The development process of biosimilars

What is the development process of biosimilars?

As slight differences in the national regulatory frameworks concerning the life cycle development of biosimilars can occur, the following breakdown concentrates on the development process according to the standards set by the U.S. Food and Drug Administration (FDA).

Research and development 

The development process starts with the selection of a reference biologic. This has to be a biologic drug that has already been approved by the FDA, with established safety and efficacy data. The chosen reference product serves as the benchmark for demonstrating similarity throughout the biosimilar development process.

In the following, researchers need to find out the amino acid sequence of the reference biologic protein through characterization, in order to confirm equal immunogenicity and efficacy between both biotherapeutic products.

The next steps are cell line and expression system development. This may involve selecting the same cell line used in manufacturing of the biologic to closely mimic its production process. After weeks of cell growth, the mixture is purified and proteins can be harvested.

Testing and clinical trials of biosimilars

Biosimilar development involves extensive analytical testing to demonstrate similarity to the reference product in terms of structure, function, and quality attributes. Analytical techniques such as mass spectrometry, chromatography, and spectroscopy are used to compare critical parameters between the biosimilar and the reference product in non-clinical and clinical assays.

The testing process is heading towards a totality of evidence, meaning the establishment of biosimilarity instead of an individual proof of the product’s safety and efficacy. During testing, preclinical studies are mostly performed in animal models to assess the pharmacokinetics, pharmacology, pharmacodynamics, and toxicity of the biosimilar.

After that, the proposed biosimilar enters the stage of clinical trials, where safety, efficacy, and tolerability are demonstrated. Furthermore, biologics are assessed for immunogenicity. The clinical trials typically include comparative pharmacokinetic and pharmacodynamic studies, as well as comparative clinical efficacy and safety studies in patients.

FDA approval and market surveillance of biosimilars

Once the biosimilar candidate has demonstrated similarity to the reference product in analytical and clinical studies, a comprehensive regulatory submission is prepared for review by the FDA. The submission includes data on the biosimilar's manufacturing process, analytical characterization, preclinical and clinical studies, and proposed labeling.

After approval, biosimilars are subject to post-marketing surveillance to monitor their safety and effectiveness in clinical practice. This includes pharmacovigilance activities to detect any unexpected adverse events or differences in clinical outcomes compared to the reference product’s formulation. Moreover, pharmacovigilance aids in further improving the product and its safety, if need be.^{7 8 9 10 11} 

Scalability

Maintaining product quality and consistency can be challenging when it comes to scale-up the volume in biosimilar manufacturing. This is especially true when changing to larger batch volumes or primary packagings, as alterations in their handling must be taken into account.

However, meeting the requirements set by regulatory agencies for biosimilar manufacturing at scale is essential to ensure product safety, efficacy, and quality. These standards have to be applied to the manufacturing processes, facility design, and quality control measures.

Scaling up production while complying with regulatory expectations requires careful planning, documentation, and validation of manufacturing processes and systems. A particular focus must be put on the transferability of individual technologies: Having to replace complex manufacturing systems in order to scale-up production capacities can be costly.

By investing in modular and scalable solutions, on the other hand, saving time and costs from development to manufacturing becomes possible. The production can move easily between different scales, while even the interface may remain the same, allowing to easily transfer freezing protocols.

Supporting manufacturers of biosimilars with single-use technology

The regulations surrounding the production process of biosimilars can be challenging for manufacturers. New advances in biotech, such as the implementation of single-use technologies, can help manufacturers of biosimilars to streamline the production process, while meeting demands more easily.

Single Use Support provides fully automated process solutions that minimize the risk for contamination and human errors to prevent product loss, relieving workers from strenuous tasks. The aseptic filling platform RoSS.FILL requires only a minimum of human intervention and is highly scalable. In addition, it enables an aseptically closed system minimizing further the risk of contamination.

The RoSS.pFTU automated plate freezing platform is designed to freeze and thaw single-use bags or containers homogeneously and in a controlled manner. It is able to reach ultra-low temperatures with full control over freezing rates, in accordance with the demands of the respective products.

During transport and transfer between workstations, single-use bags can be stored in the RoSS® shell, which are protective and space-saving secondary packagings. These prevent damage and product loss and ensure both integrity of the cryobag and compliance with quality standards from development to upscaling of biosimilar drug products.