Academic Sciences International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 6, Issue 1, 2014

Reveiw Article

QUALITY BY DESIGN (QBD): A COMPREHENSIVE UNDERSTANDING OF IMPLEMENTATION

AND CHALLENGES IN PHARMACEUTICALS DEVELOPMENT

SHASHANK JAIN
College of Pharmacy and Health Sciences,St. John’s University, Queens, NY, USA. Email: [email protected]
Received: 10 Oct 2013, Revised and Accepted: 07 Nov 2013
ABSTRACT
Pharmaceutical industry is constantly looking for ways to ensure and enhance product safety, quality and efficacy. However, drug recalls,
manufacturing failure cost, scale up issues and regulatory burden in recent past suggest otherwise. In traditional quality by testing (QbT) approach,
the product quality and performance are predominantly ensured by end product testing, with limited understanding of the process and critical
process parameters. Regulatory bodies are therefore focusing on implementing quality by design (QbD), a science based approach that improves
process understanding by reducing process variation and the enabling process-control strategies. In this regards, pharmaceutical industry is
currently undergoing a significant transformation to streamline their R&D process, provide greater manufacturing flexibility and control, and to
reduce regulatory burden. However, there is limited understanding and major concerns regarding the implementation of QbD principles in the
pharmaceutical arena. The objective of this review article is therefore to provide a comprehensive understanding on various aspects of QbD, along
with addressing the concerns related to its implementation.
Keywords: Quality by design, Design of experiment, Pharmaceutical manufacturing, Critical quality attributes, Quality risk management, Design
space, Quality target product profile

INTRODUCTION drug substance or excipients, they can be utilized for the

manufacturing of the products. Since only limited numbers of drug
In past few decades, pharmaceutical companies had spend an product (e.g. tablets) out of several million are tested, drug
enormous amount of resources in their unflagging efforts to assure manufacturers are usually required to conduct comprehensive in-
quality, achieve regulatory compliance, and produce drugs as cost- process testing, such as blend uniformity, tablet hardness, tablet
effectively as possible. Consequently, they employ advance disintegration in order to ensure that the outcome of in-process
processes and technologies that entail a great deal of scientific testing meets the FDA approved testing specifications [4].
sophistication and operational complexity. However, such effort Furthermore, due to lack of confidence, in the manufacturing
lacks comprehensive, rationale based understanding of these processing, on part of FDA, the manufacturers are not permitted to
complex processes, associated critical variables and strategies to make modifications to the operating parameters specified in the
control these variables, which is pivotal in assuring quality of the batch record without filing supplements with the FDA [4].
product. Little emphasis is paid to identify the root cause of Consequently, pharmaceutical companies incurred high cost
manufacturing failures. Furthermore, no rationale-based approach associated with manufacturing failures while delaying the approval
is followed to predict the effects of scale-up on the final product process due to stringent specification and additional paperwork
[1]. This has led to a gap between product quality attributes and required by regulatory authorities.
their clinical performances, forcing regulatory authorities to set
stringent specifications and guidelines for approval of drug In this regards, with the assertion of regulatory authorities to
products. implement QbD, pharmaceutical industry is undergoing a significant
transformation to streamline their R&D process, provide greater
In order to overcome these roadblocks, in 2002, US Food and Drug manufacturing flexibility and control, and to reduce regulatory
Administration (FDA) had announced a new initiative- burden. However, there is limited understanding and some major
Pharmaceutical Current Good Manufacturing Practices (CGMPs) for concerns regarding the implementation of QbD principles in the
the 21st Century, intended to modernize the FDAs regulation in pharmaceutical arena. The objective of this review article is
regards to pharmaceutical manufacturing and product quality. The therefore to provide a comprehensive understanding on various
initiative challenged industry to look beyond quality by testing aspects of QbD, along with addressing the concerns related to its
(QbT) for ensuring product quality and performance. Additionally, implementation.
International Conference on Harmonization (ICH) Q8 guideline was
published in May 2006 for pharmaceutical product development, Quality by Design (QbD)
and has been complemented by the ICH Q9 on Quality Risk
Management and ICH Q10 for a Pharmaceutical Quality System. Regulatory authorities consider that incremental and
These guidelines emphasize quality by design (QbD), a science- unsystematic improvement in unit operations, in isolation, would
based approach for designing formulations and manufacturing only have little effect on overall process performance or quality.
processes in order to ensure predefined product quality objectives. To assure the quality of the product, a more holistic approach
The fundamental assumption underlying QbD is that the quality of provided by QbD should be adopted. QbD is defined in the ICH Q8
the product can be assured only if critical sources of variability is guideline as “a systematic approach to development that begins
understood and is suitably mitigated or controlled within a defined with predefined objectives and emphasizes product and process
design space [2]. understanding and process control, based on sound science and
quality risk management” [5]. In manufacturing of new or
In the traditional QbT approach, pharmaceutical quality is defined as marketed products, QbD can help in pre-determining the risk
the product meeting the pre-specified quality and regulatory potential of various operation, assuring that suitable control
specification [3]. QbT framework typically encompasses raw strategies can be applied on time. Since Qbd is a science-based
material testing, drug substance or drug product manufacturing approach, it provides a basis for optimizing and improving the
process, in-process material testing, and end product testing. The manufacturing operation without facing additional regulatory
quality of raw materials including drug substance and excipients is filings or scrutiny. Furthermore, for technology transfer, QbD
monitored by traditional testing methods. If they meet the generated process understanding can make the transition more
manufacturer’s proposed and/or FDA approved specifications for efficient [6].
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Table 1: Quality Target Product Profile (QTPP) for Generic Acetriptan Tablets, 20 mg [9]
QTPP Elements Target Justification
Dosage form Tablet Pharmaceutical equivalence requirement: same dosage form
Dosage design Immediate release tablet without a Immediate release design needed to meet label claims
score or coating
Route of administration Oral Pharmaceutical equivalence requirement: same route
Dosage strength 20 mg Pharmaceutical equivalence requirement: same strength
Pharmacokinetics Immediate release enabling Tmax in 2.5 Bioequivalence requirement
hours or less; Bioequivalent to RLD Needed to ensure rapid onset and efficacy
Stability At least 24-month shelf-life at room Equivalent to or better than RLD shelf-life
temperature
Drug product Physical Pharmaceutical equivalent requirement. Must meet the compendial or other applicable (quality) standards
quality Attributes (i.e., identity, assay, purity, and quality).
Attributes Identification
Assay
Content
uniformity
Dissolution
Degradation
Products
Residual solvent
Water content
Microbial Limits
Container closure system Container closure system qualified as Needed to achieve the target shelf-life and to ensure tablet
suitable for this drug product integrity during shipping
Administration/Concurrence with Similar food effect as RLD RLD labeling indicates that a high fat meal increases the AUC and
labeling Cmax by 8-12%. The product can be taken without regard to
food.
Alternative methods of None None are listed in the RLD label.
administration

Table 2: Critical Quality Attributes (CQAs) of Generic Acetriptan Tablets, 20 mg [9]

Quality attributes of the Target Is this Justification
drug product a
CQA?
Physical Appearance Color and shape No Color, shape and appearance are not directly linked to safety and efficacy.
attributes acceptable to the patient. Therefore, they are not critical. The target is set to ensure patient
No visual tablet defects acceptability.
observed.
Odor No unpleasant odor No In general, a noticeable odor is not directly linked to safety and efficacy,
but odor can affect patient acceptability. For this product, neither the drug
substance nor the excipients have an unpleasant odor. No organic solvents
will be used in the drug product manufacturing process.
Size Similar to RLD No For comparable ease of swallowing as well as patient acceptance and
compliance with treatment regimens, the target for tablet dimensions is set
similar to the RLD.
Score Un-scored No The RLD is an un-scored tablet; therefore, the generic tablet will be un-
configuration scored. Score configuration is not critical for the acetriptan tablet.
Friability NMT 1.0% w/w No Friability is a routine test per compendial requirements for tablets. A
target of NMT 1.0% w/w of mean weight loss assures a low impact on
patient safety and efficacy and minimizes customer complaints.
Identification Positive for acetriptan Yes Though identification is critical for safety and efficacy, this CQA can be
effectively controlled by the quality management system and will be
monitored at drug product release. Formulation and process variables do
not impact identity. Therefore, this CQA will not be discussed during
formulation and process development.
Assay 100% w/w of label claim Yes Assay variability will affect the safety and efficacy. Process variability will
affect the assay of the drug product. Thus, assay will be evaluated
throughout product and process development.
Content uniformity Conforms to USP <905> Yes Variability in content uniformity will affect safety and efficacy. Both
Uniformity of Dosage Units formulation and process variables impact content uniformity, so this CQA
will be evaluated throughout product and process development.
Dissolution NLT 80% at 30 minutes in Yes Failure to meet the dissolution specification can impact bioavailability.
900 mL of 0.1 N HCl with Both formulation and process variables affect the dissolution profile. This
1.0% w/v SLS using USP CQA will be investigated throughout formulation and process
apparatus 2 at 75 rpm development.

Components of QbD system, pharmacokinetic consideration and drug product quality

criteria (e.g., sterility, purity, stability, and drug release).
A] Quality target product profile (QTPP)
It is important to acknowledge that QTPP should only include
FDA defines QTPP as the quality attributes related to safety and patient relevant product performance elements. For example, tablet
efficacy of the product. It may include route of administration, density or hardness may be included as a specification for process
dosage form, delivery systems, dosage strength(s), container closure monitoring but may not be included in QTPP. Also, if particle size is

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critical to the dissolution of a solid oral product, then the QTPP development process. However, QTTP attributes such as assay,
should include dissolution but not particle size [7]. content uniformity, dissolution, and permeation flux will also be a
part of CQA as they may be altered by formulation or process
For an NDA, the QTPP is under development while for the ANDA variables. List of potential CQAs for immediate release dosage form
product, the QTPP is well established based on the properties of the drug for generic product development is described in Table 2 [9].
substance (DS), characterization of the reference listed drug (RLD)
products, RLD label and intended patient population [7, 8]. Therefore, a Identification of CQA can be performed based on prior knowledge
generic drug product is expected to have same QTPP as that of brand or and/or quality risk management (QRM). Prior knowledge may be
reference product. A typical example of QTPP for immediate release attained by literature review, manufacturing experience, technology
dosage form for generic product development is described in Table 1 [9]. transfer, stability reports, raw material testing data, adverse event
report and recalls. Quality risk management, on the other hand,
B] Critical quality attributes (CQA) applies various tools to identify and prioritize potential CQA. QRM is
Once QTPP has been identified, the next step is to identify the discussed in detail in the next section.
relevant CQAs. A CQA is defined as “a physical, chemical, biological, C] Quality risk management (QRM)
or microbiological property or characteristic that should be within
an appropriate limit, range, or distribution to ensure the desired FDA defines QRM as a systematic process for the assessment,
product quality” [5]. This indicates that CQAs are subsets of QTPP control, communication and review of risks to the quality of the drug
that has a potential to be altered by the change in formulation or product across the product lifecycle. The goal of QRM is therefore to
process variables [3]. For example, QTPP may include additional identify risks within a process or event, analyzing the significance of
quality attributes of the drug product such as strength and dosage these risks, and take appropriate measures to mitigate such risks if
form, which are not the part of CQA as it will not change during drug deemed unacceptable [10, 11].

Fig. 1: Overview of typical quality risk assessment process [12]

QRM is integral part of QbD as it helps in identifying the extent of the or equipment. Once failure modes are established, FMEA tool
impact of critical material attributes (CMA) and critical process evaluates the effect of these failures and prioritizes them
parameter (CPP) on CQAs, which can eventually assist in prioritizing the accordingly [15]. Risk control activities can then be performed to
CQAs [13, 14]. They are particularly important in complex processes, avoid such failures modes. Since FMEAs require a good
especially that are involved in cases of biologics or bio-similar. understanding of cause and effects, a thorough process
understanding is essential [16].
FDA suggest various tools that can be applied for QRM, among which
the relevant ones are discussed below: Case study: QRM of typical manufacturing process by FMEA
approach [17]
Failure mode effects analysis (FMEA)
FMEA is one of the most commonly used risk-assessment tools in the In this case study, risk identification was performed initially based
pharmaceutical industry. It is a systematic and proactive method to on the prior understanding in relation to drug substance, excipient
identify and mitigate the possible failure in the process. Failure and process. Risk analysis and evaluation was then performed based
modes represent any errors or defects in a process, material, design, on potential harm(s) associated with each potential risk.

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Table 3: QRM of typical manufacturing process by FMEA approach [17]

Risk area Failure mode Failure effect Risk analysis*
Raw materials P S D RPN
Drug Change in particle size or properties like Change in dissolution performance, thus impacting 4 5 5 100
substance shape or surface energy clinical performance
Excipient Increasing binder levels Slow tablet disintegration affecting clinical performance 4 5 5 100
Decreasing level of disintegration Impeded tablet disintegration affecting clinical 4 5 5 100
performance
Magnesium stearate variability affecting Changing dissolution behavior affecting clinical 3 5 5 75
wetting of drug particle performance
Variability in amount of diluents Change in granule properties altering 2 5 5 50
disintegration/dissolution
Process
Dry mixing Insufficient mixing, poor blending Large range of active ingredient content in the batch 2 3 4 24
Wet Failure to control granulation end point Decrease granule porosity, decreased water ingress and 4 5 5 100
granulation decrease dissolution rate
Excessive ware added or holding the wet Decrease disintegration performance and decrease 3 5 5 75
mass for significant time before drying dissolution rate
Dry milling Incorrect dry milling parameters Effect on granule size leads to altered dissolution and 3 5 5 75
adverse effect on clinical performance
Lubrication Blending time too long, leading to Decreased dissolution rate leads to adverse effect on 3 5 5 75
hydrophobic coat of lubricant around clinical performance
granules
* P is probability, S is severity and RPN is risk product number
The risk score or risk product number (RPN) was determined by following equation:
RPN = probability score × severity score × detectability score
Where, the score was defined prior to the risk analysis stage. A RPN of < 40 was considered a low risk; a RPN of 40–99 was identified as an
intermediate risk; and a RPN of ≥ 100 was defined as a high risk. The risk-control strategies were then applied by identifying the unit operations or
procedures where the RPN was above a certain threshold (Table 3). After implementing mitigating strategies to reduce the high-risk areas, the RPN
values were recalculated to ensure that the projected risks were appropriately minimized.

The risk analysis results were latter document and communicated to following the company policy for quality and quality systems, a
the management and experts in QRM assigned to the project. The report describing the rationale, risk-assessment process, action plan,
knowledge gained through this risk assessment was communicated and conclusions were forwarded to internal quality groups for
with the employees at the company’s other development sites as review and future follow-up (e.g., audit, preapproval inspection, risk
well as externally through various industry forum presentations. In analysis).

Fig. 2: Fault tree diagram for a cross-contamination between two products [15]

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2. Fault tree analysis (FTA) design can also be utilized to identify the range of various variables.
The response variable should be a CQA or closely related to them.
The fault tree analysis (FTA) was first introduced by Bell
Laboratories and is one of the most widely used methods in system 2. Select appropriate experiment design and perform the run:
reliability, maintainability and safety analysis [16, 18]. FTA is a The choice of experimental design may depend on the purpose of the
deductive analysis approach for resolving an undesired event into study (e.g., a screening, optimization, or robustness study), the
its causes in a top down fashion [15]. Typically, assumed failures are factors and interactions involved in the studied and available
listed at the top as main event and all of the associated elements in resources (e.g., literature knowledge, time, labor, cost and materials)
that system that could cause the event are listed as subsequent [23, 24].
branches till the root condition or cause is identified [15, 16]. The
results are represented pictorially in the form of a tree of fault 3. Model diagnostic: After obtaining the initial model, foremost
modes and there relationship are described with logical operators step is to check whether the model is appropriate or not. Generally,
like “AND”,”OR”, etc. [15]. A case study on cross-contamination the significance of a parameter is verified using the analysis of
between two products, is illustrated in form of FTA in Figure 2[15]. variance (ANOVA) method. ANOVA is a statistical method based on
As shown in this figure, a fault tree diagram can grow rapidly and the F-test to estimate the significance of model terms [23]. It
can become quite complex. involves subdividing the total variation of a data set into variation
due to main effects, interaction and residual error. Model terms can
3. Hazard analysis and critical control points (HACCP) be added or eliminated from analysis, depending upon their
significance. The new model, with more or fewer model terms, is
HACCP provides detailed documentation to show process or product again forced through this cycle until all terms included in the model
understanding through identifying parameters to control and satisfy F-test statistics.
monitor [16]. The definition of hazard includes both safety and
quality concern in a process or product. Examples of hazards within Once the overall model satisfies an ANOVA check, the next step is to
the pharmaceutical setting include environmental aspects of the determine what cannot be modeled (i.e. the errors resulting from
facility (environmental conditions, hygiene aspects); material flow; the model). This is done using a residual analysis technique.
manufacturing steps; personnel hygiene and gowning; and technical Residuals are the difference between the experimental response and
aspects relating to process design.HACCP consists of the following the value predicted by the chosen model. A model is considered a
seven steps: (i) conduct a hazard analysis and identify preventive “good fit” if its residuals are normally and independently distributed
measures for each step of the 
 process, (ii) determine the critical with zero mean and constant variance. Such distribution can be
control points, (iii) establish critical limits, (iv) establish a system to analyzed either by the normal probability plot of residuals, residuals
monitor the critical control points, (v) establish the corrective action plotted against predicted values and residuals plotted against
to be taken when monitoring indicates that the critical 
 control experiment run order [23].
points are not in a state of control, (vi) establish system to verify
that the HACCP system is working effectively, (vii) establish a 4. Illustration of design space: The design space can be tabulated
record-keeping system [15] or graphically displayed using various methods. Graphically the
design space can be illustration by the following:
D] Design space
A] Contour plots: A contour plot is a graphic representation of the
A design space is a multidimensional combination of input variables relationships among three numeric variables in two dimensions.
(e.g., material attributes), their interactions and process parameters Two variables are for X- and Y-axes, and a third variable Z is for
that have been demonstrated to provide assurance of quality [5, 19, contour levels. You can interactively identify, label, color, and move
20]. A design space may be constructed for a single unit operation, contour levels, and change the resolutions of rectangular grids to get
multiple unit operations, or for the entire process. Though according better contouring quality and performance.
to FDA guideline, defining design space is optional since the product
and process understanding can be established without a formal B] Three-dimensional plots: These plots are used to illustrate
design space, nevertheless, such approach can assist to better and study the effect of two input variables on an output variable
understanding and attain overall control of a system. simultaneously. These plots are ideal for showing the process
shape, however, contour plots are more useful for determining
In this regards, one can apply one-factor-at-time (OFAT) approach, or displaying acceptable operating ranges for process
which vary only one factor or variable at a time while keeping others parameters [22].
constant. However, design of experiment (DoE) approach that vary
several input variables simultaneously are more efficient when C] Overlay plots: When there is more than one quality
characteristic in the design space, the use of overlay plots is helpful.
studying two or more factors [21, 22]. Factorial designs (full or
The overlay window shows the design space, which indicates the
fractional) and the response surface methodology (RSM) are
various combinations of the factors that will provide results within
characteristic tools for this kind of application. The key advantages
the acceptable range.
of using DOE approach are summarized as following [23]:
From FDA perspective, regulatory submission in regards to design
 Exhaustive information from a minimum number of space should include the following aspects [25]:
experiments
 Description of design space, including critical and other
 Study effects individually by simultaneously varying all relevant parameters. The design space can be presented as
operating parameters ranges of material inputs and process parameters, graphical
 Can account for variability in experiments, process, materials, representations (contour, interaction or overlay plots) or
or operators through more complex mathematical relationships.

 Able to provide understanding about the interaction between  The interaction of various inputs variables (e.g., material
attributes and/or process parameters) and their relationship
various variables
with the CQAs. Interaction plots can be used to illustrates these
 Determine acceptable ranges of critical process parameters relationships
contributing to identification of a design space
 Data supporting justification of design space, which can include
Basic steps involved in DoE approach are as follows: but not limited to historic knowledge base, conclusions from
QRM and experimental studies.
1. Defining input and output variables and range: Based on prior
knowledge and risk assessment the input variables and their range  The relationship between the proposed design space and other
can be defined. Screening design like full or fractional factorial unit operations or process steps.

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 Results and conclusions of the studies, if any, of a design space International Forum Process Analytical Chemistry (IFPAC) meeting,
across different scales. Dr. Daniel Peng from FDA reported that there is a steady increase
multiple elements of QbD in recent ANDA filings (Table 5).
 Justification that the control strategy ensures that the
manufacturing process is maintained within the boundaries Table 4: QbD implementation in recent ANDA filings
defined by the design space.
Month/year % ANDA including multiple QbD element
E] Control Strategies June 2012 24.6
July 2012 25.5
ICH Q10 defines a control strategy as “a planned set of controls August 2012 53.3
derived from current product and process understanding that October 2012 62.5
assures process performance and product quality. The controls can January 2013 82.9 (as of 1/13/2013)
include parameters and attributes related to drug substance and
drug product materials and components, facility and equipment However, three key observations were found in the recent QbD
operating conditions, in process controls, finished product based ANDA filling-
specifications and the associated methods and frequency of
monitoring and control.” A control strategy ensures that the process 1. Exhaustive information being presented with no justification or
is maintained within the boundaries described by design space. interpretation of data. Often there were no conclusions from
the data presented.
Specifically, the control strategy may include [26]: 2. Improper use of basic QbD terminology, such as CQA’s, CPP’s
and, in particular, design space.
1. Control of input material attributes (e.g., drug substance, 3. Prior knowledge is often presented without necessary context
excipients, primary packaging materials) based on an or justification for its use.
understanding of their impact on process-ability or product
quality. Such issues may indicate an ineffective communication and
2. Product specifications collaboration between FDA and generic drug companies in regards
3. Procedural controls to QbD implementation. It is expected that as the time will progress,
4. Facility controls, such as utilities, environmental systems and more effective knowledge database will be developed and

 operating conditions communicated from both sides that can help in resolving these
5. Controls for unit operations that have an impact on critical issues.

 downstream processing or end-product quality (e.g. the
impact of drying on degradation, particle size distribution of Advantage of implementing QbD
the granulate on dissolution) 1. The ability to design products and processes and bring fewer
6. A monitoring program (e.g., full product testing at regular setbacks at critical stages such as scale-up, validation, and
intervals) for verifying multivariate prediction models. transfer.
It is important to appreciate that when developing a control 2. Since the operation is working in a well-defined design space, it
strategy, a manufacturer can consider implementing single or allows greater flexibility of adjusting variables within such
multiple points of control for a specific CQA, depending on the risk space.
associated with the CQA and the ability of individual controls to 3. Greater regulatory flexibility based on a science-based
detect a potential problem. For example, with sterilized drug approach to risk management.
substances or biotechnological/biological products, there is an 4. Ability to continue to optimize and improve the manufacturing
inherent limitation in the ability to detect low levels of bacterial or operation without facing additional regulatory filings or
viral contamination in the drug substance[27]. In these cases, scrutiny.
endproduct testing is considered to provide inadequate assurance of 5. Faster time to market and reduced rework, resulting in
quality, so additional points of control (e.g., attribute and in-process reduced costs and increased revenues.
controls) are incorporated into the control strategy.
Challenges
QbD and ANDA
1. Lack of understanding regarding the pharmaceutical process is
Historically, FDA ensured high quality of generic drug products by
the cause and also the major limitation for Qbd
requiring two fundamental evidences during ANDA filling-
implementation. Pharmaceutical companies are traditionally
pharmaceutical equivalence and bioequivalence. Drug products are
tuned to care more about the end product, with little emphasis
considered pharmaceutical equivalents if they contain the same
on the science-based understanding of the process involved.
active ingredient(s), are of the same dosage form, route of 2. Collaboration and consensus between field inspectors and the
administration and are identical in strength or concentration.
FDA review and compliance sectors on how to handle QbD
Bioequivalence, on the other hand, refers that the rate and extent of
remains an unmet challenge.
absorption of the test drug has no significant difference with that of
3. The majority of pharmaceutical companies feels that there is a
the reference drug, when administered at the same molar dose
need for a more tangible guidance on how to actually implement
under similar experimental conditions in either a single dose or
QbD. Companies wanted clarification from FDA on QbD
multiple doses. terminologies, acceptable methods, criteria to select and deselect
While this approach has been successful, it should be acknowledged critical quality attributes, standards by which to judge adequacy
that majority of generic drug products approved under this of controls, and criteria for analytical method substitution.
paradigm were solution and immediate release oral products, which 4. There is a need for greater cooperation across multiple
are inherently simple in design [28]. Drug products, however, have disciplines within the company, including process
increased in design complexity to encompass modified (oral) release development, manufacturing, and quality control for effective
products, transdermal delivery systems, medical devices and other implementation of QbD.
complex dosage forms. As these drug products have increased in 5. Pharmaceutical companies also feels that QbD would slow time
complexity, especially in likes of modified release products, to file approval application, or could provide unnecessary
transdermal delivery systems and medical devices, the review information to the regulatory authority that might create an
paradigm to ensure the quality of generic products must also evolve obstacle in the approval process.
to provide assurance of high quality in generic drug products [28].
In this regards, from January 2013, FDA has implement QbD into CONCLUSION
their Abbreviated New Drug Applications (ANDA). Despite the initial
QbD is an essential tool that fosters process understanding that is
resistance from the pharmaceutical companies, in the recent
pivotal in assuring product quality and performance. It

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