The term critical quality attributes (CQAs) refers to the objectives established for some of the relevant physical, chemical, biological, or microbiological properties of a drug substance, which must be within appropriate limits or ranges in order for the products to acquire quality.
A CQA is not merely any quality test item in a specification. It is critical because it refers to the risk that is posed to product safety, effectiveness, or quality. One is able to link a CQA identification process with Quality Target Product Profile (QTPP), product development, process understanding, and control strategy creation as per the ICH Q8(R2).
Possible quality attributes are then determined based on scientific knowledge, prior knowledge, experiments, and Quality Risk Management (QRM).
When dealing with such a dosage form as an immediate release tablet, possible quality attributes may include:
This is especially true for development reviews where the list of attributes labelled “critical quality attribute” is long the process is undermined and does not contribute to an initiation of the process of quality-by-design (QbD).
A critical process parameter (CPP) is defined as a parameter that may influence one or more CQAs and that, therefore, must be monitored or controlled to guarantee adequate quality of the outputs.
As an example, suppose we determine the dissolution of a tablet to be the CQA. Depending on the formulation and the process used, factors affecting dissolution may include granulation, compression force, hardness of the tablet, lubricant amount, or any coating conditions.
It is important to point out that the parameter should not be deemed to be critical just because it appears in the batch production document. There should be proof of a connection between the parameter and the relevant CQA.
The International Conference on Harmonization (ICH) provides a definition of the relationship between material attributes, process parameters, and CQAs in its guideline Q8(R2).
Despite the fact that the two concepts are somewhat interconnected, their meanings differ.
The CQA is a characteristic of the product whose importance lies in aspects of safety, quality, or efficacy. Meanwhile, a specification represents a series of tests, analytical procedures, and acceptance criteria indicating whether the product meets certain standards.
In particular, ICH Q8 Implementation Material states the fact that it is not necessary for all CQAs to be included in the specifications. A CQA is controlled by means of upstream material and process controls, in-process testing, and at the technological level of the manufacturing process.
Such points are especially important in analyzing the controlling actions. The company must provide evidence of quality control actions rather than relying on the tests and results of the finished product.
An evaluation should factor in the scientific basis of the characteristic along with its potential implications for patients. According to ICHQ9(R1), quality risk management must be grounded in scientific understanding and closely linked to patients' safety.
In the course of carrying out the risk assessment, there are three main points I would be looking for:
1. Scientific reasoning: What is the basis for believing that the attribute's variations may affect the product quality?
2. Impact on the patient/product: What would happen if the attribute deviates from its target?
3. Evidence: What supports the categorization of the attribute like prior experience, tests done during development, or modeling?
Utilizing specialized risk management tools, such as Failure mode and effects analysis (FMEA), is good practice, but it should not be regarded as a substitute for effective scientific reasoning.
A common failing of assessments is framing the FMEA score as the ultimate verification.
The FDA's process validation approach uses lifecycle thinking and includes process design and process qualification integrated into an overall methodology for ensuring effective process control.
In the process validation phase, the rules must incorporate CQAs into the criteria for acceptance and the monitoring strategy. For the CPV, CQAs provide an insight into whether the process is under control or not.
An example may illustrate how a single observation can be misleading. The fact that the result complies with the standards may not be enough to conclude that all is in order with the process. By looking at the gradual change in dissolution, impurities, assay, or consistent content, one may consider the increasing variability of the process even before the actual control deficiency arises.
Hence, statistical tracking approaches become more valuable than just relying on the pass/fail results alone.
The development documentations, risk assessment documents, validation documents, method of control, specifications, analytical procedures, and continuous process verification documentation should tell us a similar technical narrative.
If a Qualitative Analyst has classified a certain process as critical, there must be a clear understanding of:
According to the ICH guideline, classifying critical quality attributes and critical process parameters is a dynamic process.
This means that periodic review does not just aim to find if there are any changes in qualities of product or process. If there is any evidence that would influence the understanding of the process, CQA evaluation has to be changed accordingly.
An advanced pharmaceutical organization does not only have a list of CQAs. It also knows the meaning of every CQA, the factors determining them, their significance for the product, and how their parameters may vary over time in a controlled manner. This cycle-based approach can empower CQAs to be used not only for GMP compliance but also for effective pharmacological manufacturing.
The Process of Identifying Critical Quality Attributes
Identifying Critical Quality Attributes (CQAs) usually begins with understanding the Quality Target Product Profile (QTPP). The first step relates to understanding the desired outcome of the product by considering aspects such as dosage form, route of administration, strength of the product, stability, bioavailability, and the purpose of using the product.Possible quality attributes are then determined based on scientific knowledge, prior knowledge, experiments, and Quality Risk Management (QRM).
When dealing with such a dosage form as an immediate release tablet, possible quality attributes may include:
- Assay and uniformity of content
- Dissolution
- Related substance and degradation
- Identity
- Content water percentage
- Microbial quality where applicable
- Other attributes that could impact product quality
This is especially true for development reviews where the list of attributes labelled “critical quality attribute” is long the process is undermined and does not contribute to an initiation of the process of quality-by-design (QbD).
Understanding CQAs with Relation to Material Properties
To comprehend CQAs better, one of the most effective methods is to examine their link to material properties as well as process parameters.A critical process parameter (CPP) is defined as a parameter that may influence one or more CQAs and that, therefore, must be monitored or controlled to guarantee adequate quality of the outputs.
As an example, suppose we determine the dissolution of a tablet to be the CQA. Depending on the formulation and the process used, factors affecting dissolution may include granulation, compression force, hardness of the tablet, lubricant amount, or any coating conditions.
It is important to point out that the parameter should not be deemed to be critical just because it appears in the batch production document. There should be proof of a connection between the parameter and the relevant CQA.
The International Conference on Harmonization (ICH) provides a definition of the relationship between material attributes, process parameters, and CQAs in its guideline Q8(R2).
Criticality and Specification are not One and the Same
One of the greatest misconceptions regarding quality control lies in assuming that all specifications are CQAs and vice versa.Despite the fact that the two concepts are somewhat interconnected, their meanings differ.
The CQA is a characteristic of the product whose importance lies in aspects of safety, quality, or efficacy. Meanwhile, a specification represents a series of tests, analytical procedures, and acceptance criteria indicating whether the product meets certain standards.
In particular, ICH Q8 Implementation Material states the fact that it is not necessary for all CQAs to be included in the specifications. A CQA is controlled by means of upstream material and process controls, in-process testing, and at the technological level of the manufacturing process.
Such points are especially important in analyzing the controlling actions. The company must provide evidence of quality control actions rather than relying on the tests and results of the finished product.
Using Risk Assessment to Establish CQAs
Quality risk management (QRM) is frequently used to determine potential critical quality attributes (CQAs) as well as which characteristics deserve critical consideration.An evaluation should factor in the scientific basis of the characteristic along with its potential implications for patients. According to ICHQ9(R1), quality risk management must be grounded in scientific understanding and closely linked to patients' safety.
In the course of carrying out the risk assessment, there are three main points I would be looking for:
1. Scientific reasoning: What is the basis for believing that the attribute's variations may affect the product quality?
2. Impact on the patient/product: What would happen if the attribute deviates from its target?
3. Evidence: What supports the categorization of the attribute like prior experience, tests done during development, or modeling?
Utilizing specialized risk management tools, such as Failure mode and effects analysis (FMEA), is good practice, but it should not be regarded as a substitute for effective scientific reasoning.
A common failing of assessments is framing the FMEA score as the ultimate verification.
CQAs During Process Validation and Continued Process Verification
CQAs play a role in pharmaceutical business even after the development phase of the medication's manufacturing process is over. They act as a springboard connecting the productivity of the process with the quality of the drug delivered.The FDA's process validation approach uses lifecycle thinking and includes process design and process qualification integrated into an overall methodology for ensuring effective process control.
In the process validation phase, the rules must incorporate CQAs into the criteria for acceptance and the monitoring strategy. For the CPV, CQAs provide an insight into whether the process is under control or not.
An example may illustrate how a single observation can be misleading. The fact that the result complies with the standards may not be enough to conclude that all is in order with the process. By looking at the gradual change in dissolution, impurities, assay, or consistent content, one may consider the increasing variability of the process even before the actual control deficiency arises.
Hence, statistical tracking approaches become more valuable than just relying on the pass/fail results alone.
What QA Should Look for During a CQA Review
From the point of view of Qualitative Analysis, the quality assessment should be coherent all throughout the life cycle involved in product production.The development documentations, risk assessment documents, validation documents, method of control, specifications, analytical procedures, and continuous process verification documentation should tell us a similar technical narrative.
If a Qualitative Analyst has classified a certain process as critical, there must be a clear understanding of:
- What will cause it to vary
- Which material properties are important
- Which parameters are important
- How it can be controlled
- How it can be measured
- What the consequences are in case of negative trend in the process
CQAs Must Evolve with Product Knowledge
The identification of CQAs is not always a linear process. New data from manufacturing operations, issues, stability testing, process control, investigation, as well as other regulatory processes could contribute to the better understanding of CQAs.According to the ICH guideline, classifying critical quality attributes and critical process parameters is a dynamic process.
This means that periodic review does not just aim to find if there are any changes in qualities of product or process. If there is any evidence that would influence the understanding of the process, CQA evaluation has to be changed accordingly.
An advanced pharmaceutical organization does not only have a list of CQAs. It also knows the meaning of every CQA, the factors determining them, their significance for the product, and how their parameters may vary over time in a controlled manner. This cycle-based approach can empower CQAs to be used not only for GMP compliance but also for effective pharmacological manufacturing.
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