Biopharma is absolutely not for the fainthearted. That's the big lesson that many new entrants are learning after some bruising early experiences. Although biopharma is certainly one of the pharmaceutical industry's most attractive sectors, new players regularly trip over its many complexities. Whether they are financially strong contenders from related industries medical product makers, for instance or traditional pharma companies that are shifting resources toward biologics, the operational hurdles are the same.
The hard fact is that biopharma operations are significantly more complex than traditional pharma operations, and they have little in common with the production of small-molecule drugs. For a start, building a new biopharma facility takes longer than for chemical or finished-dosage plants (typically four years compared with two years for conventional pharma plants) and requires a much higher investment (capital expenditure is seven to ten times greater). No surprise, then, that companies with business processes tailored to small molecules or non-pharma products have found these capital projects difficult to manage.
New contenders getting into biosimilars specifically need to develop production processes to ensure that product quality and cost are comparable to those of originator drugs. But primary production processes are complex and entail many input parameters, requiring in-depth expertise in process development. In biopharma, far more so than in traditional pharma, product quality is a function of production-process development and manufacturing.
Newcomers also find it tough to gain access to patents on the molecule itself and tougher still to circumvent intellectual property relating to production technology. Companies that fail to tackle these issues may have to shut down development.
What the newest players are learning is that they must quickly build up expertise in completely new technologies and create a biopharma culture that helps them attract and retain the best people. To be truly competitive in biopharma, newcomers must demonstrate much higher levels of skills and more sophistication in development, manufacturing and testing. The last thing they need is the talent drain that many of them find themselves suffering from.
THE DETAIL ON WHY BIOPHARMA IS DIFFERENT
So, what is required to overcome these hurdles? Success in biopharma starts with understanding the technological differences that make the sector's operations so complex. The exhibit provides an overview of the technological differences between biologics and small molecules and the implications for biologics. In fact, the marked differences have far-reaching implications for production, supply chain, labor and talent, and science and technology. We examine each of these areas:
Production of biologics is a highly technical, multistep process that entails very long lead and cycle times. For example, consider the process required to produce a recombinant monoclonal antibody (mAb) by mammalian cell culture (mAbs are the type of molecule used in several blockbuster biologicals, meaning those that have annual sales of $1 billion or more).
Manufacturing is based on genetically modified living organisms that express the protein. Molecular biologists prepare the DNA (the software) coding for the mAb, and cell biologists insert the DNA into living cells by transfection (a recombinant DNA technology). Cell biologists also apply sophisticated methods to select clones for high quality and productivity. The lead time from the design of the genetic code to the final clone is 9 to 15 months.
To enable reproducible results, modified cell clones have to be frozen, stored at -120 degrees C or below, and then thawed for use. This process, carried out by a cell biologist, is called cell banking. It provides the master cell bank and working cell banks. These banks will be critical over the lifetime of the product because they are its single source. It takes three to six months to prepare, test and release a master cell bank.
Cell clones need to grow in number and reach sufficient volumes before it's possible to start producing the protein (e.g., a mAb). To enable this, cell culture technologists must undertake the challenging endeavor of developing a production process that delivers consistently robust growth, high titer, high yield, and reliable product quality.
Manufacturing the drug substance
This production stage entails cell cultivation and purification. Once, blood or serum were used as the media in which cells were cultivated, but nowadays manufacturers use highly complex, chemically defined media that mimic the properties of those original media. The cultivation and the protein fermentation processes are run in stainless-steel vessels or disposable bags. Because protein molecules are sensitive to heat, pH and organic solvents, complex and expensive purification technologies must be applied technologies such as affinity chromatography, ultrafiltration (UF), and tangential flow filtration (TFF). It takes five to seven weeks to go from vial crack to final formulated bulk.
Production of final drug products
Biopharmaceuticals are typically delivered to patients by injection. This is because the drugs degrade in the digestive system (owing to pH sensitivity and protease, for example) and because of their size (most therapeutic proteins are not able to permeate mucosae). Delivery by injection requires the use of medical devices, such as prefilled syringes, dual-chamber capsules, or injection pens. The high quality standards and stringent sterility of the primary packaging needed for this delivery method drive higher costs of goods sold and can compromise patient safety if operations are mismanaged. The recent increase in warning letters to sterile facilities from the U.S. Food and Drug Administration, such letters now make up about 25 percent of all letters, compared with approximately 10 percent in previous years, speaks volumes about the extent of the quality challenges.