Quality by Design relies on the use of certain tools. These
include prior knowledge, risk assessment, mechanistic models, design of
experiments and data analysis, and process analytical technology.
Prior Knowledge
As per ICH guidelines, prior knowledge is the information or
knowledge or skills that have been acquired through previous experience of
similar processes and published information. This tool can be used at the
beginning of the developmental process and may be regularly updated using data
generated during the process. Prior knowledge can be applied as a part of
control strategies, in relation to QTPP and CQAs. However, it is important to
avoid too much reliance on prior knowledge as it may result in a loss of
control over the manufacturing process. It is best to use this tool to confirm
data rather than to build data from scratch.
Risk Assessment
As per ICH Q9, quality risk management must be done before
development studies to detect the high-risk variables that have an impact on
drug product quality. Risk evaluation must be done on the basis of scientific
knowledge and is often used to determine critical variables. These variables
must then be further investigated through experimentation, so that a control
strategy may be established.
Some of the common risk assessment tools used are
flowcharts, fault tree analysis, failure mode effects analysis, hazard analysis
and critical control points, risk ranking and filtering, etc.
FMEA and HACCP
Failure Mode Effect Analysis (FMEA): Failure mode
refers to defects or errors in material, equipment, design, or process. After
establishing these failure modes, the tool evaluates their effects and ranks
them in order of priority. This method may also include a study of how critical
the consequences of the failures are. Sometimes, Ishikawa diagrams
(fishbone/cause-and-effect) are also used.
Hazard Analysis and Critical Control Points (HACCP):
Hazards that can cause safety and quality issues are identified (for example,
hygiene of personnel, material flow, environmental aspects, process design, and
manufacturing steps). Preventive measures for each of these are established.
Next, critical control points are determined for these hazards, and limits are
established. A system is set up to monitor these critical control points, and
corrective actions to be taken when these are not in a state of control, are
determined. Finally, record-keeping systems are set up to monitor and confirm
that the HACCP system itself is working as expected.
Design of Experiments
This tool involves setting up a series of structured tests
where changes to the variables of a process are made in a planned manner. Then,
the impact of these changes on a chosen output is assessed. This tool is very
effective in identifying all the factors that together impact the output
responses. The interaction of the variable factors can also be quantified.
Process Analytical Technology (PAT)
The US FDA defines PAT as “A system for designing,
analyzing, and controlling manufacturing through timely measurements (i.e.,
during processing) of critical quality and performance attributes of raw and
in-process materials and processes, with the goal of ensuring final product
quality.
PAT allows real-time monitoring of CMAs, CPPs, or CQAs to
demonstrate that the process is in a state of control. It enables online
measurements that are very useful to detect failures and also allows adjustment
of the operational parameters when variations that have a negative impact on
product quality are detected.
PAT includes a wide variety of tools to acquire physical,
chemical, microbiological, analytical, and mathematical data and risk analysis.
By creating an interface of process with instrument, and also a feedback loop
that can modify processing conditions, PAT helps to control process parameters
as well as product quality.
Advantages of QbD:
1. Better assurance of product quality due to improved
process design and better quality risk management during the manufacturing
process.
2. Innovation increased efficiency and reduced the potential
for errors leading to cost savings.
3. Improves regulatory compliance and streamlines change
management.
4. Real-time testing during the process ensures faster
releases as compared to traditional end-testing of finished products.
Challenges to QbD:
1. Requires cultural change in the organizational approach
to quality.
2. Expensive, requires management support.
3. Calls for collaboration between departments and there may
be resource/workload limitations.
In conclusion, we can understand QbD as a quality system
that helps to manage the life cycle of a product. It aims at designing a
capable process through better product and process understanding and through
this, hopes to reduce the risk of patients taking drug products. The emphasis
in QbD is on continuous improvement, building on past experience, using risk
management approaches, and documenting knowledge to achieve high-quality drug
products that consistently meet their quality specifications.