The biosimilar industry comprises a wide array of hybrid and pure-play biosimilar companies. But the companies that have approved biosimilars in the U.S. so far — Amgen, Sandoz, and Pfizer — all have had significant experience in the innovator biologics realm, and, in Sandoz’s case, the generics market.
If we look at the EU biosimilar market, there are many of the same leaders — but with one addition: Samsung Bioepis. The Korean company, which just celebrated its fifth anniversary in February 2017, was launched as a joint venture of Samsung BioLogics and Biogen. But in the last five years, the company has become a leading player in the biosimilar space.
I met Paul Song, VP at Samsung Bioepis, at the IQPC Analytical Similarity, Clinical Studies, and Market Entry Biosimilars Conference, where he gave a presentation on Samsung Bioepis’ process innovation. We also touched base one-on-one to discuss some of the lessons learned and challenges presented during Samsung Bioepis’ brief but impressive tenure in the biosimilar industry.
The Components Of An Innovative Process
“Innovation” is one of the most commonly used — and most vague — terms in the pharmaceutical industry. It’s often used to broadly describe new classes of medicines or a whole company and the breadth of the work it’s done. But to Samsung Bioepis, innovation means establishing methods to cost-effectively reduce the failure rate of the complex biosimilar development process.
In January 2016, Samsung Bioepis became the first biosimilar company to win an approval from the European Medicines Agency (EMA) for Benepali (formerly known as SB4), an Enbrel biosimilar. The company’s infliximab biosimilar, Flixabi (SB2), was also approved by the EMA and has been launched in the EU and in several other countries. SB2 is currently under review at the FDA, as well. In addition to these two biosimilars, the EMA is currently reviewing two more Samsung Bioepis biosimilars, including SB5, a Humira biosimilar, and SB3, a Herceptin biosimilar.
Though it may seem as though the company rose to success overnight, at least by pharma standards, Song was realistic about the journey. “Because we were a late starter in the biosimilar industry, we had to operate with a different mindset than other more established pharmaceutical companies,” he explained. “Establishing a development process isn’t something you do in one day and then see results the next.”
On an external level, Samsung Bioepis struck commercialization partnerships with Biogen and Merck & Co. But internally, the company needed to be aggressive.
On the surface level, Samsung Bioepis’ biosimilar development process contains the same steps other companies go through to create biosimilars. The process starts with extensive characterization of the reference product, followed by cell-line and process development, and, finally, scale-up for commercialization.
But to make up for its late start, the company chose to implement some less traditional processes to mitigate risk and speed production. This final overall production process is what the company has termed its “process innovation.”
There are four key elements to this process: Quality by Design (QbD), Failure Mode Effects Analysis (FMEA), Agile, and Toll Gates. “We have embedded these four concepts throughout the whole process from cell line development to the regulatory filing,” Song outlined.
Some of these elements are likely more familiar than others to the pharma industry. For instance, QbD has been emphasized by the FDA and EMA for the past few years because it enables companies to address problems in the midst of the development process. On the other hand, FMEA is a process that originated in the automobile industry, and Agile was adopted from the software industry.
Unpacking The 4 Elements
The goal of QbD is to establish a science- and risk-based understanding of the development process. Implementing QbD helps a company determine if the manufacturing process will ultimately produce a high-quality biosimilar.
Song emphasized the importance of QbD in determining the necessary Critical Quality Attributes (CQAs), or the quality goalposts for a biosimilar. During the implementation of QbD, the company gathered a large number of reference products from the EU and U.S. for analytical characterization. For instance, the company purchased approximately 130 different lots of Enbrel when developing Benepali. “Having solid CQAs in place reassures that we’ll generate a quality biosimilar batch-after-batch in a consistent manner,” Song added.
In addition to QbD, FMEA was used to establish a risk management plan. Samsung Bioepis approaches each new project by developing a process map based on prior knowledge gleaned from previous project development experiences, scenario building, and simulation exercises. “These efforts establish and identify potential risks in the process and lead to the development of a mitigation strategy,” said Song. Implementing FMEA was no mean feat; it required more effort upfront to implement, he admitted. “But the FMEA reduced unwanted downtime and failures in later projects, which would have been more costly.”
Agile, which originated in the software industry, was created to ensure a more controlled, step-by-step process. For instance, in the software world, a company would approach developers with an idea for software. Prior to Agile, developers would create the software and present the final product to the company. But, in many situations, the company would realize the final product was not what was expected or that it wouldn’t fit their needs. But Agile created a more cooperative, back-and-forth process between the two parties. The developers would come back to the company at each step of the development process to ensure the project was turning out how the company needed it to.
The process works similarly in Samsung Bioepis’ drug development process. At each major step of cell line development, process development, clinical development, and regulatory development, a series of core activities are carried out in a parallel, iterative manner. Thanks to the integration of Agile in the process, Samsung Bioepis has been able to monitor the processes in real time and make any corrections in order to eliminate future problems and reduce development time. As such, it took less than four years to bring Benepali from cell line development to regulatory approval.
Finally, the Toll Gates function as their name implies: they are gate checks established at major inflection points throughout each project. Each Toll Gate represents a set of particular quality goals, so only the highest-quality products are capable of moving forward toward regulatory review and commercialization.
The Important Correlation Between Preclinical And Clinical Data
The biosimilar industry is no stranger to physicians’ reliance on clinical trials when determining a drug’s safety and efficacy. But meeting preclinical targets should be the primary goal of a company’s biosimilar development strategy. After all, as Song described, the strategy a company employs to meet its preclinical targets can — and should — be a good predictor of how the drug will perform in the clinic.
For instance, during the development of Benepali, Samsung Bioepis developed 85 different assays, which helped determine the CQAs for each of the four primary clinical endpoints: safety, efficacy, pharmacokinetics (PK), and immunogenicity. Upon looking at the totality of data from extensive preclinical quality evaluations, the company found a strong correlation between the preclinical and the clinical data for all the clinical endpoints.
A topic often brought up in biosimilar discussions is the importance of the analytical work in biosimilar development (as opposed to the importance of clinical trials for novel biologics). In many cases, advancements in technology have aided the industry in getting a more thorough picture of a molecule than was available when the reference drug came to market. These insights into the molecule can also provide a more accurate profile of the biosimilar than a clinical trial. Some experts have even argued that certain biosimilars could one day be approved without late-phase clinical trials.
Though Song did not explicitly argue this point, Samsung Bioepis’ experiences serve as a good example of the important correlation between preclinical and clinical data — and, in turn, the quality of biosimilars.
“We applied process innovation to our biosimilar development strategy, with a focus on meeting the preclinical quality targets,” Song offered. And, given the successes of the company’s pipeline thus far, it’s apparent, “This quality-focused approach has successfully demonstrated that it can predict what will happen in the clinic.”