NEW PRODUCTS REQUIRE FLEXIBLE MANUFACTURING
Fortunately, there is still a very dynamic pipeline of new products in the biopharmaceutical industry. Figure 2 compares this
pipeline as recorded by the Pharmaceutical Research and Manufacturers of America (PhRMA), first in 2004 and then in 2006.4,5 Within two years, antibody-related projects grew from 76 to an impressive 160. The combination of various recombinant proteins—including
growth factors, interferons, and interleukins—amounted to 94 projects in 2006, up from 57 in 2004. At an average success rate
of 20%, these two parts of the pipeline will lead to more than 50 approved products in the near future. Additional products
such as vaccines are likely to be added.
Figure 2. Dynamic portfolio driven by monoclonal antibodies
One conclusion to be drawn from these data is that increased numbers of companies will manufacture more than one protein drug.
To achieve this, some companies will use contract manufacturing organizations (CMOs). Others will invest in new manufacturing
facilities of their own. And a few will convert existing facilities originally designed for single-product manufacturing.
As more drugs enter the market, the need for multiproduct manufacturing facilities with sufficient flexibility to match the
diverse production schedules of different drugs—both now, and in a dynamic, difficult-to-predict future—will increase. As
described above, many of the manufactured proteins will be relatively small-scale products, so the issue of a lack-of-scale
advantage will also need to be considered.
Figure 3 shows the production scenarios that may emerge when companies deal with an increasing number of diverse approved
biopharmaceuticals manufactured at widely varying scales.
Figure 3. Emerging production scenarios. More companies will have more than one product in production, many of them small
TRADITIONAL FACILITIES VERSUS DISPOSABLE SOLUTIONS
The traditional "stainless-steel space" is a facility that includes fixed installations, such as several bioreactors at any
scale from 100 to 25,000 L, combined with one or two purification suites with chromatography columns and membrane skids, together
with the corresponding buffer and intermediate product storage tanks. For products required at ton scale, this type of manufacturing
facility is currently used and will continued to be used in the future. Many mid-scale products are also manufactured in production
units with fixed stainless-steel installations. Beginning with facilities owned by CMOs such as Lonza and Boehringer Ingelheim,
however, some first-generation sites have been expanded to add capacity, or have been redesigned to become multiproduct facilities.
On the other hand, the "disposables space" is gaining importance for efficient manufacturing. For some time now, disposable
production tools have been used in pilot plants to make material for preclinical trials or product and process characterization.
In addition, current practice in clinical trials is to produce product in few batches often at 2,000-L bioreactor scale, within
reach for disposable solutions. Disposables enable the manufacturer to be flexible and cost-efficient. No major upfront equipment
investment is required and the company can avoid the delays associated with waiting for equipment to be installed and with
validating cleaning regimes for operating this equipment in re-use mode.
However, disposables have some drawbacks. Neither disposable bioreactors nor single-use bags for buffer and product storage
are regularly available, and many companies do not find them useful above 1,000 liters. In addition, because of the cost of
replacing disposable devices after every production run, many companies limit the use of disposables in regular production
to processes that run only a few batches per year. For large batch numbers—that is, for regular manufacturing that uses most
of the available facility time—traditional re-use is still considered economically favorable. It is still common practice
to make even the few clinical batches for Phase 1 and 2 trials in, for example, a 2,000-L stainless-steel bioreactor, mimicking
the full-scale designs envisioned for later development stages. This practice is established because clinical manufacturing
serves not only to formulate products for patients, but also to study the processes involved in manufacturing under commercial