Comparability study Summary of Biologics Comparability Studies

Apr 28,2025

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In the R&D process and post-approval stage of biological products, changes in the production process are inevitable. Reasons for changes include improving the production process, increasing scale, improving product stability, and making changes according to regulatory requirements. When the production process changes, quality, safety and effectiveness of the product may be affected, which requires manufacturers to comprehensively evaluate the relevant quality characteristics of the product to prove that the change has no adverse effect on the safety and effectiveness of the stock solution and preparation, so as to successfully obtain the recognition and approval from regulatory authorities.

Regulatory requirements for comparability studies

Comparability study serves as the foundation and key to the success of the pharmaceutical changes evaluation in biological products. In order to provide companies with better guidance when managing process changes, including more effective communication with regulatory agencies, drug regulatory agencies around the world have issued several different regulatory guidelines, including:

ICH Q5E <Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process>

FDA <Comparability Protocols for Post-approval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA , or BLA >

EMA <Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process>

In addition, the State Food and Drug Administration issued the Technical Guidelines for the Development and Evaluation of Biosimilars, which is also of great guiding significance for guiding the conduct of comparability studies.

What is a comparability study?

The purpose of the change is to determine whether the change in the production process has any adverse effects on the product by collecting and evaluating relevant data, so as to ensure the quality, safety and effectiveness of the product after the production process change. Comparability studies determine whether non-clinical studies and clinical studies conducted using the product before the change are still relevant to the product after the change by evaluating the differences in quality that may affect the safety and effectiveness of the product. Ideally, comparability of product quality before and after the change can be confirmed. However, if it can not be confirmed, or in the case of significant differences affecting safety and effectiveness of the product, additional non-clinical and /or clinical bridging experiments are required to prove comparability.

Comparability does not necessarily mean that the quality characteristics of the products before and after the change must be the same. Nevertheless,the safety, identification, purity and activity of the products should be highly similar and can be fully predicted based on existing knowledge to ensure that any differences in quality characteristics will not have an adverse effect on the safety or efficacy of the drug preparation.

Risk assessment

The types of process changes range from minor changes to major changes. For minor changes, the risk of comparable products unavailability is low, while major changes also have a certain risk of such kind. In order to determine whether a comparability study is needed, and if so, how to determine the depth of the comparability study, ICH is generally used. The risk assessment process outlined in Q9 is used for assessment.

Risk assessment helps determine the scope of comparability studies, assists in batch selection, analytical methods, and studies need to be conducted (e.g., extended characterization, forced degradation, etc.). Risk assessment should focus on the product and its characteristics.

Table 1.Lists some comparability risks and their requirements for study content

Comparable research content

Batch selection

 Product development stage,  type of changes, as well as the understanding the process and product need to be considered when deciding the number of batches to include in the comparability study. Although the use of multiple batches can demonstrate process robustness, it may be unfeasible or unnecessary, especially for projects in the development phase.

Description of the research batches in the guidance document is not clear. The FDA recommends comparing and testing multiple separate product batches in parallel; while the ICH Q5E stipulates that for products already on the market, appropriate batches should be analyzed for the changed products to demonstrate process consistency.

For major changes, ≥ 3 batches of commercial-scale samples are generally selected after the change; Whereas for medium changes, that number is 3 . Minor changes can be studied with fewer batches, which number is generally ≥1 batch.

To cut the number of batches in a comparability study(using bracketing, matrix approach, etc.), or scale down the study (except for changes to scale up), sufficient justification should be provided on the basis of science and risk assessment.

Acceptable Standards

Prospective acceptance criteria should be established. The acceptance criteria for comparability studies does not necessarily translate into quality standards. Acceptable criteria should be set based on historical data of process and product quality, and sufficient reasons shall be presented for excluding any data. The set acceptance criteria cannot be lower than the quality standard unless it is proven to be reasonable. According to the nature of the research method, the acceptance criteria for comparability studies can be divided into quantitative criteria and qualitative criteria. Quantitative criteria must meet the scope requirements, while qualitative criteria are based on the comparison of the charts.

When evaluating the acceptance criteria for a changed product, basic principles for setting quality standards in ICH Q6B shall be considered. For instance, the impact of changes on validated manufacturing processes, characterization study results, batch analytical data, stability data, nonclinical and clinical experience.

Refer to Table 2 for acceptable standards for comparability studies

Table 2. Acceptable standards for comparability studies

Comparison of process performance

The process comparability study is mainly to prove the robustness of the process and the consistency between batches , so that the processes and intermediate products (before and after the change) are comparable, the process control after the change is not lower than that before the change.

Many factors should be considered in process evaluation, including process steps, process parameters, comparison of process control results with historical data, as well as comparison of additional process control parameters (if necessary). If it can be proved that a single change has no impact on subsequent processes and products, the validation can be limited to the affected process steps; if there is an impact on subsequent processes, the subsequent steps should be validated.

Attention should be paid to the comparability of ability to remove relevant substances, impurities and exogenous factors before and after change in production process. If necessary, verification of virus removal/inactivation effects, intermediate product preservation studies, service life studies of filter membranes and chromatography columns should be carried out. Meanwhile, verification of the impact of extractables and leachables of disposable products on product quality should also be performed.

Comparison of quality

The quality comparison data used for comparability studies usually come from routine batch release testing and extended characterization, comparing the quality of the changed product with historical data. When the change of the stock solution affects the finished product, a comparability study of the quality of the stock solution and the finished product should be carried out simultaneously.

Table 3.Lists the commonly used Mab stock solution release detection items

In addition to routine release testing, extended characterization analysis testing is also performed to more comprehensively detect the impact of product changes on safety and efficacy, or to obtain a more detailed assessment of the molecular structure changes in the product after the change. Commonly used extended characterization analysis methods are mainly used to analyze the primary structure, secondary structure and higher-order structure, charge isomers, glycosylation, oxidation and purity of the product. Since these analytical methods are more complex than the conventional methods used for product testing and release, plus there is not enough historical data for comparative analysis of products before and after the change, head-to-head comparative analysis is usually used.

Comparison of stability

Stability studies can detect subtle differences which cannot be detected by structural confirmation studies. Similarly, when changes to the stock solution affect the drug product, stability studies of both the stock solution and the drug product should be conducted. The stability program should include stability studies under accelerated conditions, real-time conditions, and forced degradation studies if applicable. ICH Q5E emphasizes "necessary stability data, including stability data under accelerated or forced degradation conditions, to gain a deeper understanding of potential differences in product degradation pathways and the resulting potential differences in product-related substances and product-related impurities."

Accelerated, especially forced degradation stability studies, by producing relatively high degradation levels, allow head-to-head comparisons of batches before and after changes in a short period of time, which can better establish product degradation trends, as well as compare degradation products and degradation kinetics.

Comparability studies conducted earlier may not require forced degradation studies.

Comparability bridging study

Quality characteristic studies. When quality data are insufficient to determine comparability, additional evidence can be obtained from nonclinical and clinical studies. The non-clinical and clinical studies involved in Q5E include pharmacokinetic ( PK ) studies, pharmacodynamic ( PD ) studies, clinical effectiveness studies, specific safety studies, immunogenicity studies and pharmacovigilance studies.

The scope and type of non-clinical and clinical studies should be analyzed based on specific issues based on different factors. The main factors to be considered are the following three points: First, the results of quality studies. For example, new impurities may require further toxicology studies. Second, understanding of the product. Specifically, the relationship between product quality attributes, safety and effectiveness, as well as product mode of action and site of action, etc. Third, the existing non-clinical and clinical data of the product. For example, the risk posed on a certain disparity may be higher for long-term administration than for short-term administration; subcutaneous injection is more likely to cause immunogenicity than intravenous injection, etc.

Comparable research results

（1） For data based on product quality characterization studies meet predefined acceptance criteria, no additional studies are required.

（2） For differences in the product quality attribute research data (before and after the change), in the case when manufacturer can prove the difference has no adverse effect on safety and efficacy based on the understanding of the molecule and scientific knowledge, additional research may not be required even if the quality attributes (before and after the change) exceed the predefined acceptance standards.

（3） If comparability cannot be established merely based on assessment of quality data, further nonclinical and/or clinical studies are required to demonstrate comparability (before and after the change).

（4） If all research data cannot prove the comparability of the products(before and after the change), the changed product should either be developed as a new product or changed process implementation shall be terminated.

References

ICH Q5E <Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process>

FDA <Comparability Protocols for Post-approval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA , or BLA >

EMA <Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process>

NMPA " Technical Guidelines for Pharmaceutical Change Studies of Marketed Biological Products (Trial) "

NMPA "Technical Guidelines for Pharmaceutical Research and Changes of Biological Products during Clinical Trials (Trial)"

NMPA Technical Guidelines for Clinical Comparability Studies of Preventive Vaccines

The Development of Therapeutic Monoclonal Antibody Products: A Comprehensive Guide to CMC Activities from Clone to Clinic