One of the latest trends in biotechnology is the application of the concept of quality by design (QbD). QbD entails designing therapeutic products to meet patients' needs and then consistently producing them. Consistency is achieved by understanding the impact of starting materials, critical process parameters and product quality attributes, and controlling variability. In today's marketplace, concomitant with designing in quality, companies producing biotherapeutics need to consider economy. "Quality" does not have to mean "expensive" because economy and quality can be built into a process at the same time. It isn't logical to design a high-quality biotherapeutic that no one can afford.

Fortunately, today's technology enables reasonable production costs. For example, in the manufacture of monoclonal antibodies (mAbs), the cost for producing one gram is estimated to be $100–300 (€68.32–204.95), depending on scale of operation. Lower costs have been published based on a production estimate of 10 tons per annum. More specifically, the cost for Protein A resins used in a capture step for mAbs is normally 3% of the total costs when used for more than 30 batches. The cost for ion exchangers in antibody purification is in the order of $0.5–1.0 (€0.34–0.68) per gram.¹

Table 1 Six heuristics for economy by design.

More than 15 years of successful production in the biotechnology industry have resulted in downstream processing heuristics (i.e., rules-of-thumb) that point towards economical purification strategies (Table 1). We will look at these individually.

Address current and future costs in development

For companies with a history of producing biopharmaceuticals, the cost-effectiveness of various production tools is usually known. However, this is not the case for many start-ups, especially those in which the downstream process developer has little or no industrial experience. (For information on protein purification heuristics, see Protein Purification Handbook 18-1132-29 [GE Healthcare, Sweden.]) Cost-effectiveness is designed by understanding processing needs.

In some downstream processes, utilization of reusable chromatography media and filters may be necessary to obtain good process economy. This is particularly true for large-scale production as multiple batches per year are required to meet market needs. In one economic evaluation of reuse, media and validation costs were calculated. The greatest cost for establishment of reuse was related to its validation. Incremental annual savings were approximately $113 million (€77.18)/year for 10 lots, $15 million (€10.25)/year for 30 lots, but by 90 lots the savings were down to $0.7 million (€0.48) and the validation costs had risen significantly.²

For large volume processes, throughput requirements are often critical, especially to reduce initial volume and minimize contact with proteases. In this case, chromatography media with higher capacity and higher flow properties will enable a more economical process design. By reducing initial volume, buffer, including costly water-for-injection (WFI), consumption needs will be lowered. A reduction of buffer consumption by one-third has been estimated to reduce cost by 6%.¹

For other processes, disposables afford better economy as they can provide sanitary, ready-to-use processing equipment that reduces time to first-in-human (FIH) studies. Replacing chromatography and filtration media after each use may be less costly than trying to validate cleaning routines, particularly early in process development. Disposables are often the most economical solution for multiproduct facilities.

Storage of dilute buffers can also increase costs, but these can be minimized by using an automated in-line dilution of concentrated solutions. Clearly, there are many cost-saving measures that can be taken. During development, evaluate the process transfer capabilities of the technologies intended to decrease processing costs. If they cannot be transferred and new tools are needed, there could be a significantly negative impact on costs.

Evaluate the costs for buffers and other processing agents; column re-use, repacking production columns; storage; cleaning; extractable studies for disposables; automation and personnel costs. For example, packed column storage costs include facility space, storage solutions, removal of storage solutions and their disposal, and testing for bioburden and column integrity after storage.