Where is Biopharmaceutical Manufacturing Heading? - An analysis of current and upcoming industry challenges. - BioPharm International

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Where is Biopharmaceutical Manufacturing Heading?
An analysis of current and upcoming industry challenges.


BioPharm International
Volume 21, Issue 10

THE BIGGEST DRIVER OF MANUFACTURING COST

Facility Use

Facility use is the most important factor in a good manufacturing economy. Using 80% of available facility time can be considered excellent, but new facilities rarely enjoy such high utilization from the beginning. For companies making a single product (and sometimes for other companies, as well), this percentage can be achieved only indirectly when assigning manufacturing to a CMO.

Cost of Sales

Cost of sales (CoS) represents the ratio of manufacturing costs to revenue. Some companies with portfolios of protein drugs report CoS as low as 15–16% of revenue. The lowest level of production costs per gram of antibody is allegedly approximately $100. However, such numbers invite skepticism. To maintain confidentiality, companies tend to give incomplete explanations for economic information in presentations or papers, or they use model calculations. Nevertheless, the models used at GE Healthcare BioSciences are based on a large variety of independent and publicly available input data points, and this information suggests that $100 per gram (including both fixed and variable costs) can be considered a top value.

Process Yield

After CoS, process yield is the next most important economic driver, as long as all products can be sold. Overall process yield should not be lower than 70%. Ideally, it should approach 80%.

Analytical Costs

Analytical costs are another significant cost driver for this industry. Successful companies have created analytical platforms that serve their entire product research and manufacturing ranges. More indirectly, hold times and batch times have been reduced to minimum levels in these companies. But analytical efforts result in more hold times or longer batch times. Proper risk management allows continued processing of intermediates without first waiting for this information.

Batch time is decisive in determining how many batches can be produced in a given facility time for a given product. The best values for upstream batch times seem to be 10 to 12 days in mammalian cell culture, and two days for the corresponding downstream process. These values allow parallel operation with six bioreactors feeding product to a single downstream production line (i.e., one that produces a new batch every second day).

Yield

While many approved processes still show product titers of approximately one gram per liter or even less, indications are that novel processes now reach three to five grams per liter. Even higher product titers are envisioned by some mammalian cell-culture scientists. To achieve basic economic competitiveness in the future, titers should probably be at least three grams per liter.

Protein A Media

For downstream processing of monoclonal antibodies, media capacity and lifetime are among the key cost influencers. For a Protein A–based capture step, the best capacities currently achieved are approximately 40 g/L. For subsequent ion exchange steps, the best values range from 80 to 100 g/L. If the antibody product is not bound to the medium, and if capacity can be reserved for impurities (flow-through mode), several hundred grams to several kilograms of antibody can be processed in one step, depending on where in the process sequence the step is located.

Even a relatively sensitive affinity medium with Protein A as ligand can tolerate several hundred process runs, if the best combination of medium and cleaning method is chosen. This is the key to the cost of the downstream process. Cleaning is best performed with solutions containing sodium hydroxide; a Protein A medium resistant to NaOH cleaning was introduced a few years ago specifically to achieve this goal. Cleaning with sodium hydroxide solutions is also desirable in terms of cleaning costs. The best published values for buffer costs (assuming large-scale buffer production) range from 30 to 50 cents per liter.

Finally, a number of best-in-class practices are closely related to avoiding unnecessary steps or hold times throughout the process. These include in-line buffer preparation or exchange.


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