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batch number) and (4) any signicant equipment differences (e.g. different design,
operating principle, size) (PDA 2023).
2.2.5.1.5 Container Closure System
It is essential to discuss the decision and justication behind choosing the container
closure method for the commercial product. The selection of leading packaging
materials, primary packaging materials and secondary packaging materials should
be justied. When suitable, the storage and shipping container for bulk DPs should
also be considered, as well as the intended use of the DP and the suitability of the
container closure system for storage and transportation (shipping) (Gandhi and
Roy 2016).
2.2.5.1.6 Microbiological Attributes
Justify performing microbiological tests for sterile products and not for non-sterile
products. Selecting and implementing preservative systems in antimicrobial prod-
ucts, including those with inherent antimicrobial properties and those that rely on
added preservatives (Chavan etal. 2016).
2.2.5.1.7 Compatibility
To provide pertinent and helpful information for the labelling, the compatibility of
the medicinal product with reconstitution diluents (such as precipitation and stabil-
ity) should be addressed. The recommended in-use shelf life at the recommended
storage temperature should be covered with an emphasis on changes in shelf life at
extreme concentrations (Csóka etal. 2018).
2.2.5.2 Q8(R2): Structure—Annex
1. Introduction
2. Elements of Pharmaceutical Development
(a) Quality Target Product Prole
(b) Critical Quality Attributes
(c) Risk Assessment: Linking Material Attributes and Process Parameters to
Drug Product CQAs
(d) Design Space
(e) Control Strategy
(f) Product Life Cycle Management and Continual Improvement
3. Submission CTD-Q
(a) Quality Risk Management and Product and Process Development
(b) Design Space
(c) Control Strategy
(d) Drug Substance-Related Information
2.2.5.2.1 Introduction
This annex, part of ICH Q8 Pharmaceutical Development annex, further claries
the core guideline’s essential concepts. Its focus is to explain the concept of QbD
and describe how Q8 guidelines will be practised in pharmaceutical development.
2 Design ofMaterials andProduct Specications forPharmaceutical Dosage Forms
48
2.2.5.2.2 The Elements ofPharmaceutical Development
It should include:
• Dened quality target product prole (QTPP)
• Recognising the important critical quality attributes (CQAs) of drug substances,
excipients and drug products
• Choosing a suitable manufacturing method
• Making a control plan (Zhang and Mao 2017)
Quality Target Product Profile
Some factors to consider for the quality goal of the product include delivery sys-
tems, dosage strength, container closure system, dosage form, use in a clinical set-
ting and route of administration. The factors affecting pharmacokinetic data as per
the nished product (FP) should also be considered, including sterility, stability,
purity and drug release (Debevec etal. 2018).
Critical Quality Attributes (CQA)
A CQA is a property that should fall within a suitable limit to guarantee the intended
product quality. It can be chemical, physical and biological. It is applicable for
excipients, DS, FP and in-process materials. For example, CQAs of solid oral dos-
age forms are usually elements that affect the product strength, stability, drug release
and purity. Some other attributes can be added depending on the delivery system,
such as sterility, a critical quality attribute for parenteral. When the dosage form and
manufacturing process are chosen, the possible CQAs list may change (Holm
etal. 2017).
Risk Assessment: Linking Material Attributes andProcess Parameters toDrug
Product CQAs
Early in developing a pharmaceutical, risk assessment is usually carried out to rec-
ognise which material characteristics and process parameters inuence the CQAs of
a product. This tool helps rank the potential parameters depending on their impact
on product quality with past knowledge and experimental data. The list of parame-
ters can be rened based on experimental data to understand the variables and their
interaction using statistical tools (Holm etal. 2017).
Design Space
The design space explains the connection between process inputs, such as material
characteristics, process variables and the CQAs. Selecting potential variables with
their dened ranges is essential to achieving a quality product. Material properties
and process parameters are crucial parts of the design space. Proper justication
should be provided for the selection of a particular variable and its range. Process
parameters, material attributes or complex mathematical relationships can dene a
design space. The applicant should discuss potential risks in the scale-up operation
and justify the importance of creating a design space from a small or pilot scale to
the planned production-scale manufacturing process (Debevec etal. 2018).
A. Kishore et al.
49
Control Strategy
A control strategy is created to guarantee that a product will be consistently pro-
duced at the required standard. The control system should be based on dosage form,
material properties and process. While real-time release testing can replace nal
product testing, it cannot replace the batch review and quality control procedures
required by GMP.There should be control over material properties (excipients, drug
substance, packaging material), unit operations, product specications, in-process
testing and monitoring programmes (Holm etal. 2017).
Product Life Cycle Management andContinual Improvement
Companies can assess novel methods to raise product quality throughout the prod-
uct life cycle. As more experience is acquired through routine manufacturing, this
monitoring could include a trend analysis of the manufacturing process. With more
process information, the design space might need to be expanded, shrunk or rede-
ned (Ramnarine and O’Donnell 2018).
2.2.5.2.3 Submission ofPharmaceutical Development andRelated
Information inCommon Technical Documents (CTD) Format
The applicant must provide complete information with proper justication related
to product life cycle management.
Quality Risk Management andProduct andProcess Development
Quality risk management can be applied at various phases when developing prod-
ucts, processes and starting a manufacturing operation. For instance, risk analyses
and functional relationships can relate material qualities and process parameters to
product CQAs.
Design Space
Design spaces should be explained with essential critical controls and intermedi-
ates. Its relationship with the control strategy can also be mentioned.
Control Strategy
In the relevant CTD format sections, comprehensive details about input material
controls and process controls should be provided.
Drug Substance-Related Information
Some discussions on drug substance CQAs may be appropriate in pharmaceutical
development and should be part of the application if drug substance CQAs can
potentially inuence the CQAs or manufacturing process of the DP (Mishal and
Rathod 2014).
2 Design ofMaterials andProduct Specications forPharmaceutical Dosage Forms
50
2.3 Conclusion
The pharmaceutical industry’s primary duty is to give society access to high-quality
medicines. The fundamentals determining whether pharmaceutical items are of
high quality are guiding documents, regulations and compliance programmes. One
control strategy for maintaining the quality of pharmaceutical products is setting
specications for the raw ingredients to the FP. ICH guidelines are crucial docu-
ments that help preserve the quality of pharmaceutical products from start to nish,
which manufacturers must abide by to register their products. This document
includes many acceptance criteria that each product must meet to be considered.
The specic instructions offered by ICH for preserving the quality of products dur-
ing and after manufacturing are known as ICHQ6A, ICHQ6B and ICHQ8 R2. For
NDS and NDP, ICHQ6A administers universal and specic tests, while ICHQ6B
administers only specic tests for biotechnological and biological goods. The
opportunities provided by ICHQ8R2 are to understand better how well a product
performs across a broad range of material characteristics, process parameters and
processing options, which can be converted into scientic understanding that estab-
lishes a more expansive design space. The QTPP, product and process design and
knowledge, scale-up, control strategy and continuous improvement are some of the
essential components of pharmaceutical quality by design. Utilising all these qual-
ity concepts in design makes a reproducible product easy to manufacture.
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3
Optimization Techniques
fortheDevelopment ofPharmaceutical
Products
SunnyRathee, ShivaniSaraf, PritishKumarPanda,
SarjanaRaikwar, PoojaDasBidla, andSanjayK.Jain
Abstract
Quality by design (QbD) is a systematic approach for the development of a prod-
uct that begins with predened objectives and emphasizes product, process
understanding, and process control, based on sound science and quality risk
management (QRM). Quality by design (QbD) has the potential to enhance per-
formance, offer regulatory relief and adaptability, and bring about signicant
nancial gains throughout the product life cycle. Due to its numerous advan-
tages, the quality by design (QbD) method is now widely employed in the phar-
maceutical industry. Prior to the development, this method provides a greater
understanding of the process and the result, which eventually helps in the devel-
opment of a higher-quality product. Formulation-based design (FbD) is under
extensive investigation by budding scientists for better know-how of the product
and process development for an unequivocal universal acceptance. Nowadays,
the development of pharmaceutical products, biotechnological products, and
new chemical entities using QbD and FbD techniques has resulted in the ling of
S. Rathee
Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences,
Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India
College of Pharmaceutical Sciences (COPS), School of Health Sciences, Dayananda Sagar
University, Kanakapura Road, Ramanagara Dt., Bengaluru, Karnataka, India
S. Saraf
Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences,
Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India
Babulal Tarabai Institute of Pharmaceutical Sciences, Sagar, Madhya Pradesh, India
P. K. Panda · S. Raikwar · P. D. Bidla · S. K. Jain (
*)
Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences,
Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India
56
various new drug applications and abbreviated new drug applications. This chap-
ter focuses on the emergence of QbD and FbD as quality tools, applications of
QbD and FbD in different elds and various regulatory guidelines, and hurdles
in the implementation of QbD and FbD.
Keywords
Quality by design · Formulation by design · New drug application · Quality risk
management
3.1 Introduction
The traditional method used in pharmaceutical product development, which relies
on quality by testing, is no longer in use. These methods ensured the quality of
products by regulating the raw materials and manufacturing technology. The n-
ished products must pass all quality control tests, and when products fail the quality
control tests, the manufacturer must restart the process and identify the error or
reason for failure. Therefore, the traditional methods (quality by testing) are very
expensive and can lead to variances that reduce the safety of the nished pharma-
ceutical products (Cunha etal. 2020; Zhang and Mao 2017).
To solve these problems, the quality by design (QbD) strategy was investigated
to improve manufacturing processes and ensure the safety and efcacy of nished
products. The QbD strategy was developed to establish rigorous specications and
guidelines for the approval of pharmaceutical products. Dr. Joseph M. Juran
described the approach QbD rst time and utilized it to ensure the quality of the
product from planning or design not from evaluation and control. The QbD was
approved by regulatory agencies such as FDA (Food and Drug Administration) and
EMA (European Medicines Agency) after the publication of various guidelines by
ICH, i.e., Q8, Q9, Q10, and Q11. The ICH Q8 guideline described the QbD approach
and dened the main objectives of the process, facilitating knowledge and control
and controlling risk to nal product quality (Bastogne 2017). The concept used in
QbD is that quality can be “designed in” to processes through the systemic optimi-
zation technique. In optimization, we determined the response of a given variable to
the quality of the product was determined, by the implementation of systematic
optimization (Jagtap etal. 2022). QbD is a scientic approach that helps in design-
ing pharmaceutical formulations having the intended product qualities (Jain 2014).
QbD approach aims to identify the critical parameter that affects the quality of a
product. The parameters involved in product variability were identied and elimi-
nated or controlled in a predetermined design space to ensure product quality (Adam
etal. 2011). In nanotechnology, statistical tests like Bonferroni, t-tests, and others
can be used to compare various treatments and determine differences among them,
but QbD approaches enable the optimization of evaluation results (dependent vari-
ables) and the analysis of study factors (independent variables). Additionally, the
QbD approach also determined the level of an impact on responses in a linear,
S. Rathee et al.