A REVIEW ON QUALITY BY DESIGN APPROACH (QBD) FOR

www.wjpps.com Vol 7, Issue 10, 2018.

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Joshi et al. World Journal of Pharmacy and Pharmaceutical Sciences

A REVIEW ON QUALITY BY DESIGN APPROACH (QBD) FOR

PHARMACEUTICAL DEVELOPMENT

*Arjun Joshi, Anil G. Raval, Dr. Yogesh K. Patel and Kanchan M. Mandal

Mr. Arjun L Joshi: Student, Sharda school of pharmacy, Pethapur, Gandhinagar, Gujarat.

Mr. Anil G Raval: Assistant Professor, Sharda school of pharmacy, Pethapur,

Gandhinagar, Gujarat.

Dr. Yogesh K Patel: Associate Professor, Sharda School of Pharmacy, Pethapur,

Gandhinagar, Gujarat.

Mr. Kanchan M Mandal: Student, Sharda school of Pharmacy, Pethapur, Gandhinagar,

Gujarat.

ABSTRACT

Quality by Design is the modern approach for quality of

pharmaceuticals. It describes use of Quality by Design to ensure

quality of Pharmaceuticals. In this review, the Quality by Design is

described and some of its elements identified. Process parameters and

quality attributes are identified for each unit operation. Benefits,

opportunities and steps involved in Quality by Design of

Pharmaceutical products are described. It is based on the ICH

Guidelines Q8 for pharmaceutical development, Q9 for quality risk

management, Q10 for pharmaceutical quality systems. It also gives

application of Quality by Design in pharmaceutical development and manufacturing of

pharmaceuticals. The aim of the pharmaceutical development is to design a quality product

and its manufacturing process to consistently deliver the intended performance of the

product. Quality cannot be tested into products but quality should be built in by design. It

includes the Quality target product profile, critical quality attributes and key aspects of

Quality by Design. It also gives comparison between product quality by end product testing

and product quality by Quality by Design. The foundation of Quality by Design is ICH

Guidelines.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 7, Issue 10, 624-644 Review Article ISSN 2278 – 4357

Article Received on

06 August 2018,

Revised on 27 August 2018,

Accepted on 17 Sept. 2018

DOI: 10.20959/wjpps201810-12426

*Corresponding Author

Arjun Joshi

Sharda School of Pharmacy,

Pethapur, Gandhinagar,

Gujarat.


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KEYWORDS: Quality by Design (QbD), Process Analytical Technology (PAT), Quality

target product profile, Critical quality attributes.

INTRODUCTION[1-4]

The annex of International Conference on Harmonization (ICH), ICH Q8 (R2) guidance,

describes the principles of quality by design (QbD). This guidance further clarifies the key

concepts mentioned in the parent guidance ICH Q8. It defines quality as “the suitability of

either a drug substance or drug product for its intended use.” ICH Q8 (R2) defines QbD as “a

systematic approach to development that begins with predefined objectives and emphasizes

product and process understanding and process control, based on sound science and quality

risk management.” The concept and application of the principles of QbD has been an

emerging topic in the pharmaceutical industry. In QbD, the product quality is assured by

understanding and controlling formulation and manufacturing variables. Thus, the consistent

product quality results from the design control of formulation, and the manufacturing process.

This article focuses on the application of QbD for pharmaceutical product development.

Application of QbD approach in pharmaceutical product development can lead to robust

formulations and high success rate in regulatory approvals. QbD involves the use of

multivariate statistics and design of experiments technique.

QbD involves a thorough understanding of the relationship of product performance with

product attribute and process. Traditionally, formulations are manufactured to meet quality

control tests outlined in product specifications. If the product is deemed fit for commercial

purpose, then it should meet quality control tests. In case of a batch failing to comply with

these tests, it is reprocessed or rejected which opens doors for regulatory questions and

obvious cost burden. The application of QbD in pharmaceutical product development is

systematic, involving multivariate experiments utilizing process analytical technology (PAT)

and other tests to identify critical quality attributes (CQAs) based on risk assessments (RAs).

The QbD begins with predefined objectives and requires an understanding how formulation

and process variables influence product quality. Though end product testing can confirm

product quality, it cannot be a part of a process consistency or process control.

Figure 1 depicts an overall QbD system where RA and risk control for the product and

process are involved.


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Figure 1: Quality by design system.

The important components of product development by QbD are target product profile (TPP),

target product quality profile (TPQP), design and development of product, developing the

manufacturing process, identifying the CQA, assessment and management of the risks

involved in the process, establishment of design space, and defining a control strategy for a

product to stay within the design space. Control strategy is the knowledge driven from the

relationship between formulation and manufacturing process variables that must be controlled

in manufacturing a product of consistent quality. Product lifecycle management further adds

to the knowledge base, helps in continuous product monitoring and improvement.

Figure 2 shows a schematic representation of how various ICH guidelines dealing with

pharmaceutical quality can influence and result in a desired product quality.

Figure 2: Pharmaceutical quality systems for quality by design.


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DEFINITION[5-6]

As per [ICH Q 8(R1)]

“Systematic approach to development that begins with predefined objectives and emphasizes

product and process understanding and process control, based on sound science and quality

risk management.”

As per FDA

“A system for designing, analyzing and controlling manufacturing through timely

measurements (i.e. during processing) of critical quality and performance attributes of new

and in-process materials and processes, with the goal of ensuring final product safety.”

The concept of “Quality by Design” (QbD) was defined as an approach which covers a better

scientific understanding of critical process and product qualities, designing controls and tests

based on the scientific limits of understanding during the development phase and using the

knowledge obtained during the life-cycle of the product to work on a constant improvement

environment. QbD describes a pharmaceutical development approach referring to formulation

design and development and manufacturing processes to maintain the prescribed product

quality. Guidelines and mathematical models are used to ensure the establishment and use of

the knowledge on the subject in an independent and integrated way.

Historical Background[7,8]

In 2007, the FDA received a total of 5000 proposals for new drug applications (NDAs) and

biological license applications and abbreviated new drug applications (ANDAs).

„Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach‟ was launched by the

FDA in August 2002.

A further guidance on process analytical technology (PAT) was released as part of the,

cGMPs for the 21st Century‟ initiative, which hoped to encourage the adoption of more

modern and flexible manufacturing technology in the pharmaceutical industry. In March

2004, the FDA launched The Critical Path Initiative (CPI) to address the steep decline in the

number of innovative pharmaceutical products submitted for approval.

The national strategy was to modernize the pharmaceutical sciences through which FDA-

regulated products are developed, evaluated, manufactured and used. This prompted to the

publishing of a guideline to aid manufacturers implementing modern quality systems and risk


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management approaches to meet the requirements of the Agency‟s current thinking for

cGMP regulations.

The impetus is to have quality in-built. Quality by design, in conjunction with a quality

system, provides a sound framework for the transfer of product knowledge and process

understanding from drug development to the commercial manufacturing processes and for

post-development changes and optimization Good manufacturing practices for the 21st

century has been continually evolving as the ICH quality initiatives have been adopted.

The move from empirical assessment based on performance to the concept of “building

quality in” based on critical attributes has gained traction as new guidance documents have

been published.

BENEFITS OF QBD[9]

QbD is good Business

Eliminate batch failures

Minimize deviations and costly investigations

Avoid regulatory compliance problems

Organizational learning is an investment in the future

QbD is good Science

Better development decisions

Empowerment of technical staff

OPPORTUNITIES[10]

Efficient, agile, flexible system

Increase manufacturing efficiency; reduce costs and project rejections and waste

Build scientific knowledge base for all products

Better interact with industry on science issues

Ensure consistent information

Incorporate risk management

STEPS INVOLVED IN QUALITY BY DESIGN PRODUCTS[11]

1. Development of new molecular entity �

Preclinical study �


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Nonclinical study �

Clinical Study �

Scale up �

Submission for market Approval

2. Manufacturing Design Space�

Process Analytical Technology �

Real time Quality Control

3. Control Strategy

Risk based decision �

Continuous Improvement �

Product performance

SEVEN STEPS OF QUALITY BY DESIGN START UP PLAN[12,13]

1. Hire an independent Quality by design expert.

2. Audit your organization and process with the expert conducting a gape analysis.

3. Hold a basic quality by design workshop with all your personal.

4. Review the expert’s report and recommendation.

5. Draft an implementation plan, timelines and estimated costs.

6. Assign the resources (or contract out).

7. Retain the independent expert as your “Project Assurance” advisor.

Table 1: Difference between current approach and Qbd approach.


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ELEMENTS OF PHARMACEUTICAL DEVELOPMENT[12,13,15,16]

QbD comprises all elements of pharmaceutical development mentioned in the ICH guideline

Q8. Pharmaceutical Development section is projected to provide a complete understanding of

the product and manufacturing process for reviewers and inspectors. To design a quality

product and its manufacturing process to consistently deliver the intended performance of

product is the aim of pharmaceutical development.

The information and knowledge gained from pharmaceutical development studies and

manufacturing experience provide scientific understanding to support the establishment of the

specifications, and manufacturing controls.

Different elements of pharmaceutical development include

a. Defining an objective

b. Determination of critical quality attributes (CQA)

c. Risk assessment

d. Development of experimental design

e. Designing and implementing control strategy

f. Continuous improvement

Figure 2: Elements of QbD.

A. Define an objective

Quality target profile (QTP) forms the basis of QbD, which is in relation to the predefined

objective criteria mentioned in the definition of QbD. As per ICH guideline Q8 R2 the

Quality Target Product Profile forms the basis for design and the development of the product.

Considerations for the Quality Target Product Profile could include:


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Intended use in clinical setting, route of administration, dosage form, suitable delivery

Systems.

Dosage strength(s), container and closure system.

Therapeutic moiety release or delivery and attributes affecting, Pharmacokinetic

parameters (e.g., dissolution, aerodynamic performance).

Drug product quality criteria like sterility, purity, stability and drug release as appropriate

for dosage form the intended for marketing.

QbD requires a Target Product Profile; it may be called as Quality Target Product Profile

(QTPP) which defines the expectations in the final product. In case of analytical method

development it is called as analytical target profile (ATP), it is also called as Target Product

Profile (TPP). The TPP can play a pivotal role in the entire drug discovery and development

processes like optimization, planning and decision making, and designing of clinical research

strategies. The Target Product Profile (TPP) can be used to design the clinical trials, safety

and ADME studies, as well as to design the drug product. The TPP will help to identify

critical quality attributes such as potency, purity, bioavailability or pharmacokinetic profile,

shelf-life, and sensory properties.

B. Determination of critical quality attributes (CQA)

According to ICH Q8 R2 “A CQA is a physical, chemical, biological, or microbiological

property or characteristic that should be within an appropriate limit, range, or distribution to

ensure the desired product quality”.

CQAs are generally linked with the drug substance, excipients, intermediates (in-process

materials) and drug product. For example CQAs of solid oral dosage forms are typically

those aspects affecting product purity, strength, drug release and stability whereas for

parenterals these are sterility and clarity.

The CQAs can additionally include properties like particle size distribution, bulk density that

affect drug product. Mostly CQAs are derived from the Quality Target Product Profile and/or

prior knowledge is used to guide the product and process development and subsequently

CQAs are assessed for risk management. It is stated in ICH Q9 that in case of potential drug

substance CQAs are used to guide process development. Inclusion and exclusion in list of

potential CQAs can be done as knowledge drug substance and process understanding

increases. In case of biotechnological/biological products, most of the CQAs of the drug


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product are associated with the drug substance and thus are a direct result of the design of the

drug substance or its manufacturing process.

A quality attribute that must be controlled within predefined limits to ensure that the product

meets its intended safety, efficacy, stability and performance. It means all the factors which

affect final quality and safety should be controlled. Dissolution test is crucial for a controlled

release drug product and on the other hand dissolution test for an immediate release drug

product which belongs to the high aqueous solubility and high permeability i.e. BCS class I

drug will not prove as a critical attribute for quality control parameter. CQA differs

depending on the type of process, dosage form, and type of method to be developed hence

thorough knowledge of real time data to working scientists is important.

Figure 3: Role of CQA.

C. Risk assessment

It is commonly understood that risk is defined as the combination of the probability of

occurrence of harm and its severity. Risk assessment helps to increase quality of method or

process. Also it is determinant for effect of input variable on method or processes. From risk

assessment one can recognize critical attributes that are going to affect final quality of

product.

A risk assessment is helpful for effective communication between FDA and industry,

research/development and manufacturing and among multiple manufacturing sites within

company. There may be risk and uncertainty in validation of bioanalytical method though the

guidelines for validation are given by various regulatory bodies there may be a variation in


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interpretation of those guidelines and hence in experimental method designing which leads to

unfit method development for intended purpose. Risk management for excipients to

determine shelf life can be done by statistical parameters.

Principles of quality risk management are

Scientific knowledge based evaluation of the risk to quality which eventually links to the

protection of the patient.

Adequate effort should be taken; formality and documentation of the quality risk

management process should be done with the level of risk involved.

Risk management is the joint responsibility of the quality unit, business development,

engineering, regulatory affairs, production operations, sales and marketing, legal,

statistics and clinical department.

Methods of risk assessment: Some methods of risk assessment are mentioned in ICH

guideline Q9 as follows:

Failure Mode Effects Analysis (FMEA);

Failure Mode, Effects and Criticality Analysis (FMECA)

Fault Tree Analysis (FTA)

Hazard Analysis and Critical Control Points (HACCP);

Hazard Operability Analysis (HAZOP);

Preliminary Hazard Analysis (PHA);

Risk ranking and filtering;

Supporting statistical tools.

ICH guideline Q9 gives description of risk management and various terminologies associated

with it, like Risk Acceptance, Risk Analysis, Risk Assessment, Risk Communication, Risk

Control, Risk Evaluation, Risk Identification, and Risk Management. Quality management

policies should mention procedures and practices to the tasks of assessing, controlling,

communicating and reviewing risk. Risk Reduction is actions taken to lessen the probability

of occurrence of harm and the severity of that harm.


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Figure 4: Quality risk management process.

D. Development of experimental design

Experimental design is the multidimensional combination and interaction of input variables

(e.g., material attributes) and process parameters that have been demonstrated to provide

assurance of quality. Design space is proposed by the applicant and is subject to regulatory

assessment and approval of ICH Q8 (R2).

Pharmaceutical development scientists have begun making use of computer-aided process

design (CAPD) and process simulation to support process development and optimization of

manufacturing. Risk assessment can be a guide to understand linkage and effect of process

parameters and material attributes on product, and ranges for variables within which

consistent quality can be achieved.

These parameters or attributes are selected for addition in the design space. Information

regarding reason for inclusion of some variables in design space as well as exclusion of other

variable has to be stated. Operation within the design space will result in a product meeting

the defined quality. Independent design spaces for one or more unit operations can be

applied; a single design space can be applied for multiple operations. For example impact of


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excipient variability on particle size distribution, blend segregation propensity can be

included in experimental design.

Different mathematical models are available for design of experiment like Placket–Burman,

Box Behnken, Taguchi, Surface Design, Full and fractional factorial designs. Full factorial

design was used to study the effect of formulation factors on pharmaceutical properties of

tablet; in which independent variables were binder and disintegrant concentration, resistance

to crushing while dependant variable was drug release. Such a multidisciplinary approach is

beneficial as manufacturing process improvement can be done in previously approved space;

it decreases the number of variation after marketing. It is a risk based approach which is

based on timely quality control rather than final testing of finished product.

Figure 5: Development of experimental design.

E. Designing and implementing control strategy

Control strategy is required to ensure that material and process are within the expected lower

and upper limits. Parameter and material are routinely controlled during production in order

to assure reproducibility. The control space should be within the design space. Generally

scale up is trial and error basis. During scale up processes parameters may differ but

attributes which affect quality remains the same hence control strategy is required. QbD gives

trace on reproducibility and robustness. Process capability index expresses reproducibility of

process. Control space should be within the design space, it is an upper and lower limit for

raw material or a process within which parameter and material are regularly controlled which

assures quality of product. Design space covers control space. If control space is smaller than

design space it is considered as robust. Usually in-process quality control tests are performed

to examine quality and trace out defects but QbD approach being proactive in the initial steps

the potential attributes which could possibly give out of range result and affect the quality are


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identified. Deliberate variations in those attributes are studied in the design space. Control

strategy involves but is not limited to – control on excipients, drug substance, packaging

materials (inputs), specifications, operational control like drying downstream processing

dissolution etc., real time testing or in process testing, finished product testing at regular

intervals.

Continuous improvement throughout product life cycle Product quality can be improved

throughout the product lifecycle; companies have opportunities to opt inventive approaches

to improve quality. Process performance can be monitored to make sure consistency in

quality. Additional experience and knowledge is gained during routine manufacturing which

contributes to method/process development. Periodic maintenance can be done within a

company’s own internal quality system; but design space should be unchanged.

The QbD approach avails the continuous improvement throughout products‟ life cycle this is

a distinguishing point from the conventional method which is much frozen process.

APPLICATIONS OF QUALITY BY DESIGN (QbD)[14,16,17]

Quality by design (QbD) – a comprehensive systematic approach to pharmaceutical

development and manufacturing Advancement in the pharmaceutical development and

manufacturing by QbD can be explained against traditional approach.

In Pharmaceutical Development

To design a quality product and a manufacturing process to consistently deliver the intended

performance of the product.

In life cycle management

Continual improvement enabled within design space.

Qbd IN CMC REVIEW OFFICES

Office of New Drug Quality Assessment (ONDQA) �

Science-based assessment �

Restructured organization and reorganized staff – �

Premarket staff and post market �

CMC Pilot �

A number of applications submitted �


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Lessons learned �

Evaluation of information �

Implementation of PMP

Benefits to Industry

Ensures better design of products with less problems in manufacturing

Reduces number of manufacturing supplements required for post market changes –rely on

process and risk understanding and risk mitigation

Allows for implementation of new technology to improve manufacturing without

regulatory scrutiny

Allows for possible reduction in overall costs of manufacturing –less waste

Ensures less hassle during review –reduced deficiencies –quicker approvals

Improves interaction with FDA –deal on a science level instead of on a process level o.

Allows for continuous improvements in products and manufacturing process.

Pharmaceutical Development

Widely used in pharmaceutical development and manufacturing:

Figure 6: Pharmaceutical developments.

Used in PAT

A system for designing, analyzing and controlling manufacturing through timely

measurement of critical quality performance attributes of raw and in process materials and

processes with the goal of ensuring final product quality.


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Figure 7: Off-line & On-line Analysis.

For experimental design

A structured organized method for determining the relationship between factors affecting a

process and the output of that process.

Figure 8: For experimental design.

Design Space

Multidimensional combination of and interaction of input variables and process parameters

that have been demonstrated to provide Quality Assurance.

Figure 9: For design space.


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Linkage between process inputs (inputs variables and process parameters) and critical

quality attributes

Proposed by Applicant

Subject to regulatory assessment and approval

Implementation before or after MA

Established for one or more unit operation(s) or up to complete process

Working within the design space: not considered as a change.

CHANGE MANAGEMENT SYSTEM (CHANGE CONTROL)[18-20]

A proper change management system should be established in a company which should be

able to monitor, approve, and implement changes. The evaluation of the changes is carried

out by quality risk management. The impact of all the changes should be evaluated using this

system even though a change is within the permissible boundaries of design space. As a

consequence, the need for regulatory filings/approval should be considered on a case basis.

The approved changes should not be having any deleterious effect on the product quality after

its implementation.

Since QbD/PAT management awareness is still low, product quality and process performance

should be evaluated properly by the management review board of the company throughout

the life cycle of the product. The review should include regulatory aspects, customer

satisfaction, process and product performance, and the corrective actions and preventive

actions taken. The scope of improvement to manufacture process and product quality should

be identified and considered by the management review systems.

TOOLS OF QUALITY BY DESIGN[21-23]

I] Design of Experiments (DOE)

Design of experiments (DOE) is a structured and organized method to determine the

relationship among factors that influence outputs of a process. It has been suggested that

DOE can offer returns that are four to eight times greater than the cost of running the

experiments in a fraction of the time. Application of DOE in QbD helps in gaining maximum

information from a minimum number of experiments. When DOE is applied to a

pharmaceutical process, factors are the raw material attributes (e.g., particle size) and process

parameters (e.g., speed and time), while outputs are the critical quality attributes such as

blend uniformity, tablet hardness, thickness, and friability. As each unit operation has many


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input and output variables as well as process parameters, it is impossible to experimentally

investigate all of them. DOE results can help identify optimal conditions, the critical factors

that most influence CQAs and those who do not, as well as details such as the existence of

interactions and synergies between factors as in Figure 10, Design of experiments.

Figure 10: Design of experiment (DOE).

II] Process Analytical Technology (PAT)

PAT has been defined as “A system for designing, analyzing, and controlling manufacturing

through measurements, during processing of critical quality and performance attributes of

raw and in-process materials and processes, with the goal of ensuring final product quality”.

The goal of PAT is to “enhance understanding and control the manufacturing process, which

is consistent with our current drug quality system: quality cannot be tested into products; it

should be built-in or should be by design.” The design space is defined by the key and critical

process parameters identified from process characterization studies and their acceptable

ranges. These parameters are the primary focus of on-, in- or at-line PAT applications. In

principle, real-time PAT assessments could provide the basis for continuous feedback and

result in improved process robustness. NIR act as a tool for PAT and useful in the RTRT

(Real Time Release Testing) as it monitors the particle size, blend uniformity, granulation,

content uniformity, polymorphism, dissolution and monitoring the process online, at the line

and offline, thus it reduces the release testing of the product.

III] Risk Management Methodology

Quality Risk Management is defined as “A systematic process for the assessment, control,

communication and review of risks to the quality of the drug (medicinal) product across the


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product lifecycle”. Risk assessment tools can be used to identify and level parameters (e.g.,

process, equipment, input materials) with potential to have an impact on product quality,

based on prior knowledge and primary experimental data. The early list of potential

parameters can be fairly broad, but can be modified and prioritized by additional studies (e.g.,

through a combination of design of experiments, mechanistic models). Once the considerable

parameters are identified, they can be further studied (e.g., through a combination of design

of experiments, mathematical models, or studies that lead to mechanistic understanding) to

achieve a higher level of process understanding.

QUALITY BY DESIGN (QBD) – A COMPREHENSIVE SYSTEMATIC APPROACH

TO PHARMACEUTICAL DEVELOPMENT AND MANUFACTURING.[24-25]

Table 2 Advancement in the pharmaceutical development and manufacturing by QbD

can be explained against traditional approach.

CONCLUSION

The major objectives with regard to quality issues are addressed by the ICH guidelines. These

are Q8 Pharmaceutical development, Q9 Pharmaceutical risk management and Q10

Pharmaceutical quality systems. Quality-by-design (QbD) is a new concept which has been

added in the annex to guideline Q8. The QbD approach leads to enhanced understanding,

welldefined system and regulatory flexibility. Well adoption of QbD tools is the key to


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achieve longterm benefits. Not to be disorientated among all aspects of QbD, appropriate risk

assessment tools such as flow-down maps and Ishikawa diagrams can be considered in the

beginning. It will be instructive to keep the processes in perspective. Tools of DoE and PAT

should be determined based on the specific intentions and to make their outcome assessment

capably, well-trained staff are necessary as well as for establishing a design space which

requires mathematical and statistical knowledge. As shown with mentioned case studies,

implementation area of QbD is extremely wide. QbD can provide extended knowledge about

all phases in any drug‟s lifecycle. In product development studies, combination of several

material attributes and unit operation parameters are evaluated. But, it is also possible to

focus on only one unit operation such as fluidised bed granulation, roll compaction and tablet

coating. With the contribution of different bodies of the pharmaceutical area, all of the case

studies exemplify to encourage the implementation of QbD. As long as pharmaceuticals get

more complex in the meaning of advanced manufacturing techniques and the new areas such

as personalised medicine, the importance of a well-constructed quality system will gradually

increase.

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Documents

A REVIEW ON QUALITY BY DESIGN APPROACH (QBD) FOR