About the Author
Regulatory Editor
Published by regulatory affairs team in PharmaKnowl, Riyadh office.
Biosimilars (BS) provide cost-effective alternatives to biologics while maintaining similar efficacy and safety. The Saudi Food and Drug Authority (SFDA) has established a regulatory framework for biosimilars registration, ensuring the safety, efficacy, and quality of the approved product. With a growing market, biosimilars are expected to contribute significantly to value-based healthcare advancements in the region.
In this post, we focus on the quality considerations for biosimilars; for other types of drugs, you may refer to our articles on drug Registration.
Table of contents
Regulatory Landscape
Due to the complexity of biological molecules, biosimilar approval is tightly regulated. Regulatory agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require manufacturers to demonstrate comparability to reference product (RP) through extensive studies on structure, biological activity, efficacy, safety, and immunogenicity.
The FDA’s Biologics Price Competition and Innovation Act (BPCI Act) of 2009 established an abbreviated pathway for BS, allowing approval based on demonstrated similarity rather than full clinical trials. Similarly, the EMA’s biosimilar guidelines established in 2003 set stringent comparability standards to ensure equivalent quality and performance.
The SFDA follows a globally aligned approach, combining regulatory reliance with independent scientific assessment to maintain high safety and efficacy standards in biosimilar approvals.
Biosimilars Registration in SFDA
The SFDA has established a comprehensive regulatory framework to ensure the safety, efficacy, and quality of biosimilar products entering KSA.
A key requirement is the comparability assessment, where manufacturers must demonstrate BS equivalence to the RP through structural and functional analyses. The authority defines quality/CMC requirements for obtaining marketing authorisation (MA) and ensuring manufacturers submit complete data for both drug substances (DS) and drug products (DP).
Additionally, the Comparative Quality Exercise (CQE) is required as part of the electronic common technical document (eCTD) submission, with supporting data included in Module 2 (Quality Overall Summary) and Module 3 (Quality/CMC dossier) of the marketing authorisation application (MAA).
Development and Manufacturing Key Considerations
The SFDA outlines biosimilar development and requires documentation across two key areas:
I. Molecular Characteristics and Quality Attributes (QA)
The molecular characteristics and QA of the target product profile should be comparable to the RP. The quality target product profile (QTPP) should be based on extensive characterisation of the RP, guiding biosimilar development.
II. Manufacturing Consistency and Performance
Each BS follows its own controlled development while adhering to best practices and regulations.
- The BS should be manufactured using state-of-the-art processes, ensuring control over product characteristics. Read: GMP Requirements
- The active substance composition, process-related impurities, and molecular variants must be closely monitored and managed.
- Expression system selection should minimise variability and undesirable attributes such as atypical glycosylation patterns or impurity profiles.
- Formulation considerations should focus on stability, compatibility, integrity, and activity of the active substance. Differences from the RP must be justified.
- Stability must adhere to Stability Requirements and claims regarding stability and compatibility should be supported by data rather than inferred from the RP.
- Any manufacturing changes require comparability assessments as per ICH Q5E guidelines. Development-related process changes must be separately documented from biosimilarity assessments.
Biosimilars have independent lifecycles, requiring thorough documentation of all modifications throughout development and manufacturing.
Quality Aspects of Comparability Exercise
For MAA submission, biosimilar quality attributes must be evaluated using highly sensitive analytical tools. The comparability exercise follows a three-tiered approach:
- Comparative Quality Exercise (CQE)
- Comparative (head-to-head) preclinical in vivo study
- Comparative clinical data
The CQE determines the need for additional preclinical and clinical studies required by SFDA, ensuring any minor differences do not affect clinical outcomes to maintain the biosimilar’s therapeutic equivalence to the RP.
Biosimilars Comparative Quality Exercise (CQE)
The CQE establishes and demonstrates molecular biosimilarity by thoroughly evaluating quality attributes (QAs), with a strong focus on the BS and RP’s critical quality attributes (CQAs). It employs sensitive and orthogonal analytical methods to compare structural properties—primary, secondary, tertiary, and higher-order structures—along with in vitro bioassays to assess functional attributes.
The selection and number of RP and BS batches must be justified based on QA criticality, analytical method performance, production process variability, and acceptance criteria approach (visual, qualitative, quantitative, statistical). Given the natural variability in RP and BS manufacturing, a larger batch size may be required to ensure a reliable assessment of batch-to-batch variability and confirm biosimilarity with high confidence.
Analytical Considerations for CQE
Physicochemical properties
This includes detailed physicochemical analysis of the structural identification of product-related substances and impurities. Using sensitive analytical methods, it encompasses physical properties, primary sequence, and higher-order structures. The BS primary sequence must match the RP, though minor sequence variants may arise from biosynthesis processes. Structural heterogeneity, such as post-translational modifications and disulfide bond mismatches, should be identified, quantified, and controlled. Manufacturers must assess the potential impact of these variations on biosimilar function and clinical outcomes to ensure consistency and therapeutic equivalence to the RP.
Biological activity
Assessing biological properties is crucial for establishing a complete characterisation profile of the BS and RP. A range of complementary bioassays should be used to compare all relevant mechanisms of action (MoAs) and ensure alignment with the RP’s clinical activity.
Multiple assay formats should be considered, leveraging orthogonal approaches to address validation limitations, ensuring a comprehensive and reliable evaluation of the biosimilar’s biological activity.
Immunochemical properties
For monoclonal antibodies and related substances (e.g. fusion proteins), immunological functions must be fully compared between the BS and RP, including specificity, affinity, and binding activity to the target. Fc binding to receptors (FcγR, C1q, FcRn) should also be evaluated unless justified.
Binding assays (e.g., surface plasmon resonance, biolayer interferometry) and effector function assessments (ADCC, ADCP, CDC) should be conducted using validated methods. A public reference standard should be used to calibrate an in-house potency reference standard from the BS production process.
Purity and stability
The BS and RP must be compared qualitatively and quantitatively for purity and impurity profiles using advanced analytical techniques.
- Product-related impurities such as sequence variants, PTMs, oxidation, deamidation, aggregation, and fragmentation, should be assessed with orthogonal methods to identify degradants. Forced degradation studies help determine if differences stem from batch age variations.
- Process-related impurities such as HCPs, HC-DNA, and cell culture residues are expected to vary due to different manufacturing processes.
- Stability data of the DS and DP must comply with SFDA requirements, supporting shipping, handling, long-term storage, and shelf life. Additionally, accelerated and stress studies (e.g., temperature, light, humidity, agitation) must be conducted to establish degradation profiles.
How We Support Biosimilar Registration in SFDA
Pharmaknowl provides regulatory registration services for biosimilars, assisting marketing authorisation holders (MAH) with compliance guidance, dossier preparation, and application submission in Saudi Arabia. Our expert team ensures a smooth regulatory journey, allowing companies to navigate the SFDA’s biosimilar requirements efficiently.
Contact us to fast-track your biosimilar approval.
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