Quality by Design Approach Regulatory Need PDF

Arabian Journal of Chemistry (2014) xxx, xxx–xxx
King Saud University
Arabian Journal of Chemistry

www.ksu.edu.sa
www.sciencedirect.com
REVIEW
Quality by design approach: Regulatory need

Jaiprakash N. Sangshetti a,*, Mrinmayee Deshpande a, Rohidas Arote b,
Zahid Zaheer a, Devanand B. Shinde c
a
Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad 431001, India
b
Department of Molecular Genetics, School of Dentistry, Seoul National University, Seoul, Republic of Korea
c
Department of Chemical Technology, Dr. B. A. M. University, Aurangabad 431004, India
Received 17 July 2013; accepted 30 January 2014
KEYWORDS Abstract In this era of competition quality has been given prime magnitude; failure to meet such
Quality by design (QbD); quality allied goals produces massive shift of company in share of market. In this context pharma-
USFDA; ceutical industry is utmost regulated industry as it is governed by authoritative regulatory bodies.
Analytical techniques; ‘‘Quality could be planned and most of quality deficit arises in the way process is planned and devel-
Design of experiment; oped’’, this thought of well known quality expert Joseph Moses Juran gives foundation to the con-
Risk assessment cept of quality by design (QbD). USFDA launched a pilot programme in 2005 to permit
participating firms a prospect to submit chemistry, manufacturing, and controls (CMC) of NDA
information representing application of QbD. Now USFDA is accelerating QbD drive by making
warning to generic manufacturers from January 2013. QbD has its perspectives to contribute the
drug design, development, and manufacture of high-quality drug products. In the present review
basic consideration of the QbD approach, its historical background, and regulatory needs are dis-
cussed. In detail explanation of elements of QbD i.e. method intent, design of experiment, and risk
assessment is given. Application of QbD to pharmaceutical and biopharmaceutical processes,
development and unit operation associated with it are briefly mentioned. Detail account of QbD
to analytical technique is explained thoroughly by referencing examples.
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Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
* Corresponding author. Tel./fax: +91 2402381129.

E-mail address: jnsangshetti@rediffmail.com (J.N. Sangshetti).
Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
1878-5352 ª 2014 Production and hosting by Elsevier B.V. on behalf of King Saud University.
http://dx.doi.org/10.1016/j.arabjc.2014.01.025
Please cite this article in press as: Sangshetti, J.N. et al., Quality by design approach: Regulatory need. Arabian Journal of Chemistry (2014),
2 J.N. Sangshetti et al.
3. Regulatory aspects to QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.1. FDA perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. ICH guideline and QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Regulatory challenges and inspection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Basic considerations of QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Elements of pharmaceutical development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.1. Define an objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.2. Determination of critical quality attributes.(CQA). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.3. Risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.4. Development of experimental design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.5. Designing and implementing control strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.6. Continuous improvement throughout product life cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Application of QbD in analytical methods of measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Aspects of application of QbD to analytical method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.1. Analytical target profile (ATP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.2. Method design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.3. Critical quality attributes (CQA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.4. Risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.5. Method qualification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.6. Control strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.7. Life cycle approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Literature reports of application QbD or elements of QbD to analytical method. . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. For chromatographic technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.1. In determination of impurity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.2. In screening of column used for chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.3. In development of HPLC method for drug products/substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.4. In capillary electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.5. In stability studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.6. In UHPLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. For hyphenated technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2.1. In LC–MS method development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. In bioanalytical method development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.4. In dissolution studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.5. For spectroscopic measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.5.1. In handling complex spectroscopic data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.5.2. In mass spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.5.3. In near infrared . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Other applications of QbD or elements of QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1. Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.1. In modified release products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.2. In sterile manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.3. In solid oral dosage form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.4. Contribution of (SEM/EDX) to QbD by investigation of pharmaceutical materials . . . . . . . . . . . . . . . . . . . 00
7.1.5. In gel manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.6. QbD for ANDAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.7. In tableting process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.8. Impact of genotoxic impurities on process development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.9. In co-precipitation process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.10. Nanosuspension preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.11. In analysis of excipients and API . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2. Biopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2.1. In manufacturing of protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2.2. In production and characterization of monoclonal antibody- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2.3. For chromatographic technique used for purification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2.4. PAT and QbD for biopharmaceutical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2.5. In nanomedicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2.6. Challenges and solution for application of QbD to biopharmaceutical . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.3. Clinical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.4. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Quality by design approach: Regulatory need 3
8. Problems in adoption of QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction products and ultimately flourish industry by means of fame

as well as financial assets.
Quality has been given an importance by all regulatory bodies
for pharmaceutical products. Quality means customer satis- 2. Historical background
faction in terms of service, product, and process. Many of
these quality related activities reflect need for companies to In 2007 FDA received an 5000 supplements, it was actually a
excel in global competition. Customer demands the perfection striking raise in the number of manufacturing supplements to
in quality, reliability, low cost and timely performance. Cus- applications of New Drug Applications (NDAs), Biological
tomer satisfaction can be achieved by two ways i.e. features License Applications (BLAs) and Abbreviated New Drug
and free from deficiencies in goods. The features like perfor- Applications (ANDA’s). FDA recognized that there is an in-
mance, trustworthiness, robustness, ease of use, and service- crease in lapse of NDA or ANDA submissions by the firms,
ability have to built in the product and such product should large number of a supplemental application for every manufac-
be free from deficiencies. Quality, productivity, cost, cycle turing change were received. In both original applications and
time and value are interrelated terms. Quality activities must supplements the data mainly focused was on chemistry. And
try to detect quality problems early enough to permit actions the least attention was given on other important aspects of
without requiring compromise in cost, schedule or quality. the manufacturing, such as engineering, product development.
The emphasis must be on precaution rather than on just cor- Eventually, the FDA acknowledged that more and more con-
rection of quality problems. Quality can be the driving force trols were required for drug manufacturing processes for effi-
to empower results in other parameters. Hence the quality cient drug product and no doubt for better regulatory
has to be built in the product as well as services through decision making. It resulted in more stringent regulatory
proper planning, so that the forth coming failure can be upbringing. To solve this issue in 2002, the FDA implemented
avoided. Mere analysis of final product will not work but changes through the Pharmaceutical cGMP (good manufac-
the quality should be designed in the product. The concept turing practice) for the 21st Century. Expectations were men-
of quality by design was summarized by a well known quality tioned in Process Analytical Technology (PAT) which is a
expert Joseph Moses Juran; he believed that quality could be system for designing, analysing, and controlling manufactur-
planned and that most quality associated problems have their ing processes based on understanding science and factors
origin in the way which quality was planned in the first place. which affect the quality of final product. In 2005 here came
The principles of QbD have been used to advance the product the time to implement QbD for more systematic approach
and process quality in every industry. Because of need of po- and USFDA asked some firms to submit their CMC in QbD
tent drug with safety profile, pharmaceutical industries are format (Patricia, 2007). Question base review (QbR) forms
investing billions of money in the drug discovery and develop- the platform of QbD principle (Aloka and Robert, 2009). Re-
ment process with endeavour to design quality product and cent interview by Nick (2011) with Lawrence Yu Deputy
that to with consistency in manufacturing process to deliver Director, Science and Chemistry, FDA indicates warning that
the intended performance of product. The information and 2013 is deadline for generics to implement QbD.
knowledge gained from pharmaceutical studies and manufac-
turing provide a base for scientific understanding to support 3. Regulatory aspects to QbD
establishment of design space, specification and manufactur-
ing control. Information from pharmaceutical development 3.1. FDA perspective
studies can be a root for quality risk management. Lifecycle
management allows making changes in formulation and man- In 2005 USFDA asked participating firms to submit chemistry
ufacturing processes during development and providing addi- manufacturing control (CMC) information demonstrating
tional opportunities to gain added knowledge and it further application of QbD as part of New Drug Application. QbD in-
supports establishment of the design space. Design space is volves thorough understanding of process; a goal or objective
planned by the applicant and will undergo regulatory assess- is defined before actual start of process. Design space and real
ment and approval. Working within the design space is not time release risk assessment are other parameters for imple-
considered as a change. But an operation out of the design mentation of QbD. International conference on harmonization
space is considered to be a change and has to face a regula- in its Q8 pharmaceutical development, Q9 quality risk assess-
tory post approval change process. During the drug development and Q10 pharmaceutical quality system gives stringent
ment process, the aspects like drug substances, excipients, requirements regarding quality of product. FDA also states
container closure systems, manufacturing processes and qual- the importance of quality of pharmaceutical products by giv-
ity control tests are critical to product quality. Critical formu- ing Process Analytical Technology (PAT) which is a Frame-
lation attributes and process parameters are generally work for Innovative Pharmaceutical Development,
identified and controlled to the extent of assurance of quality Manufacturing and Quality Assurance (Patricia, 2007).
which is also an important task. This scientific and knowledge QbD ultimately helps to implement Q8 and Q9. FDA’s
rich understanding will help industry to manufacture quality view of QbD is ‘‘QbD is a systematic approach to product
and process design and development’’. This concept was ac- importance; and to achieve this target QbD assist it by thor-
cepted by FDA in 2004 and detailed description was given in ough understanding of process which is the ultimate goal of
‘pharmaceutical cGMPs for 21st century – a risk based QbD.
approach’. Advantages of QbD can be summarized as,
In nutshell,
Patient safety and product efficacy are focused.
Product quality and performance can be assured by Scientific understanding of pharmaceutical process and
designing efficient manufacturing processes. methods is done.
Product and process specifications are based on a scien- It involves product design and process development.
tific understanding of how process factors affect prod- Science based risk assessment is carried.
uct performance. Critical quality attributes are identified and their effect
Risk-based regulatory approaches are for scientific on final quality of product is analysed.
understanding and control related process for product It offers robust method or process.
quality and performance. Business benefits are also driving force to adopt QbD.
Related regulatory policies and measures are modified
Method design concept helps to avoid cost involved with
to accommodate the real time scientific knowledge.
post approval changes (Vince et al. (2011a)).
Quality assurance is continuous process.
4.1. Elements of pharmaceutical development

3.2. ICH guideline and QbD (ICH guideline Q8, 2012; ICH
guideline Q10, 2012; ICH guideline Q9, 2012) QbD comprises all elements of pharmaceutical development
mentioned in the ICH guideline Q8. Pharmaceutical Develop-
The underlying principles of QbD i.e. science- and risk-based ment section is projected to provide a complete understanding
product development, risk assessment, lifecycle approach and of the product and manufacturing process for reviewers and
method design are explained in the quality guidelines of inter- inspectors. To design a quality product and its manufacturing
national conference on harmonization i.e. ICH Q8 Pharmaceu- process to consistently deliver the intended performance of
tical Development, ICHQ9 Quality Risk Management, and ICH product is the aim of pharmaceutical development. The infor-
Q10 Pharmaceutical Quality System. mation and knowledge gained from pharmaceutical develop-
ment studies and manufacturing experience provide scientific
3.3. Regulatory challenges and inspection understanding to support the establishment of the specifica-
tions, and manufacturing controls (Patricia, 2007).
According to Anastasia G. Lolas and Anurag S. Rathore ‘‘In a – Different elements of pharmaceutical development
QbD concept, the regulatory burden is less because there are include,
wider ranges and limits based on product and process under- – Defining an objective
standing. Changes within these ranges and limits do not re- – Determination of critical quality attributes (CQA)
quire prior approval’’. – Risk assessment
Traditionally, inspections have been conducted using the – Development of experimental design
FDA system-based approach and in accordance with CDER’s – Designing and implementing control strategy
Compliance Program ‘‘Inspection of Licensed Bio-logical – Continuous improvement.
Therapeutic Drug Products’’. But now query arises that how
the inspection will take place in the present scenario where
QbD is mandated. During prelicense or preapproval inspec- 4.1.1. Define an objective
tions under a QbD concept, the FDA inspection team will as- Quality target profile (QTP) forms the basis of QbD, which is
sess the implementation and effectiveness of the process design in relation to the predefined objective criteria mentioned in the
as described in the application and whether knowledge and definition of QbD.
risk management have been transferred successfully from As per ICH guideline Q8 R2 the Quality Target Product
development to manufacturing. The inspection will evaluate Profile forms the basis for design and the development of the
the quality system and its effectiveness regarding consistent product. Considerations for the Quality Target Product Profile
product quality, change in control procedures, process could include:
improvements, deviation management, and knowledge and Intended use in clinical setting, route of administration,
risk management during the product lifecycle. Inspection of dosage form, delivery Systems.
facility and equipment qualification and maintenance as well Dosage strength(s), Container closure system.
as raw material screening and supplier management will be Therapeutic moiety release or delivery and attributes
same as it was performed previously. But design, testing, and affecting, Pharmacokinetic characteristics (e.g., disso-
monitoring programmes that demonstrate robustness and con- lution, aerodynamic performance).
sistency would be highlighted (Anastasia and Anurag, 2012). Drug product quality criteria like sterility, purity, sta-
bility and drug release as appropriate for dosage form
4. Basic considerations of QbD the intended for marketing.
As far as pharmaceutical industry is considered safety of pa- QbD requires a Target Product Profile; it may be called as
tient and providing a quality product have been given prime Quality Target Product Profile (QTPP) which defines the
expectations in final product. In case of analytical method uncertainty in validation of bioanalytical method though the
development it is called as analytical target profile (ATP), it guidelines for validation are given by various regulatory bodies
is also called as Target Product Profile (TPP). The TPP can there may be a variation in interpretation of those guidelines
play a central role in the entire drug discovery and develop- and hence in experimental method designing which leads to
ment processes like optimization, planning and decision mak- unfit method development for intended purpose (Rozet
ing, and designing of clinical research strategies (Lawrence, et al., 2010). Risk management for excipients to determine
2008). The Target Product Profile (TPP) can be used to design shelf life can be done by statistical parameters (Harry and
the clinical trials, safety and ADME studies, as well as to de- Lanju, 2012).
sign the drug product. The TPP will help to identify critical Principles of quality risk management are:
quality attributes such as potency, purity, bioavailability or Scientific knowledge based evaluation of the risk to
Pharmacokinetic profile, shelf-life, and sensory properties quality which eventually links to the protection of the
(Vince et al. (2011a)). patient.
Adequate effort should be taken; formality and docu-
4.1.2. Determination of critical quality attributes.(CQA) mentation of the quality risk management process
According to ICH Q8 R2 ‘‘A CQA is a physical, chemical, bio- should be done with the level of risk involved.
logical, or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution Risk management is joint responsibility of quality unit,
to ensure the desired product quality’’. CQAs are generally business development, engineering, regulatory affairs, produc-
linked with the drug substance, excipients, intermediates (in- tion operations, sales and marketing, legal, statistics and clin-
process materials) and drug product. For example CQAs of so- ical department.
lid oral dosage forms are typically those aspects affecting prod- Methods of risk assessment: Some methods of risk assess-
uct purity, strength, drug release and stability whereas for ment are mentioned in ICH guideline Q9 as follows:
parentrals they are Sterility and clarity. The CQAs can addi- Failure Mode Effects Analysis (FMEA);
tionally include properties like particle size distribution, bulk Failure Mode, Effects and Criticality Analysis
density that affect drug product. Mostly CQAs are derived (FMECA);
from the Quality Target Product Profile and/or prior knowl- Fault Tree Analysis (FTA);
edge is used to guide the product and process development Hazard Analysis and Critical Control Points (HACCP);
and Subsequently CQAs are accessed for risk management. Hazard Operability Analysis (HAZOP);
It is stated in ICH Q9 that in case of Potential drug sub- Preliminary Hazard Analysis (PHA);
stance CQAs are used to guide process development. Inclusion Risk ranking and filtering;
and exclusion in list of potential CQAs can be done as knowl- Supporting statistical tools.
edge drug substance and process understanding increases. In
case of biotechnological/biological products, most of the ICH guideline Q9 gives description of risk management and
CQAs of the drug product are associated with the drug sub- various terminologies associated with it, like Risk Acceptance,
stance and thus are a direct result of the design of the drug sub- Risk Analysis, Risk Assessment, Risk Communication, Risk
stance or its manufacturing process. Impurities are an Control, Risk Evaluation, Risk Identification, and Risk Man-
important class of potential drug substance CQAs. A quality agement. Quality management policies should mention proce-
attribute that must be controlled within predefined limits to en- dures and practices to the tasks of assessing, controlling,
sure that the product meets its intended safety, efficacy, stabil- communicating and reviewing risk. Risk Reduction is actions
ity and performance. It means all the factors which affect final taken to lessen the probability of occurrence of harm and
quality and safety should be controlled. the severity of that harm.
Dissolution test is crucial for a controlled release drug
product and on other hand dissolution test for an immediate 4.1.4. Development of experimental design
release drug product which belongs to the high aqueous solu- Experimental design is the multidimensional combination and
bility and high permeability i.e. BCS class I drug will not prove interaction of input variables (e.g., material attributes) and
as critical attribute for quality control viewpoint (Vince et al. process parameters that have been demonstrated to provide
(2011a)). CQA differs for type process, dosage form, and type assurance of quality. Design space is proposed by the applicant
of method development hence thorough knowledge of real and is subject to regulatory assessment and approval of ICH
time data to working scientists is important. Q8 (R2). Pharmaceutical development scientists have began
making use of computer-aided process design (CAPD) and
4.1.3. Risk assessment process simulation to support process development and opti-
It is commonly understood that risk is defined as the combina- mization of manufacturing. (Lawrence, 2008) Risk assessment
tion of the probability of occurrence of harm and the severity can guide to understand linkage and effect of process parame-
of that harm. Risk assessment helps to increase quality of ters and material attributes on product, and ranges for vari-
method or process. Also it is determinant for effect of input ables within which consistent quality can be achieved. These
variable on method or processes. From risk assessment one parameters or attributes are selected for addition in the design
can recognize critical attributes that are going to affect final space. Information regarding reason for inclusion of some
quality of product. A risk assessment is helpful for effective variables in design space as well as exclusion of other variable
communication between FDA and industry, research/develop- has to be mentioned. Operation within the design space will re-
ment and manufacturing and among multiple manufacturing sult in a product meeting the defined quality. Independent de-
sites within company (Patricia, 2007). There may be risk and sign spaces for one or more unit operations can be applied; a
single design space can be applied for multiple operations. For approach being proactive in the initial steps the potential attri-
example impact of excipient variability on particle size distri- butes which could possibly give out of range result and affect
bution, blend segregation propensity can be included in exper- the quality are identified. Deliberate variations in those attri-
imental design (Joseph et al., 2011). Gel was prepared using butes are studied in design space (Lawrence et al., 2009). Con-
QbD approach, the design space used was developed by a D- trol strategy involves but not limited to – control on excipients,
optimal design from a total of 15 gel batches, with five factors drug substance, packaging materials (inputs), specifications,
ethanol, water, carbomer, acid neutralized fraction, and reac- operational control like drying downstream processing disso-
tor temperature (Juan et al., 2011a,b). Different mathematical lution etc.., real time testing or in process testing, finished
models are available for design of experiment like Placket– product testing at regular intervals.
Burman, Box Behnken, Taguchi, Surface Design, Full and
fractional factorial designs. Full factorial design was used to 4.1.6. Continuous improvement throughout product life cycle
study the effect of formulation factors on pharmaceutical Product quality can be improved throughout the product life-
properties of tablet; in that independent variables were binder cycle; companies have opportunities to opt inventive ap-
and disintegrant concentration, resistance to crushing while proaches to improve quality. Process performance can be
dependant variable was drug release. Such a multidisciplinary monitored to make sure consistency in quality. Additional
approach is beneficial as manufacturing process improvement experience and knowledge is gained during routine manufac-
can be done in previously approved space; it decreases number ture which contributes to method/process development. Peri-
of variation after marketing. It is a risk based approach which odic maintenance can be done within a company’s own
is based on timely quality control rather than final testing of internal quality system; but design space should be unchanged.
finished product (Ivan et al., 2012). The QbD approach avails the continuous improvement
throughout products’ life cycle this is distinguishing point from
4.1.5. Designing and implementing control strategy the conventional method which is much frozen process.
Control strategy is required to ensure that material and pro-
cess are within the expected lower and upper limits. Parameter 5. Application of QbD in analytical methods of measurement
and material are routinely controlled during production in or-
der to assure reproducibility. The control space should be ‘‘QbD does not necessarily mean less analytical testing’’ rather,
within the design space. Generally scale up is trial and error it means the right analysis at the right time, and is based on
basis. During scale up processes parameters may differ but science and risk assessment. Implementation of QbD helps to
attributes which affect quality remain the same hence control develop rugged and robust method which helps to comply with
strategy is required (Lawrence et al., 2009). QbD gives trace ICH guideline hence for that reason pharmaceutical industries
on reproducibility and robustness. Process capability index ex- are adopting this concept of QbD. Factors which improve
presses reproducibility of process. robustness are taken into consideration for the development
of analytical method in QbD environment. This approach
Process capability indexðCp KÞ
facilitates continuous improvement in method. Parallel oppor-
upper limit of specification lower limit of specification tunities of application of QbD to analytical method as that of
¼
6standard deviation manufacturing process are available in the literature (Mark
ð1Þ et al., 2010). It suggests that approaches like target profile,
CQA, design space, and risk assessment are applicable to ana-
Control space should be within the design space, it is an upper
lytical method also. Though it is not adopted by all pharma-
and lower limit for raw material or a process within which
ceutical industries it has future perspective because it may
parameter and material are regularly controlled which assures
become mandatory by regulatory bodies. Voluntary adoption
quality of product. Design space cover control space (see
of this concept by industries is possible because of its various
Fig. 1). If control space is smaller than design space it is con-
benefits, and ease of compliance with regulatory authorities.
sidered as robust. Usually in process quality control tests are
Pharmaceutical research and manufactures of America
performed to examine quality and trace out defects but QbD
(PhRMA), Analytical Technical group (ATG) and European
Federation of Pharmaceutical Industries and Association (EF-
PIA) have given clear ideas about parallel implementation of
QbD to analytical method (Mark et al., 2010. QbD can be ap-
Design space plied for various analytical methods which include,
Chromatographic techniques like HPLC (For stability
studies, method development, and determination of
impurities in pharmaceuticals).
Hyphenated technique like LC–MS.
Advanced techniques like mass spectroscopy, UHPLC,
control and capillary electrophoresis.
space Karl Fischer titration for determination of moisture
content.
Vibrational spectroscopy for identification and quanti-
fication of compounds e.g. UV method.
Analysis of genotoxic impurity.
Figure 1 Control space within the design space. Dissolution studies.
To biopharmaceutical processes (Frederick and Ali- buffers) (Devesh and Smita, 2011). Data are collected and
reza, 2011). software is generated by entering obtained results in terms
of values from actual experiments. Then that data base is
Potential benefits of adopting QbD for analytical method generated which helps to predict the effect of various chro-
The developed method will be more robust which gives matographic conditions in large number. This type of soft-
greater level of confidence in case of variations in ware helps to predict outcome without actual
conditions. experimentation. Response from design also includes resolu-
This approach gives greater transfer success when tion and run time (Frederick and Alireza, 2011). Hence it
method is transferred from research level to quality is cost effective as well as time effective. Software also assists
control department. the future changes in method. Method design also involve
It provides a space for invention of new techniques by selection of different analytical techniques that can be used
continuous improvement throughout life cycle. for particular method development; for example different
It helps for enhanced understanding of the method. instrumental method that can be opt like HPLC, LC, Raman
Design space concept avoids the post-approval changes and the most effective method amongst is chosen. Among
which may cause to pay a high cost for any of the firm. various methods; suitable method to serve the desired pur-
It provides greater compliance with regulatory author- pose is chosen. For example, to determine impurities, HPLC
ities (Mark et al., 2010; Phil et al., 2007). with detector like PDA can be used. In method design, meth-
od that meets method requirement is established. Method de-
5.1. Aspects of application of QbD to analytical method sign may be repeated or modified as and when required
throughout the life cycle. Thorough understanding of design
Various aspects explained in pharmaceutical development are intent will form a better Method design. Method design
also put into practice for development of analytical method should be done according to standardized approach. This ap-
in QbD paradigm. Some key aspects are discussed hereunder. proach helps in method transfer step from research to quality
control department. Method development strategy (MDS) in-
cludes design of experiments (DoE) (Frederick and Alireza,
5.1.1. Analytical target profile (ATP) 2011). It is helpful in risk assessment by gaining knowledge
‘‘QbD is a systematic approach to product and process design about existing method and allows for effective control strat-
and development,’’ (Patricia, 2007). Hence it begins with deter- egies for critical parameter. K.E. Monks and et al. present a
mination of goal or method intent. In this emphasis is given on novel approach to applying Quality by Design (QbD) princi-
the product and process understanding (Mark et al., 2010). ATP ples to the development of high pressure reversed phase li-
is way for method development or it is simply a tool for method quid chromatography (HPLC) methods. They developed a
development. It describes the method requirements which are good, robust method for the separation of nine model com-
expected to be measured. In general the goal of the chromato- pounds of pharmaceutical interest in a multidimensional
graphic method is separation, quantification and identification space comprised of four critical parameters: gradient time,
of drug substance, impurity or degradents. Impurity is consid- temperature, pH of eluent and stationary phase. The criteria
ered to be the critical quality attribute (CQA) (Peter and Ber- of separation success are maximum resolution, maximum ro-
nard, 2008). While dealing with traces of impurities it will be bust tolerance windows and minimum run time. In this paper
beneficial to have knowledge of previous synthetic and manu- three dimensional experimental designs for optimization of
facturing processes and all other possible pathways which lead method are given (Monks et al., 2011). Method design is
to the encounter of impurities (Yan et al., 2012). The method made considering the ICH guidelines for validation hence
requirements will be the accuracy precision, robustness, rugged- validation remains formality.
ness and so on as described in ICH guideline (Phil et al., 2007). Various experimental design methods are mentioned in the
Whether it is a conventional method or QbD method detailed literature. An experimental design is an experimental set-up to
information of compound should be collected like its solubility, simultaneously evaluate several factors at given numbers of
pka, pH, UV chromophore, and stability. Yan et al. (2012) strin- levels in a predefined number of experiments. Experimental de-
gent method goals can be set to obtain a best method. It pro- signs are as follows,
vides framework to method development which helps for full factorial,
further planning. It decides what to be measured and within fractional factorial,
what limit it is required to be measured. ATP is in complete Plackett–Burman designs (Bieke and Yvan, 2011).
accordance with ICH guideline.
5.1.2. Method design 5.1.3. Critical quality attributes (CQA)

Method design is prepared for appropriate availability of Factors which directly affect the quality & safety of the prod-
material and setting various experimental conditions. In this uct are first sorted out, and its possible effect on method devel-
the reagents required are made available. Regional and geo- opment is studied. Understanding of the product and method
graphical conditions are taken into consideration. Feasibility will help to sort the CQA. If drug product contains the impu-
of instruments is checked and experimental design is pre- rity which may have direct effect on quality and safety of drug
pared. In this use of various flowcharts decision tree can be product it is being considered the critical quality attribute for
made for correct implementation. In case of HPLC method the HPLC method development of that particular drug com-
development scouting is done. In this large number of exper- pound. Safety and efficacy can be achieved by demonstrating
imental conditions were tried (pH, temperature, columns, and measurable control of quality attributes i.e. product
specification, intermediate specification, and process control ment, the next step comes is method qualification this is to en-
(Mark et al., 2010). sure that method is being performed as intended. It involves
equipment qualification which is part of method qualification.
5.1.4. Risk assessment It is divided in, method installation qualification (MIQ), meth-
It is link between input process variable and CQA. Various od operational qualification (MPQ), and method performance
tools for risk assessment are, qualification (MPQ).
For demonstration of instrumental qualification HPLC
1. Ishikawa or fishbone diagram, instrument is considered. While developing a chromatographic
2. Failure mode effect analysis (FMEA), method on HPLC following qualification can be done (Lukas
3. Pareto analysis. et al., 2010; Phil et al., 2007). Design Qualification
An Ishikawa or fishbone diagram is used to identify all po- 1. Installation Qualification

tential variables, such as raw materials, instrumental factors, 2. Operational Qualification
and environmental factors, which can have an impact on a par- 3. Performance Qualification
ticular CQA. A FMEA can then be used to rank the variables
based on risk (i.e. a combination of probability, severity, and Considering user requirement specifications (URS), design
delectability) and to select the process parameters with higher and technical specification of an instrument are defined, it is
risks for further studies to gain greater understanding of their ef- part of DQ. As HPLC is commercial-off-the-shelf system in
fects on CQAs (Patricia, 2007. Main aim of chromatographic this case the users should make sure that the instrument is suit-
method development is separation and identification of com- able for their desired applications. User must confirm that the
pound. In QbD approach the emphasis is given on rugged and installation site fulfill all vendor-specified environmental
robust method through risk assessment. Risk based approach requirements. Here IQ part begins. Equipment is assembled
is based on the ICH guideline Q8 and Q9. Small changes in at the user’s site and checked for proper working of all the
method parameter like reagents, instruments, analyst, laborato- assembled parts.
ries, days, temperature, and humidity are included in risk assess- The combined parameters for operational qualification and
ment. Available tools for analysis of data are Design of performance qualification are given below in Table 1:
Experiments (DoE) and Method System Analysis (MSA). If
the primary method fails, then a backup method is risk-assessed 5.1.6. Control strategy
until a suitable method is identified. If both methods are chal- It is important that set method performs as intended and con-
lenging each other in advantages then methods are weighed sistently gives accurate results, for that purpose control on
against robustness and ruggedness for choosing best method. method is required. A factor identified to have risk has to be
The other factors known as risks during the risk assessment controlled. More attention is given to the high risk factors.
can be tested by ruggedness studies, or, to by tested robustness System suitability can be checked and verified time to time
studies. Method which is insensitive to small variations in by having control over it (Phil et al., 2007). On ground of prac-
parameters like instrument settings is robust, whereas a rugged tical example; the risk assessment can also help identify a spe-
method is one that can bear any noise likely to be encountered cific control strategy. For example, during robustness studies
during use. The risk assessment approach differs from the older for an Atomoxetine hydrochloride HPLC impurity profile
non-QbD approach. Each and every step starting from sample method, it was found that resolution of the impurities of inter-
preparation including dilution, extraction is analysed for possi- est followed the same trend when method parameters such as
ble risk involved in it. A fishbone diagram is divided into catego- n-propanol and temperature were varied. As a result, an early
ries like instrumentation, materials, methods, measurements, eluting impurity pair was chosen for system suitability and be-
laboratory climate, and human factors. Once the risk is assessed came a convenient method control strategy because the two
it is grouped into three categories.
1. High-risk factors that should be stringently controlled,

typical high-risk factors that can be fixed at the time of Table 1 Combined parameters for operational qualification
method development that includes data analysis meth- and performance qualification.
ods and sample preparation methods. Module Parameter
2. Potential noise factors,
Injector Precision of injection volume
3. Factors that can be explored experimentally to deter-
Linearity of injection volume
mine acceptable ranges. Injection carryover
For impurity profiling by HPLC method staggered cross Autosampler Thermostatting precision
nested design was used and for Karl Fisher Titration (KFT) Solvent delivery system Flow rate accuracy
Mobile phase proportioning
Method System Analysis (MSA) was found to be useful. De-
Flow rate precision
sign of experiment was done for the robustness studies (Fred-
erick and Alireza, 2011). Detector Wavelength accuracy
Noise
Drift
5.1.5. Method qualification Linearity of detector response
Once the method is designed keeping analytical target profile
Column oven Thermostatting precision of column oven
(ATP) in mind with taking care of the risk involved in develop-
Figure 2 Analytical method development in QbD.
compounds involved were easily obtained (Peter and Bernard, 6. Literature reports of application QbD or elements of QbD to
2008; Frederick and Alireza, 2011). Validation remains the for- analytical method
mality it is done in similar way to that of traditional method
development in validation (ICHQ2) but in traditional ap- 6.1. For chromatographic technique
proach method validated after development i.e. it is like check-
box tool, and in QbD the validation parameter in ICHQ2 are 6.1.1. In determination of impurity
consider as method intent.
Gavin gives a quality by design approach to impurity method
development for atomoxetine hydrochloride. An ion-pairing
5.1.7. Life cycle approach
HPLC method was developed and associated system suitability
Life cycle approach differs from that of the traditional ap- parameters for the analysis of atomoxetine hydrochloride are
proach of method development. According to Morefield it in- studied. Statistically designed experiments were used to opti-
cludes continuous improvement of method performance and mize conditions and demonstrate method robustness for the
the design space allow flexibility for Continuous improvement separation of atomoxetine and impurities. Weiyong Li de-
in analytical method can be done without prior regulatory scribes a three-step method development/optimization strategy
approval because of design space made previously (Mark for HPLC assay/impurity methods for pharmaceuticals i.e.
et al., 2010). Knowledge gained from risk assessment and data multiple-column/mobile phase screening, further optimization
collected from design of experiments can be used as the repos- of separation by using multiple organic modifiers in the mobile
itory of knowledge to make justified changes wherever re- phase, and multiple-factor method optimization using Plack-
quired. A complete process analytical method development ett–Burman experimental designs. Commercially available
in QbD environment is summarized in the following flow chart chromatography optimization software, DryLab was used to
(see Fig. 2). perform computer simulations. This approach significantly
reduces the number of runs in method development. When sat- degradant. The method optimization was done using Fusion
isfactory separation was obtained, a method optimization is AE software that follows a DOE approach. The QbD based
done with Plackett–Burman experimental designs (Weiyong method development enabled in developing a design space and
and Henrik, 2003). operating space with particulars of all method performance
Peter et al. (2010a,b) given A QbD with Design-of-Experi- characteristics and limitations and method robustness within
ments Approach to the Development of a Chromatographic the operating space.
method for the Separation of Impurities in Vancomycin using
specialized software with UPLC Technology. Traditional 6.1.6. In UHPLC
HPLC gradient methods have capability to separate out 13
Szabolcs et al. (2009) developed Rapid high performance li-
of these impurities, while the use of QbD approach with sub-
quid chromatography with high prediction accuracy, with de-
2-pm ACQUITY UPLC Column separation of as many as
sign space computer modelling, which demonstrates the
26 impurities could be possible.
accuracy of retention time prediction at high pressure (en-
hanced flow-rate) and shows that the computer-assisted simu-
6.1.2. In screening of column used for chromatography
lation can be useful with enough precision for UHPLC
Connie et al. (2009) describes the particulars of the experimen- applications.
tal design, evaluation criteria used and some of the most com-
monly used analytical columns from reputed column 6.2. For hyphenated technique
manufacturers. A systematic approach is used to evaluate se-
ven RP-HPLC columns against predefined performance crite- 6.2.1. In LC–MS method development
ria. This approach is a fundamental part of a QbD method
development. The data generated for commonly used columns Joseph Turpin gives the QbD approach to liquid chromato-
provide help to practicing analyst to meet challenge of devel- graphic method development. The article is divided in three
oping robust and rugged methods for use in a QbD environ- parts which includes current approaches to column screening
ment. Recently better selection of column has been explored in terms of experimental region, knowledge space, design space
in UPLC using quality by design (Kormány et al., 2013). coverage, data treatments to quantitation of the column
screening experiment, and quantitative method robustness esti-
6.1.3. In development of HPLC method for drug products/ mation. Parameters are classified in two types depending upon
substances their influence on separation; (1) Primary effectors of separa-
tion are column type (column screening), pH, organic solvent
Monks et al. (2011) presents a novel approach to applying type, and Gradient Time (Controls Slope) (2) Secondary effec-
quality by design (QbD) principles to the development of high tors of separation are pump flow, gradient conditions, temper-
pressure reversed phase liquid chromatography (HPLC) ature, and ion pairing agent (Joseph, 2012; Peter et al.,
methods. Four common critical parameters in HPLC – gradient 2010a,b).
time, temperature, pH of the aqueous eluent, and stationary
phase are evaluated within the quality by design framework
by the means of computer modelling software and a column 6.3. In bioanalytical method development
database. David et al. (2012) worked on Application of quality
by design elements for the development and optimization of an Torrealday et al. (2003) developed a HPLC-fluorimetric bioan-
analytical method for protamine sulphate. A robust method alytical method for quantitation telmisartan in urine using
was developed. A Box–Behnken experimental design with re- Experimental design approach for the optimization chromato-
sponse surface methodology was then utilized to evaluate the graphic variables that had influence on the fluorescent re-
main, interaction, and quadratic effects of these three factors sponse. Two designs were applied to fractional factorial
on the selected responses. Method requirements applied to the design, to evaluate which of the studied variables had an influ-
optimized conditions predicted peak resolutions between 1.99 ence on the response, and the central composite design to ob-
and 3.61 and tailing factor between 1.02 and 1.45 for the four tain the response surface from which the optimal conditions
peptide peaks of protamine sulphate (David et al., 2012). for the target response could be deduced.
6.1.4. In capillary electrophoresis 6.4. In dissolution studies

Yi-Hui et al. (2007) worked on Experimental design and cap-
illary electrophoresis for simultaneous analysis of arbutin, Miroslav et al. (2010) developed HPLC method for digoxin
kojic acid and hydroquinone in cosmetics. Statistical parame- quantification in dissolution samples in this the experimental
ters were used to optimize method. design is used to demonstrate the robustness. Effect of minor
changes in acetonitrile fraction, flow rate of the mobile phase,
6.1.5. In stability studies column temperature and column length on the characteristics
Karmarkar et al. (2011) reported an application of quality by of the digoxin peak are found using full factorial design (24).
design (QbD) concepts to the development of a stability indi- Presented HPLC method was applied in quality and stability
cating HPLC method for a complex pain management drug testing of digoxin. Jun et al. (2011) worked on quality by de-
product containing drug substance, two preservatives, and sign approach to investigate tablet dissolution shift upon accel-
their degradants are described. The initial method lacked any erated stability by multivariate methods. And presented article
resolution in drug degradant and preservative oxidative degra- on quality by design case study: An integrated multivariate ap-
dant peaks, and peaks for preservative and another drug proach to drug product and process development.
6.5. For spectroscopic measurements 7.1.2. In sterile manufacturing

Warren (2009) presented details of the applying quality by de-
6.5.1. In handling complex spectroscopic data sign to sterile manufacturing processes.
Zengping et al. (2011) in his review focused on Process analytical
7.1.3. In solid oral dosage form
technologies and real time process control of some spectroscopic
issues and challenges for purpose of process understanding. Pro- Deliang and Yihong (2010) in their article, ‘Understanding
cess analytical technologies (PAT) are more and more being dis- Drug Properties in Formulation and Process Design of Solid
cover and adopted by pharmaceutical and biotechnology Oral Products’, discuss scientific and technical principles asso-
companies. To reach this goal there is a need to extract the detail ciated Product and Process Design and development for phar-
information, and gain knowledge from complex spectroscopic maceutical product. This approach is consistent with the basic
data. A number of new approaches are shown to overcome principle of QbD.
the limitations of existing calibration/modelling methodologies Betterman et al. (2012) given A Tale of Two Drugs: How
and describe a practical system which would improve robustness Using QbD Tools Can Enhance the Development Process.
of the process control system and overall control strategy. This article explains how Quality Target Product Profile, map-
ping, and risk assessment tools are used. A case study of com-
6.5.2. In mass spectroscopy parison of a traditional development approach with a QbD
enhanced approach of Tradium and Qbidium is explained.
Lianming and Frederick (2012) in their review of recent ad-
vances in mass spectrometric methods for gas-phase chiral
7.1.4. Contribution of (SEM/EDX) to QbD by investigation of
analysis of pharmaceutical and biological compounds explain
pharmaceutical materials
Practical projection and existing challenges in quantitative
chiral MS techniques for QbD (Quality-by-Design) based According to Jennifer et al. (2008) Scanning Electron Micro-
pharmaceutical applications. scope (SEM/EDX) and microanalysis are used for the identifi-
cation and analysis of pharmaceutical materials. Detailed
6.5.3. In near infrared observations and measurement of their microstructures can
be done by SEM. Hence it can be used as a PAT tool in mul-
Mark (2011) has presented a review on Quality-by-Design
ti-disciplinary functions to contribute to QbD for process
(QbD) Approach to Quantitative Near-Infrared Continuous
development and control in pharmaceuticals.
Pharmaceutical Manufacturing. Krause (2009) in his review
on QbD for Analytical Methods describes elements of QbD
7.1.5. In gel manufacturing
principle in relation with analytical methods.
Juan et al. (2011a,b) developed quality by design Approach
7. Other applications of QbD or elements of QbD of a Pharmaceutical Gel Manufacturing Process, by Near
Infrared Monitoring of Composition and Physical Parame-
ters gel by using the near infrared spectroscopy (NIRS) tech-
QbD has been applied to pharmaceutical, biopharmaceutical, nique with multivariate chemometric tools. For this purpose,
clinical, and genetics. Some examples where QbD is applied a D-optimal experimental design having normal operational
are mentioned hereunder. condition (NOC) was used. McMahon, shares his experience
of PAT and QbD in Understanding PAT and QbD. He says
7.1. Pharmaceuticals that PAT and QbD are only stations on the road to ultimate
objective (Terry, 2010).
The delivery of medicine at the appropriate purity, potency,
and delivery rate, is expected from the pharmaceutical prod- 7.1.6. QbD for ANDAs
ucts. While pharmaceutical regulations have undoubtedly pro- Robert et al. (2008) in his review discussed quality by design
tected the human beings from any of unwanted harms which for generics and gives a summary of the key terminology.
occurred early in the twentieth century. Hence recent guide-
lines in Q8 for pharmaceutical development are milestone in 7.1.7. In tableting process
the way of making quality products. Application of QbD to Stephanie (2012) recently optimized the Tableting Process with
various pharmaceutical dosage forms reported in the literature a quality by design Approach. Critical quality attributes like
are explained below, powder properties and granulation are covered in this article.
Andrew Prpich worked on Drug product modelling predic-
7.1.1. In modified release products tions for scale-up of tablet film coating. He used two funda-
André et al. (2011) in his review of Pharmaceutical Equiva- mental tablet film coating models in a quality by design
lence by Design for Generic Drugs: Modified-Release Products (QbD) approach to determine the operating parameters for
describes quality by design initiative (QbD) provides an en- scale-up of Varenicline IR. Role of Design space fundamental
hanced evaluation of equivalent drug approach by introducing of QbD in scale up is mentioned.
the concept of a Quality Target Product Profile (QTPP). The Defne et al. (2013) developed a Quality by design approach
concept of ‘‘pharmaceutical equivalence by design’’, for mod- for wet granulation in pharmaceutical processing: Assessing
ified-release generic drug products is illustrated in this article. models for a priori design and scaling.
Joseph et al. (2011) studied A Quality-By-Design Study for Vince et al. (2011b) discussed the current status and pro-
a Roller Compactor. Immediate Release Tablet is used to spective of role of quality by design (QbD). Experience of Pfiz-
examine the impact of inconsistency in excipient material er with FDA’s recent chemistry manufacturing, and controls
properties on the quality attributes. pilot and implementing QbD in its operations is shared.
Morten et al. (2008) applied quality by design for Spray evaluated for their potential impact on safety and efficacy
drying of insulin intended for inhalation. using risk management tools.
Recently quality by design approach for formulation develop- Xiaoming et al. (2012) worked on application of quality by
ment for dispersible tablets has been applied (Naseem et al., 2012). design to formulation and processing of protein liposomes.
Quality by design (QbD) principles are used in research work
7.1.8. Impact of genotoxic impurities on process development
to gain a complete understanding of the preparation of super-
A current review on ‘Overall impact of the regulatory require- oxide dismutase (SOD) containing liposome formulations pre-
ments for genotoxic impurities on the drug development process’ pared using freeze-and-thaw unilamellar vesicles.
discusses analytical assessment of genotoxic impurities and the
regulations in the toxicological background for establishing 7.2.2. In production and characterization of monoclonal
limits. It overall light on genotoxic impurities concerns during antibody-
the development of new drug substances (Antonio et al., 2011).
A systematic quality by design (QbD) strategy was used to de-
7.1.9. In co-precipitation process velop and characterize a monoclonal antibody production pro-
cess (Amit, 2010).
Quality-by-Design (QbD) has been applied recently for a dy-
Sheryl et al. (2011) present a systematic approach to bio-
namic pharmaceutical co-precipitation process (Huiquan
pharmaceutical drug product development using a monoclonal
et al., 2009, 2011).
antibody as an example.
7.1.10. Nanosuspension preparation
7.2.3. For chromatographic technique used for purification
Sudhir et al. (2009) worked on quality by design approach to
Anurag et al. (2011) give High-throughput tools and ap-
understand the process of nanosuspension preparation.
proaches for development of process chromatography steps
Lynn (2011) says that in mid-1982 their team on a develop-
which are used for purification of biotechnology products.
ment project used a statistical tool and some approaches for
Hence separation of the various entities that are present at
optimization, today it is considered as a quality-by-design
the microbial fermentation or mammalian cell culture, stages
(QbD). He has presented a case study in which the project
of process development are focused. Contribution of QbD in
met its objectives and did it in fewer days than expected. The
biopharmaceutical is explained in review of High-throughput
use of DOE resulted in a better understanding of critical
process development for biopharmaceutical drug substances
parameters in his article of quality by Design Circa 1982.
by Bhambure et al. (2011).
7.1.11. In analysis of excipients and API
Angie and Patricia (2010) applied QbD to excipient formula- 7.2.4. PAT and QbD for biopharmaceutical
tion and development. Jarka et al. (2011) presented review on Process analytical tech-
Anurag and Duncan (2010) presented Managing raw materi- nology (PAT) for biopharmaceuticals. He has mentioned that
als in the QbD paradigm, understanding risks. Better process a PAT forms a part of the quality by design (QbD) concept
and product understanding are the basic belief of quality by de- which provides tools to facilitate the quality. According to
sign (QbD). Advanced characterization and risk involved in him number of analytical methodologies and tools referred
manufacture of raw materials that are typically used in biotech as PAT tools are also useful for QbD.
processes are discussed in this article.
Yong et al. (2011) discussed interdependence of Drug Sub- 7.2.5. In nanomedicine
stance Physical Properties and Corresponding Quality Control Eniko}et al. (2010) worked on rational development of a stable
Strategy. In quality by design (QbD) concept, active pharmaceuti- liquid formulation for nanomedicine products. In this work
cal ingredients (APIs) are considered as a critical component. The some of the key steps that must be taken for the implementa-
overall control strategy to ensure drug product quality is discussed. tion of ‘‘Quality by Design’’ (QbD) approach for a biotech
7.2. Biopharmaceuticals product are used.
7.2.6. Challenges and solution for application of QbD to

QbD has also been applied to biopharmaceuticals. It is a fast
biopharmaceutical
growing industry parallel to pharmaceutical. High expectation
of regulatory bodies is the one of the reasons for adoption of Anurag (2010) explains that manufacturing of biotech prod-
QbD by industries. Manufacturing of biopharmaceuticals in- ucts involves the number of complex steps, hence there exist
volves number of complex process, Chromatography is also number of quality attributes to control, in his article Quality
the most important unit operation in downstream processing by Design for biotechnology products: challenges and
of biomolecules, many of the times it is the primary step for solutions.
purification. Hence it is beneficial to apply QbD to biopharma-
ceutical products. Recently QbD has been successfully applied 7.3. Clinical
by determining design space for HPLC method for analysis of
water soluble vitamins (Wagdy et al., 2013). Steven et al. (2010) in his work explained the Relationship be-
tween Processes Critical Control Parameters and clinical per-
7.2.1. In manufacturing of protein formance of theophylline extended-release tablets.
Alex et al. (2012) reported application of the quality by design According to Cook (2012) it may be possible to establish
approach to the drug substance manufacturing process of An relationships between CQAs and pharmacokinetic parameters
Fc fusion protein. Quality attributes of the product were in healthy volunteer trials and then also to establish relation-
ships between pharmacokinetics and safety and efficacy. But process but it will avoid loss raised due to hurry and unethical
cost involved does not make it feasible. struggle of private firms to market their product as early as
possible, because QbD involves thorough understanding of
7.4. Genetics process through science and risk based approach.
Mariana Landin used Design space as an element of QbD in References

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Arabian Journal of Chemistry (2014) xxx, xxx–xxx

King Saud University

Arabian Journal of Chemistry

Quality by design approach: Regulatory need

Received 17 July 2013; accepted 30 January 2014

* Corresponding author. Tel./fax: +91 2402381129.

Production and hosting by Elsevier

3. Regulatory aspects to QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

8. Problems in adoption of QbD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction products and ultimately ﬂourish industry by means of fame

4.1. Elements of pharmaceutical development

5.1.2. Method design 5.1.3. Critical quality attributes (CQA)

An Ishikawa or ﬁshbone diagram is used to identify all po- 1. Installation Qualiﬁcation

1. High-risk factors that should be stringently controlled,

Figure 2 Analytical method development in QbD.

6.1.4. In capillary electrophoresis 6.4. In dissolution studies

6.5. For spectroscopic measurements 7.1.2. In sterile manufacturing

7.2.6. Challenges and solution for application of QbD to

Mariana Landin used Design space as an element of QbD in References

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