Biosimilars are biological products that are similar in structure and function to already approved medications. With a much shorter regulatory pathway and fewer R&D costs, they can be significantly cheaper than the original, brand-name biologic. This makes them a particularly attractive option for low- and lower-middle-income countries seeking pharmaceutical products, says Gupta and Boulais.
As expected, biosimilars are gaining popularity worldwide, with sales expected to more than double to US$15bn by 2025, according to a report from management consulting firm, McKinsey & Company. Roughly US$5-8bn of those sales are expected to come from emerging markets, they noted.
While these biologics are in great demand, producing such drugs presents unique challenges that threaten the manufacturers’ capacity to produce them in a cost-effective manner. The first challenge is competition: The industry is developing biosimilars for just 10 to 15 biologics. As a result, companies that do not reach the market first will struggle to gain any share of the profits. Biosimilar manufacturers also face additional pressure from the producers of the original biologics, which are streamlining their workflows and reducing the cost of their own products, making them even harder to undercut.
The main barrier to success is the cost of goods sold, highlight Gupta and Boulais. "Biosimilar developers must spend time and money proving their molecule’s biosimilarity to their corresponding reference products to achieve approval. And although their ultimate goal might be to sell to emerging markets, they must also achieve approval in the US and EU. This adds to the cost of developing a biologic. The most effective way to make biosimilars worth the investment is to reduce the cost of production," said the Sartorius team.
In addition to biosimilars, companies are also starting to develop more advanced therapies, including gene-, tissue-, and cell-based products. Patients are already experiencing the benefits of CAR-T cell therapies.
To date, the US Food and Drug Administration (FDA) has approved 10 cell and gene therapies, many of which are showing commercial success. That includes two gene therapies: Luxturna from Spark Therapeutics, indicated for retinal dystrophy, and Zolgensma from Novartis/Avexis, indicated for the treatment of spinal muscular atrophy. Both of these therapies use an AAV viral vector to deliver a healthy copy of the problem gene.
Meanwhile, more than 1,000 therapies are currently in the pipeline and the FDA anticipates that 10 to 20 of these will be approved by 2025. As a result, the cell and gene therapy market is expected to grow at a 30% compound annual growth rate.
Gupta and Boulais said they expect the gene therapy field to expand beyond the initial rare diseases to oncology and other chronic conditions. The cancer gene therapy market, is expected to reach US$2bn in sales by 2023, according to a report by Allied Market Research. Gene therapy is also being investigated as a novel approach to treating heart failure and diabetes. As these novel modalities become the norm, manufacturers will need to broaden their skillset and facilities to cater to the new breadth of products, said the Sartorius team.
Increased competition and a wider range of therapeutic modalities is forcing biopharmaceutical companies to be more flexible and resilient with their manufacturing, said Gupta and Boulais. "While this may seem daunting, the industry’s performance during the COVID-19 pandemic showed us that it can be done by prioritizing flexibility in production."
On January 10, 2020, the genome for the novel coronavirus was made publicly available online. By December of that year, multiple vaccines were rolling out to inoculate people against SARS-CoV-2. "This incredible feat showcases the incredible agility of leading companies in the biopharma industry. Manufacturers were able to transition from established workflows to a new workflow that enabled the swift development of an effective vaccine. One reason the industry was able to adapt so quickly was because of the method by which they chose to develop these vaccines: an mRNA vaccine platform."
The mRNA vaccine platform is a true platform technology: A single process can be used to produce vaccines for a myriad of indications by switching out one reagent in the workflow – the genetic sequence of the target antigen, said Gupta and Boulais. "The ease by which a manufacturer can switch from one sequence to another means they have the capability to address health threats quickly. At the same time, the technology transfer for this type of vaccine is simpler and can allow easier transfer to CDMOs around the globe."
Another tool that increases efficiency and helps companies keep an edge in this competitive landscape is the concept of Bioprocessing 4.0, said the Sartorius team.
"This approach uses digitization to give biopharmaceutical companies the flexibility needed to adjust process parameters quickly and easily while maintaining quality and reducing time and costs. It improves workflows in several ways: it improves downstream processes, thereby shortening process development cycles and accelerating time to market; it increases product titers and yields; and it enhances product quality and similarity," said Gupta and Boulais.
As time goes on, the industry is continuing to adopt tools and technologies that allow it to connect all of their equipment within a workflow digitally, from end to end. In addition, manufacturers are incorporating sophisticated feedback loops and machine learning to continuously optimize their workflows along the way. This approach increases the speed of production, they said.
Bioprocessing 4.0 can be implemented through a number of pathways. "Companies can begin, for example, by acquiring products such as fully automated, upstream single-use bioreactors. These bioreactors introduce flexibility into workflows by using high cell density fed-batch cultures or perfusion cultures, which facilitates rapid production. These bioreactors also feature single-use in-line sensors that report data in real-time, helping scientists measure Critical Quality Attributes (CQAs) and make modifications to the workflow to improve it," said the Sartorius team.
Finally, scientists can improve their process controls even further by replicating their bioprocesses digitally and running simulations. This method for optimization can shave weeks off manufacturing timelines. It can also reduce the downtime associated with testing data off-line and cleaning equipment, they noted.
While Bioprocessing 4.0 promises to bring the industry closer to an optimized bioprocess, achieving the ultimate goal of maximum efficiency requires companies to not only address the process, but also the materials and equipment used to enact it. Today, biopharmaceutical companies are taking a hard look at all elements that go into their bioprocess and seeking ways to set themselves up for maximally efficient production, said Gupta and Boulais. "This means finding ways to boost productivity while lowering costs – for example, by using fewer input materials, shortening timelines, and simplifying workflows in a smaller space. This approach is called process intensification."
One factor that underlies the growing need for process intensification is the specialization of biopharmaceutical products. This trend towards specialization will lead to a greater demand for low-volume batches and will introduce new variables to the manufacturing process, they remarked.
According to one analysis of commercial R&D pipelines, more than 80% of drug candidates between now and 2025 will meet demand with production of less than 500kg per year. To accommodate this trend, biopharmaceutical companies must simultaneously manage their high-throughput therapies and other, smaller-volume modalities within the same facility. To manage these workflows efficiently, companies must embrace process intensification, said the experts.
Process intensification has many layers, and it requires a multipronged approach to achieve its goals, commented Gupta and Boulais.
"In fact, several of the solutions we addressed so far fit a broader process intensification strategy. For instance, process intensification creates flexibility, which provides long-term benefits by enabling companies to more easily and quickly adapt to dynamic market needs. Single-use products reduce the use of harsh cleaning products and the time needed for cleanup, providing long term benefits over stainless steel only facilities. Advances in rocking motion and stirred tank bioreactors enhance flexibility and lower the cost of goods by giving manufacturers a choice of flexible upstream single-use seed train options. Together, all of these strategies lead to faster, more efficient production and less waste, the ultimate goal of process intensification."
The Future of Biologic Manufacturing
Even after the COVID-19 pandemic is over, the biopharma industry will continue racing to optimize their bioprocesses to save money and time. "We predict that process intensification will graduate from a nice-to-have to a need-to-have, as companies work to produce more with less. By investing in an intensified bioprocess, companies will be able to produce novel biologics quickly and efficiently, equipping them to handle threats to our health more effectively. We saw a preview of what optimization can look like amidst the race to develop a SARS-CoV-2, and in 2021 and beyond, this trend towards efficiency will continue."
