‘Our goal is to lead the field of biosimilars, just like we lead in generic medicines’
Dr. Nir Shapir, Vice President of Teva’s global research and development team and CMC of the company’s biosimilars division, explains the rationale behind the company’s entry into the biosimilars market. He additionally describes the complexity involved in the manufacturing process, and presents existing biosimilars projects, which comprise roughly half of the company’s biological projects today
Written by Asaf Levanon, in collaboration with Teva.
Reprinted with permission from the original Haaretz article:
The pharmaceuticals market that we all know today began to develop in the 19th century; first as extracts from minerals and herbs, and later as wholesale drug production, via chemical synthesis processes. Chemical synthesis is the main way in which most novel drugs are developed, which is why these medications are called “chemical drugs.” Once the drugs’ patent expires, generic versions can be developed (by copying the active ingredient) – a specialty led by Teva Israel, the world’s largest generics producer. Each day, approximately 200 million people from 60 different markets across six continents around the world consume Teva medications.
In recent decades, unique biological medications have been developed around the world, leading to significant therapeutic benefits, when treating severe illnesses, such as cancer. Biological medications mainly contain high molecular weight complex-structure proteins, created by living cells (such as bacteria, yeast cells, and animal cells). These differ from chemical drugs, which are synthesized through chemical reactions and have relatively small sizes and simple structures.
What happens when you want to create a generic version of a biological medication? After all, it’s a natural next step, as biological drugs are extremely expensive, and generics enable significant cost reduction. Here’s where a new term enters the picture: biosimilar. The term refers to a biological medication that operates with the same mode of action on the disease. It has a very similar structure – albeit not identical – to that of the original drug, as an identical structure cannot be created, using living cells. The goal of developing biosimilars is to make expensive biological drugs accessible and affordable to many more patients. Since Teva’s establishment 120 years ago, the company has endeavored to improve patients’ lives and enable them access to advanced treatments, and attainable prices. As such, the company’s entry into the field of biosimilars – similarly to that of generics – was its natural next step.
Researchers from different disciplines collaborating to achieve a common goal
“Biological drugs are so complex, because they consist of a large size protein with complex, and complicated structure that is created by a living cell. They cannot be produced through chemical synthesis; only through cellular process,” says Dr. Nir Shapir, Vice President of Teva’s Global Research and Development team and CMC of the company’s Biosimilars division. “With chemical drugs, the challenge is different, and simpler: create the same active material through the same process, so that it comes out identical or nearly identical to the original drug. As such, it is ostensibly easier to create generics of chemical drugs. But, when it comes to the complex structure of a protein created using a living cell – it’s impossible to create something that is completely identical. You can only create something that is similar, hence the use of the word “similar,” instead of “identical.”
How do you decide if the resulting medication is similar enough to be considered parallel to the original drug?
“There’s a regulatory definition. Biosimilar drugs must be identical to the original drugs in their primary structure (amino acids sequence), as well as along three main parameters: purity, safety, and potency. This definition is so precise; if the biosimilar drugs that are developed perform better than the original drug, it is no longer considered biosimilar and must be inhibited, until it can be considered as such. Drugs can only be considered biosimilar if it can be proven that any structural change has no bearing – good or bad – on the above three parameters. To achieve this goal, we integrate the work of researchers from various disciplines: biochemistry, biology, molecular biology, chemical engineering, and bio analytics. The biosimilars labs in Netanya are equipped with state-of-the-art science and technology tools. Each group of researchers is responsible for a different part of the development process. There’s a group that develops the cell lines, a group that’s responsible for the development of the production processes, a group that’s responsible for the biosimilar purification processes, a group that deals with the physicochemical characterization of the protein, and a group that defines the protein’s performance/activity, using biological methods. Chemical engineering experts help us with bioreactors, and there’s a lot of work with automation tools and robotics, which increase our teams’ efficiency and enable precision.
“My role in the biosimilar drug development chain is to lead the initial development processes: to construct the producing cell line and to develop robust and scalable manufacturing and purification processes, so as to ensure large-volume production that generates identical products. When our group completes its work, the task is transferred over to Teva’s Pennsylvania site, where our colleagues perform scaling up processes and produce the substance under GMP conditions, to examine its performance through clinical trials.”
What are the main challenges pertaining to developing biosimilars?
“Despite there being protein in the market that can be studied, it can be very hard to create something similar to it, as many factors can influence the quality of the protein that comes from the living cell. When we want to cause a target cell to create a protein that it never created before, we have to use technologies that introduce the target gene into the living cell and bring it to a state in which it produces the target protein, in addition to all the proteins it already creates in order to sustain itself. Different cells create (proteins) in different ways, which influences the quality of the protein and, therefore, the quality of the produced drug. Production conditions must also be upheld: an acidic environment or too much oxygen, for example, can influence the final product quality. The purification process also influences the final product; it must be ascertained that it provides the necessary level of cleanliness, without harming the protein’s structure. And if you’ve cleaned the protein and have a handle on it – know that it is not a chemical molecule, but rather, a different, more complex molecule. This protein is also likely to change throughout the drug’s shelf life, such as via oxygenation processes. Thus, there are quite a few challenging parameters that affect the protein’s structure, and make it difficult for the ‘generic’ drug production process to produce a drug that performs identically to that of the original drug. To achieve this goal, we must understand the molecule, the protein, the connection between the structure and function, and which conditions must be ensured to obtain the desired structure that achieves the necessary performance.”
Returns on development investments and significant gains
The biological drugs market is relatively new, and the biosimilars market is even newer. The first biological drugs hit the market in the 1980s, and since patent protections generally prevent their duplication for roughly 20 years, biosimilars only started being produced in the early 2000s. Even today, approximately two decades later, the market remains relatively small. About 70 biosimilar drugs are approved for use in Europe, and only half of that amount is approved for use in the US. That said, the growth rate is clear. The FDA’s approach in the field is currently more lenient, and the expectation is that this market, which currently rakes in roughly 18 billion dollars a year, will quadruple in size, over the next ten years.
“More medications will enter the market, and these drugs will be more accessible and affordable,” Dr. Shapir promises. “One of the limitations of developing a new drug is its high cost. Often, once tens – of even hundreds – of millions of dollars have been invested, the drug fails during the third phase of clinical trials, and all the money and work invested go down the drain. This is why pharmaceutical companies are anything but ‘trigger happy,’ but at the same time, they understand that the proper development of biosimilars brings with it a great chance that development costs will not only be returned, they will be exceeded, in the form of significant gains.
We, at Teva, have always made it our mission to produce inexpensive and more accessible drugs. As such, it was only natural that we turn to the development of biosimilars – just like we turned towards generics. Even though we have to wait 20 years until we can distribute a biosimilar drug, it doesn’t mean we have to wait 20 years to develop it. The process of developing biosimilar drugs is time-consuming. Once we complete the task, we (patiently) wait for the permitted distribution date.”
Describe this type of work process
The first thing we do is gather all theoretical material on the original drug. This can be found with the published patent documents, the original drug’s certificate of analysis, and sometimes, in the form of articles published on the subject. We do our best to find information on the composition, the primary structure, the three dimensional structure, the mode of action, and the shelf life. We aren’t usually able to find much of the information we seek, maybe just the gene or the amino acids sequence. However, when we combine the little information we do find with the vast knowledge we have accumulated over the years, we are able to predict what the protein’s three dimensional structure will likely be, while running relevant models on the primary structure. This is how we create a theoretical structure; one that enables us to identify the location of the antibody’s binding sites, and which receptors can banish it from the body. This teaches us where sensitive areas are located, which ultimately affect the drug’s performance. If, for example, there’s an amino acid in the antibody binding site that can undergo an oxidation process under certain conditions, we can understand that this is a sensitive area that our production process can affect.
In the next stage, our teams begin to work in parallel on the following areas: one group works on developing producing cell lines. They construct the DNA with the target gene expression cassette that has to be inserted into the target living cell’s nucleus. Its entry into the living cells creates hundreds of thousands of cells with the potential to produce the target protein. At the same time, a group comprised of biologists and bioanalysts start developing physicochemical and functional characterization tool in order to characterize the original drug. We break the molecule into pieces and develop tens of approaches, in order to understand each and every one of its components, so as to find a direct link between the original drug’s structure and function.
“As the work progresses, these diverse disciplines work simultaneously. We run in parallel, start reducing the potential cell lines to a workable amount, and the production process development team starts its part of the process. They examine the reduced cell lines and start working with a series of bioreactors (tools that control the various growth conditions within them). At first, only small volumes are handled, using autonomous systems that are capable of running tens of bioreactors at once, testing the effect of various parameters on the cells and the produced product, in an automatic and efficient way. At this stage, purification process development also gets underway. The living cell produces hundreds of proteins, from which the target protein must be extracted and purified; without any process related contaminants. As you can understand, this process is classic ensemble work; several groups that, rather than working in silos, work together in synergy and synchronicity. The developed process must be scalable and robust. At the end of the day, a list of production, purification and characterization protocols and a small test tube of cells are transferred over to our colleagues in the US. They are the ones who complete the scaling-up process, using large bioreactors that are capable of reaching 5,000 liters, to create materials suitable for clinical trials.”
Just how dominant is Teva’s biosimilar drug development activity today?
“Today, roughly half of Teva’s biological projects fall under the biosimilars development category. Out of our 13 existing projects, six are collaborations with other companies, and seven are our own internal production lines, executed by my team. These projects are at various stages of development; two are already in Phase 3 clinical trials. We believe that this is only the beginning.
Our goal, at Teva, is to lead the world with biopharmaceutical drugs (including biological and biosimilar drugs), just like we lead the world with generic chemical drugs; it’s even in our company mission statement. Teva heavily invests in the development of new biological medications. We have an advanced innovative-biological research and development center in Abic, and we participate in approximately 30 new drug development initiatives and collaborations with brilliant Israeli researchers from the country’s leading universities. Most of them are biological and are in the fields of oncology, central nervous system, and respiratory.
In addition to all of those, half of our biopharmaceutical pipeline is comprised of biosimilars. Thus, we are most certainly headed in that direction, and will continue to expand our biosimilar activity in the future.”