The elements of QbD include:
1. Quality Target Product Profile (QTPP) – it identifies the
CQAs of drug products.
2. Product design and identifying Critical Material
Attributes (CMAs).
3. Process design and identifying Critical Process
Parameters (CPPs). This includes linking the CMAs and CPPs with CQAs.
4. Controls strategy: developing specifications for active
pharmaceutical ingredients (APIs), excipients, and final drug product; also
controls for every step of the production process.
5. Process capabilities and continued improvement.
The flow of events in QbD
Quality Target Product Profile (QTPP):
Study impact of CMAs on CQAs Identify CPPs QTPP is a summary
of the quality parameters that must be present in the drug product to ensure
the desired quality is achieved. This is the basis on which product design will
commence. When formulating the QTPP, the points to be considered include:
1. The intended use of the product, its route of
administration, desired dosage form, and system used for drug delivery.
2. Strength of the dose.
3. Container-closure system to be used.
4. Release of the therapeutic component and factors that
will influence pharmacokinetic parameters (such as dissolution of drug) in the
proposed dosage form.
5. Quality criteria for the final product – stability,
purity, sterility, drug release, etc.
Critical Quality Attributes (CQAs):
After finalizing the QTPP, it is possible to identify the
CQAs of the drug product. CQAs are properties of the finished product –
physical, chemical, biological, or microbiological – that must lie within a certain
range, limits, or distribution, to ensure that the desired quality of the product
is attained.
Some examples of quality attributes of drug products include
the identity of the drug, assay values, content uniformity, drug release
profile, degradation products, microbial levels, moisture content, and physical
properties such as size, color, shape, and friability. Not all of them may be
critical attributes. Whether an attribute is critical or not depends upon the
severity of the damage that will be caused if the product falls outside the
acceptable range for that particular attribute.
Product Design:
A well-designed product meets patients’ requirements and
this can be confirmed through clinical studies. Such a product will maintain
its performance throughout its shelf life, and this can be confirmed by
stability studies. Thus, product design must be geared towards developing a
robust product that delivers the desired QTPP over the entire shelf life of the
product.
For good product design, it is important to study the
following in detail:
• Physical, chemical, and biological characteristics of the
drug (examples: particle size, polymorphism, solubility, melting point, pKa,
oxidative stability, partition coefficient, bioavailability, membrane
permeability, etc.).
• Type of excipients and their grade, and details of
intrinsic excipient variability (common excipients such as binders, diluents,
disintegrants, glidants, coloring agents, sweeteners, suspending agents, film
coatings, preservatives, flavors, etc.).
• Interactions of drug substances with excipients by
carrying out drug-excipient compatibility testing.
• The critical material attributes (CMAs) of both drug and
excipients to ensure the development of a robust formulation.
CMA vs CQA
CMA: Physical, chemical, biological, or
microbiological characteristics of raw material that must lie within
appropriate limits or range to ensure desired quality.
CQA: Physical, chemical, biological, or
microbiological characteristics of drug product intermediates or finished
drug products that must lie within appropriate limits or range to ensure
desired quality.
Process Design:
The manufacturing process for a drug product is made up of a
set of unit operations run in a particular sequence, to give the final product.
The term unit operation refers to any activity where there is a physical or
chemical change in the substance. Milling, mixing, granulation, drying, tablet
compression, and coating, are all examples of unit operations in tablet
manufacture.
Processes must be designed in such a way that each unit
operation is performed as expected to deliver the necessary product. For this,
it is important to:
(a) Identify the critical causes of variations.
(b) Manage these variations during the process.
(c) Predict quality attributes of the product with accuracy
and reliability.
Any parameter whose variability can have an adverse impact
on a CQA is critical to the process and is called a Critical Process Parameter
(CPP). All CPPs for a given process must be first identified; then they must be
monitored and regulated to make sure that desired quality products are
produced.
Process robustness studies must be performed to check if the
process can tolerate variability in the input materials and processing
parameters and still deliver a product of acceptable quality. These studies
will also serve to identify CPPs that have an impact on drug quality.
Evaluation of CMAs, CPPs, and CQAs for unit operation of
tablet compression
|
CMAs |
CPPs |
CQAs |
|
Particle size
distribution Proportion of oversize/fines Shape of granules Cohesive
properties Hardness Density values – bulk/tapped/true Electrostatic
properties Brittleness Moisture content Polymorphism |
Type of press
Design of hopper, vibration, height Feed mechanism 0-force feed/gravity feed,
rotational direction Tool design – metal quality, score configuration Maximum
punch load Pressing speed Compression force (pre, main) Penetration depth of
punch Dwell time Ejection force |
Appearance of
tablet Tablet weight and uniformity Hardness Friability Content uniformity
Thickness Tablet density/porosity Defects Disintegration time Moisture
content Dissolution profile |
How to understand processes?
1. List all process parameters that may impact the process
performance
2. Using scientific knowledge and risk assessment, identify
the potentially high-risk parameters
3. Establish ranges for these high-risk potential parameters
4. Design and carry out experiments to test these parameters
5. Obtain experimental data and analyze it using first
principle models to confirm how critical the process parameter is. Connect CPPs
and CMAs to CQAs wherever possible
6. Develop a control mechanism by defining acceptable ranges
for critical parameters and non-critical parameters.
Control Strategy:
The data generated during developmental studies must be used
to set up a control strategy. It is common to have controls at three levels as
follows:
Level 1: Automated engineering controls are used for
real-time monitoring of CQAs of the output materials. The system is designed to
monitor the input material attributes and adjust the process parameters
automatically so that CQAs consistently meet the predetermined acceptance
criteria. Process Analytical Technology (PAT) systems are an example of this
type of control.
Level 2: Here, the emphasis is on understanding the
process and product, and designing it with control over the pharmaceutical
process. This is QbD and it allows the control of variables, and thus, ensures
drug product quality.
Level 3: This strategy depends on detailed testing of
end-products as seen in conventional pharmaceutical manufacturing. As the
sources of variability have not been identified, and there is no study of CMAs
and CPPs on the quality of drug products, the likelihood of product problems is
high.
In real-life situations, it is best to combine level 1 and
level 2 control strategies to arrive at a hybrid approach that involves:
1. Controlling attributes of input material based on a study
of their impact on product quality and processability.
2. Establishing product specifications.
3. Controlling unit operations that have the biggest impact
on product quality.
4. Testing in-process, in real-time instead of relying on
end-product testing.
5. Setting up a monitoring program to verify control over
the process and product.
Process Capability and Continued Improvement:
Process capability is a measure of the level of inherent
variability shown by a stable process that is under control when compared with
the established acceptance criteria. Variability may be short-term or
long-term, and the QbD program must result in the identification and reduction
of the variations that impact the quality of the product.
Continuous improvement methods need to be adopted to remove
these sources of variability. This includes several activities in different
phases such as:
1. Defining the problem and setting up specific goals
2. Measuring key areas of the process and collecting
necessary data
3. Data analysis to find cause-effect relationships
4. Use results of data analysis to optimize the process
5. Perform pilot runs to check optimized process
capabilities
6. Monitor processes to make sure they stay in a state of
statistical control