« BIOTECHNOLOGY Rank
1 2 3 4 5 6 7 8 9
10 11 12 13 14 15 16 17 18 19 20
Humira
Remicade Enbrel
Adevair/seretide Rituxan/MabThera Lantus
Herceptin Crestor Avastin
Cymbalta Plavix
Neulasta Lycria
Januvia Lipitor
Nexium Singulair Atripla
Symbicort Truvada
Drug
Table 1. Top 20 best-selling drugs in 2012 (modifi ed from [6]) Company
Small Molecule/Biologic AbbVie
Johnson and Johnson Amgen and Pfi zer GSK
Roche Sanofi Roche
AstraZeneca Roche Eli Lilly
Sanofi & BMS Amgen Pfi zer
Merck&Co. Pfi zer
Astra Zeneca Merck&Co.
Gilead Sciences AstraZeneca
Gilead Sciences
Biologic Biologic Biologic
Small Molecule Biologic Biologic Biologic
Small Molecule Biologic
Small Molecule Small Molecule Biologic
Small Molecule Small Molecule Small Molecule Small Molecule Small Molecule Small Molecule Small Molecule Small Molecule
proteins and antibodies based on today’s products will be a “facelift” by manipulating molecular frameworks to further improve binding specifi city and effi cacy, reduce needed therapeutic dose, conjugation to immunoactive substances, bi-specifi c binding antibodies, cytokine coupled entities, etc. A major breakthrough comparable to the fi rst antibody technology is still pending. It should be stated that recent progress has been made in developing antibodies which interact more directly with the immune system – up-regulating its behavior towards antigens (e.g. cancer cells), in what is termed immunotherapy.
For today and tomorrow’s molecular formats, the major challenges will be funding and increased success rates in R&D. Although there is clear growth and trend towards the use of biologics, the pharmaceutical industry still faces signifi cant challenges. Patent expiry is one of these major threats for biologics developers and manufacturers, particularly given the high R&D costs associated with bringing these biologics to market. This “patent cliff ” is well known in the small molecules world, and its impact has been felt with several drugs. In upcoming years, several biologics will run out of patent protection, and several “biosimilar” or “biobetter” manufacturers will enter the arena. In addition, increasing safety requirements, shift of signifi cant growth to emerging markets, restricted market access, increased development costs and declining R&D productivity will put more pressure on the value and supply chain of innovation-driven companies.
However, this pressure has been vital to the industry in terms of innovating both, process and product development. Maturation of technologies and processes, higher degrees of automation, and process robustness driven by science and process management has been seen over the last decade.
Sales 2011 [MUSD]
7932 8159 7367 7928 6523 5249 5706 6622 5747 4161 9823 3952 3693 3324 9577 4429 5479 3225 3148 2875
Sales 2012 [MUSD}
9265 8215 7963 7904 7285 6648 6397 6253 6260 4994 5318 4092 4158 4086 3948 3944 3853 3574 3194 3181
19.3 0.7 8 1 9
19.3 11 -4 6
20
-45.9 3.5
12.6 22.9 -58.8 -10
-29.7 10.8 5
10.6
In process development, high throughput robotics for both upstream and downstream process development have been vital to screen and improve cell lines, media compositions, chromatography media, etc. Increased titer results are due to improved expression vectors and media optimization supported by the higher automation degree and decreased scale (e.g. micro titer plates and tube bioreactors), allowing broader screens.
The “omics” approaches, including transcriptomics, proteomics, and metabolomics, along with the sequencing of the CHO genome have provided tools and data to support and enhance these eff orts. Most of the signifi cant improvements to date, however, have been based on the more conventional cell line/media approaches, with “omics” approaches still in search of signifi cant success stories.
Another advancement which has increased effi ciencies and enabled rapid startup of new manufacturing operations was the development and implementation of disposable / single-use technologies early on in the development processes. Now, the fi rst concepts are well- established in manufacturing processes (e.g., fi lters, containers, culture fl asks, bioreactors, etc.). With increasing titers and smart integrations of mature technologies, even fully disposable facilities have been reported. However, this is not only due to the availability of disposable technologies. The signifi cant improvements in product titers and downstream purifi cation yields driven by resin capacity and process throughput have enabled a highly effi cient and commercially viable manufacturing based on disposables. One commercial provider of custom contract manufacturing, development services, and optimized technologies reported titers in their XD technology (integrated perfusion cell culture and product concentration by UF)
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