Getting the balance right with biosimilars
As many of the top-selling biotech drugs face loss of patent in the next few years, a large number of companies are seeking to be first to market with their biosimilar. As these companies know, being one of the first to the market with a biosimilar product ensures the company can obtain their share of the known market value.
Challenges of manufacture
Biosimilars have the same amino acid sequence (primary structure) as the reference product or originator protein, but are not identical because they arise from different cell lines as biosimilar manufacturers do not have access to the working or master cell banks of the originator. The challenges in manufacturing biological medicines lie with the modifications that occur after the cell machinery uses the mRNA sequence to produce a protein, which is then folded into a 3D structure. These post-translational modifications include, for example, phosphorylation and glycosylation which may have varying effects on immunogenicity in human subjects. Manufacturers embarking on this journey are seeking to simulate the manufacturing process of the originator (from information gathered in the public domain) in the attempt to produce an almost an identical version of the molecule from a living cell.
The pathway for biosimilars to market is shorter than that travelled by the originator, if accompanied by a carefully crafted and robust regulatory strategy. The regulators have much higher expectations for earlier phases of the program such as the requirement of fully validated analytical methods. Thus, it is critical for these programs to have a strong strategy in place, one that can understand and anticipate regulatory requirements. Often, development involves a series of small-scale consistency batches followed by a couple of large-scale commercial batches for the early phase. With appropriate limits and criteria, these scale-up batches could be considered representative batches and thus save time and money.
Small players in this space must understand the criticality of implementing Good Manufacturing Practices (GMP) as early as possible. Maintaining GMP from early development ensures that the process is compliant with regulatory expectations for product quality and safety. Additionally, some companies fail to achieve regulatory expectations as they give into the temptation to continuously develop and improve their manufacturing process with every batch. A firm decision should be made to halt further process development and instead consider the ‘current’ process as a defined process. Any further changes must therefore be made post-approval.
There is a fine balance to strike with biosimilars as their characteristics and function cannot significantly differ from the reference product. A poor biosimilar product could be rejected due to concerns of safety and GMP, while a product that has significantly different chemical and physical properties with a better profile would fail biosimilarity and instead be considered novel (or biobetter).
Nevertheless, that balance is an achievable goal with the support of experts in product development who can interpret the available information and fill the gaps to create a cheaper alternative for patients.
Patient safety is the priority
When developing a biosimilar, companies must consider both the regulatory requirements, which ensure the product has the same amount of potency with the same modifications, and balance that with the business perspective, which is to maximize the yield in order to make the product commercially viable.
The regulators, meanwhile, need to know that the product has the same potency within parameters, and therefore the same safety profile as the originator. Their priority is patient safety, so they expect the manufacturer to demonstrate that the drug is sterile. The company must therefore delicately balance biosafety whilst creating an enriching environment for the cell-line to manufacture the protein of interest during upstream process; one which every bug under the sun would blissfully enjoy. The downstream process, known as the protein purification stage, must further ensure that all bugs (microbial and viral) as well as process and product-related impurities are successfully removed. The process may utilize harsh conditions such as a virus inactivation step in which the pH of the solution is dropped to 2. This is not without risks to the delicate protein which could denature and aggregate resulting a loss of all or a significant proportion of the product. Critically, large molecules must be treated carefully, as a denatured protein may never be able to refold correctly (in 3D) and thus impact potency and product related impurities.
Picking the best clone
The process of developing a biosimilar begins with selecting a cell-clone. Unlike generic small molecule products, creating and selecting the best cell-clone for a biosimilar is far from straightforward and is the most rate-limiting and critical step in the process as a sub-optimal decision at this stage will lead to the reselection of a clone and development starting from ground zero once again. Biological systems are live cells and as such there are always unpredictable factors because it’s not possible to control how a cell will behave in development, especially during scale-up.
Companies tend to make cell-clone selection based on yield and correct for other characteristics during the upstream development phase to align with the critical quality attributes to achieve biosimilarity. This often leads to a balancing act whereby one attribute such as yield may negatively correlate with another attribute such as potency. Unfortunately, there are cases whereby some characteristics of biosimilarity cannot be achieved without significant detriment to the commercial viability of the program, and thus the company finds itself back at square one – re-selecting the cell-clone.
As with many other stages of biosimilar development, technology has the potential to improve this process and contribute to a better final product and a simpler process for product developers.
The available technology to develop and manufacture biologics has significantly changed and improved within the last two decades. One area where technology advances have become industry standard is the adoption of single-use technologies and closed systems. Single-use technologies, such as lining the bioreactor with a bag, have lowered the chance of microbial contamination and product cross contamination especially at contract manufacturing organizations which deal with multiple different products on a frequent basis. However, it will be interesting to see this develop further with today’s global focus on reduced waste and use of recycled of materials. Single-use bags that line the bioreactors are in contact with many biological entities such as enzymes, thus the use of bio-degradable material for these single-use bags remains a significant challenge.
In other areas, some commercial drug manufacturing organizations (CDMOs) are developing next-generation technologies for biosafety testing, particularly viral testing, and challenging the current regulatory paradigm of classical test methods. High-throughput testing is becoming more common, allowing the user to gain much more information in a matter of hours compared to the classical test method which was more labor-intensive and would often take several days. However, some of these new methods are yet to be validated by the regulators and may take shape upon updates to the ICH guidelines.
Equally, there are advances underway to better support cell-clone selection, using high-throughput methods to ensure the cell-clone selected not only accounts for the yield but also for other characteristics, such as potency, charge heterogeneity and purity. This change in industry mindset would be a large step forward, particularly within the biosimilar space as it would reduce development time and overall costs.
Development of biosimilars comes with significant challenges, but with the right technical expertise and strategic regulatory support, these challenges can be overcome.
About the author:
Peter Lavrencic is a consultant at BioPharma Excellence, specializing in CMC. Peter provides tailored solutions to development programs and strategic guidance for established products and processes.