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CASE STUDY

CQA Assessment

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 global regulatory initiative for enhancing pharmaceutical development. CQAs is an important first step for QbD development of biopharmaceuticals, and it becomes a regulatory requirement for market submission.

Ø CQA assessments can: 

• Guide product life cycle management, continuous improvement of process and product quality 
• Guide the setting of product specifications 
• Guide process characterization: risk assessment, design space, control strategies…


3. How to do CQA assessment

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

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

 • Product variants and process-related impurities represent two categories that will be assessed on a product-specific basis 

 • The common practice of criticality assessment is to employ a scoring system based on two factors: impact and uncertainty. Theses two factors are scored independently against different scales. The two values are then multiplied to assign a risk score for each product quality attribute 

 • Non-bioactive process components can be considered for their potential safety risk by evaluating an impurity safety factor (ISF = LD50 ÷ Level in Product Dose) 

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


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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 ATAs, the score for immunogenicity 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 SAEs (SAE: serious adverse event) during the A-Mab clinical trials, none of which could be directly attributed to the level of aggregate. In addition, 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), so aggregates are assigned a risk score of 60 and considered a very high risk quality attribute.

CASE STUDY