Study of Critical Quality Attributes (CQAs) of RLD

Introduction of CQAs

Deviations in the quality attributes of generic drugs can affect product performance and even threaten patient safety. Among a series of quality attributes of generic pharmaceuticals, ICH defines some of them as critical quality attributes (CQAs) that determine the effectiveness or safety of a product. The CQAs of the product is an indispensable index in the consistency evaluation, which can be used to evaluate the quality of the product. Therefore, in the development of generic drugs, CQAs need to be controlled within appropriate limits, ranges or distributions to ensure desired product quality.

All attributes that make up CQAs of a product are divided into two parts:

• Quality Attributes (QAs), which are contained in quality standards
• Process Attributes (PAs), which are affected by process consistency.

Different Reference Listed Drugs (RLDs) have different CQAs that are usually associated with APIs, excipients, intermediates and drug products. For example, CQAs of small-molecule drugs will affect the purity, drug release and stability of the drug, and the CQA of biologics will affect the final clinical safety and efficacy of the product.

Figure 1. Flow chart of analytical similarity assessment process following a QbD strategy. (Erhui, Z.; et al. 2020)

Application of Study of CQAs of RLDs

• Raise quality standards of the generic drugs
• Investigate the link between product attributes and expected clinical performance
• Predict the potential patient impact of RLDs

Importance of CQAs for the Consistency Evaluation of Generic Drugs

In order to be approved by the FDA, the CQAs of a candidate generic drug must be within specified ranges compared to the originator reference drug. However, the determination of CQAs is difficult, time-consuming, and costly, often requiring an interdisciplinary team to perform with experts from multiple fields. Alfa Chemistry provides QCAs study services for RLDs to demonstrate the quality consistency of your manufactured generic drugs and RLDs.

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Figure 2. Workflow of Study of CQAs of RLDs.

Identification of CQAs

Multivariate analysis methods are powerful tools to determine the sensitivity of an attribute to changes in product quality in the quantification of the impact of CQA on drug quality, Alfa Chemistry's expert teams identify all potential CQAs of the RLD manufacturing process using multivariate analysis by employing a combined strategy of factor analysis, one-way ANOVA, and cluster analysis.

Determination of CQAs

In general, scientists identify potential CQAs and use them to guide the manufacturing process for generic drug products. At Alfa Chemistry, our experts determine optimal CQAs using the following process:

• First, we characterize different batches and shelf life of RLD separately;
• Then, CQAs are selected based on their probable impact on potency and clinical safety;
• Finally, their criticality scores are given, respectively.

CQAs are identified based on:

• Clinical characteristics of RLD
• RLD Product label
• In-vitro drug release and physicochemical characteristics

Risk Assessment and Scoring of Potential CQAs

We rank the list of potential CQAs to determine how their variation affects the quality of the RLD by using quality risk management guidelines outlined by ICH Q9. Moreover, risk ranking and filtering methods are used to assess the impact of these CQAs on pharmacokinetics (PK), pharmacodynamics (PD), and safety, among others.