Understanding the Development and Manufacturing Process of Biosimilars
The development process for biosimilars involves an extensive testing period in order to establish similarity to the reference biologic. To ensure that the drug doesn’t have unwanted side effects, there is a broad regulatory framework developers of biosimilars must adhere to. In this article, we provide an introduction to biosimilars. We take a closer look at the challenges involved in the development of biosimilars, and strategies for successful development and manufacturing practices. Further, we will talk about how these can be optimized with single-use technologies. Challenges in the development and manufacturing of biosimilars What are biosimilars? Biosimilars are drugs that resemble to biological products like monoclonal antibodies or gene therapies in terms of quality, efficacy, and safety. Just like biologics, biosimilar products are crafted with the help of living cells or microorganisms, thus may show minimal variety between batches. Biosimilars enter the pharma market after the expiry of the biologics patent. Interchangeable biosimilars are a special category of biosimilars, as they come especially close to their reference product. Due to their great resemblance to the original biologic, interchangeable products can be given out by pharmacies instead of the corresponding biologic without further consultation with the prescribing healthcare professional, similar to a generic drug being given out instead of a brand-name drug. To achieve this status, they have to fulfill additional requirements by national health authorities like the U.S. Food and Drug Administration or the EMA (European Medicines Agency) in the approval process. [[1]] [[2]] Biologics vs. biosimilars: What is the difference? Even though biosimilars and biologics have a lot in common, they are not the same. This is due to a level of variability that exists between the biosimilar and the reference product. While chemical drugs can be replications of generic drugs, the manufacturing process of biosimilars is more complex and depends on factors such as the selected cell line, temperature, manufacturing environment and much more. This is why biosimilar drugs inevitably show some level of variety between batches, even though there are no clinically meaningful differences for patients. Although biologic drugs have the potential to change the lives of patients suffering from different immune diseases and are an effective treatment option for a lot of cancer varieties, patient access is still limited due to high costs. These result from pharmaceutical research and development, with only a few products ultimately being able to enter the market, which are then patented for several years in order to keep the work on these innovative drug products attractive and to drive scientific progress. Biosimilars are a lower cost alternative to brand name drugs due to cost savings during the development process. A comprehensive introduction to biologics Who manufactures biosimilars? The market for biosimilars is expanding. By 2028, revenue of $66.9 billion and an increase by 17,8% is expected. While there are several companies entering the market, the main players are established companies like Pfizer, Novartis, Amgen, Sandoz, and Biogen. The areas of application for their biosimilars have a strong focus on oncology and immune diseases like crohn’s disease or psoriasis. [[9]] FDA approved biosimilars While the European Union (EMA) gave way to the first biosimilar drug called Omnitrope in 2006, the first biosimilar approved by the FDA was Zarxio (filgrastim-sndz) in 2015. Among the latest FDA approvals are biosimilars to the arthritis drug Humira with adalimumab as the active ingredient. The full list of approved biosimilars as of today, with reference biologics, manufacturers and information on formulary changes, can be found on the FDA’s website. Top biosimilars excerpt: Biosimilar name Approval date Reference product More information Hyrimoz(adalimumab-adaz) October 2018 Humira (adalimumab) Hyrimoz Information Retacrit(epoetin alfa-epbx) May 2018 Epogen (epoetin-alfa) Retacrit information Semglee(Insulin glargine-yfgn) July 2021 Lantus (Insulin glargine) Semglee Information Inflectra(Infliximab-dyyb) April 2016 Remicade (infliximab) Inflectra information Press Release: FDA approves Inflectra Amjevita(Adalimumab -atto) September 2016 Humira (adalimumab) Amjevita information 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) and also inline with European Medicines Agency (EMA). Research and development The development process starts with the selection of a reference biological product. This has to be a biologic drug that has already been approved by the FDA or EMA, 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 phase I-III studies, and proposed labeling. Once the patent for the biologic has expired, biosimilars can be approved. 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]] Biosimilar manufacturing – what to consider 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]] Safe handling of biosimilars Efficient safe handling of biosimilars during production is critical to ensure product quality, minimize contamination risks, and maintain a safe working environment for manufacturing personnel. Manufacturers can ensure the safe and reliable production of biosimilars by implementing comprehensive safety measures and quality assurance practices, contributing to the delivery of high-quality and effective biologic therapies for patients. Furthermore, a reduction of manual processing minimizes the risks that come with the processing of potentially hazardous substances. Read more: Safe handling of bulk drug substances Process efficiency 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 meet cGMP relevant quality standards, 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]] Freeze thaw processes in biosimilar production 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, for biosimilar production it is equally important to have current good manufacturing practices (cGMP) in place, 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 meet cGMP relevant quality standards 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]] [[download-1-email-detailed]] Efficient strategies for manufacturing biosimilars Optimized biosimilar manufacturing should combine high quality, compliance with regulatory standards, and efficiency. To reach this balance, manufacturers can rely on automated single-use technologies that make it easier to monitor the whole process, react quickly if adjustments are needed, and to boost production times significantly. Innovative solutions are needed to close technological gaps in fluid management for biosimilar production. To bring cutting-edge automated solutions to the table, Single Use Support has developed RoSS.FILL, an automated fill and filtration system that is able to fill multiple single-use bags and bottles with up to 300 litres per hour. Multiple racks can easily be attached. To guarantee best results and even protein distribution, solutions in single-use bags are homogenized with RoSS.PADL. Scalability is also one of the most important features of Single Use Support’s modular fluid and cold chain management solutions. This includes RoSS.pFTU, an automated plate freezing platform that can be scaled up to 400 litres or more for each batch. In combination with single-use bags, covered in RoSS® Shell as a protective packaging, or bioprocess containers by other manufacturers, the system allows for homogenous freeze-thaw processes for biosimilars with controlled cooling rates down to -80°C. And should even lower temperatures be required, the cryogenic freezer RoSS.LN2F is ready for controlled cryogenic freezing of biosimilars to temperatures as low as -170°C. For the safe storage of biologics and biosimilars, Single Use Support’s ultra-cold storage freezer RoSS.ULTF keeps solutions cool at temperatures down to -75 °C. Additionally, the smart cold chain shipping container RoSS.SHIP allows for an uninterrupted cold chain during transport. These cold chain shipping containers are trackable, coolable and robust to guarantee that biosimilar products reach their destination safely. It holds up to 55 single-use bags protected in the RoSS® shell to make shipping drug substances most efficient for manufacturers. To sum up: The challenges in biosimilar manufacturing are manifold, but can be mastered with the help of innovative single-use solutions. Single Use Support provides manufacturers with new systems that help streamline the production process to improve safety and efficiency. Freeze thaw and fluid management solutions in biosimilar production References Biosimilars basics for patients, https://www.fda.gov/drugs/biosimilars/biosimilars-basics-patients, Published Biosimilar and Interchangeable Biologics: More Treatment Choices, https://www.fda.gov/consumers/consumer-updates/biosimilar-and-interchangeable-biologics-more-treatment-choices, Published “Interchangeable biosimilar products”. Food and Drug Administration., https://www.fda.gov/media/151094/download, Published Accessed April, 20, 2024. Future Evolution of Biosimilar Development by Application of Current Science and Available Evidence: The Developer’s Perspective, http://dx.doi.org/10.1007/s40259-023-00619-0, Published 2023-08-05 How Similar Are Biosimilars? What Do Clinicians Need to Know About Biosimilar and Follow-On Insulins?, http://dx.doi.org/10.2337/cd16-0072, Published 2017-10-12 The ‘totality-of-the-evidence’ approach in the development of PF-06438179/GP1111, an infliximab biosimilar, and in support of its use in all indications of the reference product, http://dx.doi.org/10.1177/1756284819852535, Published 2019-06-13 Development of biosimilars, http://dx.doi.org/10.1016/j.semarthrit.2016.01.002, Published 2016-01-21 Review and approval, https://www.fda.gov/drugs/biosimilars/review-and-approval, Published 22.04.2024 “Biosimilar market”. Markets and Markets, https://www.marketsandmarkets.com/Market-Reports/biosimilars-40.html, Published Accessed April 21, 2024. Biosimilars: Key regulatory considerations and similarity assessment tools, http://dx.doi.org/10.1002/bit.26438, Published 2017-08-26 Regulatory evaluation of biosimilars throughout their product life-cycle, http://dx.doi.org/10.2471/BLT.17.206284, Published 2018-03-28 , Published The process defines the product: what really matters in biosimilar design and production?, http://dx.doi.org/10.1093/rheumatology/kex278, Published 2017-07-03 Use of a Design of Experiments (DoE) Approach to Optimize Large-Scale Freeze-Thaw Process of Biologics, http://dx.doi.org/10.1208/s12249-021-02034-6, Published 2021-05-12 An Overview of Biosimilars—Development, Quality, Regulatory Issues, and Management in Healthcare, http://dx.doi.org/10.3390/ph17020235, Published 2024-02-12 “Good manufacturing practices”. World Health Organization. , https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards/gmp, Published 22.04.2024 Staffing Shortages: Major Hurdle for Bioprocess Contract Manufacturing Services in 2023, https://www.pharmtech.com/view/staffing-shortages-major-hurdle-for-bioprocess-contract-manufacturing-services-in-2023, Published 08.2023 A look into biologic scale-up strategies, https://www.biopharminternational.com/view/a-look-into-biologic-scale-up-strategies, Published 08.2023
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