As this special issue of BioProcess International goes to press, an increasing number of cell-based therapies are advancing through preclinical investigation into clinical development and on toward commercialization. Although clinical efficacy will be the primary metric for product approval, the ability to manufacture these therapeutic products consistently, reliably, and cost-effectively will continue to be a key driver and predictor of commercial success.
Several articles presented herein describe major issues and challenges facing developers of cell-based therapies. Although some of the development and manufacturing strategies described depend on whether a therapy is autologous or allogeneic, a few key considerations apply equally to both types of products.
The Importance of Product Understanding
At the top of that list is the dictum, “know thy product.” Developing a thorough understanding of the composition and critical quality attributes of a cell-based product is central to developing a successful and effective manufacturing platform. But what does that mean? Simply put, an early investment toward establishing robust and reliable assays can demonstrate your product’s physicochemical and potency/activity characteristics. Such assays allow you to proceed with a product development program that monitors all changes to your product through successive manufacturing campaigns. Demonstrating product comparability is a key risk in process development, especially for processes that can be “tweaked,” scaled-up, or require changes to raw materials. Having reliable, validated assays establishes a strong foundation for future product and process improvements — such as those described by Levinson, et al. in this issue.
As noted in several of the articles in this supplement, manufacturing processes for cell therapies will in many cases need to follow current good manufacturing practices (CGMPs). Therefore, a manufacturing process must be robust enough to satisfy regulatory authorities. No cell therapy is exactly like another. The unique characteristics of each product (and relevant regulatory requirements) must be carefully factored into a manufacturing strategy.
Scaling Up or Scaling Out?
Also important to understand is the scale of production (number of cells) that will be needed for an intended clinical indication once a product is approved. This is a function of the required cell dosage (patient dose) and the number of doses planned per year. Such information can help a company select the best type of technology for its commercial manufacturing process as part of its overall business strategy.
For example, in an autologous process, each patient represents one manufacturing lot. If only a relatively small number of cells/dose (105–107) is needed for treatment, the process is unlikely to require scale-up of cell culture steps typically used in such instances (such as T-flasks or stacked, multitray vessels). Instead, the process will need to be “scaled out” by running multiple-patient– specific products at the same time. This, then, suggests the need for closed single-use systems with smaller footprints that require less cleanroom capacity and expense, along with automation where possible to limit operator error as a source of variability.
On the other hand, an indication requiring a relatively high number of cells/dose (107–109) and producing several hundred or more doses per manufacturing lot suggests the need for an upstream (cell culture) process that can be scaled up. This might incorporate an automated two-dimensional bioreactor or a three-dimensional suspension bioreactor that uses microcarriers as the substrate for mesenchymal stem cells (MSCs) or other adherent cells. In such scale-up instances, downstream processing also becomes an important consideration. Several approaches can be considered for volume reduction and cell concentration, including centrifugation-based methods and tangential-flow filtration. It is therefore important to determine the required scale of production early in process development work so you can proceed toward the desired scale and in time for later stage clinical trials and commercial-scale manufacturing.
Cost of Goods and Reimbursement Expectations
As well-noted in this issue’s article by Grant et al., cost of goods (CoGs) is another key consideration because it ultimately affects the price at which a product can be provided. It also may help determine whether reimbursement from third-party providers will be approved. The lower the CoGs, the greater the probability that an approved treatment will be accepted by public and private healthcare insurance plans. This will, in turn, increase demand for the product and ultimately enable its manufacturer to achieve even further reductions in CoGs through economies of scale in manufacturing.
For these reasons, it is important to understand how and where costs are distributed within a manufacturing process (such as for raw materials, equipment, consumables, labor, QC, and so on). That may help identify areas where savings can be achieved — depending also on the manufacturing platforms being used. In that regard, and when possible, implementing single-use bioreactors can significantly lower overall costs while also streamlining compliance with both quality control and quality assurance requirements. In the future, further decreases in CoGs may also derive from an ability to produce more potent cells, perhaps through more specific cell-selection methods or more efficient and “gentle” cell-expansion technologies, both of which could allow for fewer cells/ dose to be used to achieve clinical efficacy at lower costs.
Benefits of a Collective Knowledge Base
Other articles in this supplement point to additional considerations for cell therapy manufacturing: optimizing cell freezing and thawing methodologies, effectively transferring manufacturing technology to contract manufacturers, and adopting newly emerging techniques for large-scale expansion of stem cells and exosomes. With all these things to consider, it is clear that cell therapy manufacturing still has a number of challenges that need to be addressed for products to be successfully developed and licensed.
However, it is important to note that the cell therapy industry has benefited and continues to benefit greatly from the previous work of companies developing more “traditional” biologics (vaccines, monoclonal antibodies, and recombinant proteins) as well as by the specialized suppliers of bioprocessing equipment. This collective knowledge and experience base — along with the types of careful planning and decision making discussed within this issue — should help move more cellular therapies out of the laboratory and into everyday clinical use in the years ahead.
For Further Reading
Rowley J, et al. Meeting Lot Size Challenges of Manufacturing Adherent Cells for Therapy. BioProcess Int. 10(3) 2012: S16–S22.
Smith D. Assessing Commercial Opportunities for Autologous and Allogeneic Cell-Based Products. Regen. Med. 7(5) 2012: 721–732. •
Harvey Brandwein is vice president of business development at Pall Corporation, 25 Harbor Park Dr, Port Washington, NY 11050; 1-516-484-5400; firstname.lastname@example.org.