prediction not
ODF CQAs becomes imperative. The authors introduce a only significantly minimized both cost and time but exhib-
Risk Estimation Matrix (REM) (Fig. 4(A)) to evaluate the ited both a shorter onset time compared to a previously
risk associated with each material attribute and processing developed oral tablet, plus prolonged therapeutic e"ects
parameter concerning ODF CQAs (62). (45, 66).
Saha et al. applied QbD principles to develop a lab-scale Lee and Kim employed a similar approach to develop
resveratrol-loaded mucoadhesive lecithin/chitosan nano- fixed-dose combination tablets of rabeprazole sodium and
particle system for prolonged ocular drug delivery that met sodium bicarbonate for treating gastroesophageal reflux dis-
pre-defined patient-centric QTPPs targets, which considered ease. QTPP parameters were considered, including clinical
quality, safety‚ and efficacy product attributes. In an initial use, route of administration, formulation, delivery system,
96 Page 14 of 23 The AAPS Journal (2025) 27:96

Fig. 4 A REM describing the risk levels (Low, Medium, High) of mulation; D Ishikawa fishbone diagram systematically identificat-
material attributes and process parameters in ODFs with specific ing the key parameters crucial for resveratrol-loaded mucoadhesive
attention to Particle Size Distribution (PSD); B Pareto charts focus- lecithin/chitosan nanoparticles production. CMAs – Critical Material
ing on QAs, and on the identification of CMAs/CPPs; C Desirability Attributes; CPPs – Critical Process Parameters; ODFs – Orodispers-
plot (left) and particle size/zeta potential (right) graphs illustrating ible films; PSD – Particle size distribution; REM – Risk Estimation
the optimum design point's high desirability of the optimized for- Matrix

content, container, packaging, API release, pharmacokinetic optimized compositions. Ex vivo permeation studies showed
properties, sterility, purity, stability, and dissolution. CQAs sustained release through goat ear skin, confirming the QbD
were identified through QTPPs, prior knowledge, and evalu- strategy's success in addressing solubility challenges in drug
ated for feasibility. RA involved FMEA and hazard analysis development while emphasizing prudent surfactant use for
(PHA), with a risk priority number (RPN) > 30 indicating patient safety (68).
a CMA or CPP. A central composite design of DoE opti-
mized the outer layer's binding and disintegration proper- Manufacturing
ties. The final composition of the tablet was determined,
ensuring physicochemical stability for over 24 months. QbD Apart from its utilization in research and development,
guaranteed quality by detecting and managing risks, provid- QbD also o"ers advantages for large-scale routine manu-
ing valuable insights into sensitive issues like stability and facturing. A considerable number of papers are committed
tableting properties in drug manufacturing (67). to improving conventional dosage form products through a
Rapalli et al. employed a QbD approach to create a topi- QbD approach, particularly tablet dosage forms, considering
cal hydrogel containing ketoconazole-loaded cubosomes their significant prevalence in the pharmaceutical market.
with reduced surfactant concentration. CQAs were identi- Vemula et al. employed a QbD strategy in formulating
fied from the QTPP, focusing on surfactant and stabilizer fast-dissolving flurbiprofen tablets. Through Response Sur-
concentrations as key MAs a"ecting particle size and dis- face Methodology (RSM) and CCD, the study optimized
tribution. CPPs included stirring speed and stirring time, carrier and adsorbent concentrations, revealing their inter-
influencing pre-emulsion size and entrapment efficiency. The actions with critical responses such as solubility, angle
study utilized a 32-factorial design, with Design-Expert® of repose, Carr’s index, and cumulative % drug release
(version 9.0, Stat-Ease Inc.) for screening, that accurately (Fig. 5(A)). The resulting optimized formulation, deter-
predicted the optimized formulation. Post-DoE analy- mined through numerical optimization, underwent thorough
ses guided the preparation of scale-up batches mirroring analyses using FTIR spectroscopy, di"erential scanning
The AAPS Journal (2025) 27:96 Page 15 of 23 96

Fig. 5 A 3D response surface plots depicting the influence of carrier the desirability and design space plot; C Release profiles comparing
and adsorbent concentrations on key responses: solubility (Y1), angle flurbiprofen release from plain drug, control tablets, and F4 Fast-Dis-
of repose (Y2), Carr’s index (Y3), and cumulative % drug release solving Tablets (FDTs) (n = 6). FDTs – Fast-Dissolving Tablets
(Y4); B The optimized formula and its responses are highlighted in

calorimetry, and X-ray di"ractometry. When compressed in rats further highlighted the superiority of fast-dissolving
into tablets, the optimized formulation exhibited rapid drug tablets, showing a 1.38-fold higher peak plasma concentra-
release within 15 min in in vitro dissolution studies, a nota- tion (Cmax) and 1.39-fold higher bioavailability compared
ble improvement compared to conventional tablets requiring to conventional tablets and emphasizing QbD pivotal role
around 60 min for complete dissolution (Fig. 5(C)). The uti- in enhancing formulation characteristics and overall drug
lization of a multiple response optimization approach made performance (69).
it possible to determine the amount of the optimized carrier Lee and colleagues manufactured and utilized a D-opti-
and adsorbent necessary for achieving maximum flowabil- mal mixture design to optimize formulations for the tel-
ity and % Cumulative Drug Release (CDR). Employing a misartan and amlodipine layers in a bilayer tablet. In the
numerical and graphical optimization approach, the study initial risk assessment, D-mannitol, crospovidone, and MCC
considered a desirability function, ranging from 0 to 1, levels in the telmisartan layer, and CCM-Na, PVP K25,
where 0 denotes a completely undesirable response and 1 and Prosolv levels in the amlodipine layer were evaluated
signifies the most desirable response. The numerical optimi- (Fig. 6(A)). The study systematically assessed the quan-
zation method focused on maximizing solubility (Y1), mini- titative e"ects of these formulation factors on the tablet's
mizing the angle of repose (Y2), minimizing Carr’s index response factors. The best-fit equations accurately pre-
(Y3), and maximizing % CDR (Y4). Independent variables dicted these e"ects, demonstrating high linearity between
were set within defined minimum and maximum ranges. predicted and actual values. Pharmaceutical formulation
The graphical optimization technique established lower optimization sought to identify optimal variable values for
and upper limits for the studied responses, yielding a flex- achieving desired characteristics. Through statistically vali-
ible design space characterized by a lower angle of repose dated model equations elucidating the intricate relationship
(22.25°) and a higher dissolution rate (Q15 min % 75%). The between independent and response variables, the formula-
overlay plot (yellow area in (Fig. 5(B)) visually represents tion underwent systematic optimization to attain the most
this design space, illustrating the robustness of the formula- favorable response values (Fig. 6(C)). For the telmisartan
tion within specified parameters. Pharmacokinetic studies and amlodipine layers, specific constraints and intermediate
96 Page 16 of 23 The AAPS Journal (2025) 27:96

Fig. 6 A Initial risk assessment; B Design Space overlay: (left) DS ment of telmisartan layer (top) and amlodipine (bottom); D Plasma
overlay plot for the telmisartan layer, (right) DS overlay plot for the concentration–time profiles for telmisartan (a) and amlodipine (b)
amlodipine layer, whereas the yellow regions satisfy all target values; obtained following the oral administration of both control and test
C Contour plots correlating response factors for formulation develop- drugs. DS – Design space

ranges for critical parameters were meticulously defined, optimum extrusion processing parameters. DoE experi-
concluding in an overall optimum region. This optimiza- ments underscored the significant influence of drug loading
tion process is graphically represented in Fig. 6(B), where on the sole quality attribute—paracetamol sustained-release
the yellow space represents the concurrent attainment of the formulations’ dissolution rate. These findings demonstrate
desired responses. The resulting optimized bilayer tablet, the valuable application of QbD in tablet manufacturing by
named Telmiduo®, was obtained using numeric optimization providing crucial insights into critical parameters and their
and, upon comparison with the control, Twynsta®, through impact on essential quality attributes, thereby contributing
various physical evaluations, exhibited greater physical sta- also to the optimization of sustained-release formulations
bility when stored in a humidity chamber. More so, Raman (71). QbD is versatile, extending likewise to attain optimal
imaging confirmed a highly homogeneous distribution of tel- manufacturing settings of processes operated at sub-optimal
misartan in Telmiduo®. In vivo pharmacokinetic parameters settings, such as tableting process parameters (72).
indicated pharmaceutical equivalence and bioequivalence Additionally, it allows for assessing the impact of phar-
between Telmiduo® and Twynsta® (Fig. 6(D)), suggesting maceutical active ingredients, excipient variability, and
that the bilayer tablet could be produced more economically processing methods on the final product quality attributes
and easily prepared than Twynsta® (70). (QAs) (73–75). For instance, in a study, this methodology
In a di"erent approach Islam et al., optimized paraceta- was employed to manufacture ibuprofen-loaded granules via
mol sustained-release formulations through hot-melt extru- hot-melt extrusion processing. A DoE was implemented to
sion. In this study, in-line near-infrared (NIR) spectroscopy evaluate the e"ect of formulation compositions and process-
served as a PAT. A DoE was implemented to assess the ing parameters (76). Moreover, QbD addresses challenges
impact of process critical parameters and identify CQA in in pharmaceutical tablet manufacturing, compensating for
extrusion processing. The investigation focused on blends lot-to-lot variability in incoming raw materials by employ-
of paracetamol, ethyl cellulose, and Compritol® 888 ATO ing, for example, partial least squares models. These mod-
using a twin-screw extruder, exploring the e"ects of screw els integrated raw material attributes and tablet process
speed, feed rate, and drug loading on dissolution rates and parameters, facilitating an optimization framework to iden-
particle size distribution. PCA of the NIR signal identified tify optimal process parameters for consistent final tablet
The AAPS Journal (2025) 27:96 Page 17 of 23 96

attributes despite raw material variations (77). It may also 83). For example, a study applied the QbD methodology for
be used to optimize manufacturing processes, as evidenced the production of curcumin-loaded nanoemulsions using the
by a study focused on enhancing a tablet formulation. The catastrophic phase inversion technique, which was optimized
methodology involved varying filler grades and consider- and successfully scaled up. The researchers identified CQAs
ing API particle size distribution to improve critical qual- such as particle size, stability, and encapsulation efficiency,
ity attributes (CQAs). Through a pilot-scale mixture DoE, and determined critical process parameters CPPs including
real-time monitoring with near-infrared (NIR) spectroscopy, surfactant concentration, temperature, and mixing speed.
and Raman imaging, the study successfully computed design By systematically optimizing these parameters, the process
spaces using a risk-based Bayesian approach. These design ensured the production of stable, high-quality nanoemul-
spaces provided expected probabilities for achieving CQAs sions. Furthermore, the study demonstrated that the process
within specifications in the future. The validated optimal could be scaled up without compromising product quality,
conditions underscore the pivotal role of QbD in refining illustrating the practical application of QbD in achieving
and ensuring manufacturing quality (78). consistent, reproducible manufacturing outcomes for bioac-
Implementing QbD offers advantages irrespective of tive delivery systems (84).
the dosage form's nature. Particularly in non-conventional QbD extends beyond conventional pharmaceuticals, sup-
dosage forms, where intricate multi-step manufacturing porting the development of more advanced therapies such
processes and limited comprehension of material impacts as RNA-based vaccines, where stringent quality control and
prevail, QbD emerges as highly advantageous. It provides rapid deployment are critical. A van de Berg, D. study used
a systematic framework for identifying critical inputs and QbD principles to enhance process robustness, scalability,
establishing quantitative relationships, contributing signifi- and regulatory alignment, ensuring that CPPs were system-
cantly to enhanced processes and outcomes in these complex atically controlled to achieve consistent product quality and
scenarios (8, 43). efficacy. By employing QbD modeling, researchers estab-
Sheth and colleagues, applying QbD, developed Metered lished a DS that enabled precise adjustments in formulation,
Dose Inhalers (MDIs) that addressed complexity in both for- purification, and encapsulation processes, thereby optimiz-
mulation and device combination. The study systematically ing yield while maintaining stringent quality standards.
assessed how formulation, device, and process CQAs impact The study highlights how applying QbD to RNA vaccine
MDI aerosol performance, aiding in designing formulations manufacturing not only accelerates production timelines
with desired outcomes. Unique to this QbD approach is the but also ensures batch-to-batch reproducibility, meeting
inclusion of medical device performance parameters, high- the rigorous regulatory expectations for safety, stability,
lighting its value in handling complex systems. Therefore, and potency. Exemplifying the important role of QbD in
in this study, QbD proved essential in the development of streamlining biopharmaceutical manufacturing, reinforcing
inhaled products, managing intricate interactions among for- its significance in the development of next-generation vac-
mulation attributes, devices, and process parameters (12, 79, cine platforms for global health preparedness (85).
80).
In recent years, the application of QbD principles has Quality Control
extended beyond traditional pharmaceuticals and embraced
the manufacturing of nanotechnological pharmaceutical Safeguarding drug efficacy and safety is paramount to the
products. Since the integration of nanotechnology in drug pharmaceutical industry. Traditionally, QbT has been a
delivery systems, such as lipid-based systems, polymeric common approach for quality control in this sector, empha-
nanoparticles, among other nanocarriers, has introduced sizing the assessment of randomly selected drug products.
unique opportunities but also significant challenges (81). In However, relying exclusively on QbT introduces inherent
this sequence, QbD provides a systematic and risk-based risks, as the random sampling may inadvertently overlook
approach to address these obstacles that sustain the repro- specific issues, leading to the potential supply of drugs
ducibility, robustness, and quality of the nanomaterial fab- with insufficient quality. Recognizing these challenges, the
rication processes. Namely, through the identification of industry has been progressively adopting a more proactive
CMAs and CPPs, by conducting thorough RAs analysis, and and comprehensive approach, such as QbD, which, unlikely
by establishing the design space, QbD enhances the under- QbT, focuses on risk management throughout the entire
standing and control of these challenging manufacturing pro- drug development and manufacturing process. By embrac-
cesses. Therefore, the use of this proactive and holistic tool ing QbD, pharmaceutical manufacturers can identify and
aligns with regulatory expectations and contributes to the address potential quality issues at the early stages of drug
development of safe, e"ective, and consistently high-quality development, minimizing the likelihood of non-compliant
nanopharmaceutical products, bridging the current bench-to- final products. This approach involves a systematic and sci-
bedside gap and maximizing the possibility of success (82, ence-based methodology integrating product and process
96 Page 18 of 23 The AAPS Journal (2025) 27:96

understanding, enabling more precise control and optimi- and quality of the manufacturing processes for these diverse
zation (2, 27, 46). pharmaceutical forms.
Thus, the pharmaceutical industry is transitioning towards
a new quality control paradigm that emphasizes the inte- Quality Assurance
gration of QbD principles. Acknowledging that increased
testing alone does not guarantee enhanced product qual- Originally confined to product development, QbD has
ity, regulatory bodies, such as the US FDA, advocate for evolved into a central pillar of the global pharmaceutical
the incorporation of quality into the product development market, serving as a fundamental standard for quality assur-
process. Therefore, guided by influential documents such ance (55). Beyond its regulatory utility, QbD also emerges
as ICH Q8 (R2), Q9 (Quality Risk Management), Q10 as a key player in achieving cost-efficient and robust phar-
(Pharmaceutical Quality System), and Q11 (Development maceutical quality assurance (5). By proactively pinpointing
and Manufacture of Drug Substances), the industry has crucial factors in the manufacturing process, this method-
embraced QbD principles, traditionally applied in batch ology reduces the likelihood of recalls and rejections not
manufacturing. While QbD has traditionally been applied only during the development process but also reduces post-
in batch manufacturing, recent years have seen remarkable market complications. As a risk management strategy, QbD
progress in adopting QbD and PAT in continuous manu- enhances the overall cost-e"ectiveness of quality assurance
facturing (86, 87). This evolution aims to enhance agility, and supports a culture of continuous improvement (2, 7,
flexibility, and robustness in pharmaceutical development 15, 102). The implementation of QbD principles encour-
and manufacturing. The FDA's recognition of continuous ages pharmaceutical companies to draw insights from data,
manufacturing as an emerging technology underscores its refine processes, and make well-informed decisions, creating
increasing importance. Notably, approvals for drug prod- an environment where each step forward builds upon the
ucts produced via continuous manufacturing, such as Ork- achievements of the preceding ones. More so, by emphasiz-
ambi, Prezista, Verzenio, Symdeko, and Daurismo, reflect ing the understanding and control of CQAs and CPPs, it
a strategic combination of product and process knowledge, facilitates robust risk management, enhancing the reliabil-
advanced instrumentation, automation systems, and metic- ity and consistency of pharmaceutical quality assurance.
ulous quality control protocols. Apart from the inherent Therefore, this holistic methodology promotes a proactive
advantages of flexibility and cost-e"ectiveness, continuous approach to addressing potential quality concerns, fostering
manufacturing introduces a distinctive feature—the real- continuous learning, innovation, and optimization across the
time monitoring and control of CQAs and CPPs. This real- pharmaceutical research, development, manufacturing, and
time approach not only ensures product quality assurance quality control landscapes. In essence, QbD is not only a
but also sets the stage for Real-Time Release (RTR), which regulatory requirement but also a strategic tool for elevating
represents a paradigm shift in pharmaceutical quality con- quality assurance throughout the pharmaceutical industry.
trol. This evolution stands as a testament to the industry's Advancements in computational methods have fur-
commitment to innovation, efficiency, and meeting the high- ther reinforced the QbD framework, specifically in design
est regulatory standards (25, 87, 88). space characterization. Kusumo et al. proposed a Bayesian
These principles have been successfully applied across approach utilizing nested sampling to define probabilistic
a diverse array of pharmaceutical forms within the context design spaces. This method o"ered a quantitative measure
of continuous manufacturing. This strategic approach has of reliability and risk, supporting more informed decision-
demonstrated efficacy in the production of oral solid dos- making in pharmaceutical manufacturing. The method's
age forms (89–91), including tablets, where continuous pro- efficacy was demonstrated through two industrial case stud-
cesses are optimized using QbD to ensure consistent qual- ies, underscoring its potential to enhance quality assurance
ity. Moreover, QbD has been instrumental in the continuous processes within the QbD paradigm (103).
manufacturing of oral dissolvable films (92), delayed-release
pellets (93), injectables (94), topical creams (95) and trans-
dermal patches, inhalation products (96), such as dry powder Quality by Design Regulatory Affairs
inhalers and metered-dose inhalers, biologics, vaccines, and
nanotechnological products like liposomes (97) and poly- The International Council for Harmonization of Techni-
meric nanoparticles (98). The application of QbD extends to cal Requirements for Pharmaceuticals for Human Use
oral liquids, oral suspensions (99), oral films (100), strips, as has issued numerous important guidelines that have sig-
well as pharmaceutical pellets (101) and beads. In each case, nificantly shaped the development of pharmaceutical
QbD principles facilitate real-time monitoring and control of QbD. Notably, the pharmaceutical industry's QbD land-
critical parameters, ensuring the reproducibility, robustness, scape has been significantly shaped by these recommen-
dations, which include ICH Q8 (R2), ICH Q9 (Quality
The AAPS Journal (2025) 27:96 Page 19 of 23 96

Risk Management), ICH Q10 (Pharmaceutical Quality Another challenge lies in inconsistent regulatory accept-
System), and ICH Q11 (Development and Manufacture ance and industry hesitation. Despite supporting QbD
of Drug Substance). These documents have encouraged principles, regulatory agencies’ assessment of QbD-based
a greater understanding of the QbD concepts and their submissions is not always consistent. This unpredictability
practical application by o"ering high-level recommenda- discourages pharmaceutical companies from fully integrat-
tions and encouraging a consistent approach. The princi- ing QbD into their development pipeline, fearing that the
ples mentioned in these guidelines have been adopted by additional upfront investment in extensive data collection
pharmaceutical companies and regulatory bodies alike, and modelling may not translate into streamlined regula-
which has resulted in better product quality, increased pro- tory approvals. In addition, the lack of clearly defined path-
cess control, and a more systematic risk-based approach ways for managing post-approval changes under QbD fur-
to drug development. The adoption of these rules has also ther undermines its advantages, as companies may still face
prompted more cooperation and openness among di"er- significant regulatory hurdles when implementing process
ent stakeholders, fostering more uniformity and coherence optimisations or scale-up strategies.
throughout the world's pharmaceutical industry. These rec- A further barrier is the high upfront investment needed for
ommendations work as crucial reference points as QbD QbD implementation. Companies must invest in advanced
develops and gains popularity, ensuring that pharmaceuti- PAT, DoE, and MVDA to develop robust QbD-based man-
cal development keeps its attention on patient safety, prod- ufacturing processes. This upfront cost is often a limiting
uct efficacy, and general quality. factor, particularly for small and mid-sized pharmaceutical
Despite its well-documented benefits, QbD adoption in firms, which may lack the financial resources and expertise
the pharmaceutical industry still faces several regulatory to adopt QbD fully. Additionally, there is industry resist-
challenges that prevent its widespread implementation. ance to change, as many pharmaceutical manufacturers are
One of the most significant obstacles is the lack of global accustomed to the traditional QbT model.
harmonisation of regulatory requirements, as ICH Q8, Q9, Further e"orts towards regulatory harmonisation are
and Q10 provide a general framework, but interpretation essential to overcome these barriers, particularly through
and implementation di"er across regulatory agencies. For initiatives such as the ICH and mutual recognition agree-
instance, the FDA actively encourages QbD, o"ering regu- ments between agencies. The development of structured
latory flexibility when manufacturers demonstrate a solid QbD submission formats, such as standardised Electronic
understanding of CQAs and CPPs, while agencies such Common Technical Document modules, can help simplify
as the EMA often require extensive comparability studies the approval process by ensuring consistency in the way data
between traditional and QbD-based approaches, adding is submitted. Resolving these challenges will be crucial to
complexity to the approval process. Similarly, in Japan, utilising the full potential of QbD, ensuring its integration
the Pharmaceuticals and Medical Devices Agency imposes not only as a regulatory expectation but also as a transforma-
strict pre-approval requirements, which make post-approval tive approach to developing and manufacturing pharmaceuti-
modifications within a QbD framework more difficult. These cal products.
inconsistencies create uncertainty for pharmaceutical com-
panies seeking global market approval, as they have to
adapt their regulatory submissions to di"erent expectations, Conclusion and Prospects
increasing cost and causing longer approval timelines.
Beyond regulatory inconsistencies, the QbD-based fil- The global pharmaceutical landscape is transforming with
ing process itself presents significant challenges, as, unlike the increasing integration of QbD methodology. However,
traditional QbT approaches, QbD requires extensive docu- while international regulatory agencies and several progres-
mentation, including risk assessments, multivariate sta- sive pharmaceutical entities are heading toward full-scale
tistical analysis, and DoE data to justify the selection of implementation, challenges persist, particularly in navigating
CQAs and CPPs. Although regulatory agencies advocate a the paradigm shift and addressing the shortage of special-
science-based approach to quality assurance, the absence of ized expertise. More so, QbD's holistic approach, spanning
standardised submission templates or clear guidelines for the entire drug development life cycle, demands a departure
reporting QbD often results in approval delays or requests from traditional methodologies and requires comprehensive
for additional data. Moreover, post-approval changes, risk assessment and a pre-established control strategy, lev-
which should, in theory, be more flexible under QbD, con- eraging statistical techniques and real-time manufacturing
tinue to require extensive regulatory oversight, limiting analyses for a nuanced understanding of evaluated risks.
manufacturers'ability to efficiently implement continuous Beyond conventional product development, QbD advo-
improvements to their processes. cates for a proactive evaluation of risk factors, emphasizing
the importance of a meticulously crafted control strategy. In
96 Page 20 of 23 The AAPS Journal (2025) 27:96

this scenario, statistical techniques and real-time analyses data management, knowledge sharing, and regulatory
emerge as key enablers, o"ering a sophisticated means to submissions.
comprehend and manage assessed risks. The demand for Despite the complex journey towards embracing QbD
vast data in QbD applications also underscores the need principles, the potential benefits are profound. This is
for a robust information infrastructure to ensure consistent because, by imbuing quality management into every stage
pharmaceutical quality. While existing literature showcases of drug development, QbD o"ers a pathway to more robust,
strides in implementing QbD systems to enhance quality, reliable, and patient-centric pharmaceutical products. In
the methodology's broader adoption in drug development essence, QbD is not just a regulatory necessity; it emerges
remains a work in progress. as a strategic imperative, steering the pharmaceutical indus-
Nevertheless, as the industry faces these challenges, try toward a future where product quality, patient safety,
the success of major pharmaceutical companies in apply- and regulatory compliance seamlessly converge. As QbD
ing QbD provides a strong testament to its transformative matures, bridging the gap between regulatory aspirations
potential. For instance, Vertex Pharmaceuticals applied QbD and practical implementation remains a shared responsibil-
principles in developing Orkambi® and Symdeko®, refining ity. Industry collaboration, knowledge-sharing, and ongoing
their combination drug formulations to improve dissolution education will be pivotal in realizing the full potential of
profiles and therapeutic e"ectiveness (104). Similarly, Jans- QbD, ensuring a future where pharmaceutical development
sen Pharmaceuticals (Prezista®) and Eli Lilly (Verzenio®) is synonymous with excellence, innovation, and unwavering
utilized DoE and risk assessments to control raw material commitment to patient well-being.
variability and optimize manufacturing parameters, result-
ing in more predictable batch outcomes and enhanced Acknowledgments The authors acknowledge the support given by
FCT, Fundação para a Ciência e Tecnologia, I.P. to the Research Center
product stability (105, 106). A groundbreaking example is through project UIDB/00285./2020.
Spritam® (Aprecia Pharmaceuticals), the first FDA-approved The authors acknowledge the support from BRIDGES—Biotech-
3D-printed tablet, which leveraged QbD to define critical nology Research, Innovation and Design of Health Products, Polytech-
printing parameters, ensuring dose uniformity, rapid disin- nic University of Guarda.
tegration, and consistent mechanical strength (107). QbD
Authors’ contributions Conceptualization, Supervision and Project
has also played a crucial role in large-scale biopharmaceuti- Administration: F.M-M.; Methodology: J.G.D. and F.M-M.; Investiga-
cal and vaccine production, particularly in addressing com- tion, Resources, Data Curation and Writing—original draft preparation:
plex formulation challenges associated with mRNA-based J.G.D. and M.G.D.; Writing—review and editing and Visualization:
therapies. The accelerated development of Comirnaty® A.P.P. and F.M-M.; Validation: A.P.P. and F.M-M. All authors have
read and agreed to the published version of the manuscript.
(Pfizer-BioNTech) and Spikevax® (Moderna) was enabled
through QbD-driven optimization of mRNA integrity, lipid Funding Open access funding provided by FCT|FCCN (b-on).
nanoparticle formulation, and stability profiles (108). By
implementing PAT and real-time monitoring, manufactur- Declaration
ers ensured consistent product quality across global supply The authors declare that they have no known competing financial in-
chains, even under expedited regulatory timelines. Another terests or personal relationships that could have appeared to influence
successful biopharmaceutical case is Daurismo® (Pfizer), the work reported in this paper.
which utilized multivariate statistical analysis and particle
Open Access This article is licensed under a Creative Commons Attri-
size optimization to enhance drug solubility and dissolution bution 4.0 International License, which permits use, sharing, adapta-
properties, ensuring a more predictable therapeutic e"ect tion, distribution and reproduction in any medium or format, as long
(104). as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
Beyond formulation and biopharmaceutical advance-
were made. The images or other third party material in this article are
ments, QbD has revolutionized continuous manufacturing, included in the article’s Creative Commons licence, unless indicated
representing a significant shift from traditional batch produc- otherwise in a credit line to the material. If material is not included in
tion. One of the most prominent cases is Xarelto® (Bayer), the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
which incorporated real-time release testing and in-line PAT
need to obtain permission directly from the copyright holder. To view a
monitoring to ensure batch-to-batch consistency (109). copy of this licence, visit [Link]
Looking ahead, the integration of cutting-edge technolo-
gies such as artificial intelligence, machine learning, and
digital twins holds great potential to further strengthen the
QbD framework. These tools can enhance process modeling,
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