1. What is CQA (Critical Quality Attributes)

Ø Definition in ICH Q8 (R2): 

A CQA is 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.

Ø CQA Categories: 

Taking antibody products (mAb, BsAb, etc.) as an example, (potential) CQA can be divided into three categories:

(1) Product specific variants: Size, charge, post-translational modifications, higher order structure variants…

(2) Process-related impurities: HCP, DNA, protein A leachate, raw materials (media, buffers), leachables…

(3) Obligatory CQA: Composition and strength (pH, osmolality, quantity…), adventitious agents (bioburden, mycoplasma, endotoxin…), Other (appearance, particulates)…

2. Why Do CQA Assessments

Quality by Design (QbD) is a systematic approach to pharmaceutical development that emphasizes understanding and controlling manufacturing processes to ensure product quality. It is based on sound science and risk management principles. One of the crucial components of QbD is the identification and management of Critical Quality Attributes (CQAs).

Ø Benefits of CQA Assessments: 

Lifecycle Management & Improvement:

• Guides lifecycle decisions and process optimizations.

Setting Specifications:

• Defines quality standards and ensures regulatory compliance.

Process Characterization:

• Enables targeted risk assessment, defines design space, and informs control strategies.

Summary:

Decision-Making: Prioritizes key attributes.

Regulatory Alignment: Aids in approvals.

Efficiency: Focuses on critical controls, reducing issues.

Patient Safety: Ensures consistent, effective products.

CQA assessments are essential for high quality, compliance, and better patient outcomes in biopharmaceuticals.

3. How to Conduct A CQA Assessment

 • CQA assessment is a cyclic and phased activity based on product& process knowledge and clinical experience 

 • CQAs are defined early in development prospectively based on the quality target product profile (QTPP). Identification and selection of CQAs begins with compiling a comprehensive list of relevant product attributes that may impact product quality 

 • Product variants and process-related impurities are two categories assessed on a product-specific basis 

 • The common practice of criticality assessment employs a scoring system based on two factors: impact and uncertainty. These factors are scored independently on different scales, and the values are multiplied to assign a risk score for each product quality attribute 

 • Non-bioactive process components can be assessed for their potential safety risk by evaluating an impurity safety factor (ISF), which is calculated as follows: ISF = LD50 ÷ Level in Product Dose

This formula compares the lethal dose for 50% of the population (LD50) to the concentration of the impurity in the product dose. 

 • The overall result is a list/report of quality attributes along a criticality continuum

Reference:

1. Nadja Alt, et. al. Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals, 2016, 44 (5): 291-305

2. A-Mab: a Case Study in Bioprocess Development, Version 2.1

Ø Case Study: Aggregation

• Aggregation is a common behavior for protein molecules in aqueous solution, here we give an example using A-Mab:

• Because A-Mab aggregates have been purified and demonstrated to have no significant impact on potency, the score for biological activity/efficacy is 6 (2 for no impact and 3 for in vitro data for this molecule). 

• Aggregates have the potential to have a moderate impact on PK based on literature data, so the score for PK/PD is 60 (12 for impact and 5 for literature data). 

• Because aggregates have been present in A-Mab clinical lots and there were limited anti-therapeutic antibodies (ATAs), the immunogenicity score is 8 (4 for low impact and 2 for the uncertainty rank being based on A-Mab specific clinical trials). 

• There have been a small number of serious adverse events (SAEs) during the A-Mab clinical trials, none of which could be directly attributed to the level of aggregate. Additionally, there is no known safety risk of aggregate independent of immunogenicity. Safety is scored as 8 (4 for low impact (acknowledging SAEs) and 2 for the basis that A-Mab aggregates have been in clinical trials). 

• The highest score is 60 (for PK/PD). Therefore, aggregates are assigned a risk score of 60 and considered a very high risk quality attribute.