Biopharmaceuticals are now center stage and a hotbed of activity in the pharmaceutical industry. For mature, small-molecule-dominated companies dealing with the patent cliff, biopharma is a new lifeline. Many generic companies are investing in and planning to make biosimilars.
Biotech advances made biopharmaceutical manufacturing possible. But, where innovation has been seen in screening and other technologies designed to identify chemical entities to treat disease, little has changed in the way that biopharmaceuticals are manufactured.
A biopharmaceutical manufacturing process must be extremely responsive to the nature of proteins. Its inefficiencies are in yield, the high cost of manufacturing and downstream processing.
Innovation in vaccine manufacture has stemmed from knowledge gained from the therapeutic protein industry, but some of the myths and “best practices” of vaccines have crept into the manufacture of proteins, the main one being the idea that “the product is the process and the process is the product.”
Rather than resulting in feedback control, this phrase has usually delivered process sameness. Even pharmaceutical Quality by Design failed to dislodge this mindset. The case studies and examples being presented or published rely on the tried and tested rather than provide a solid basis for process control.
Biopharmaceuticals’ challenges and opportunities are somewhat different from those of small-molecule manufacturing. Biosimilar guidances are sensible and not too daunting; new biological entities are numerous; the products are very profitable even when the processes not very efficient and yields low. Is this scenario all that different from the small-molecule sector, where profit margins concealed inefficiencies? Shouldn’t its past be a warning for biopharm’s future?
Major challenges are already here, evidenced by a burgeoning number of biosimilar manufacturers. The impact of regulations on startup costs will force these new companies to innovate. Those that survive will be lean and mean. Consider Samsung, which plans to launch biosimilars by 2015, offering generic biopharmaceuticals at half the current prices of name-brand biopharma products.
The manufacturing challenges of yield and downstream processing are still with us. The old way of dealing with them has been to scale up. The clever way of dealing with yield is to scale down.
An answer to these problems can be single-use process equipment, whether it’s used upstream, downstream or both. Vendors claim that use of disposables can reduce the cost of manufacturing by 30-50%, with cost per gram reduced fivefold.
Purification processes can also be greatly improved if one is willing to look beyond resin-based columns and consider single-use, high-capacity membrane chromatography.
At this point, more manufacturers are adopting single use, but the biopharmaceutical industry still seems wary of it. It’s not what we’re used to.
Our industry has been very shy about embracing change, justifying its response as concern about regulations. Regulations per se are not the cause, but enforcing adherence to rigid practices is. Where is the manufacturing innovation in biopharmaceuticals? For example, the low-risk flu vaccine lends itself to continuous manufacturing, yet bio-continuous manufacturing does not feature in any discussion. Why?
I believe we fail to develop efficient processes because we are not willing to deviate from our prior knowledge, from a rigidly defined and enforced development process, that unravels a product rather than delivers what has been desired and planned for.
In the Harvard Business Review, Tim Brown wrote about an alternative to the tried-and-true process that could invigorate pharmaceutical development. “The design process is best described metaphorically as a system of spaces rather than a predefined series of orderly steps. The spaces demarcate different sorts of related activities that, together, form the continuum of innovation. Design thinking can feel chaotic to those experiencing it for the first time. But over the life of a project, participants come to see . . . that the process makes sense and achieves results, even though its architecture differs from the linear, milestone-based processes typical of other kinds of business activities.”
He goes on. “Design projects must ultimately pass through three spaces . . . inspiration, for the circumstances (be they a problem, an opportunity, or both) that motivate the search for solutions; ideation, for the process of generating, developing, and testing ideas that may lead to solutions; and implementation, for the charting of a path to market."
For biopharma, the inspiration is clearly there and many companies are already in the ideation stage. Will they get to the implementation stage? Will we act differently, and establish a different “prior knowledge” and “best practices”? Can we stop thinking so linearly, and save biopharm from the lackluster fate of small-molecule manufacturing?