1. What is Analytical Comparability? Why is it important?

• Manufacturing process changes are inevitable in the life cycle of biologics. When a process change occurs, the essential first step is to establish whether quality attributes are comparable between the pre- and post-change products. This is established by various analytical studies, known as analytical comparability. 

• ICH Q5E: A determination of comparability can be based on a combination of analytical testing, biological assays, and, in some cases, nonclinical and clinical data. If a manufacturer can provide assurance of comparability through analytical studies (analytical comparability) alone, nonclinical or clinical studies with the post-change product are not warranted.

Risk-based Hierarchy of Comparability Assessment

PK: pharmacokinetics; PD: pharmacodynamics; CMC: chemistry, manufacturing and controls

• The application of the comparability varies depending on the clinical stage, and the scope and extent of the comparability will also depend on the nature of the process changes. HJB has extensive experience in process improvement and analytical comparability studies, which can help you to improve your process and facilitate smooth regulatory approval for process changes at any clinical development stage.

Reference:

1. Alexandre Ambrogelly, et. atl. Analytical comparability study of recombinant monoclonal antibody therapeutics. Mabs. 2018, Vol. 10, NO. 4, 513–538.

2. Fig. from: Yanli Zhuang, et. al. Risk-Based Comparability Assessment for Monoclonal Antibodies During Drug Development: A Clinical Pharmacology Perspective. The AAPS Journal (2018) 20: 109.

2. How to perform Analytical Comparability

Ø Risk assessment for CMC change

Risk assessment is a key component when perform process changes and comparability studies. It helps define the scope/extent of analytical comparability studies, driving the selection of lots & analytical methods, and the study scope (e.g., extended characterization, stress study).

Ø Typical analytical comparability study includes: 

• Batch Analysis: Utilize historical batch release/test data as the source of batch analysis data. Set acceptance criteria for the comparability study based on an evaluation of the release data using appropriate statistical approach, especially for late-stage comparability studies if sufficient batches are available. 

• Extended characterization: Review historical data to compare batches pre- and post- change. If any characterization method shows significant variation, consider side-by-side testing. Set acceptance criteria based on both quantitative and qualitative evaluations. 

• Long-term, Accelerated Stability and Stress Study: Compare the stability profile pre- and post- change using long-term and accelerated stability data. Conduct stress studies to allow a side-by-side comparison of pre- and post-change lots. Set acceptance criteria based on both quantitative (degradation kinetics) and qualitative (degradation pathways) criteria.

• Process Performance Comparison: Evaluate results from the analysis of relevant samples from appropriate stages of the manufacturing process (e.g. intermediate stages, etc.) as recommended by ICH Q5E.

Ø End to end services for process change

With a mature development & manufacturing platform for antibody products and a deep understanding of relevant guidelines, HJB has successfully performed a variety of analytical comparability studies across many projects. HJB offers services to help clients to improve existing processes and obtain regulatory approval for the process changes.

Ø Case Study: major mAb product process, change in phase I/II, FDA/NMPA filing 

• Client Objective: Required a significant increase in productivity to decrease cost of goods by transitioning process change from fed-batch to perfusion mode while ensuring quality attributes remain comparable. 

• HJB Solution: Developed a highly productive process leveraging its "Plug and Play" and "Push to High" perfusion platform. Implemented a culture mode change from fed-batch to intensified perfusion, resulting in an 8 ~ 10 times increase in productivity. Additionally, by changing the cell culture media from commercial to in-house developed media, the overall cost of goods reduced by approximately 50%. 

• HJB conducted a systematic risk assessment based on the characteristics of the change, followed by designed and successful execution of a comprehensive analytical comparability study. 

• Demonstrated good consistency in terms of primary & higher order structure, obligatory CQAs, purity, product-related variants, process-related impurities, biological & functional activities, as well as stability profiles (long-term, accelerated and stress condition). 

• The process change was successfully approved by FDA and NMPA.