The number of biotechnology-based human therapeutic products in the late-stage pipeline along with the average cost to commercialize a biotech product has been steadily increasing over time. In addition, the biotech industry is facing unprecedented challenges in the form of a sagging global economy and rising regulatory expectations. Companies have to continue to evolve their approaches to be more efficient with respect to time, resources, and cost. This article describes some of the technologies that can help optimize time and cost of biopharmaecutical manufacturing.
Creating processes that are not only optimal and robust but also economical in a time and resource efficient manner is the Holy Grail for the biotech industry today. Regulatory initiatives such as Quality by Design (QbD) and process analytical technology (PAT) require an improved process understanding earlier in the product lifecycle.1–4
Recent advances in fermentation and cell culture processes have increased cell densities and protein titers in process fluids, requiring reliable upstream technologies to handle growing production demands.5,6 Moreover, within the bioprocessing industry there is a strong trend toward the application of single-use technologies, eliminating the expense of cleaning and cleaning validation, a major cost factor involved in operating reusable systems. One of the commonly used technologies for primary separation after fermentation is tangential flow filtration (TFF).7 TFF processes have traditionally used cassettes or hollow fiber formats. Typically, TFF cassettes are installed in stainless steel housings that require post-use cleaning and validation of cleaning. The installation and preconditioning steps before process use are time consuming and require a reasonable level of skill to avoid potential malfunction. Hollow fiber filter systems provide an alternative primary separation technology. However, this open channel format tends to require relatively high pumping rates for optimal performance. Achieving these high rates with fully disposable equipment can be difficult.
Membrane chromatography has already proven to be a powerful alternative to traditional packed-bed chromatography in flow-through operations, such as polishing for the removal of viruses and contaminants in biologics manufacturing.8 Case studies have been described for the purification of monoclonal antibodies (MAbs) with a high isoelectric point and have demonstrated the popularity of their implementation. As flow-through utilization has expanded, membrane chromatography applications have also included the capturing of large molecules.9 Such bind-and-elute applications imply the demand for higher capacity and larger surface membrane area compared with flow-through applications.
Manufacturers of biopharmaceuticals are required to characterize the ability of key process steps to clear viruses. Typically, the entire manufacturing process is qualified to attain a cumulative virus reduction factor, which significantly contributes to the documentation of virus safety. In many of these manufacturing processes, a virus retentive filter is used to achieve a robust and effective virus clearance step. The key to implementing virus filtration is the assurance of virus retention and device integrity while maintaining high productivity and ease of use.
Anurag S. Rathore
While developments in chromatography media (resins) have brought the technique much closer to practical and theoretical limits of binding capacity, future advances are likely to focus on new surface chemistries and a more efficient use of chromatography as a unit operation. One way to gain productivity improvements is to use smaller equipment or the similar size equipment in a more time-efficient manner.
This article is the fifteenth in the Elements of Biopharmaceutical Production series and will present some of the most promising technologies that are being introduced in biotech manufacturing by some of the major biopharmaceutical vendors.