It should also be noted that certain efficiency improvements in one stage of development may turn out to be costly or difficult
to manage in later stages at full scale and with intensified processing. For example, using disposables is attractive for
operating a multi-purpose plant and handling a large number of candidate MAbs in development, but is not necessarily more
economical for regular, large-scale manufacturing. For certain situations, the savings created by using disposables may be
at risk due to process changes between clinical phases. It is not easy to balance straightforward process economics against
the advantages of an agile pilot plant.
Priorities Realizing Economic Advantages
Figure 3. Priority ranking of options to generate economic gains related to development and manufacturing
|
A number of generalizations are possible and a priority scheme for seeking economic improvements can be developed (Figure
3). Work on technical improvements should adhere to that order of priority to secure the greatest impact.
The industry is communicating the success of using "platform technology" approaches to process development routines and to
the ultimate process design.1 A platform consists of verified technology for cell biology, cell culture, downstream processing, and analytical work as
used for a specific category of target active drug substance such as MAbs. Platforms are regularly updated with new, verified
technology. It has been reported that using such platforms has supported time savings of several months on the critical path
to clinical trials. Using platforms has allowed some companies to reduce the need for process alteration prior to full manufacturing
scale-up. Gaining three months on the way into the clinic can potentially save tens of millions of US dollars (MUSD) in net
present value (NPV) for companies looking at an average MAb (~500 MUSD peak annual sales).6 In other words, deviating from the platform concept or not developing a platform at all is one of the most costly strategy
issues MAb- producing companies can face in relation to manufacturing process development.
Many companies view the use of Protein A chromatography as a capture step essential to a successful downstream processing
platform1 , and some results suggest that developing alternative capture steps, such as using small molecule ligands described as Protein
A alternatives, may both take longer and result in reduced robustness.1,7,8 Just one failed batch as a result of a robustness issue would cost tens of millions of US dollars in lost sales value or
a possible risk to the patient population.
Figure 4. Shortening cell culture time and increasing facility use are two ways to reduce the cost of antibody produced. As
seen in the table, reducing cell culture time from 14 to 10 days increases yearly production by 67 kg and reduces the cost
per gram by 78 USD. The graph shows that increasing facility utilization from 20 to 100% can lead to a 5-fold reduction in
the cost of goods.
|
A key economic driver relates to the output from the production facility, i.e., the quantity of product produced in it per
time. Facility output is primarily a function of its utilization (expressed as percent of total facility time used), the productivity
of the cell culture (key parameters are cell culture time and product titres), productivity of the downstream process (main
parameters are capacity to process product mass and volumes), and "smart" process engineering solutions (through the ability
to remove unproductive time from the critical path delivering product to the filling plant). Depending on these factors, the
cost per gram of antibody produced seems to vary between 100 and 1,000 USD/g (Figure 4).
|
