Streamlining and redesigning existing manufacturing processes
Many processes for biopharmaceutical manufacturing were designed at a time where process efficiency was considered unimportant
(3). More recently, manufacturers have sought to increase the efficiency of each unit operation, but they are only now starting
to consider redesigning the entire process train to see whether cost savings can be made. The trend toward process streamlining
owes a lot to FDA's quality-by-design (QbD) principles, which are derived from the design-of-experiments (DOE) concept. The
design space of a manufacturing process is littered with efficiency peaks and troughs, but there is not always a simple path
leading to the most efficient process. Therefore, process design incorporating efficiency and quality from first principles
involves going back to the drawing board and evaluating the critical attributes that contribute to an efficient process.
Most companies are applying these principles and actively streamlining their processing strategies wherever possible. Antibodies
take center stage because they represent more than half of all biopharmaceutical products in development, and their common
properties make it possible for companies to share process efficiency data that are applicable across platforms (10, 11).
It is for this reason that antibody manufacturing has benefitted from the development of so-called generic platform processes,
which are broadly similar for all antibodies but can be tweaked to match the specific properties of individual products (12).
Antibody manufacturing provides an excellent example of the application of process redesign and streamlining principles to
increase productivity, cut costs, and maintain product quality. Most manufacturers use three chromatography steps for antibody
purification, starting with a very expensive Protein A capture step that is placed immediately after clarification, followed
by anion exchange (AEX) chromatography in flow-through mode to extract negatively charged contaminants, such as host-cell
protein (HCP), endotoxins, host DNA, and leached Protein A. Then, either cation exchange (CEX) chromatography or hydrophobic
interaction chromatography (HIC) in retention mode is used to remove positively charged residual contaminants and product
related impurities, such as aggregates and degradation products (13). Modern platform processes also serve as orthogonal strategies
for virus removal.
Realizing that no further cost savings could be gained by scaling up the above process, Pfizer explored the design space around
the standard process and found that certain modifications could reduce costs considerably without affecting the quality of
the antibody (14). The company introduced two types of process modifications, one in which the order of the polishing steps
was reversed and another in which different separation technologies were used to increase process capacity (i.e., using membrane
absorbers for the flow-through chromatography step and replacing the depth filtration step with continuous centrifugation)
(15). These changes increased the efficiency of purification to such an extent that, for some antibody products, the cation-exchange
step became unnecessary reducing the process from three columns to two columns or even a single column. Not only did this
save the direct costs of column resin and buffers, but also reduced the process time by >45% which doubled the productivity
in terms of batch processing (14).