Biosimilar reference medicinal product (RMP) regulatory requirements: China, US and EU comparison

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

On September 9, 2024, the Center for Drug Evaluation (CDE) at the China National Medical Products Administration (NMPA) released a new guidance, "Questions and Answers on Biosimilar Pharmaceutical Similarity Research (Draft for Comments)"¹. This document clarifies the NMPA’s current regulatory requirements for a biosimilar Reference Medicinal Product (RMP) in China. NMPA joins the European Medicines Agency (EMA) ^{2, 3} and the United States (US) Food and Drug Administration (FDA) ⁴ in establishing regulatory expectations in this area. 

Considering the increased focus on global synchronized development for biosimilars, we compare the regulatory requirements for biosimilar reference medicinal products (RMPs) in the lead markets such as China, the US, and the European Union (EU) in this blog.  RMP-related items are assessed in relevant markets, ensuring any exceptions, or specific requirements, are outlined in “Remark” section. 
 

Table 1. Comparison of regulatory requirements relating to biosimilar RMP in China, the US, and the EU

Abbreviations used:
API = Active Pharmaceutical Ingredient
FDA = Food and Drug Administration (US and others)
IND = Investigational New Drug application (US)
NDA = New Drug Application (US and others)
MAA = Market Authorized Application (EU)
BLA = Biologic License Application (US)
CMC = Chemistry, Manufacturing and Controls
US = United State
USA = United States of America
EU = Europe Union
EEA = European Economic Area
CGMP = Current Good Manufacture Practice 

As shown in Table 1, there are several areas of commonality across the regulatory authorities in China, the US, and the EU which can help in global development planning. To investigate the specific details of the differences in regulatory requirements for biosimilar development, we have developed further assessments. The considerations below can support companies planning biosimilar development in understanding the complex global regulatory requirements and include recommendations for early R&D and clinical planning. 

Formulation consistency

Regarding the formulation of the biosimilar candidate product, the NMPA recommends that the formulation should be consistent or similar to the RMP. If a difference is inevitable (e.g. proprietary excipient or formulation), there should be strong justification, comprehensive formulation development data, and necessary risk assessment information. Safety risks should not be introduced due to changes in the formulation, including but not limited to the use of excipients with viral contamination risks, potential health impacts caused by excipients, or adverse effects on the stability of the formulation.

In the EU and US, the formulation of the biosimilar should be selected considering state-of-the-art technology and does not need to be identical to that of the reference medicinal product.³ Deviations from the RMP as regards formulation or excipients require justification.²

Source of RMP for CMC similarity study 

The NMPA guidance states that the RMP used in the CMC similarity studies should come from the target market, i.e., China. The biosimilar developer is encouraged to start collecting RMP as early as possible according to the research and development plan. In China, when it is difficult to obtain RMP (perhaps due to insufficient supply or only a few batches being produced) for global biosimilar development, foreign sources of RMP can be used in combination with Chinese RMP for the biosimilarity assessment under the premise of confirming the similarity between the RMPs from different countries/regions. For RMP that has been approved for marketing abroad but not in China, and sponsor would like to conduct clinical trials in China, it is allowed to use RMP from other countries/regions for CMC similarity studies.  

In the US and EU, an RMP with a license/marketing authorization in the US/European Economic Area (EEA) should be used for the CMC similarity assessment. In the EU, combined use of non-EEA authorized comparator and EEA authorized RMP is acceptable for the development of the Quality Target Product Profile (QTPP) of the biosimilar product.^₃

Clinical study RMP 

According to the NMPA’s "Announcement of the National Drug Administration on Matters Related to the Import of Original Research RMP for Biosimilar Clinical Studies (2019 No. 44)", it is possible to utilize an RMP manufactured at a site that differs from the site included in the Chinese license. Currently, in addition to data from the CMC similarity study, the biosimilarity package should also include data from relevant non-clinical and/or clinical studies to comprehensively demonstrate biosimilarity in PK/PD aspects.  

For a biosimilar targeted to the US or EU market, the clinical studies can use a non-locally sourced product, but this must be analytically bridged to product sourced from the non-local market. These bridging studies need to include clinical PK data comparing locally sourced RMP with the RMP used in the comparative efficacy trial. From a quality perspective, the bridging studies should rely on the same statistical approach as the biosimilarity quality comparison.

EU guidelines further require that if using non-EEA authorized RMP in clinical and non-clinical studies, in addition to bridging data these RMPs should be sourced from a region applying similar scientific and regulatory standards as the EMA (e.g. ICH countries) and the biosimilar developer will need to demonstrate that the comparator is representative of the product authorized in the EEA.² 

Multiple Strength RMP 

The NMPA guidance states that when the protein concentration, formulation, and container closure system of an RMP are the same, but the RMP is available in different strengths, a representative strength of RMP, or a combination of multi-strength RMP, can be used for the CMC similarity studies while stability studies can be simplified if justified, such as using bracketing, etc. However, when there are differences in the presentation or composition (e.g., protein concentration, formulation, and container closure system) between different strengths of RMP, comparison should be performed against the corresponding strength RMP. 

In the EU, if several RMP strengths are available the biosimilar developer must justify the strengths that are selected for the biosimilarity exercise. In the US, a multi-dosage form strategy can be justified, but must include a sufficient number of batches of different dosage strength for the CMC similarity study.  Bracketing approaches can be implemented in cases where the RMP is supplied in a range of different injection volumes or mg API amounts.

Manufacture date of RMP

As per NMPA guidance, the biosimilar developer should ensure that the RMPs are transported, stored, and used under conditions that do not affect their quality and stability. Considering the potential impact of storage time, it is recommended to choose the age of the candidate product as close as possible to the age of RMP for head-to-head CMC similarity studies. If it is necessary to use a RMP stored under more severe conditions (such as long-term freezing) for the CMC similarity study. Sufficient data should be also provided to prove that the storage conditions will not affect the product quality. 

This approach (i.e. using frozen expired RMP) is also outlined in FDA guidance⁴; however, the EMA has not yet formally detailed this approach as acceptable. The stability profile comparison between the biosimilar and RMP should come from same age of products. 

It is desirable to source product over a prolonged period to fully capture the RMP quality range, especially if this drifts over time. RMP can be stored for subsequent analytical use in a deep freeze (i.e. -70oC), split into aliquots within new containers, even after expiry. This will allow capture of a longer time period for the RMP quality range.  

Number of batches required for CTA/IND:

The exact number of test product batches required to be studied in the CMC similarity study in support of a clinical trial application, varies by region.  To support clinical trial approval in China, it is recommended by the NMPA to use at least three batches of the proposed biosimilar, manufactured by the intended commercial process and scale. At licensure, if development batches (i.e., pre-commercial batches – manufactured with an earlier process) are involved, data from these can be used as reference after confirming their representativeness to the commercial material. The RMP should include at least six batches of samples, among which some characterization items can be reduced to three batches for the RMP including: molecular weight, amino acid sequence coverage, circular dichroism, glycosylation sites, thermal stability analysis, infrared spectroscopy, fluorescence spectroscopy, the test results rely on the amino acid sequence and spatial structure of the drug. It is recommended to use at least three representative batches of candidate product and RMP for impurity spectrum comparison research. Stability studies should use at least three representative batches of candidate products and three batches of RMP for accelerated stability (six months) comparative research and forced degradation comparative research. For preparations with complex administration processes or that can be administered multiple times, in-use stability study should also be carried out.

In the EU, for a proposed biosimilar undergoing clinical development, there is no formal EMA position on the number of batches required for similarity to support a CTA application. As a reminder, EMA does not have a role in the authorization of clinical trials in the EU. Biosimilars undergoing clinical development must satisfy the same CMC requirements as any investigational biological product as per guidance⁶. Where, again, the number of batches that needs to be included is not stated.

In the US, there is no stated number for innovator batches the IND stage, but three is a good start as an understanding of the quality range needs to be started. 

Number of batches required for BLA/MAA

For quality attributes such as purity, isomers, and glycosylation modifications that are highly affected by the process and fluctuate extensively, the number of batches of candidate product and RMP should meet the minimum statistical requirements for establishing equivalence models. The NMPA guidance states that at least six batches of candidate products manufactured by the defined process and scale and at least 10 batches of RMP should be used for CMC similarity studies. Based on relevant experience, we do recommend a higher number, especially for quantitative assays, in order to obtain reasonable statistics in the similarity study.  The RMP for qualitative assays can be reduced to a lower number, for example six batches. The batch requirements for impurity profile and stability study are the same as for a clinical trial application.

In the US, individual assays are categorized as high, medium and low risk, depending on the quality attribute. High and medium risks assays apply quality range statistics to the comparison between the biosimilar and US RMPs. Low risk items (e.g.  amino acid sequence confirmation or qualitative assays) can be performed on fewer independent batches.  Thus, the number of batches need to be designed to allow meaningful statistics.

In the EU, the Agency have not defined a minimum number of batches to be included except that ‘multiple’ batches of RMP must be tested to investigate its underlying quality range⁵.

As a good business risk reduction practice when performing quality range statistics for qualitative assays, a larger number is recommended than as stated as absolutely required by guidance documents. 

Quality attribute similarity studies

For China, when different geographic sources of RMP are used in the biosimilarity studies, a stratified analysis approach should be used for the different sources of RMP (i.e. data from each source should be presented separately). If there are no significant differences between RMP from different sources, the test results for these can be combined into one data set for statistical analysis. Attention should be paid to the quality attribute range of the RMP used in clinical trials (i.e., clinically qualified), which serves as an important basis for establishing similarity criteria.

In the EU, while the use of non-EEA authorized RMP is acceptable for developing a QTPP or in certain clinical and in vivo studies (if supported by an analytical bridge to EEA-authorized RMP) the combining of analytical or clinical test results from RMPs sourced from different regions is not recommended in any formal guidance. This data should therefore be presented separately.  

In the US, innovator reference product should be sourced from the US market.

New impurities or impurities level higher than in the RMP 

Due to differences in raw materials, host cells, production processes, etc., new impurities not identified in the RMP may be found in the candidate product, or impurity content may be slightly higher than the existing impurities in the RMP.

Requirements are unified here from all the authorities, and sufficient analysis should be carried out in combination with non-clinical and/or clinical research data to prove that novel or increased impurities do not affect the safety and/or immunogenicity profile of the biosimilar.  Generally, impurity levels should be well within the release criteria of the RMP, especially for safety-related quality attributes like aggregate and HCP levels.

Conclusions

The RMP for biosimilars is a critical factor in influencing the successful development and registration of biosimilar medicinal products. Companies frequently seek global marketing approval, with China, the US, and the EU being priority regions. Understanding the similarities and differences in regulators’ requirements for biosimilar RMPs can greatly assist companies to more efficiently and effectively plan their CMC and clinical studies.  

Parexel has extensive experience in biosimilar development. Our subject matter experts include former regulators from the NMPA, FDA and EMA who have demonstrated success in navigating the complex biosimilar landscape.  With our deep knowledge of global biosimilar regulatory requirements, Parexel’s Regulatory Consulting group can help you with selecting and justifying your RMP, to support biosimilar product approval. For your questions about biosimilar product development, please contact us – we are always available for a conversation.

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References

1. Notice on Publicly Seeking Comments on "Questions and Answers on Biosimilar Pharmaceutical Similarity Research (Draft for Comments)" (https://www.cde.org.cn/main/news/viewInfoCommon/3f486fd60c1128311af3d4c6dac50f6a)
2. Similar biological medicinal products - Scientific guideline (https://www.ema.europa.eu/en/similar-biological-medicinal-products-scientific-guideline)
3. Similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues - Scientific guideline (https://www.ema.europa.eu/en/similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active-substance-quality-issues-scientific-guideline)
4. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry (May 2019) (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-therapeutic-protein-biosimilars-comparative-analytical-assessment-and-other-quality)
5. Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development (EMA/CHMP/138502/2017). https://www.ema.europa.eu/en/statistical-methodology-comparative-assessment-quality-attributes-drug-development-scientific-guideline
6. Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials - Revision 2 (EMA/CHMP/BWP/534898/2008 Rev. 2) https://www.ema.europa.eu/en/requirements-quality-documentation-concerning-biological-investigational-medicinal-products-clinical-trials-scientific-guideline

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