BP702T Industrial Pharmacy II 1

Syllabus
Quality management systems:
Quality management & Certifications: Concept of Quality, Total
Quality Management, Quality by Design (QbD), Six Sigma concept, Out
of Specifications (OOS), Change control, Introduction to ISO 9000
series of quality systems standards, ISO 14000, NABL, GLP

Short Abbreviation used

ICH- International Conference on Harmonization
QbD- Quality by Design
FDA- Food and Drug Administration
QbT- Quality by testing
CGMP-current Good Manufacturing Practice
CMC-Chemistry Manufacturing and Control
TPP-Target Product Profile
CQA-Critical Quality Attributes
CPP-critical Process Parameter
DOE-Design of Experiments
PAT-Process Analytical Technology
NIR-Near Infra Rays
R&D-Research And Development

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QUESTION ANSWER

1. What is Qbd? What are the essential elements in Qbd?

 Quality by Design (QbD) is one of the most important initiative by US FDA.
 QbD principles have been adopted by the US Food and Drug
Administration (FDA) for the discovery, development, and manufacture
of drugs.
The three ICH guidelines which throw light upon quality-by-design and
related aspects include
 Q8 Pharmaceutical development,
 Q9 Pharmaceutical risk management and
 Q10 Pharmaceutical Quality systems.
 In fact, the ICH guideline Q8 is sub-divided into two parts: part one deals
with pharmaceutical development and Part II is the annex to the
guideline which states the principles for Quality-by-Design.

 According to ICH Q8(R2) guideline, Quality by Design (QbD) is “A

systematic approach to development that begins with predefined
objectives and emphasizes product and process understanding and

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Process control, based on sound science and Quality Risk

Management”
Elements of QbD
It involves the following key elements during pharmaceutical
development
Define the Quality Target Product Profile
Identify the Quality Attributes
Perform a Risk (Assessment) Analysis
Determine the Critical Quality Attributes and Critical Process
Parameters
Determination of Design Space
Identify a Control Strategy
Life cycle Management and Continuous improvement

 There are several statements about the elements of QbD, the most widely
accepted is that, QbD consists of the following parameters.

 Quality Target Product Profile (QTPP): including dosage form,

delivery systems, dosage strength(s), etc. It is a prospective summary of
quality characteristics of a drug product to be achieved, taking into
account dosage strength(s) and container closure system of the drug
product, together with the attributes affecting pharmacokinetic
characteristics (e.g., dissolution, aerodynamic performance) and drug
product quality criteria (e.g., sterility, purity, stability and drug release)
appropriate for the intended marketed product.
 Critical Quality Attributes (CQAs): including physical, chemical,
biological, or microbiological properties or characteristics of an output
material including finished drug product. Potential drug product CQAs
derived from the QTPP and/or prior knowledge are used to guide the
product and process development and they should be within an
appropriate limit, range, or distribution to ensure the desired product
quality.

 Critical Material Attributes (CMAs): including physical, chemical,

Biological, or microbiological properties or characteristics of an input
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material. CMAs should be within an appropriate limit, range, or

distribution to ensure the desired quality of that drug substance,
excipient, or in-process material.
 Critical Process Parameters (CPPs): parameters monitored before or
in process that influence the appearance, impurity, and yield of final
product significantly.
During the QbD process, product design and understanding include the
identification of CMAs, which are different from CQAs. CQAs are for
output materials while CMAs are for input materials including drug
substance, excipients, in-process materials.
While process design and understanding include the identification of
CPPs and a thorough understanding of scale-up principles, linking CMAs
and CPPs to CQAs is of special importance.
From the viewpoint of QbD, CMAs and CPPs can vary within the
established Design Space without significant influence on CQAs, and as a
Result, the quality of the final product will meet the QTPP.
Performing Risk Assessment
 It is nothing but linking material attributes and process parameters to
CQAs.
 ICH Q9 Quality Risk Management indicates that, the manufacturing and
use of a drug product necessarily lead to some degree of risk.
 The evaluation of the risk of quality should be based on scientific
knowledge and link to the therapeutic benefit to the patient.
 The level of effort, formality and documentation of the quality risk
management process should be proportionate with the level of risk.
 Performing a risk assessment before pharmaceutical development helps
manufacturers decide which studies to conduct.
 Study results determine which variables are critical and which are not,
which then guide the establishment of control strategies for in-process,
raw-material, and final testing.

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Tools used in the risk assessment included the Ishikawa or Fishbone

diagram, failure mode effect analysis (FMEA), Pareto analysis.
An Ishikawa or Fishbone diagram is used to identify all potential
variables, such as raw materials, compression parameters, and
environmental factors, which can have an impact on a particular CQA
such as tablets hardness.
An FMEA can be used to rank the variables based on risk (i.e., a
combination of probability, severity, and detectability) and to select the
process parameter with higher risks for further studies to gain greater
understanding of their effects ion CQAs
Identify Control Strategy
ICH Q8 (R1) defines control strategy as: “A planned set of controls, derived
from current product and process understanding that ensures process
performance and product quality”.
The controls can include parameters and attributes related to drug substance
and drug product materials and components, facility and equipment operating
conditions, in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control.
Particularly, the control strategy may include:
 Control of raw material attributes (e.g., drug substance, excipients
and primary packaging materials) based on an understanding of
their impact on process-ability or product quality.
 Product specifications
 Procedural controls
 Facility controls such as utilities, environmental systems and
operating conditions
 Controls for unit operations that have an impact on downstream
processing or end-product quality (e.g. the impact of drying on
 degradation, particle size distribution of the granulate on
dissolution)
 A monitoring program (e.g., full product testing at regular
intervals) for verifying multivariate prediction models.

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 The Control Strategy should establish the necessary controls based on

patient requirements to be applied throughout the whole product life
cycle from product and process design through to final product, including
API and Drug Product manufacture, packaging anddistribution
Life cycle Management and Continuous improvement
 After approval, CQAs are monitored to ensure that the process is
performing within the defined acceptable variability that served as the
basis for the filed process design space.
 The primary benefit of an expanded process design space would be a
more flexible approach by regulatory agencies.
 In the QbD paradigm, process changes within the design space will not
require review or approval. Therefore, process improvements during the
product life cycle with regard to process consistency and throughput
could take place with fewer post approval submissions.
 In addition to regulatory flexibility, the enhanced understanding of the
manufacturing process would allow more informed risk assessment as
per ICH Q9 regarding the affects of process changes and manufacturing
deviations on product quality.
 Manufacturing experience grows and opportunities for process
improvement are identified, the operating space could be revised within
the design space without the need for post-approval submission.
 Over the lifetime of a product, process changes may be required to be
made and may require process characterization, validation and filing of
the changes to the approved process design space.
2. Define various terminology related to QbD
QTPP (Quality target product profile)
QTPP has been defined as a “prospective and dynamic summary of the quality
characteristics of a drug product that ideally will be achieved to ensure that the
desired quality, and thus the safety and efficacy, of a drug product is realized”.
Critical Quality Attribute (CQA):

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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 (ICH Q8) Drug Product / Drug Substance.
Critical Process Parameter (CPP):
A process parameter whose variability has an impact on a critical quality
attribute and therefore should be monitored or controlled to ensure the process
produces the desired quality (ICH Q8).
Critical Material Attribute (CMA)
Starting materials, Raw materials, Excipients, Packaging materials etc.
RLD (Reference Listed Drug)
A Reference Listed Drug (RLD) is an approved drug product to which new
generic versions are compared to show that they are bioequivalent. A drug
company seeking approval to market a generic equivalent must refer to the
Reference Listed Drug in its Abbreviated New Drug Application (ANDA).
By designating a single reference listed drug as the standard to which all
generic versions must be shown to be bioequivalent, FDA hopes to avoid
possible significant variations among generic drugs and their brand name
counterpart”.
RLD is generally the innovator drug product (“Brand”) which is marketed on
the basis of a full dossier (e.g., New Drug Application) that includes chemical,
biological, safety, clinical efficacy, labeling, etc.
A standard RLD may avoid possible significant variations among generic drug
products and their brand name counterparts.
Design Space
The ICH Q8(R2) States that the design space is multidimensional combination
and interaction of input variables (e.g., material attributes) and process
parameters that have been demonstrated to provide assurance of quality.
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.

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Application of DOE in QbD helps in gaining maximum information from a

minimum number of experiments.
Risk Assessment
Quality risk management is a systematic process for the assessment, control,
communication and review of risks to the quality of the drug (medicinal)
product across the product lifecycle.
The initial list of potential parameters which can affect CQAs can be quite
extensive but can be reduced and prioritized by quality risk assessment (QRA).
Risk Management
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 product lifecycle”.

3. What are Key characteristics or features of QbD

 A tool for focused & efficient drug development
 Dynamic and systematic process
 Relies on the concept that Quality can be built in as a continuum
 It is applicable to Drug Product and Drug Substance development
(chemicals / biologics)
 It is applicable to analytical methods
 Can implemented partially or totally
 Can be used at any time in the life cycle of the Drug
 Always encouraged by Regulators.

4. What are the Advantages of QbD to the Generic Industry

 Better understanding of the process and the product.
 Minimum batch failures.
 Better understanding of risks involved & mitigation.
 Minimizing variations to achieve consistency in manufacturing quality.

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 An enhance QbD approach to pharmaceutical development provides

opportunities for more flexible regulatory approaches for example:
Manufacturing changes within the approved design space can be without
regulatory review or approval.
 Reduction of post-approval submissions.
 Greater regulator confidence of robust products.
 Innovative Process Validation approaches.
 More drug availability and less recalls from market.
 Improved yields, lower cost, less investigations, reduced testing, etc.
 Timely launch of products.
 Right first time & every time concept.
 Continuous improvement over the total product life cycle.
 Real time Release thru PAT implementation.
 Return on investment

5. What are the stages are involved in development of QbD based product
development OR Briefly explain the brief Overview of Quality by Design
Process
 Quality by Design is a scientific risk based holistic and proactive approach to
pharmaceutical development.
 It involves the designing and planning of a drug product and process before
actual experiment.
 Over the past several years, pharmaceutical scientists have provided several
more specific definitions of the elements of quality by design and a draft of an
annexure to ICH Q8 has been released
Briefly a QbD development process includes stages as described below:
 A target product profile describes the use, safety and efficacy of the
product. Defining a target product quality profile is used by formulators
and process engineers as a quantitative surrogate for aspects of clinical
safety and efficacy during product development.

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 Drawing together relevant prior knowledge about the drug substance,

potential excipients and process operations into a knowledge space. Use
a risk assessment to prioritize knowledge gaps for further investigation.
 Designing a formulation and identify the critical material attributes of
the final product that must be controlled to meet thetarget product
quality profile.
 Designing a manufacturing process to produce a final product having
critical material attributes.
 Identifying the critical process parameters and raw material attributes
that must be controlled to achieve critical material attributes of the final
product. Use of risk assessment to prioritize process parameters and
material attributes for experimental veriffication. Combine prior
knowledge with experiments to establish a design space or other
representation of process understanding.
 Establishing a control strategy for the entire process that may include
input material controls, process controls. The control strategy should
encompass expected changes in scale and can be guided by a risk
assessment.
 Continuous monitoring and updating the process to assure consistent
quality.

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6. What are the Potential applications of QbD approach in product development

lifecycle? Or discuss the applicability of Qbd in pharmaceutical product
development
 Drug substance besides formulation development, the QbD concept has
now permeated into other vital areas of pharmaceutical development
including drug substance development, analytical method development,
dissolution testing, stability testing, bioequivalence testing, clinical trials,
etc.
 A formulation scientist can even continue to derive QbD benefits after a
product’s commercial launch and post-marketing surveillance.
 A brief account on QbD implementation at various product development
stages is given as follows (also pictorially depicted in Figure .
Drug excipient development
 The quality of finished products depends on the use of high quality raw
materials, which includes drug substance and excipients.
 Variability in these raw materials produces end-products with highly
variable quality, and so implementing QbD principles helps to improve
the quality of raw materials supplied by the vendors to pharmaceutical
manufacturers.
 The key CMAs of drug substance include particle size, physical form,
polymorphism, moisture content and flow properties, which impact the
disintegration, dissolution, compaction and compression characteristics
as the CQAs. Likewise, the key CMAs of excipients include particle size,
shape, viscosity grade, moisture content, Flowability, etc., which also
significantly influence the aforementioned CQAs.
Moreover, the specifications enlisted in ICH Q11 guidance are applicable to QbD
requirements for drug substance development along with critical measures on
chemistry, manufacturing and control processes.

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Analytical method development

 Use of a robust analytical method is essential for hassle-free monitoring
of quality and accelerating the product development process.
 QbD principles, in this regard, facilitate the development of highly robust
analytical methods based on predefined objectives or quality target
method profile.
 Critical method variables (CMVs) are identified on the basis of critical
analytical attributes for attaining enhanced method performance for
continuous improvement within the design space.
 In a nutshell, QbD provides a framework to identify the source of
variability and reduce it during analytical method development, thus
going beyond the traditional ICH recommended validation process.

Dissolution testing

 Considered as a quality control tool, dissolution testing helps to

monitor the drug release profile of dosage forms.

 This helps the manufacturer to make decisions in qualifying the

batches on the basis of release criteria. In this regard,

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establishment of a discriminating, robust and predictable

dissolution method is imperative.

 A QbD approach provides greater flexibility during dissolution

development by optimizing the influence of multiple factors, such
as media type, composition, volume, apparatus selection and
operating conditions on drug release performance.

 Regulatory agencies today demand highly robust drug products

with an in vitro dissolution performance close to that of the
reference listed product, so establishing a predictable in vitro/in
vivo correlation for the accomplishing biowaivers.

Bioequivalence testing
 Bioequivalence tests are used for the final assessment of the in vivo
product performance and to evaluate the plausibility of matching
between the generic product and reference product.

 Vital pharmacokinetic metrics such as the Cmax and AUC ratio

between the test and reference products must be within the
regulatory acceptance limit of 80%-125% for bioequivalence.

 In this regard, QbD furnishes formulation development by

establishing a link between the input product and process
parameters to optimise the in vivo performance.
 The concept has limited regulatory importance owing to the lack of
practical understanding in establishing direct correlation between
the in vitro and in vivo product performance parameters.

Clinical trials
 The application of QbD principles to clinical trials is one of
the most recently investigated scenarios.

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 Such an approach examines the design and objectives of a clinical trial

protocol by identifying the ‘critical to quality’ factors and managing the
impact of risk on trial quality.
 Since high expenditures are incurred from clinical trials, federal agencies
have been emphasizing the current opportunities with QbD risk-based
monitoring of clinical studies to help bring about the best possible scientific
outcomes for product safety and efficacy
Q-7 What are tool are involved in Quality Risk management ? Discuss in detail
various tools .
 The FDA defines a Risk Management as, a strategic safety program designed
to decrease product risk by using one or more interventions or tools.
 It is systematic process for the assessment, control, communication and
review of risks to the quality of the drug product across the product lifecycle
 Overview of a typical quality risk management process is given in 1.
 The ICH Q9 guideline: Quality Risk Management provides a structure to
initiate and follow a risk management process. The relevant tools of QRM are
as follows:

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 Failure mode effects analysis (FMEA)

FMEA is one of the most commonly used risk-assessment tools in the
pharmaceutical industry. It is a systematic and proactive method to identify and
mitigate the possible failure in the process. Failure modes represent any
errors or defects in a process, material, design, or equipment. Once failure
modes are established, FMEA tool evaluates the effect of these failures and
prioritizes them accordingly. This tool is further advanced with studying
criticality of the consequences and providing clear indication of situation.
 Failure Mode, Effects and Criticality Analysis (FMECA)
It is the extension of earlier said FMEA tool. Extending FEMA to incorporate an
investigation of the degree of severity of consequences, their probabilities of
occurrence and their detect-ability is Failure mode, effects and criticality
analysis.
In FMECA, each failure mode of the product is identified and then evaluated for
criticality.
This criticality is then translated into a risk, and if this level of risk is not
acceptable, corrective action must be taken.
This can be utilized for failure and risk associated with manufacturing
processes. The tool can also be used to establish and optimize maintenance
plans for repairable systems and/or contribute to control plans and other
quality assurance procedures.
As part of FMEA, a risk score or Risk Priority Number (RPN) may be assigned
to the deviation or to the stage of the process that is affected; this helps to
categorize the deviation. RPN is calculated by multiplying Probability (P),
Detectability (D) and Severity (S), which are individually categorized and
scored. Rating scales usually range from 1 to 5.
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
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- Fault tree analysis (FTA)

This tool assumes failure of the functionality of a product or process. The
results are represented pictorially in the form of a tree of fault modes. This can
be used to investigate complaints or deviation in order to fully understand their
root cause and ensure that intended improvement will resolve the issues and
not cause any other different problem.
- Hazard analysis and critical control points (HACCP)
HACCP provides detailed documentation to show process or product
understanding through identifying parameters to control and monitor. The
definition of hazard includes both safety and quality concern in a process or
product. It involves hazard analysis, determining critical control point,
establishing critical limit, establishing a system to monitor critical control point
and establishing a record keeping system.
This might be used to identify and manage risk associated with physical,
chemical and biological hazards.
The output of a risk assessment may be a combination of quantitative and
qualitative estimation of risk.

Write note on DESIGN SPACE

 ICH Q8 (R2) defines Design space as, the multidimensional combination and
interaction of input variables (e.g. material attributes) and process
parameters that have been demonstrated for provide assurance of quality.
 It will Working within the Design space is not be considered as a change,
Movement out of the Design space it is considered to be a change and would
normally initiate a regulatory post-approval change process.
 Design space is proposed by the applicant and is subject to regulatory
assessment and approval.
 Thus Design space is potentially scale and equipment dependent, the Design
space determined at the laboratory scale may not be relevant to the process
at the commercial scale.
 Space verification at the commercial scale becomes essential unless it is
demonstrated that the Design space is scale-independent.
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 For the development and refinement of the Design Space it begins at product
conceptualization and continues to evolve throughout the lifecycle of the
product.
 At the time of filing a submission, the Design Space can be considered to be a
snap-shot in the time of representative of the current process knowledge.
 It continues to evolve as additional knowledge and information is generated
during the commercialization of the product, which may lead to post-
approval changes.
 Movement out of the Design Space is considered to be a change and would be
normally initiate the regulatory post approval change process.
 A design space would be constructed for a single unit operation and multiple
unit operations, or for the entire process.
For the Submission of a design space to FDA is a pathway for obtaining the
ability to operate within that Design space without further regulatory approval.
 Reduction for post-approval submissions.
 Better innovation due to the ability to improve processes without
resubmission to the FDA when remaining in the Design Space.
 It more efficient technology transfers to manufacturing.
 Greater regulator for confidence of robust products.
 It gives Risk-based approach and identification.
 Innovative process for validation approaches.
 Less intense for regulatory oversight and less post-approval submissions.
 For the consumer, it gives greater drug consistency.
 It gives more drug availability and less recall.
 It Improved yields, lower cost, less investigations, reduced testing, etc.
 It takes Time to market reductions: from 12 to 6 years realized by amongst
others.
 First time right: lean assets management.
 It is Continuous improvement over the total product life cycle (i.e. controlled,
Patient guided variability).
 Absence of the design freeze (no variation issues).
 It takes less validation burden.
 Real time controls (less batch controls)

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