Journal of Pharmaceutical Investigation (2022) 52:649–682

https://doi.org/10.1007/s40005-022-00575-x

REVIEW

Quality by Design (QbD) application for the pharmaceutical

development process
Sang‑Ho Lee1 · Jin‑Ki Kim2 · Jun‑Pil Jee3 · Dong‑Jin Jang4 · Young‑Joon Park5 · Joo‑Eun Kim1,6

Received: 27 August 2021 / Accepted: 26 April 2022 / Published online: 29 August 2022
© The Author(s) under exclusive licence to The Korean Society of Pharmaceutical Sciences and Technology 2022

Abstract
Background Quality by Design (QbD) is a pharmaceutical quality management system that predicts, controls, and system-
atically responds to risks that may occur in the research stage and manufacturing process. There are many articles on how
to improve quality through application of the QbD system, but the methodology surrounding how to specifically apply this
process is limited. The purpose of this review was to provide accurate information on drug development process and overcome
the difficulties of developing QbD-applied drug products through an appropriate application method.
Area covered QbD-based pharmaceuticals are continuously being developed worldwide, helping to identify potential risks,
and managing all aspects, from drug design to patient consumption, further enabling the patient to be administered a high-
quality drugs based on their design. In this study, a basic knowledge of QbD, its application and effectiveness during drug
development will be discussed.
Expert opinion Our results suggest that a QbD for drug development can reduce risk to patients, improve drug quality, and
continuously produce superior quality drug products.

Keywords Quality by Design · Pharmaceutical development process · QTPP · CQAs · CMAs · CPPs

Introduction
Quality control is essential to ensure the safety and efficacy of
pharmaceuticals (Jin et al. 2014). Due to the safety and effec-
tiveness of drug products and their direct effects on patient
* Young‑Joon Park
parkyj64@gmail.com
* Joo‑Eun Kim
77jooeun@naver.com
1
Department of Pharmaceutical Engineering, Catholic
University of Daegu, Hayang‑Ro 13‑13, Gyeongsan,
Gyeongbuk 38430, Republic of Korea
2
College of Pharmacy & Institute of Pharmaceutical Science
and Technology, Hanyang University, 55 Hanyangdaehak‑ro,
Sangnok‑gu, Ansan 15588, Republic of Korea
3
College of Pharmacy, Chosun University, Pilmun‑daero 309,
Dong‑gu, Gwangju 61452, Republic of Korea
4
Department of Bio‑Health Technology, College
of Biomedical Science, Kangwon National University,
Chunchoen 24341, Republic of Korea
5
College of Pharmacy, Ajou University, 206 World cup‑ro,
Yeongtong‑gu, Suwon 16499, Republic of Korea
6
Department of Biopharmaceutical Chemistry, Kookmin
University, Seoul 02707, Korea
health, safe and effective medicines are required (Patel et al.
2013). In 1958, the American Pharmaceutical Industry
Association formed the Quality Assurance Committee in
response to the increasing frequency of compensation cases
for damages caused by defective drugs in the United States of
America. After the thalidomide drug accident in 1961, good
manufacturing practice (GMP) was enacted in 1962, and the
Food and Drug Administration (FDA) GMP was adopted
in 1963. Thus, the historic efforts by several countries to
ensure the quality of pharmaceuticals and secure interna-
tional competitiveness extends back multiple decades, and
enormous resources have been invested. For example, there is
the pharmaceutical inspection co-operation scheme (PIC/S)
(Kim and Kwon 2013; Uhlenbrock et al. 2017), which is an
international consultative body that is tasked with creating a
global consensus of pharmaceutical manufacturing, quality
control standards, and GMP inspections (Kothari and Patel
2015; Ban et al. 2019). The primary responsibility of PIC/S
is to conduct various activities to manufacture and manage
high-quality medicines, such as mutual exchange of basic
GMP inspection information, coordination of GMP regula-
tions, publication of guidelines, training of GMP inspec-
tors, and regular meetings; however, despite these efforts,
various quality problems persist. Pharmaceutical drugs are

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650
manufactured and quality controlled using the Quality by
Testing (QbT) technique, which focuses on risk management.
As quality control through QbT is performed by selecting
manufactured drug products at random, there is an increased
risk of supplying drugs with poor quality (Kader 2016;
Fukuda et al. 2018; Suciu et al. 2018). The current qual-
ity process capability index of the pharmaceutical industry
is only 2–3σ. The yield rate for 2σ and 3σ is 95.45% and
99.73%, respectively. The pharmaceutical industry spends
5–10% sometimes up to 20% annually on handling defective
products. This was a huge amount equal to 20% of the annual
sales. If there were no problems with the product process,
the company's net profit would increase immediately. If the
'lifecycle management' is pursued by QbD and the quality is
improved step by step, a yield of 6σ (99.9999998%) can be
derived. This is only two to three defective products out of
1 million. This is very effective for developing high-quality
pharmaceuticals. In comparison, the defect rate of 2–3σ in
the pharmaceutical industry is very high.
To address these issues, the US FDA sought to apply the
Quality by Design (QbD) technique as a quality management
system to pre-emptively predict and manage possible risks
in the research stage and manufacturing process of drug
products, and systematically cope with them (Rathore and
Winkle 2009; Patil and Pethe 2013; Lawrence et al. 2014;
Waghule et al. 2019). QbD was first defined by Juran and was
designed to secure the quality of drug products from plan-
ning or design, not evaluation or control (Pharm and Pharm
2013; Jain 2014; Kadam et al. 2017; Jagan et al. 2021). The
conceptual QbD approach in the pharmaceutical industry,
often considered twenty-first century GMP, was introduced
by the US FDA in 2002 through a final report of ‘Pharma-
ceutical current good manufacturing practice (cGMP) for the
twenty-first century—a risk-based approach’. Furthermore,
the FDA Guidance for Industry on Process Validation, first
published in 1987, was revised in January 2011 to incorpo-
rate QbD principles (Bhutani et al. 2004; Beg et al. 2019);
in particular, to help identify the factors affecting critical
material attributes (CMAs), and critical process parameters
(CPPs) that can affect critical quality attributes (CQAs) of
the pharmaceutical product. Overall, QbD finds solutions to
problems during phenomenon of departure, manages risks,
and enables pharmaceutical production of uniform quality.
The GMP manufacturing process and quality management
are operated as individual systems; but the most critical differ-
ence of QbD is that real-time management is possible because
it is integrated into a single system (Chen 2006; Guideline
2008; Karanakov et al. 2012; Calnan et al. 2013; Aksu and
Mesut 2015; Peltonen 2018). The application of QbD is imper-
ative in drug development (Schweitzer et al. 2010; Grangeia
et al. 2020; Kajiwara et al. 2020), and as many countries
demand advancement through QbD-based pharmaceutical
development and management, it is becoming an essential
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
quality assurance standard in the global pharmaceutical mar-
ket. In addition, many international regulatory agencies and
pharmaceutical companies have already completed the prepa-
rations and conditions for introduction, having entered the full-
scale implementation phase. However, many pharmaceutical
companies are having difficulties in setting the developmen-
tal directions due to a shortage of professional experts. As
it incorporates quality management throughout the entire life
cycle, from the initial stage of drug development, it is diffi-
cult to discard the existing paradigm and adopt QbD concepts
over a short period. Beyond simple pharmaceutical product
development, risk factors should be evaluated in advance, and
a control strategy should be pre-established using statistical
techniques and advanced, real-time manufacturing analyses
to understand the assessed risks more. Further, one compo-
nent requires a vast amount of information to be applied to the
production of pharmaceutical products to guarantee quality.
In the literature, there have been several studies to improve
quality through the QbD system, but the methodology for drug
development is limited. Further, a study on the implementation
method and procedure for QbD application in pharmaceuti-
cal development has been published (Chen 2006; Guideline
2008; Karanakov et al. 2012; Calnan et al. 2013; Aksu and
Mesut 2015; Peltonen 2018). However, research might be
hard to understand for those new to this field, and few the-
ses comprehensively deal with the easy application of QbD
in the development process of drugs. In a survey of actual
formulation, most researchers of the pharmaceutical industry
answered that the introduction of QbD was necessary. How-
ever, they stated, although they recognised the need for QbD,
it was difficult to apply QbD in drug development, further it
was difficult to understand. The need for QbD is emphasised,
but many pharmaceutical companies face difficulties applying
QbD because there are few papers with detailed descriptions
of specific implementation methods and procedures.
Therefore, the present research examines the most appropri-
ate methods for applying QbD to the drug development pro-
cess and examine its benefits to the pharmaceutical industry
and research scientists.
Comparison of conventional to QbD
development processes
In the development of conventional, orally administered
drugs, data is obtained on the active pharmaceutical
ingredients (API) through a literature search, as well as
performing API solubility tests, physico-chemical assays,
and preformulation studies. Next, through a compat-
ibility study among API, excipients that can and cannot
be used are selected in advance before the formulation
research. Subsequently, various compositions can be made
through formulation research, and it is possible to select
Journal of Pharmaceutical Investigation (2022) 52:649–682
the optimal manufacturing method among wet granulation,
dry granulation, and direct compression through manufac-
turing process research.
Approximately, three to five formulations are deter-
mined, besides evaluating the dissolution, disintegration
time, hardness, and friability of determined tablets, and
the optimal prescription quantity is confirmed within a
short time through a stability study of downscale methods.
When the lab scale formulations are complete, the prod-
uct quality is evaluated through a pilot-scale composition
study and an in-process control; whereas the stability of
the drug product is confirmed through a long- and accel-
erated-term stability test and accelerated condition for
six months. Simultaneously, a non-clinical beagle phar-
macokinetics study of the drug product is conducted to
confirm the in vivo pharmacokinetics such as the absorp-
tion, distribution, metabolism, and excretion (ADME), and
when appropriate, an investigational new drug applica-
tion (IND) for clinical trial is submitted to the appropriate
regulatory agency.
In QbT, the conventional pharmaceutical manufactur-
ing quality control method, after manufacturing the drug
through a standardised process, the batch results (interme-
diate process materials, raw materials and finished drug
product) are analysed and quality control analyses are per-
formed based on the results (Fig. 1). QbT relies on experi-
ence throughout the development, and conducts R&D on
a single variable (Bhusnure et al. 2015). In addition, it is
unfeasible to evaluate the quality of all pharmaceutical
products, so a small sample is randomly selected from the
population following manufacturing completion, and the
level of defective products is relatively high (Bhoop 2014;
Arora et al. 2016).
However, to develop a pharmaceutical drug product to
which QbD is applied, one must first define and verify
the development quality target product profile (QTPP)
and set the CQAs based on prior knowledge and experi-
ence according to the stated purpose (Fig. 1). Then, an
extracting process of formulation variables and process
parameters is required, and by using design of experimen-
tal (DoE) techniques, the results obtained that satisfy the
CQA criteria are screened using statistical methods, and
preliminary analyses of risk factors that may occur during
pharmaceutical manufacturing are conducted. CMAs and
CPPs with high risk and impact on CQA are identified,
and for the data obtained that satisfy the CQA criteria in
a robust and reproducible manner, the relationship and
interactions between these quality variables, CMA, and
CPP are modelled; thus, it is necessary to verify and build
a design space. Finally, by controlling the formulation
and process variables within the design space, as well as
establishing and executing an optimised control strategy
to consistently satisfy the CQAs, their risks are minimised
651
and the optimal quality is achieved. Similarly, the optimal
quality process and materials should be applied during
drug development. The manner of the drug development
process applying such QbD will be explained in the next
step.
Quality by Design (QbD)‑based drug
development
Quality target product profiles (QTPPs)
The initial step of the QbD is to establish the QTPPs, which
requires a clear understanding of target product profile (TPP)
of drugs. The QTPP summarises the predictive quality char-
acteristics of a drug product to be achieved to ensure the
targeted quality standards of safety and efficacy are met
(Rathore 2009; Marto et al. 2015; Finkler and Krummen
2016). By establishing QTPPs, goals and directions are pre-
set before product development, as is the basis for pharma-
ceutical formulation design (Purohit and Shah 2013; Gan-
dhi and Roy 2016; Kan et al. 2014; Thoorens et al. 2014).
Broadly, QTPPs can be thought of as the contents of the
paper insert included when purchasing a prescription drug;
however, they must be interpretable from the perspective
of the pharmacist, patient, and the doctor to comprehen-
sively convey risks and justification. The QTPP compo-
nents of synthetic drugs primarily include indications, dos-
age, route of administration, pharmacokinetic profile, shelf
life, packaging, etc. (Zurdo et al. 2015; Gupta and Jhawat
2017); whereas those for biopharmaceuticals include trans-
parency, particulates, pH, activity, sterility, stability, colour,
odour, moisture content, dissolution time, lyophilised cake
properties, etc. (Cunha et al. 2020a; Kanwal et al. 2021).
QTPP can be defined more clearly by pre-judging the risk
for each pharmaceutical in consideration of its character-
istics and development setting. Further, understanding the
needs of patients to manage their disease is helpful in select-
ing a QTPP. For example, the risk level must be set to low
when selecting a natural oral route of administration during
manufacturing, and the justification must also state that oral
administration is the route of ease with the patient’s compli-
ance. In addition, the target value of the pharmacokinetic
item is a further risk to be considered, as it can affect clinical
results such as bioequivalence, safety, and efficacy of the
active pharmaceutical ingredient, and any justifications must
consider this (Table 1).
Critical quality attributes (CQAs)
The CQAs indicate that a physical, chemical, (micro) bio-
logical characteristic, or other properties are within reason-
able distributions to ensure the desired quality. CQAs are
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652 Journal of Pharmaceutical Investigation (2022) 52:649–682

Fig. 1  a Conventional Quality by Testing (QbT) for drug develop- with permission of Zhang and Mao, Asian Journal of Pharmaceutical
ment, and the b QbT, c Quality by Design (QbD), and d QbD-based Sciences, ScienceDirect, 2016.)
drug development approaches (Zhang and Mao 2017). Reproduced

13
 Table 1  Example of quality target product profile (QTPP) definition
QTPP Target Risk Justification Related quality attributes References

Indication Ex) Reflux esophagitis Yes or No Inconsistent indications for patients tak- Appearance Raw et al. (2011), Finkler and Krummen
ing this drug as a therapeutic drug may (2016), Bhambure et al. (2011)
cause unnecessary drug misuse and
side effects to the patient. Therefore,
the indications for the drug should be
clearly explained
Dosage design Ex) Coated tablets of not more than 160 Yes or No Since the dosage form is one of the Appearance Namjoshi et al. (2020)
mg most important elements of the Drug
Ex) Transparent medical ampoule with Delivery System(DDS), it is directly
yellow liquid drug solution related to the drug efficacy. Therefore,
the concept and justification of the for-
mulation should be clearly described
Route of administration Ex) Oral, Injection, transdermal, sublin- Yes or No The route of administration is directly Test Items Gavan et al. (2017a), Syed and More
gual tablet related to patient compliance. Also, (2020)
Journal of Pharmaceutical Investigation (2022) 52:649–682

errors in the route of administration

may affect drug efficacy. For example,
in the case of a sublingual tablet, if it
is taken like a regular tablet, it will not
be able to show its proper medicinal
effect. Therefore, the route of adminis-
tration should be clearly described
Dosage strength Dosage Yes or No When administered in a certain amount Assay Djuris et al.( 2013), Hasnain et al. (2021),
or more, side effects may occur, and Mukharya et al. (2012a), Marto et al.
if administered in less than a certain (2016)
amount, the therapeutic effect may be
reduced. Therefore, it is necessary to
establish a dosage strength that can
maintain an appropriate treatment area
and prove its validity
Pharmacokinetics AUC/Cmax/Tmax Yes or No The pharmacokinetic profile can directly Assay Gavan et al. (2017b), Gavan and Porfire
affect safety and efficacy. Therefore, it (2017a), Charoo et al. (2017), Shah et al.
is required to establish a pharmacoki- (2017)
netic profile that can prove safety and
efficacy through various non-clinical
tests
Stability and Stable for a period under storage condi- Yes or No The quality attributes of the drug Assay Patel and Parmar (2013), Mesut et al.
shelf life tions must be suitable for the set period, Impurities (2015)
otherwise, the drug cannot be properly
effective. Because the shelf life of a
drug directly affects safety and effec-
tiveness, it must be clearly indicated
and the rationale for the setting must
be demonstrated

13
653
 Table 1  (continued)
654

QTPP Target Risk Justification Related quality attributes References

13
Appearance Appearance of the target formulation Yes or No Changes in product appearance can Appearance Vivekanandan (2019), Dangre et al.
lead to errors in the patient group’s (2019), Hasnain and Ahmed (2021)
selection of products for treatment.
Therefore, the appearance must be
clearly described (engraving, color,
shape, etc.)
Moisture content Not more than ~ % Yes or No Moisture may have a cause such as Moisture content Hasnain and Ahmed (2021), Cunha et al.
lowering of dissolution and increase (2020b)
of impurities. Therefore, it is neces-
sary to clearly establish the allowable
moisture range and justify it for proper
management
Identification Same peak retention time Yes or No The API must be identified. Absence of Identification Chordiya et al. (2019), Mundada et al.
API should be managed as it cannot be (2017)
effective
Assay 95–105% Yes or No If the assay is high, side effects may Assay Nayak et al. (2019), Singh et al., Gavan
occur, and if the assay is low, sufficient et al. (2017b)
drug effects may not be expressed.
Therefore, it is necessary to establish
an appropriate assay range and clearly
explain its justification
Weight Meets pharmacopoeia criteria Yes or No Content uniformity may affect clinical Assay (rights are reserved by Sharmada and
variation/ trials, and it should be managed so that Kakodkar 2015), (Singh et al. 2010)
Content a consistent product can be manufac-
uniformity tured
Dissolution Dissolution pattern suitable for drug Yes or No Dissolution is important for bioavail- Dissolution Negi et al. (2016), Mishra and Raza
properties ability. Therefore, the target dissolution (2021), Vivekanandan (2019)
profile should be clearly described and
the in vitro in vivo correlation (IVIVC)
should be verified
Impurities Select considering the stability of the Yes or No As impurities directly affect the stabil- Impurities Abhinandana and Nadendla, Zhang and
API ity of the formulation, they must be Mao (2017), Desai (2018)
managed. Therefore, it is necessary to
set the permissible range of impurities
in advance and, if necessary, identify
the structure of impurities and manage
them
Residual Residual solvent Yes or No Residual solvents can deteriorate the Residual solvent Singh and Sharma (2015), Mandlik et al.
solvent Not more than ~ ppm properties of the formulation and (2020)
should be managed
Journal of Pharmaceutical Investigation (2022) 52:649–682
 Journal of Pharmaceutical Investigation (2022) 52:649–682 655

associated with the drug substance, excipients, intermedi-

Purohit and Shah (2013), Mukharya et al.

ates (in-process materials) and the finished drug product.
Syed and More (2020), Patil and Pethe They include characteristics of quality: assay, uniformity
(2013), Kenjale et al. (2020) of dosage units, re-dispersibility, reconstitution time, and
aerodynamic property; safety: impurities related substances,

(2012b), DESIGN (2012)

residual solvents, osmolarity, isotonicity, microbiological
limits, sterility, and particulate matter; efficacy: diffusion,
dissolution, permeation; and multidisciplinary: patient
acceptance and compliance (Lawrence 2008). Because it is
Related quality attributes References

difficult for formulation researchers to understand the rela-

tively new subject of QbD, it is perhaps easier to understand
that it is the target result of the Certificate of Analysis (CoA)
report of the finished drug product; however, CQAs con-
tain an additional item asking whether it is a CQA, with the
corresponding justification written according to the target
standard. As CQAs are an important product characteris-
tic that can significantly affect the QTPP through the for-
Appearance
Impurities

mulation or process variables, a potential CQA should be

Assay

selected based on QTPP (Mandenius 2009; Rathore 2016).

For example, with a general oral tablet, the CQA items pri-
may react with drugs and promote their

to verify its justification and manage it

marily include descriptions such as appearance, identifica-

to select a packaging material that can
degradation. Therefore, it is necessary
surrounding environment. In addition,

guarantee the stability of the drug and

stability by protecting drugs from the
deterioration or degradation products
should be managed as they can cause

packaging materials in direct contact

tion test, assay, uniformity of dosage units, moisture content,

Yes or No In the case of microorganisms, they

Yes or No Packaging materials increase drug

impurities of related substances, residual solvent, and dis-

solution (Colobatiu et al. 2019). Furthermore, in the CQA
selection stage, one can more effectively attain the desired
quality of target drugs by judging and justifying the risks
of pharmaceuticals

for each quality attributes (QA) item, in consideration of

the characteristics of the drug substance and finished drug
Justification

product (Pramod et al. 2016). CQAs should be managed and

controlled throughout the product lifecycle management,
from delivery to the patient (Negi et al. 2015). For example,
with a generic oral tablet, the assay and content uniformity
test can be selected as a CQA because it indicates attributes
Risk

that can affect and compromise safety and efficacy; however,

since the identification test needs only to confirm the pres-
ence or absence of the active pharmaceutical ingredient, it
maintaining the physicochemical stabil-

does not have a significant effect on the formulation research

Packaging and container suitable for

and process parameters of the drug product (i.e., it is a gen-

Meets pharmacopoeial criteria

eral QA, not a CQA; Table 2a). The same can be said of a
general injection product, where a pH test can be selected
ity of pharmaceuticals

as a CQA; however, In addition, the aseptic and endotoxin

test can be selected as critical CQA because it is a quality
attribute that can affect and compromise safety. However,
the identification test would pertain to general QA, but not
CQA (Table 2b).
Target

Compatibility studies between API and excipients

Table 1  (continued)

The selection of excipients for the formulation step directly

Microbial limit

affects product quality; thus, the justification of the ration-

ale supporting the selection of excipients is critical. When
packaging
Primary

designing a drug product, compatibility tests should be

QTPP

performed on all excipients that may comprise part of the

13
 Table 2  Example of critical quality attributes (CQAs) determination in: (a) tablets, and (b) injections
656

Quality Attributes Objective CQA Justification Can be replaced References

with other quality

13
attributes

(a)
Appearance It should be in a shape and color for Yes or No Color, shape, and appearance are not Yes or No Chaudhury et al. (2014), Yu et al. (2019),
patients’ directly linked to safety and effective- Ha et al. (2017)
convenience in taking, and as a tablet, no ness. However, patient compliance
defects to medication can be important for
should be observed patients to take medication. There-
fore, the appearance must be clearly
described and managed for patient com-
pliance to medication
Identification The main active pharmaceutical ingredi- Yes or No Identification directly affects safety and Yes or No Kolekar (2019), Su et al. (2019), Mishra
ent should efficacy. However, in the case of Iden- and Rohera (2017), McDermott et al.
be identified tification, it can be confirmed through (2015)
assay test, and since there are almost no
cases where API is not added, most of
it is written as No
Assay Ex) API 95.0–105.0% Yes or No Process variables can affect the content of Yes or No Soans et al. (2016), Freeman et al. (2015),
the drug product. Therefore, the content Wang et al. (2015)
should be evaluated through formula-
tion research and process development
Weight variation/ Meets pharmacopoeia criteria Yes or No Variation in content uniformity can affect Yes or No Su and Bommireddy (2019), Mohurle et al.
Content uniformity safety and effectiveness. That is, this (2019)
CQA should be evaluated through drug
product research and process develop-
ment. Otherwise, the efficacy of the
medicine may be affected
Moisture content No more than ~ % Yes or No Stability may be affected if the API is Yes or No Wang and Kan (2015), Chavan et al.
sensitive to moisture. Therefore, it is (2016)
necessary to clearly establish the allow-
able moisture range and justify it for
proper management
Impurities Select considering the stability of the Yes or No Impurities may affect safety. Therefore, it Yes or No Amasya et al. (2019), Dispas et al. (2018),
API should be evaluated through formula- Jovanovska (2018)
tion research and process development.
Also, if necessary, identify the structure
of impurities and manage them
Residual solvent Not more than ~ ppm Yes or No Residual solvents can affect safety and Yes or No Mesut and Ȍzsoy (2015), Wen and Park
stability depending on the physico- (2011), Shah et al. (2015)
chemical properties of the main compo-
nent, so it should be evaluated through
process development
Journal of Pharmaceutical Investigation (2022) 52:649–682
 Table 2  (continued)
Quality Attributes Objective CQA Justification Can be replaced References
with other quality
attributes

Microbial limit Meets pharmacopoeia criteria Yes or No Failure to comply with the microbial Yes or No Amasya and Aksu (2019), Yamashita and
limit tests may affect patient safety. Sun (2020)
Therefore, a clear setting of the micro-
bial limit is required, and it must be
managed by justification its validity
Dissolution Dissolution pattern suitable for drug Yes or No The dissolution pattern can affect Yes or No Patil and Pethe (2013), Rawal et al. (2019),
properties bioavailability (efficacy). Therefore, Muntean et al. (2020), Kaushal et al.
the target dissolution profile should (2020)
be clearly described and the in vitro
in vivo correlation (IVIVC) should be
verified
(b)
Journal of Pharmaceutical Investigation (2022) 52:649–682

Appearance A colorless, transparent liquid for injec- Yes or No The appearance of the drug has a close relationship Yes or No Deng et al. (2019), Sonam and Rathore,
tion in a vial with the stability of the drug product. Stability is DESIGN (2012)
an important key quality characteristic in terms
of quality control, as it greatly affects safety and
effectiveness
Identification (thin layer chromatography) Yes or No Identification directly affects safety and efficacy. Yes or No Kenett and Kenett (2008), Stegemann et al.
R1 value ratio between standard solution However, in the case of Identification, it can be (2014), Silva and Silva (2021)
and test solution: 0.9–1.1 confirmed through assay test, and since there are
(Liquid Chromatography) almost no cases where API is not added, most of it Koeberle and Schiemenz (2017), Khurana
The standard solution and the sample is written as No et al. (2020)
solution should show the same reten-
tion time
Assay API 90.0–110.0% Yes or No The assay of the API directly affects the safety and Yes or No Amasya and Aksu (2019), Saitoh (2018),
effectiveness of the product, so it is one of the core Anderson et al. (2017)
quality characteristics that must be managed
pH 6.5–7.0 Yes or No It is one of the quality attributes that must be satisfied Yes or No Purohit and Shah (2013), Mandlik and
as an injection. In the case of pH, it may cause Dandgavhal (2020), Simões et al. (2018)
Osmotic pressure 280–340 mOsm Yes or No pain during injection. In addition, since it affects Soans and Chandramouli (2016)
the solubility of the drug, it should be managed by
setting an appropriate range and justification its
validity
Oxygen in vial Select later for the stability of the active Yes or No Oxygen in the vial can accelerate decomposition by Yes or No Alt et al. (2016), Saitoh (2018)
ingredient contact with the API, so it must be managed within
a certain limit. Therefore, if it is determined that
there will be changes according to the quantity
of product or manufacturing process variables, it
should be set as an output variable and managed

13
657
 658 Journal of Pharmaceutical Investigation (2022) 52:649–682

final drug product (Fahmy et al. 2012) (Fig. 2). Excipients

with known safety risks, which are determined by compat-

Rathore and Mhatre (2011), Shah et al.

Thombre et al. (2021), Sri et al. (2021)

ibility tests, should be excluded from consideration during

Abhinandana and Nadendla, Chavda

the formulation step (Jacques et al. 1999). The exclusion
helps to ensure the stability of the drug product in advance

Santosh et al., Saitoh (2018)

Hasnain and Ahmed (2021) (Fahmy and Kona 2012). The Placket-Burman DoE is used

Dutta et al., Mistree et al.

Djuris and Ibric (2013)
to assess compatibility, as it can identify the most criti-
Sylvester et al. (2018)

cal factors early in the experimental process (Vanaja and

Shobha Rani 2007); therefore, this represents the optimal
design to confirm compatibility between API and excipients
References

(2009)

(2016)
(compatibility test examples are listed in Table 3). Mixed
samples of API and excipients are tested in various experi-
mental conditions, across different times and storage meth-
Yes or No

ods. The stability of the API is thus confirmed, dependent

with other quality

upon the presence or absence of specific excipients. When

Can be replaced

the compatibility test fails, the impurities increases rapidly

product. Therefore, if it is determined that there will

with time, and the endo- or exothermic peaks of differential

manufacturing process variables, it should be set as
attributes

be changes according to the quantity of product or

Yes or No directly affects the safety and effectiveness of the
Yes or No As it is an essential quality attribute of injection, it

scanning calorimetry (DSC) shift due to the degradation or

denaturation. Conversely, if the level of impurities is stable,
and there is no DSC peak shift observed, the compatibility
between the API and the excipient is considered good. The
Plackett–Burman design can confirm the interaction between
an output variable and managed

the API and a single, or multiple excipients, providing a

statistical basis for optimal selection (Verma et al. 2017).

Risk assessment

Risk assessment (RA) is described in the international coun-

Justification

cil for harmonisation (ICH) Guideline Q9. By performing

RA, the CMAs and CPPs that affect CQAs can be identified.
CMAs refer to the independent formulation variables, such
as physicochemical properties of active (drug substance)
Yes or No
Yes or No

Yes or No

Yes or No

Yes or No

and inactive ingredients (excipients) affecting the CQAs of

CQA

semi-finished and/or finished drug products. CPPs refer to

the independent process parameters most likely to affect the
There should be no discoloration inside

CQAs of an intermediate or finished drug product, as they

too should be monitored or controlled to ensure the desired
Foreign Insoluble Matter No detect foreign insoluble matter

quality. In addition, it also helps to set the research direction

in the early stages of development, and properly establish a
Not more than 0.17 EU/mg

design space (Kelley et al. 2016; Raina et al. 2017; Braem

No mycosis (negative)
6000 or less (per vial)

Not less than 2.0 m L

600 or less (per vial)

and Turner 2019). The RA tools that are available are listed
Not more than 15%

in Table 4 (ICH guideline Q9), where the potential variables

Insoluble visible particle 10 μg or more:

25 μg or more:

that can affect quality of the drug products are identified

the sample
Objective

(Pallagi et al. 2018; Borchert et al. 2020; Martinez‐Marquez

et al. 2020). For the selected CMAs and CPPs, a high-level
understanding of the process should be sought after through
a combination of studies assessing experimental design, sta-
tistical modelling, a mathematical modelling, and the under-
Table 2  (continued)

Capacity deviation
Quality Attributes

lying mechanisms.
When performing RA to identify and evaluate CMAs and
CPPs influencing CQAs, there are four steps: The first is
Endotoxin

Airtight
Volume
Aseptic

risk identification, in which risks are identified and listed.

The second step involved risk analysis performed using RA

13
Journal of Pharmaceutical Investigation (2022) 52:649–682 659

Fig. 2  Compatibility test

between API and excipients

Table 3  Plackett–Burman Run API B C D E F G H I J K L M N

design for compatibility tests
1 + − + + − − − − + − + − + −
2 + + − + + − − − − + − + − +
3 + + + − + + − − − − + − + +
5 + − + + − + + − − − − + − −
6 + − − + + − + + − − − − + −
7 + + − − + + − + + − − − − +
8 + + + − − + + − + + − − − +
9 + + + + − − + + − + + − − +
10 + + + + + − − + + − + + − +
11 + − + + + + − − + + − + + −
12 + + − + + + + − − + + − + +
13 + − + − + + + + − − + + − −
14 + + − + − + + + + − − + + +
15 + − + − + − + + + + − − + −
16 + − − + − + − + + + + − − −
17 + − − − + − + − + + + + − −
18 + − − − − + − + − + + + + −
19 + + − − − − + − + − + + + +
20 + + + − − − − + − + − + + +

API active pharmaceutical ingredient, B Microcelac, C Starch, D microcrystalline cellulose (MCC), E

D-mannitol, F Lactose, G Crospovidone, H Sodium croscamellose (Na-CMC), I Sodium starch glycolate
(SSG), J Colloidal silicon dioxide, K Magnesium stearate (MG-St), L Sodium stearyl fumarate (SSF), M
citric acid, N Calcium hydroxide

tools, such as the preliminary hazard analysis (PHA). The
third stage is risk evaluation, where major measures, such
as DoE, are taken through tools such as failure mode effects
analysis (FMEA). As shown in Table 4, PHA might be use-
ful when analysing existing systems or prioritising hazards
where circumstances prevent a more extensive technique
from being used. Typically, hazards identified in the PHA
are further assessed with other risk management tools such
as those in this section. Also, FMEA can prioritise risks and
monitor the effectiveness of risk control activities. Finally,
the fourth stage is RA, with a goal to identify and organise
CMAs and CPPs affecting CQAs.
Risk identification: first stage
In risk identification, various material attributes (MAs) and
process parameters (PPs) are listed using Ishikawa and fish-
bone diagrams, besides a process map. All potential vari-
ables that can affect drug product quality are thus identified
through prior knowledge of the formulation and manufac-
turing process (Figs. 3 and 4). After mapping the MAs and
PPs that can affect CQA during the formulation step, risk
analyses should be performed.
When manufacturing a general immediate-release tab-
let, or fixed-dose combination tablet, assuming the actual
process validation (PV) situation, risks may be incurred;

13

13
Table 4  Risk assessment tools
Tools
Failure Mode Effects Analysis (FMEA)
Failure Mode, Effects and Criticality Analysis FMECA can identify places where additional The output of an FMECA is a relative risk
(FMECA)
Fault Tree Analysis (FTA)
Hazard Analysis and Critical Control Points
(HACCP)
Hazard Operability Analysis (HAZOP)
Preliminary Hazard Analysis (PHA)
660
Potential areas of use(s) References
FMEA (see IEC 60812) provides for an evalu- FMEA can be used to prioritise risks and Guideline (2005), Sreedhara et al. (2015),
ation of potential failure modes for processes monitor the effectiveness of risk control Jayagopal and Murugesh (2020), Suresh et al.
and their likely effect on outcomes and/or activities (2015), (rights are reserved by Sharmada
product performance and Kakodkar (2015), Shah and Park (2009),
Jayagopal and Shivashankar (2017), Das et al.
preventive actions might be appropriate to “score” for each failure mode, which is used (2014), Chatterjee (2016), Oh et al. (2018)
minimize risks to rank the modes on a relative risk basis
The FTA tool (see IEC 61025) is an approach FTA can be used to establish the pathway to
that assumes failure of the functionality of the root cause of the failure. FTA can be
a product or process. This tool evaluates used to investigate complaints or deviations
system (or sub-system) failures one at a time in order to fully understand their root cause
but can combine multiple causes of failure and to ensure that intended improvements
by identifying causal chains will fully resolve the issue and not lead to
other issues (i.e. solve one problem yet cause
a different problem)
HACCP is a systematic, proactive, and HACCP might be used to identify and manage
preventive tool for assuring product quality, risks associated with physical, chemical and
reliability, and safety (see WHO Technical biological hazards (including microbiologi-
Report Series No 908, 2003 Annex 7) cal contamination). HACCP is most useful
when product and process understanding is
sufficiently comprehensive to support identi-
fication of critical control points
HAZOP (see IEC 61882) is based on a theory HAZOP can be applied to manufacturing
that assumes that risk events are caused processes, including outsourced production
by deviations from the design or operating and formulation as well as the upstream
intentions suppliers, equipment and facilities for drug
substances and drug (medicinal) products
PHA is a tool of analysis based on applying PHA might be useful when analyzing existing
prior experience or knowledge of a hazard or systems or prioritising hazards where cir-
failure to identify future hazards, hazard- cumstances prevent a more extensive tech-
ous situations and events that might cause nique from being used. Typically, hazards
harm, as well as to estimate their probability identified in the PHA are further assessed
of occurrence for a given activity, facility, with other risk management tools such as
product or system those in this section
Journal of Pharmaceutical Investigation (2022) 52:649–682
Journal of Pharmaceutical Investigation (2022) 52:649–682 661

Fig. 3  Fishbone diagram (Ishikawa diagram)

Fig. 4  Mapping about MAs and PPs in the pharmaceutical development process

as such, all MAs and PPs required for process inspection sieving, post-mixing, tableting, and coating processes
and process control (IPC) must be listed. For example, gen- (Fig. 4), where presumably, a screening process is conducted
eral tablet manufacturing processes may include screening amongst each step. If the active pharmaceutical ingredient
(sifting), blending (dry mixing), wet granulation, drying, is aggregated, this material must be screened or sifted, after

13
662
which the particle size distribution and flow ability of the
API powder will be MAs, and information on how to use the
screen size, as well as mesh size are the PPs. In particular,
for the granulation process, impeller speed, chopper speed,
amount of binder, etc. are specified as PPs.
Risk analysis and evaluation: second and third
stages
After listing and specifying all PPs, MAs, and QAs related
to the manufacturing, risk analysis begins. Broadly, in both
the second and third stages of RA, the tools PHA and FMEA
are used to determine the probability, severity, and detect-
ability based on a literature review and preliminary analy-
ses, ultimately ranking these variables based (Tables 5 and
6). Thereafter, the ripple effect of prioritised variables are
evaluated via DoE or other experimental approaches, to
improve process understanding and control strategies to be
developed (Shah et al. 2016; Casian et al. 2017; Patel et al.
2017; Javed et al. 2018; Shekhawat and Pokharkar 2019). In
this risk analysis stage, RA tools are then used to perform a
simple analysis that enables the identification of materials
and PPs affecting CQAs of the drug product.
In matrix analyses, such as PHA, CQA items can be
related to identification, assay, uniformity, impurity, and
dissolution. Along the X-axis, the type of MAs used, or PPs
applied in the drug production are listed (Tables 5a and 6a).
In Table 5a, if the amount of binding agent was increased,
the dissolution profiles of a general tablet were released
slowly, and when the amount of binder was decreased, the
dissolution profiles indicated a rapid release; thus, the binder
amount affected dissolution profiles, potentially also affect-
ing bioavailability and efficacy of the finished drug product.
PHA comprises a table in which each item is indicated
by a colour: green, yellow, or red corresponding to low-,
medium-, or high risk, respectively (Tables 5a and 6a).
Green indicates a broadly accepted level of risk, and no
further investigation is needed, whereas yellow indicates a
degree of acceptable risk which may require further inves-
tigation/justification to reduce the probability. Finally, red
indicates an unacceptable risk that requires further investiga-
tion for reduction. Accordingly, the amount of binder in the
PHA table may be an unacceptable risk and is marked in red
to indicate further research is needed.
The third stage of RA, risk evaluation, is performed
through tools such as FMEA, to derive an equation that
enables the identification of MA and PP factors affecting
the CQAs of the drug product.
Among the MAs, the functional groups of excipients and
APIs are listed in the FMEA of Table 5b. For the corre-
sponding analysis, each failure mode was ranked using an
estimated frequency of probability (P), the probability of an
undetected failure later in the process (D), and severity (S).
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
P is defined as the frequency of a specific failure or event,
and it should refer to the P of the cause. Both P and S are
scored along a scale of 1–4.
The four point scale is based on the P of occurrence
of failure is divided into (1) unlikely, (2) occasional, (3)
repeated, and (4) regular; whereas the scores based of the
likely S effect on a drug product are divided into (1) minor,
(2) moderate, (3) major, and (4) extreme. The scale based
on the D of failure of detection is divided into (1) always
detected, (2) regularly detected, (3) likely not detected, and
(4) normally not detected. Failure risks were calculated
using the risk priority number (RPN), which is the product
of P, D, and S (RPNs = P × D × S). The values of P, D, and S
for each failure mode tablets were assigned based on experi-
ence and literature review, and the RPNs were calculated.
A high RPN value for a concentration of disintegrant
indicates it could introduce a lag time in dissolution. The
potential causes could be a low disintegrant concentration
with a high occurrence value (P = 4), a low detectability
value (D = 2), and an extreme severity value (S = 4); thus,
the calculated RPN for this failure mode was 32. Failure
modes with RPNs ≥ 30 were set as criteria for considering
the DoE as a possible failure; however, RPN scores differ
by case. Further, many QbD papers have been identified that
use scales from 1 to 10. There is no clear standard or criteria
for the values of P, S, and D.
Quality risk assessment case of CMAs affecting CQAs
The following is an example of the method to find CMAs
among various MAs affecting CQAs: API, binders, disinte-
grants, lubricants, and stabilisers are used in the manufacture
of general tablets (Patel and Shelat 2017). However, because
the degree of risk depends upon the API, the RA must be
made in advance during the development process. To assess
all cases that may occur during the manufacturing process,
factor mapping should be performed. When MAs have been
successfully mapped, a literature search and initial screen-
ing studies for each factor of the composition variable are
performed, and a PHA table can be established based on the
results, classified into high (red), medium (orange), and low
(green) according to the degree of risk (Table 5a). If PHA is
performed, FMEA are conducted to evaluate the initial risk
and criticality of each factor. At this time, S is scored from 1
to 4 points according to quality influence, P is scored accord-
ing to the probability of occurrence, and D is scored accord-
ing to detectability. In addition, the RPN is calculated, with
risk levels of 1–15, 16–30, and 31–64 classified into low,
medium, and high risk, respectively. Physicochemical prop-
erties of API and excipients may affect the assay of the drug,
as well as content uniformity. In addition, there is a potential
risk to the stability, dissolution pattern, and pharmacoki-
netic properties depending on the presence or absence of
Journal of Pharmaceutical Investigation (2022) 52:649–682 663

Table 5  (a) Qualitative preliminary hazard analysis (PHA), and (b) quantitative failure mode effects analysis (FMEA) of material attributes
(MAs)

References Patricio et al. (2013), Sreedhara et al. (2015), Charoo et al. (2012), Jayagopal and Shivashankar (2017), Saydam (2016), Kovács
et al. (2021), Sharma et al. 2021, Jovanovska-Klincarska et al. (2018), Borde et al. (2016), Dias et al. (2021), Sitre and Kamble (2021), VS et al.
(2017)
CQAs critical quality attributes, CMAs critical material attributes, QTPP quality target product profile, API active pharmaceutical ingredient,
PSD particle size distribution, P probability, S severity, D detect ability, RPN risk priority number

specific excipients, which must be detected and managed
in advance. Using FMEA, when the RPN score was ≥ 30, it
was defined as CMA affecting CQAs (Table 5b). For MAs
selected API, diluent, binder, granulating agent, disinte-
grant, wetting agent, glidant, anti-adherent, and lubricant
were considered. Therefore, binders and disintegrants were
selected as CMAs. Glidant and lubricant posed moderate
risks but were not CMA because they were deemed manage-
able based on screening and pre-research data. If the amount
of the binding solution selected as CMA is large, it may form

13
664 Journal of Pharmaceutical Investigation (2022) 52:649–682

Table 6  (a) Qualitative PHA, and (b) quantitative FMEA of process parameters (PPs)

References Bhattacharya et al. (2015), Nayak et al. (2017), Charoo et al. (2017), de la O Herrera et al. (2015), rights are reserved by Sharmada
and Kakodkar (2015), Jeyaprakash et al. (2020), Gupta and Khan (2013)
CQAs critical quality attributes, CPPs critical process parameters, QTPP quality target product profile, FBD fluidized bed dryer, CFM cubic feet
per minute, P probability, S severity, D detect ability, RPN risk priority number

hard granules and cause dissolution delay; whereas if the these factors were selected as CMAs, as they directly affect
amount is too small, an appropriate dissolution pattern can- the bioavailability of drugs, and must be optimised through
not be obtained. With a disintegrant, if too little is used, the additional experimental designs (Ha et al. 2018).
drug may not disintegrate within an appropriate time. Thus,

13
Journal of Pharmaceutical Investigation (2022) 52:649–682
Quality risk assessment case of CPPs with CQAs
The following provides an example of the method to identify
CPPs among all PPs affecting CQA. The granulation process
is performed via fluidised bed granulation (FBG) and high
shear mixer equipment, and the raw material and binder are
then added and kneaded. Because the risk depends on PP,
RA must be made in advance during the developmental pro-
cess. To assess all possible cases that may occur during the
drug product manufacturing, one should similarly map the
PPs. Once performed, a literature search and initial screen-
ing studies of each composition variable can be conducted,
collectively informing the creation of a PHA table. PHA
is similarly classified by colour according to the degree of
risk, and FMEA is performed to evaluate the initial risk and
criticality of each factor (Table 6a). At this time, P, D, and S
are scored, and the RPN is calculated and classified into low,
medium, or high risk. In the granulation process, the assay
of the drug product may be affected due to API loss and
regarding the assay of granules. The physical properties of
granules can affect product uniformity, and when the insolu-
ble API is formed into amorphous granules by the process,
there are potential risks to the dissolution pattern and phar-
macokinetic properties; therefore, it must be detected and
managed in advance. For PPs, generally selected co-sifting,
blending, granulation, FBD, screening, lubrication, tablet-
ing, and coating were considered (Table 6b). Also, when
the RPN score was ≥ 30, it was defined as CPP affecting the
CQAs. Therefore, granule manufacturing (impeller, chop-
per speed, and binder-granulating agent spraying rate), and
tableting (turret/feeder speed and compression/tamping pres-
sure) were selected as the CPPs. If the granulation process
time is long, large granules may be formed, which may harm
bioavailability and efficacy. According to tableting proper-
ties, granulation may affect the content uniformity of the
tablet, capping, slug, etc., deleteriously affecting efficacy.
Therefore, the selected CPP should be optimised through the
additional experimental DoEs (Zandieh 2020).
Risk assessment: fourth stage
Finally, when selecting CMAs among the MAs incorporat-
ing API and excipients (Table 5b), the P, S, and D values of
FMEA are used to rank the score. If the RPN score is > 30
points (the hypothetical risk standard), it is considered a risk
that must employ measures such as DoE (i.e., it is selected
as a CMA requiring DoE). Similarly, when selecting CPPs
involved in the unit manufacturing process (Table 6), the
results are also shown through PHA and FMEA, ultimately
determining if the CPP requires DoE. In this way, binders,
disintegrants, granulation times, etc. were selected as CMAs
and CPPs for which DoE's major measures should be taken
665
against risk. For the overall RA, each selected CMA and
CPP were set as x values, and DoE was performed.
Design of experiments (DoE) strategies
during drug development: selection
of experimental design suitable
for the purpose
DoE is a data analysis method that helps plan, conduct, ana-
lyse, and interpret controlled tests to determine the factors
affecting product quality, stability, or other key processes.
DoE helps identify all critical interactions by simultaneously
manipulating multiple factors, furthermore, it supports the
robustness of the formulation and quality of the final product
by building experimental certainty and reproducibility into
the process. Therefore, DoE must ensure that the QbD sys-
tem meets the design-specific quality requirements.
However, an appropriate experimental design method
must be applied to the purpose of the experiment (Rathore
2009). Scientific and systematic experimental design for
drug development is a product of outputs in pursuit of a
certain experimental purpose (i.e., designing an experiment
requires a purpose, and the appropriate research method to
achieve said purpose) (Fig. 5) (Lee and Kim 2019). There-
fore, to appropriately implement the DoE, the purpose of the
experiment must be defined with well-established hypoth-
eses. The strategy of experimental design is divided into
three categories: (1) Screening, (2) Optimisation, and (3)
Sequential experiments.
Screening experiments are efficient methods for identify-
ing critical factors; however, the experimental design of the
screening experiment does not exist separately. Therefore, it
is efficient to conduct a minimum experiment with many fac-
tors. The experimental design most commonly used for this
purpose is the 2-level partial factorial design. Such screening
experiments are suitable for early stage or selection evalua-
tion of new drugs in the feasibility test or RA stage.
The optimisation experimental design is suitable for
enhancing the response (Y) value by experimenting with
a few important factors. For optimisation, a curve response
model (typically a polynomial regression) should be cre-
ated that can analyse the interaction between the independ-
ent variable experimental factor, and the dependent variable
response factor in more detail; thus, experiments should be
designed to obtain higher-polynomial regression models.
Optimisation experimental design and analysis methods
include response surface methodology, and mixture experi-
ments. In addition, the central composite and Box-Behnken
experimental designs are the primary methods for obtaining
the second-polynomial regression model. In drug composi-
tion research, simplex centroid, simplex lattice, and vertex
13
666
Fig. 5  Road map for DoE selection in the pharmaceutical development process
experimental design methods are widely used for a mixture
of API and excipients.
Sequential experiments are an experimental strategy that
utilises both a screening experiment to find a major factor,
and an optimisation experiment to find an optimal response
value. This is most suitable for cases in which knowledge
of research technology is lacking, or further exploratory
research is required. Designing an experiment with a sequen-
tial experimental strategy is advantageous because optimisa-
tion can be reached within a short time through systematic
experiments.
Design space
Design space refers to a range designed to assure quality
and identify complex interactions between MAs and PPs
using DoE. The ICH has demonstrated that QA is provided
by defining a design space as a multidimensional combina-
tion and interaction of input and PPs (Raman et al. 2015).
Thus, for CMAs and CPPs that directly affect CQAs selected
based on RA are parameters, interrelationships related to
QA should be identified, as should multidimensional com-
binations between variables. The design space representing
the multidimensional combinations ensures that a product
suitable for the established QTPP and CQA can be manu-
factured (Lee and Kim 2018). However, since drug develop-
ment creates a small-scale design space, an effective quality
control strategy is needed to manage potential risks after
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
its development and establishment (Beg et al. 2015). For
example, if a process is conducted near the boundary of the
design space, the risk of deviation from the design space
may increase due to the normal process deviation (i.e., vari-
ation of general factors) (Fissore et al. 2015). Therefore,
it is essential to verify the design space before performing
scale-up for pharmaceutical manufacturing (Vo et al. 2020).
Also, it is possible to improve the reliability of quality man-
agement strategies for potential risks through the establish-
ment of control and operating space, besides design space
(Fig. 6) (Puskeiler et al. 2011). The control space is the area
of optimisation of process and formulation variables, and
the operating space is defined in the manufacturing proce-
dure (Rathore 2009). After the design space has been estab-
lished, if the process is operated within these limits, PV is
performed to demonstrate the provision of acceptable qual-
ity (Rathore 2014). Through this, the control and operat-
ing space are established, and each set range is a drug that
satisfies QTPP and CQA, with consistent quality within the
range. In addition, it enables economic and efficient moni-
toring of drug quality, providing many advantages when
manufacturing and changing drug approvals. Consequently,
running the processes within the design space is part of a
quality control strategy (Peltonen 2018), and it is necessary
to ensure that products suitable for QTPP and CQA can be
produced by deriving a design space related to the quality
management strategy.
Journal of Pharmaceutical Investigation (2022) 52:649–682
Fig. 6  Design, control, and normal operating space
Control strategy
The control strategy is defined as ‘a planned set of con-
trols, derived from current product and process under-
standing, that assures process performance and product
quality’, as described in ICH Q10 (Guideline 2008). The
main factors of the control strategy include material prop-
erty management, process variable management, process
testing, intermediate material testing, procedure manage-
ment, final product management by release testing, sta-
bility monitoring, and life cycle management (Karana-
kov et al. 2012). In addition, when describing the control
strategy for key factors, how the drug substance, semi-
finished product, container closure system, product, and
process inspection affect the final product quality must
be explained and justified (Ferreira and Tobyn 2015; de
Matas et al. 2016). These control factors should be based
on product, formulation, and process understanding, and
should include at least CMA and CPP. Therefore, it is pos-
sible to manufacture while accounting for the variability of
the input drug substance through process understanding,
and process management becomes possible to overcome
variability via adjustments to ensure consistent quality
through knowledge surrounding this product and process
with quality risk management (Flåten et al. 2012; Markl
et al. 2020).
As understanding of product performance increases, it
is possible to judge property quality suitability via other
methods for justification, namely the real-time release test-
ing (RTRT) method. For example, a disintegration test can
be performed instead of a dissolution test with an immedi-
ate-release tablet with a high API solubility. In addition, if
667
a uniformity test for unit amount is performed on the final
drug product rather than a content uniformity test in the
compendium, a high level of quality assurance is possible,
along with the RTRT. The preferred control strategy technol-
ogy is a real-time process analysis using process analytical
technology (PAT). This is an example of applying online and
in-line analysis methods to obtain qualitative or quantitative
information on intermediate and finished products (Miller
2020). Optical techniques and electrochemical methods
such as near-infrared spectroscopy, Raman analysis, laser
diffraction, and imaging are used for real-time monitoring
(Gavan et al. 2020). Assay, drying ratio, mixing ratio, tablet-
ing speed, and hardness of APIs and excipients in a general
tablet manufacturing process can be confirmed using Fourier
transform near-infrared (FT-NIR). In addition, the particle
distribution, mixing ratio, granule, particle size, and mill-
ing ratio of the API and excipient can be confirmed using
focused beam reflectance measurement (FBRM) (Murphy
et al. 2016). Thus, the control strategy in drug manufacturing
can guarantee consistent, high-quality products through test
management and process control (Singh et al. 2015).
Lifecycle management
Lifecycle management of pharmaceuticals is under discus-
sion in ICH Q12, but commonly entails methods such as
define, measure, analyse, improve, control (DMAIC), design
for six sigma (DFSS), and product quality lifecycle imple-
mentation (PQLI) based on PAT and in pursuit of under-
standing the process and evaluation technology of variables
and manufactured products (Jin et al. 2014). A scientific
approach must be applied to control and improve the quality
13
668
throughout the entire process, from drug manufacturing to
delivery and patient consumption (von Stosch et al. 2016).
One can confirm whether the process performance is main-
tained within the normal operating range (NOR) through
real-time monitoring (Ohage et al. 2016), and as part of
these monitoring activities, experience is accumulated
through routine manufacturing, permitting for trend analy-
sis throughout the manufacturing process. Further, regard-
ing the design space using a mathematical model, periodic
maintenance can help to verify and guarantee model perfor-
mance (Rathore et al. 2017). Such model maintenance rep-
resents an example of an activity that can be managed under
its own quality system when the design space is held con-
stant (Krummen 2015). When additional information about
the process is obtained, the design space can be enlarged,
reduced, and re-established as needed (Gouveia et al. 2018).
QbD drug development case study:
from QTPP to design space
A case study presenting an example of QbD application to
the wet granulation process commonly used in pharmaceuti-
cal manufacturing was examined further. The corresponding
paper. The primary research purpose was to develop tel-
misartan potassium tablets via QbD that are the bioequiva-
lent to the existing reference drug. Minitab® software (v.18,
Minitab Inc., USA) was used for statistical analyses of the
experimental design, and an experimental method suitable
for each stage was selected. The initial QTPP step of specify-
ing goals is listed in Table 7. Potential risks and feasibility
were described according to the viewpoint of pharmacists,
doctors, and patients. All items, save for the route of admin-
istration, indications, and residual solvent, were selected as
QTPP factors of risk. The considered CQAs were appear-
ance, identification, assay, dissolution, impurities, and resid-
ual solvents directly related to the established QTPP. The
risk associated with each item must be judged to determine
whether establish a CQA, and the feasibility and basis for
this decision must be presented (Table 8). Product dissolu-
tion and impurities can affect bioavailability and stability;
thus, both were selected as CQAs. Sometimes, it is possible
to confirm whether one can substitute for other quality char-
acteristics, and whether there can be variability in output
variables. Also, if it is determined there will be changes
due to the composition or variation of manufacturing PPs,
it should be set as an output variable.
RA is conducted after QTPP and CQAs selection, then
compatibility test are performed. All parameters, such as
composition, mixing, granulation, lubrication, and filling
processes should be detected in advance, as they can affect
CQA. RA was performed to select and evaluate CMAs and
CPPs, the primary factors influencing CQAs. In the risk
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
identification stage, all MAs and PPs were mapped through
a fishbone diagram until the final product was manufactured
and confirmed. As a wet granulation process was used, all
factors in the formulation (solid dispersion granules, final
mixture, and uncoated tablet, coating prescription), tab-
let prescription, and coating prescription were mapped.
Potential CQA-impact risk was classified as high, medium,
or low using the PHA tool. As QbD application involves
the detection and management of factors with potential
risk (high and medium level) in advance, it was thus con-
firmed whether the selected factors affected the product’s
CQAs within the set range through initial screening studies.
Such studies primarily used 2 k fractional factorial designs,
and based on the results, FMEA tools were used to evalu-
ate each element in terms of estimated P, D, and S. The
corresponding RPN score was calculated, and CMAs and
CPPs that could affect CQAs were selected from among the
MAs and PPs (RPN > 30). When the amount of the binding
solution increased, it had a critical effect on the dissolution
of the drug, affecting both the bioavailability and efficacy
(Table 9).
Because of performing RA on PPs in the same way, high
impeller and chopper speeds were found to potentially form
large granules, possibly increasing tablet dissolution time.
In addition, the longer the granulation time, the greater the
potential increase in dissolution time, as the larger granules
formed may affect bioavailability and efficacy; therefore, the
granulation time was selected as a CPP (Table 10).
As the curvature of the binding solution, disintegrant,
and granulation selected by CMA and CPP was confirmed
in the screening experiment, a face-centred central com-
posite design was applied. Central composite designs can
efficiently estimate the first and second terms and model
the curvature of response variables by adding experimen-
tal points to the previously performed factorial design.
The input X value (factor) was three, and the level could
be tested in a very narrow window of the knowledge space
through preliminary studies. The binder level was 4–10%,
the disintegrant level was 2–6%, and the granulation time
was 3–7 min. The table obtained through the design is listed
in Table 10, and the total number of experiments was n = 20
­(23 + (2 × 3) + 6). Finally, the output Y (response) value was
selected as hardness (kp), friability (%), disintegration (min),
and drug dissolution (%) regarding QTPP and CQA. After
completing all experiments, results for disintegration time,
hardness, friability, dissolution, impurities were input to the
statistical program, and model lack of fit tests were checked
through design analysis. Here, if p > 0.05, it was judged
that the null hypothesis could not be rejected for lack of fit.
Therefore, after DoE modelling was optimised, the results
could be interpreted through programs such as Pareto charts
and residual plots for each response value (Y 1–5).
Journal of Pharmaceutical Investigation (2022) 52:649–682 669

Table 7  Quality target product

profile (QTPP; reproduced with
permission of Oh et al., Drug
Development and Industrial
Pharmacy, Taylor & Francis
Online, 2018)

13
670
Table 8  Critical quality
attributes (CQAs; reproduced
with permission of Oh et al.,
Drug Development and
Industrial Pharmacy, Taylor &
Francis Online, 2018)
Modelling can be optimised by selecting significant
factors through the Pareto chart (Fig. 7a), and the statis-
tical significance can be confirmed through residual plots
(Fig. 7b). In addition, the degree of effect on the output
can be checked through the slopes of the main effects and
interaction plots (Fig. 7c, d). Finally, the numerical effect
of each element on the output can be accurately obtained
through the contour and surface diagrams (Fig. 7e, f). As
shown in the contour plot, the hardness increased with the
amount of binder, whereas the amount of disintegrant had
little effect. By overlapping the contour plots based on these
statistical results, it is possible to obtain a superimposed plot
capable of confirming the optimal design value of the true
space being operated. The target values for the individual
responses of the formulations are shown in Fig. 7, in which
it is possible to set a response value region where all criteria
are satisfied (i.e., the design space area can be confirmed).
As the model was developed and validated, the design space
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
was systematically established with all individual receptive
areas of each CMA and CPP.
Telmisartan potassium tablet was manufactured by the
wet granulation method using a high shear mixer, accord-
ing to the formulation composition in the design space.
The test and reference drug (Micardis®), which are the
final composition within the design space, were compared
through the pharmacokinetic profile of the beagle dog,
and the results are shown in Fig. 8. Consequently, the 90%
confidence interval (90% CI 0.9071–1.0814) for the geo-
metric least-squares mean ratio of the area under the curve
(AUC) was 0.9790 for the point estimate. In addition, the
bioequivalence criterion for telmisartan was within the
range of 0.80–1.25; therefore, through pre-clinical stud-
ies, the test drug developed via the application of QbD,
and the reference drug were proven to be bioequivalent.
By applying QbD, risks were detected and managed in
advance, improving product quality to a high level, besides
Journal of Pharmaceutical Investigation (2022) 52:649–682 671

Table 9  (a) Qualitative preliminary hazard analysis (PHA), and (b) quantitative failure mode effects analysis (FMEA) of material attributes
(MAs; reproduced with permission of Oh et al., Drug Development and Industrial Pharmacy, Taylor & Francis Online, 2018)

13
672 Journal of Pharmaceutical Investigation (2022) 52:649–682

Table 10  (a) Qualitative preliminary hazard analysis (PHA), and (b) quantitative failure mode effects analysis (FMEA) of process parameters
(PPs; reproduced with permission of Oh et al., Drug Development and Industrial Pharmacy, Taylor & Francis Online, 2018)

13
Journal of Pharmaceutical Investigation (2022) 52:649–682 673

Fig. 7  Identification of CMA and CPPs using: a Pareto charts and b space using face-centered central composite design (reproduced with
residual plots; Effects of CMAs and CPPs using: c main effects plot, permission of Oh et al., Drug Development and Industrial Pharmacy,
d interaction plot, e contour plot, f response surface plot; g Design Taylor & Francis Online, 2018)

Fig. 7  (continued)

13
674
Fig. 8  Plasma concentration–
time profiles of Micardis®
and TP tablets at an 80 mg
dose telmisartan base in
beagle dogs. Data represent
the mean ± standard devia-
tion (SD, n = 12). Reference
tablet, Micardis® (telmisartan
free base tablet); TP tablet,
telmisartan potassium tablet
(reproduced with permission of
Oh et al., Drug Development
and Industrial Pharmacy, Taylor
& Francis Online, 2018)
the manufacturing process to increase efficiency. Ulti-
mately, this study is expected to reduce costs by minimis-
ing unnecessary operation of equipment throughout the
process.
QbD application case studies
in the pharmaceutical development stage
Development of immediate‑release rabeprazole
sodium dry‑coated tablet
Lee and Kim (2021) conducted a study on the development
of rabeprazole sodium and sodium bicarbonate fixed-dose
combination tablets through the QbD approach. The purpose
was to develop a treatment for gastroesophageal reflux dis-
ease that, unlike the existing PPI formulations, can be rap-
idly absorbed by the stomach, applying the QbD approach
to the development process. Parameters of QTPP included
clinical use, route of administration, formulation, delivery
system, content, container, and packaging, API release or
delivery, characteristics affecting pharmacokinetic proper-
ties, sterility, purity, stability, and dissolution. The QTPPs
were evaluated for feasibility, and to establish the direction
of product and process development, the CQAs were iden-
tified through them and prior knowledge. To identify the
CQAs, physical characteristics, appearance, identification,
dissolution, impurities, weight variation, content uniform-
ity, assay, and residual solvents were specified. For the RA,
PHA and FMEA were used based on prior knowledge and
initial experimental data. An RPN > 30 was defined as a
CMA or CPP. The central composite design of DoE was
used to establish an appropriate management strategy for
the CQAs of the outer layer and optimise its binding and
disintegration properties. The design space was derived from
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
the overlapping contour plots, and the DS of the response
variable and influencing factor established the criteria veri-
fied within the 95% confidence level. The final composi-
tion of the dry-coated tablet was determined, and a process
study was conducted to identify the QTPP. The optimised
formulation was physicochemically stable for > 24 months,
and in a pharmacokinetic study of beagle dogs, the ­Tmax was
approximately thrice as fast as the reference drug of rabe-
prazole (Pariet®). Formulation development applying QbD
guaranteed the quality of the final drug because it detected
and managed various risks in advance. With rabeprazole
sodium used as the API here, effective quality control was
possible when comparing the stability of the formulation
to that of the existing reference drug with poor stability.
Therefore, the QbD system strategy provided information
for drug development, which involved sensitive issues in
drug manufacturing, such as stability and tableting proper-
ties (Lee and Kim 2021).
Development of topical hydrogel containing
ketoconazole loaded cubosomes
Rapalli et al. (2021) explored the development of topical
hydrogel containing ketoconazole loaded cubosomes with
lower surfactant concentrations via the QbD approach. The
secondary step in the QbD design was identification and
selection of CQAs. As CQAs are the prominent product QA
selected from the QTPP which influence the finished dos-
age form, their effects required exploration and monitoring.
Surfactant and stabiliser concentration were selected as the
dominant MAs affecting particle size and size distribution,
respectively. These two properties affect entrapment effi-
ciency and drug release (%). Stirring speed and stirring time
were selected as CPPs because they could affect the size
of the pre-emulsion and entrapment efficiency by avoiding
Journal of Pharmaceutical Investigation (2022) 52:649–682
coalescence of the two oil types. High RPN scores ≥ 100
were critical parameters/attributes. Screening and optimi-
sation of formulations with 32 factorial designs were con-
ducted with Design-Expert® (version 9.0, Stat-Ease Inc.).
Keeping the combination of constituents similar to that of
the optimised batches, as predicted post DoE analyses, scale-
up batches were prepared. The 32 factorial design model
successfully predicted the composition of the optimised
formulation within the confidence limits, with the produced
ketoconazole loaded cubosomes showing a release pattern
similar to the Korsmeyer–Peppas model experiencing Fick-
ian diffusion (67% cumulative ketoconazole release within
24 h). Ex vivo permeation study of hydrogel containing
ketoconazole loaded cubosomes revealed a sustained release
pattern through goat ear skin with ~ 92.73% release within 24
h. Thus, with drug development addressing the problem of
solubility, using surfactants was necessary; however, exces-
sive use of surfactants in drug development can affect patient
safety. Overall, it is judged that the QbD system strategy
here was appropriately utilised in formulations for develop-
ing ribosomes as a method of improving solubility (Rapalli
et al. 2021).
Development of topical arginine solid lipid
nanoparticles
Patel et al. (2021) assessed development through QbD for
additional rational forethought and step-by-step develop-
ment of solid lipid nanoparticles (SLNs). Considering the
type of dosage form and formulation method, the QTPP was
established, and a list for SLNs can be found in this paper.
For CQA identification, the Ishikawa diagram was devel-
oped, providing a transparent picture of CPPs and CMAs
affecting the particular outcomes of each variable. FMEA
was established to classify the parameters with higher risks
of failure in the quality of SLNs, and the CPPs and CMAs
with the highest RPN were the concentrations of surfactant,
oleic acid, and the sonication amplitude. Following FMEA
analysis (RPN number) and preliminary screening studies,
the three highest ranked CPs that influenced the final formu-
lation quality were included in DoE by applying 3 factor-2
level experimental design for SLN optimisation. Therefore,
by utilisation of all the concepts, the SLNs containing a con-
centration of 2.00% poloxamer 188, 1.5% oleic acid, and
59.78% sonication amplitude was optimal, having a particle
size of 273.6 nm, and 8.57% of drug loading. This research
revealed the significance of the QbD approach in develop-
ing a novel drug delivery system with fewer experimental
trials by applying the predicted model of DoE software. As
per the concept of QbD, the FMEA method combined with
the experimental design was appropriate for optimising the
critical parameters affecting QTPP. With topical formula-
tions, particle size and drug loading affected QTPP for skin
675
penetration. When manufacturing pharmaceuticals, critical
factors can function as various variables in the final prod-
uct; therefore, it is imperative to investigate the interaction
of critical factors through minimal experimentation using
DoE. This study provided knowledge of the more efficient
application of QbD by describing its use topical formulation
development (Patel et al. 2021).
Development of liposomes including hydrophilic
APIs
Xu et al. (2011) is a paper on the development of liposomes
including hydrophilic APIs also applied the QbD approach.
Tenofovir was selected as the hydrophilic API, and the
potential risk variables were selected through RA, before
the Plackett–Burman design was used to confirm the effect
of liposomes on the properties (drug encapsulation effi-
ciency, particle size, and physical stability). Accordingly,
it was confirmed that lipid and drug concentration had a
major effect on drug encapsulation. The multidimensional
interaction between lipid concentration, drug concentration,
and encapsulation efficiency was investigated through cen-
tral composite design, and design space was also derived.
Thus, a liposome formulation containing hydrophilic APIs
was optimised via the QbD approach. This helped to ensure
product quality by minimising variability (Xu et al. 2011).
Plackett–Burman design is efficient at identifying critical
factors in the experimental design, and the interactions
between various factors can be confirmed through minimal
experimentation. Therefore, the application of the QbD sys-
tem using the Plackett–Burman design effectively informed
critical factor selection and optimisation.
Liposomes for nasal administration
Pallagi et al. (2019) assessed the early development of
liposomes for nasal administration through the QbD
approach. In this study, the authors adapted QbD and RA
methods to the early development phase of a new nano-
sized liposomal formulation for nasal administration with
brain target. This research displayed how to apply this risk-
focused approach concentrated on the first four stages of
QbD implementation. In this way the QTPP was defined, the
critical factors were identified, and an RA was performed.
The RA results helped in the factorial design-based lipo-
some preparation by the lipid film hydration method. The
initial step was to define the TPP and its quality criteria,
where diagrams are useful for QTTP selection, as well as
the critical factors during the next QbD-guided develop-
ment steps. The second step was to select the factors with
critical effects on the targeted product quality. CQAs may
include information on particle or vesicle size, size distri-
bution, drug release, etc. In the next step, the CMAs and/
13
676
or the CPPs potentially affecting CQAs were determined.
In the RA-based formulation development, the critical fac-
tors were analysed, the interrelations between them were
estimated, and the factors were ranked by their critical effect
on the final product. The RA results helped establish the
experimental design. The Main Effect Screening Design 2
program was selected for screening the effects of the for-
mulation parameters on the quality of the final liposomal
product and revealed the importance of the concentration
of phospholipids (Phospholipon 90G®), which were the
third data on the list of the CQAs and chosen as variable
X1. According to the selection methodology, the size of the
liposome vesicles and size distribution, located in the first
position on the critical list of CQAs, were selected as the
response variable and second factor, respectively, whereas
the API was held constant. From the CPPs, the temperature
of ultrasonication was chosen as variable X2, and because
the type of the organic solvent was constant, the critical fac-
tor pertaining to the number of the second filtration was
designated as variable X3. The investigational results of the
prepared liposomes (API and API-free samples were pre-
pared following the same factorial design pattern), namely
vesicle size, size distribution, specific surface area, and sur-
face characteristics, verified the exactness of the RA and
the critical factor-based theoretical prediction showed strong
relationships between the product design (composition of the
liposomes and PPs, such as temperature, number of filtra-
tions, etc.) and the product characteristics of the prepared
liposomes. The results demonstrated how the QbD approach
could improve the formulation process in the development
of liposomes, lead to an effective product preparation pro-
cess, and help in the optimisation and the rationalisation
of liposomal development, even in special circumstances
when a lipophilic active ingredient was incorporated into
the liposomes. This research contained explanations of the
development of liposomes with the QbD approach applied
to drugs with low solubility. It was judged that through this
innovative design and development model, it was possible
to provide a platform to help resolve problems of drugs with
low solubility (Pallagi et al. 2019).
Development of a transdermal patch
Akhlaq et al. pursued the development of a transdermal
patch for dexibuprofen (DXIBN) using the QbD approach.
To optimise patch formulation, Box–Behnken (three-fac-
tor-three-level) design was used for the determination of
quadratic response surfaces with Design-Expert®. The
polynomial equation (Eq. 2) was generated, and the mod-
elled response was validated using the F-value (ANOVA;
significant terms identified as values of ‘Prob ˃ F’ < 0.05.
The modelled steady state flux of selected patches was
thereafter experimentally obtained and subjected to
13
Journal of Pharmaceutical Investigation (2022) 52:649–682
further evaluation. DXIBN transdermal patches were for-
mulated using various concentrations of selected poly-
meric excipients (matrix material: ethyl cellulose and pol-
yvinylpyrrolidone, plasticiser (di-N-butyl phthalate) and
a conventional permeation enhancer (almond oil). Initial
patch formulations were evaluated for their physiochemi-
cal properties (such as the thickness, moisture uptake,
final moisture content, and DXIBN content). Also, impact
of patch components on resulting tensile strength and
in vitro permeation were used to predict an optimal patch
formulation using a QbD approach, which was evaluated
and compared to a commercial oral tablet dosage form
for in vitro and in vivo release (rabbit model). Predicted
properties (tensile strength and DXIBN steady state flux)
for the QbD optimised formulation closely agreed with
experimental results, and the QbD optimal patch formula-
tion behaviour differed significantly from the commercial
tablet formulation in vivo. Such QbD approach model
based predictions thus reduced cost and time in formu-
lation development sciences here, besides the derived
formulation maintaining a shorter onset time than the
previously developed oral tablet (Propen®, Global Phar-
maceuticals, Pakistan), with long-lasting effects. Consid-
ering the scale-up step, applying QbD can be considered
an industrially useful strategy for minimising cost and
time (Akhlaq et al. 2016).
Development of resveratrol‑loaded mucoadhesive
lecithin/chitosan nanoparticles for prolonged ocular
drug delivery
Saha et al. reported on drug-containing nanoparticles
using the QbD approach. The QbD workflow began with
defining the patient-centric QTPPs, considering the qual-
ity, safety‚ and efficacy of the product. Then, the relative
potential QAs were identified, and their appropriate targets
were fixed with respect physicochemical and biological
properties of the intended lecithin/chitosan mucoadhesive
nanoparticles based on the literature and experimental
values. Next, the MAs, PPs, and other factors likely to
affect the QAs, were illustrated by the fishbone diagram as
the initial RA, and the high- and medium-risk QAs were
considered as CQAs. Ten CQAs obtained from the RA
study were experimented upon by the definitive screening
design (DSD) to determine the influential CPPs and CMAs
for further optimisation, DoE analysis. The final RA of
the MAs and PPs were performed in two steps: The high-
and medium-risk MAs and PPs were considered CMAs
and CPPs, respectively. Following the determination of
two crucial CMAs from DSD, a two-factor, five-level,
eleven run central composite design (CCD) was gener-
ated to optimise and define a design space. For the CCD,
the lecithin concentration and drug concentrations were
Journal of Pharmaceutical Investigation (2022) 52:649–682
expressed by X1 and X2, respectively. Thus, the experi-
ments were planned based on DoE; accordingly, the design
point with the highest desirability value provided a nano-
sized, stable, and optimum drug-entrapped formulation.
The optimised formulation, developed within the lab scale,
met the pre-defined, patient-centric QTPPs targets. This
study provided a case of successful development of QbD-
based resveratrol-loaded mucoadhesive lecithin/chitosan
nanoparticles for prolonged ocular drug delivery; however,
it has limitations, as it was developed and optimised in
a laboratory-scale. Therefore, it is necessary to set the
applicable range in the industry within the design space,
set through a scale-up study along with the experimental
design (Saha et al. 2021).
Biopharmaceutical
Sharma et al. (2021) analysed the improvement of the
biological properties of sorafenib tosylate (SFN) through
QbD. To improve the biological properties of SFN, a type
III self-emulsifying delivery system (Type III-SEDDS)
was applied, with an optimised formulation through the
QbD approach. Initially, the QTPP embarked upon defin-
ing all the requisite quality characteristics of the formula-
tion to be developed for achieving maximal therapeutic
efficacy of SFN, and CQAs were selected. Through first-
order 7-variables-2-level Taguchi OA design, with eight
experimental runs, screening tests were performed for
MAs and PPs that could create risk for the CQA. Based on
the results of preformulation and screening studies, type
III LFCS SEDDS formulations were optimised, employ-
ing a 3-factor-3-level D-optimal mixture design. A total
of 16 Type III-SEDDS formulations, including the quin-
tuplicate runs, were prepared according to the D-optimal
design matrix and characterised for CQAs: % drug release
at 60 min (Rel60), Dnm, mean dissolution time (MDT) and
% dissolution efficiency (DE). The optimised formulation
improved the dissolution rate by ~ 8 times or more, whereas
the drug permeability and absorption also increased > 8
times compared to the conventional SFN. Therefore, using
QbD optimised the formulation, and the bioavailability of
SFN was improved. Also, stability studies of SFN formu-
lations indicated that the ambient storage conditions (i.e.,
25 °C) were suitable for maintaining the robustness of the
self-emulsifying formulation, reporting inconsequential
changes in the CQAs. (Sharma et al. 2020). Compared
to synthetic drugs, biopharmaceuticals have many criti-
cal factors sensitive in scope, so it is necessary to detect
and manage risks in advance; therefore, through this study,
an appropriate QbD system strategy for biopharmaceuti-
cal development was identified. Furthermore, an efficient
description of the Taguchi OA design and D-optimal mix-
ture design was also put forth.
677
Conclusion
In the pharmaceutical industry, drug development is lim-
ited by product development and quality, as these essential
steps rely on experience. These issues can be overcome by
introducing a QbD system, which utilizes science and statis-
tics-based technologies. Applying QbD based on risk man-
agement enables the development of high-quality and safe
drugs for patients. This review paper is expected to solve
the difficulties surrounding drug development via QbD by
providing accurate information and application methods for
a functional system.
Funding This research was supported by the Industrial Strategic Tech-
nology Development Program (20008909, Development of AI-based
smart platform for pharmaceutical formulation design and manufac-
turing process) funded by the Ministry of Trade, Industry & Energy
(MOTIE, Korea).
Declarations
Conflict of interest All authors (S.‑H. Lee, J.‑K. Kim, J.‑P. Jee, D.‑J.
Jang, Y.‑J. Park, and J.‑E. Kim) declare that they have no conflict of
interest.
Research involving human and animal rights This article contains no
studies with human and animal subjects performed by the authors.
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