ABSTRACT
Challenges in the purification of monoclonal antibodies (MAbs) include reducing production cost, developing robust processes for both product purity and viral clearance, and integrating upstream and downstream processes. Increases in titers for MAb feed streams and clinical doses have led to the need to develop new products and technologies or adapt existing ones to meet these challenges. This paper will discuss the status of some of these new technologies and products and their potential for improving platform processes, as well as issues related to their implementation.

(Pfizer, Inc.)

The lowest production cost is achieved not by increased process complexity but by the opposite: Operating faster and with the fewest and most efficient downstream steps reduces investments in validation and subsequent batch failures.³ Some high-dose monoclonal antibody (MAb) products require an annual production of metric tons of material to supply the market. Demand for quantities this large exceed current manufacturing capabilities requiring companies to invest in additional capability to meet demand. This delay can contribute to missed revenue. Current platforms for the large-scale production of MAbs, for example, show that it is essential to design and operate an integrated series of purification steps that are both high yielding and product molecule–specific.⁴

Disposables

Although some types of disposables such as media and buffer bags have been in use for years, the use of purification-related disposables is relatively new. The advantages in their implementation include reductions in preparation and product changeover, ease of implementation and validation, elimination of cleaning procedures, and a reduction in capital outlay.⁵ New and improved disposable technologies include single-use chromatography membranes and ready-to-use columns, ultrafiltration cassettes, and chromatography and ultrafiltration flow paths containing single-use monitors and transducers. However, it is not always easy to incorporate into existing processes as a one-for-one swap without additional development work. In addition, manufacturing costs must be considered, taking into account the advantages of disposables discussed above compared to disadvantages such as increased material demand and validation of leachables.⁶

The use of disposable membranes in MAb purification has shown potential to replace traditional resins, especially for anion exchange (AEX) membranes that are used in flow-through mode, in which the impurities bind to the membrane while the antibody flows through. The binding capacity of the target protein has previously been a problem for membranes because of their lower surface-to-bed volume ratio as compared to resins,⁷ so flow-through operations present an ideal situation for membrane use. The advantages of these membranes include improved mass flow properties because of the porous structure of the membrane hierarchy, and ease of preparation before use.⁸ The initial preparation time is significantly reduced because column preparation operations such as packing and qualifying, and post-use cleaning and storage are eliminated.

Figure 1

Figure 2

The question that remains for these disposable membranes relates to the cost of goods. Given the higher cost of membranes, their use makes sense during early-phase manufacturing when the number of batches is small, but how do they stack up in commercial manufacturing? The answer may lie in the ability of the membrane to be used multiple times. We have shown that reusing the Sartobind Q membrane up to 10 times does not affect its ability to remove DNA, but validation for reuse is an issue because it has yet to be proven.

Figure 3