Understanding the Development and Manufacturing Process of Biosimilars

The development process of biosimilars

While new biologic medicines are designed to ensure their safety and effectiveness, the development process of biosimilar drugs is centered around the characterization of the reference biologic. This can save a significant amount of time and cost. Both products have to undergo a rigorous number of trials and clinical studies before they are deemed safe by national health authorities. 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. [[4]] [[5]] [[6]] [[7]] [[8]]

There are several areas that require special consideration to produce a successful biosimilar product. These include the safe handling of biosimilars, designing the manufacturing process to be as efficient as possible to stay economically competitive, as well as finding effective ways to comply with regulatory requirements.

With the help of biotechnological advances, these areas can be optimized by streamlining the manufacturing process, reducing the need for manual intervention and potential contamination risks while increasing production speed. [[10]]

When handling sensitive biological substances, time and cost efficiency are crucial. The costly and meticulous process profits from solutions that help to minimize product loss and maximize throughput. 

For instance, the traditional procedure of cell culture involves stainless-steel or single-use bioreactors designed for large scale productions. This approach requires a lot of time until sufficient cell growth is reached. In contrast, seed train intensification allows more flexible manufacturing in large quantities. 

By using technology that applies high cell density cultivation (HCDC), i.e. the cryopreservation of a master cell bank in single-use bags, production times are shortened, and it becomes easier to react to varying needs in the industry.

Compliance in biosimilars manufacturing

To reach cGMP compliance, manufacturers must establish a comprehensive quality management system that encompasses every aspect of production. This system includes protocols, standard operating procedures (SOPs), and thorough documentation to ensure adherence to regulatory requirements and industry standards.

Facilities must be designed and maintained according to cGMP guidelines, providing adequate space and infrastructure to support efficient and compliant biosimilar manufacturing. This includes regular inspections, maintenance, and validation of facility systems and equipment, as well as materials: Raw materials must meet established specifications for identity, purity, potency, and quality before use in production. [[11]]

Manufacturing process of biosimilars – efficiency is key

In order to stay economically competitive and provide a high quality product, efficiency is crucial when manufacturing biosimilars. Standardized, automated process solutions and single-use equipment can help to streamline the production from cell line cultivation to the final product, while minimizing contamination risks and product loss and complying with regulatory requirements.

Cell line cultivation and upstream processing

Reducing manual intervention during cell line cultivation is crucial for preventing cross-contamination from the start. As traditional cell line cultivation in large bioreactors takes a significant amount of time, davanced technologies like High-Density Cell Culture (HCDC) in single-use bags and the use of frozen working cell banks can save significant time and resources, eliminating the need to restart the entire process from scratch. [[13]]

Downstream processing and fluid management of biosimilars

Enhanced purification efficiency leads to higher product yields, improved purity, and reduced manufacturing costs. Single-use technologies, such as disposable chromatography columns and filtration systems, offer greater flexibility and scalability. Platforms like RoSS.PADL help ensure consistent drug substance mixtures, while RoSS.FILL accelerate aliquoting of cells and minimize contamination during filling and filtration.

RoSS.PADL Homogenizing RoSS.PADL is an automated platform to cool and gently knead your single-use bag to ensure a homogenous mixture of your substance. More information

Freezing, storage and transportation

Controlled freezing methods are essential for maintaining the integrity of sensitive biopharmaceutical products. Advanced technologies like plate freezing (RoSS.pFTU) and cryogenic freezing (RoSS.LN2F) provide precise temperature control, preventing protein degradation and ensuring product stability. For storage, specialized freezers like the RoSS.ULTF offer secure, ultra-low temperature environments. The use of protective containers, such as RoSS® Shells, further safeguards products during the cold chain, maintaining quality from production to patient. [[14]]

What are the main challenges in the development and manufacturing of biosimilars?

There are several challenges manufacturers have to face when it comes to the development and manufacturing process of biosimilars. These are often connected to the extensive regulatory framework surrounding the process, as well as ensuring product purity and up-scaling.

Demonstrating biosimilarity

Demonstrating biosimilarity is difficult due to the inherent complexity of biological molecules, variability in the manufacturing process, and the need to establish equivalence in terms of structure, quality, and clinical performance.

Addressing these challenges requires a multidisciplinary approach, including advanced analytical techniques, robust manufacturing processes, and well-designed clinical studies, to ensure the safety, efficacy, and tolerability of biosimilars.

Product purity

Compared to smaller molecule drugs, drug development from living cells that is involved in the production of monoclonal antibodies, for instance, is more complex and bears more risks. While the development process of biosimilars is centered around similarity to an already established biologic medicine, obstacles like contamination risks and product loss are just as relevant.

New advancements in biotechnology can help manufacturers to minimize these risks that are often caused by human errors. Therefore, Single Use Support has designed a fully automated, closed fluid management system for biosimilars and biologics: RoSS.FILL aids in state-of-the-art manufacturing practices, helping to streamline the whole process of handling drug substances. Consequently, this will lead to lower costs in biomanufacturing while maximizing product quality. [[10]] [[15]]

RoSS.FILL | Fill-Filtration RoSS.FILL is a fully automated single-use bag filling system. It is possible to full unlimited volumes per batch with a speed of up to 300 liters per hour. More information

Regulatory requirements for biosimilars

Just like the manufacturing of biologics, biosimilar production has to comply with current good manufacturing practices (cGMP) as set by national health authorities, which orient themselves on the guidelines defined by the World Health Organization (WHO). As the organisms involved in the development and manufacturing of biosimilars are highly sensitive substances, this regulatory framework ensures that quality and safety of biological drugs stay consistent.

To comply with cGMPs means that manufacturers have to establish quality management systems into the process, ensure the sterility of raw materials and establish a consistent operating procedure with state-of-the-art technology. Further, they have to make sure to document the production process thoroughly and that laboratory standards are up-to-date to obtain reliable clinical data. [[16]]

Efficient fluid and cold chain management

Time is of the essence when it comes to manufacturing biosimilars. As the production process as a whole is a costly endeavor, process efficiency in biomanufacturing needs to be increased.

This risk is especially high during filling, transport and storage settings, where bioprocessing containers can easily get damaged when they are moved around or shipped to other manufacturing locations, as bag breakages can occur due to incorrect handling.

Another challenge is the continuation of the cold chain when handling biosimilar substances. Depending on the type of biosimilar product, it needs to be kept at specific temperatures for storage or transport to prevent any undesired product alterations. For instance, monoclonal antibodies and gene therapies require storage temperatures of -80 °C.

As reproducibility is key in biosimilar production to guarantee a safe product, reliable control and testing systems are needed to intervene in case of deviations. Therefore, it is important to develop streamlined manufacturing strategies to stay as time efficient as possible. With the help of closed automated systems, these hurdles can be overcome more easily.

Scaling up biosimilar production

Scale-up is one of the most challenging steps for many manufacturers because there are several difficulties connected with the production of larger batches. One of them is the need for appropriate equipment, as not every production site has the needed machines in different sizes at hand.

Also, limited space capacities for large bioreactors can present problems for manufacturers. In smaller and mid-range facilities, the investment in scale-up equipment is also often connected to the investment into larger production halls and the need for more staff. As statistics show, the latter is especially hard to come by.

Further, large-scale equipment is a costly investment. Not every production site has the resources to finance them and the willingness to put large capital expenditures in hand to keeping up with state-of-the-art manufacturing devices that are typically needed to stay competitive.

The ability to react to changing demands and move from small volumes to scale-up biosimilar production is key for manufacturers. With scalable single-use solutions for upstream to downstream bioprocessing, the gap between the development of biosimilars and their manufacturing can be filled. [[17]] [[18]]

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