An introduction to biosimilars

micheal-eder

Michael Eder

May 8, 2024

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Biosimilars are versions of biological reference drugs and are intended to be on a par with in terms of safety, efficacy, and quality. While biologics have changed many lives for the better and are successfully used in oncology, as vaccines, or in the treatment of different immune diseases, they remain quite costly. This is due to the fact that they are usually patented for several years in order for the extensive research and development efforts to be amortized.

Biosimilars can present a more accessible option once the patent for the reference drug expires, and may broaden patient access to prescription drugs against rheumatoid arthritis, bowel diseases such as Crohn’s disease, psoriasis, and different cancers.

In the following, we will give an introduction to biosimilars, describe the differences between biosimilars and biologics, and provide an overview of FDA approved biosimilars. Further, we will talk about their development and manufacturing processes and how these can be optimized with single-use technologies.

Biosimilars definition

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.

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 in the approval process.1 2 3 

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. 4 5 6 

History of biosimilars

The concept of biosimilar medicines emerged in the 1980s and gained traction in the following decades, as biologic therapies became increasingly important for the pharma industry. However, the regulatory pathways for approving biosimilar products were not established until the early 2000s. In 2005, the European Medicines Agency (EMA) introduced guidelines for biosimilar approval, leading to the approval of Omnitrope as the first biosimilar in Europe in 2006.

The USA followed suit with the Biologics Price Competition and Innovation Act (BPCIA) in 2010, creating a regulatory pathway for biosimilars. The first biosimilar in the U.S., Zarxio (filgrastim-sndz), was approved in 2015. Since then, biosimilar approvals by the FDA have increased across various therapeutic areas.

Globally, biosimilars have gained acceptance and are now integrated into healthcare systems to enhance patient access and reduce costs. While facing challenges such as regulatory complexity and market acceptance, biosimilars continue to offer opportunities for innovation, competition, and affordability in biologic therapies.7 8 9 

Overview of FDA approved biosimilars

While the European Union gave way to the first biosimilar drug called Omnitrope in 2006, the first biosimilar approved by the FDA was Zarxio (filgrastim-sndz) in 2015. Since then, 49 biosimilar medicines have been approved to date (April 2024).

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 or in our latest article on FDA-approved biosimilars.10 

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.

Analytical characterization

The analytical characterization of biosimilars involves a multidisciplinary approach combining advanced analytical techniques, biological assays, and comparative studies to demonstrate similarity to the reference product and ensure product quality, safety, tolerability, and efficacy.

Regulatory agencies such as the U.S. FDA (Food and Drug Administration) and EMA (European Medicines Agency) provide guidelines and requirements for analytical characterization, ensuring consistency and reliability in biosimilar development and approval.

Testing

The non-clinical testing phase of biosimilars is focused on the evaluation of safety, pharmacokinetics, pharmacodynamics, and immunogenicity of the biosimilar in preclinical models. In most cases, this involves the use of animal models before the drug enters clinical trials.

Clinical studies

After the testing phase, biosimilars are subjected to several clinical studies. The aim of pharmacology studies is to prove that the biosimilar drug has the same effects on the body as the reference product. In immunogenicity assessments, the immune response is examined. In some cases, comparative clinical studies are conducted to investigate possible minor differences. 11 12 

Development-Biosimilars

Manufacturing biosimilars – what to consider

Manufacturing biosimilars is a sensitive process that can easily be impacted by various challenges, such as molecule variability, contamination risks, or product loss through human errors. One important part of the manufacturing process is taking precautionary measures for efficient and safe fluid management, freezing and thawing, as well as ideal transport and storage conditions – necessary to be able to guarantee high quality products. 

Fluid management

Effective fluid management during cell culture, purification, formulation and filling and dispensing mechanisms is of the essence to guarantee a successful product. By using state-of-the-art fluid management systems, contamination risks can be minimized through a reduction of exposure times. Fully automated closed systems are the solutions for handling sensitive protein formulations in a way that is compliant with current good manufacturing practices (cGMPs).

To allow for more flexibility, it is important that fluid management solutions in biosimilar production are scalable, to move quickly from development phase to manufacturing. Regular controls are necessary to minimize microbial contamination or cross-contamination risks between batches and help manufacturers intervene if necessary. 

Freezing and thawing biosimilars

In many cases, freezing and thawing biosimilars is part of the manufacturing process of these biological drug substances. This can be for transport to other production facilities or for storage. As proteins are sensitive to changes in temperature, quick and even freezing rates are desirable to prevent protein denaturation, which can lead to product alterations and undesired side effects.

Controlled freezing and thawing can prevent the risk of product loss due to damages related to unsuitable freeze-thaw processes. Plate freezing liquids in single-use bags has proven as a safe and effective way to freeze drug substances, as even freezing prevents protein denaturation and alterations in the product.

While thawing is often overlooked in the scope of the bigger manufacturing picture, thawing frozen substances is just as important for a successful outcome. Yet again, control over the thawing rates is essential to obtain optimal product quality.13 

RoSS.pFTU Mid Scale_In Process-4

Transport and storage

To prevent damage during transport and storage of biologics and biosimilars, containers need to be protected and stored safely to prevent alterations and product loss. Stable temperature and precise monitoring are additional prerequisites for storage freezers used in biomanufacturing. 

Ideally, products can be transferred easily and in short time from freezers to storage, to prevent temperature changes that could affect the product’s efficacy and safety. Additionally, space is typically limited in storage facilities and during transport. This produces a need for space-saving stackable solutions that can be kept reliably at the required low temperatures. 14 

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Challenges involved in the manufacturing of biosimilars

As already established, there are numerous challenges in the manufacturing of biosimilars. These range from contamination risks and drug substance exposure to product damage through uneven freezing and thawing rates. Further, product loss, often caused by human errors if manual intervention is necessary, are problems that can occur in the manufacturing process of biosimilars.

The regulatory framework surrounding the manufacturing of biosimilars was designed to ensure their safety and efficacy. Current good manufacturing practices or cGMPs include factory design, documentation, standardized labeling practices, cleanroom requirements, and staff safety precautions when handling drug substances. Compliance is necessary but bears its challenges for manufacturers.

To stay economically competitive in the expanding market of biological and biosimilar drugs, which is predicted to double its revenue until 2034, it is important to streamline processes, save time, and reduce costs. Automated solutions and state-of-the-art technology can support manufacturers in building an efficient manufacturing process.15 

Efficient strategies for manufacturing biosimilars

With innovative strategic solutions from Single Use Support, efficiency in the manufacturing process of biosimilars can be optimized. With the help of automated fluid management systems, the need for human intervention and the risk of cross contamination can be reduced. At the same time, production speed is increased.

To reach maximum efficiency, it is possible to seamlessly incorporate different single-use technologies into the production chain. All products are scalable, to allow for more flexibility during the production cycle. Single-use bags are aseptically and precisely filled with RoSS.FILL and protected in RoSS® shells against product damage during storage and transport.

If the single-use bags must be frozen for transport, they can be cooled down efficiently to -80°C with RoSS.pFTU. This freezer uses plate freezing for stable freezing to prevent protein denaturation. Should even lower temperatures be required, the cryogenic freezer RoSS.LN2F is ready to achieve them in a safe and controlled manner.

To maintain stable temperatures during transport and storage, RoSS.FRDG keeps containers reliably at temperatures as low as -75°C, helping them to preserve their effectiveness and safety until they are needed.

Frequently Asked Questions

What do you mean by biosimilar?

A biosimilar is a biological product that is highly similar to an already approved biologic drug, known as the reference product or originator biologic. Biosimilars are developed to be highly similar to the reference product in terms of structure, biological activity, efficacy, and safety. However, due to the complex nature of biologic drugs and the variability inherent in biological systems, biosimilars are not identical copies of the reference product like generic drugs are to their brand-name counterparts.

What is an example of a biosimilar?

An example of a biosimilar is filgrastim-sndz (Zarxio®), which is a biosimilar to filgrastim. Filgrastim is used to stimulate the production of white blood cells in patients undergoing chemotherapy or bone marrow transplantation.

What is the difference between a biosimilar and a generic drug?

The main difference between a biosimilar and a generic drug lies in their manufacturing processes and regulatory pathways. Generic drugs are chemically synthesized and are exact copies of their brand-name counterparts, known as small molecule drugs. They have identical active ingredients, dosage forms, and routes of administration. In contrast, biosimilars are developed to mimic a reference biologic as closely as possible. Due to the complexity of these large-molecule drugs, they are not identical to the reference product. Thus, they undergo a separate regulatory approval pathway that requires comprehensive analytical and clinical testing to demonstrate similarity in terms of safety, efficacy, and quality.

Read more about biosimilars

Development-Biosimilars

The development process of biosimilars

The development process of biosimilars slightly differs from the one of their reference biologics. In this article, we will discuss each phase in detail.

Challenges-manufacturing-biosimilars

Challenges in manufacturing biosimilars

The manufacturing process of biosimilars is a complex endeavor, accompanied by several challenges. We will discuss some of the biggest hurdles in this article, along with solutions to overcome them.

RoSS.FILL CGT_Product photo

Fluid management solutions for biosimilar production

In biosimilar production, fluid management takes on an overarching role, as it is encountered at several manufacturing steps. This is all the more reason to deal with efficiency in fluid management – which we will do in this article.

Efficient strategies for the safe manufacturing of biosimilars

Efficient strategies for manufacturing biosimilars

Establishing both efficient and safe manufacturing processes for biosimilars requires planning, expertise, and state-of-the-art equipment. In this article, we will shed light on different steps in the manufacturing process and discuss ways to improve them.

Freezing and thawing in biosimilar production

Freeze thaw processes in biosimilar production

Freezing and thawing are essential steps in the cold chain management of biosimilars. With several methods eligible, we have chosen some prominent ones, explaining their advantages, limitations, and our preferred choices.

Overview of FDA approved biosimilars

Overview of FDA approved biosimilars

Over the years, several biosimilars have been approved as alternatives for often more costly biologics. We have listed them, along with the product they refer to.

  1. Biosimilars basics for patients, https://www.fda.gov/drugs/biosimilars/biosimilars-basics-patients, Published
  2. Biosimilars and interchangeable biologics: More treatment options, https://www.fda.gov/consumers/consumer-updates/biosimilar-and-interchangeable-biologics-more-treatment-choices, Published
  3. Biosimilar and Interchangeable Biologics: More Treatment Choices, https://www.fda.gov/consumers/consumer-updates/biosimilar-and-interchangeable-biologics-more-treatment-choices, Published
  4. 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 2017-10-11
  5. Conversion from Filgrastim to Tbo-filgrastim: Experience of a Large Health Care System, http://dx.doi.org/10.18553/jmcp.2017.23.12.1214, Published 2017-11-27
  6. Biosimilars or Biologics: What’s the difference?, https://www.ncbi.nlm.nih.gov/books/NBK598450/, Published 10.2019
  7. Biosimilars: Exploring the History, Science, and Progress, http://dx.doi.org/10.1188/18.CJON.S1.5-12, Published 2018-09-21
  8. Biosimilar medicines: An overview, https://www.ema.europa.eu/en/human-regulatory-overview/biosimilar-medicines-overview, Published
  9. The number of biosimilars released in the U.S. and Europe, https://www.researchgate.net/figure/The-number-of-biosimilars-approved-in-the-EU-and-US-as-of-June-2023-shows-a-downward_fig1_373720974, Published
  10. Biosimilar Product Information, https://www.fda.gov/drugs/biosimilars/biosimilar-product-information, Published 04.2024
  11. Biosimilars entering the clinic without animal studies, http://dx.doi.org/10.4161/mabs.29848, Published 2014-07-14
  12. Review and approval, https://www.fda.gov/drugs/biosimilars/review-and-approval, Published 04.2024
  13. , https://, Published
  14. Impact of Uncontrolled vs Controlled Rate Freeze-Thaw Technologies on Process Performance and Product Quality., Published 2010 Jul-Aug
  15. Biosimilar and biologics market, https://www.futuremarketinsights.com/reports/biosimilars-and-follow-on-biologics-market, Published 04.2024
micheal-eder

Michael Eder

Senior Marketing Manager

Michael Eder, MA, is Senior Marketing Manager at Single Use Support. He is expert in pharma and health communication with his 8+ years experience in pharma. After completing his master's degree in International Healthcare Management at MCI The Entrepreneurial school in Innsbruck, he has gained experience in the pharmaceutical field. Michael creates articles about Freeze Thaw applications and Platform solutions from Single Use Support and is the author of current news with Single Use Support worldwide. 

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