No process delivers 100% yield, but what level of product loss, as a result of the manufacturing process, is acceptable?
The answer is in some ways simple, and in others, much more complex. The simple answer is “as little as practical.” The reality is that the answer changes depending on the importance and value of the product itself. This is not a particularly insightful conclusion, but it is no less true. The answer is always subjective and varies with the perspective of the person being asked the question and the process context.
Product loss, for any reason, has a financial impact, and the magnitude of that impact is directly related to the value of the product being produced. Pharmaceutical products vary enormously. Simple fluids such as ophthalmic solutions and large volume parenterals (LVPs) may be valued in cents per liter. Other fluids such as monoclonal antibody-based products for infusion could be hundreds of thousands of dollars per liter. These same therapies, if formulated at higher concentrations for subcutaneous injection, could be $1M per liter. Beyond the financial value, there is also often a human cost. COVID-19 vaccines, for example, provide a very humbling perspective, where any lost product directly links to lost doses and to people who may not be given the protection they need. Whatever perspective you have, the need to consciously minimize product losses for many processes is clear.
So how do we minimize losses?
Product loss cannot be avoided, and every unit operation has some impact upon yield. Most of the time this will be low, typically <10%, however, these losses are cumulative. A typical mAb manufacturing process for example may lose as much as 50% of the mAb created in the bioreactor in the process journey to the final drug substance container. Other processes can be lower than this. Individual unit operations can be optimized to maximize productivity and yield, and this is already a common part of process development and receives active consideration. Surprisingly, later, less science-driven stages of the manufacturing process may receive less attention, and it is not uncommon for product losses during operations such as bulk filtration and filling of drug substance to be seen as a natural and unavoidable reality.
This is understandable, however, as product value rises, these late-stage processes receive increased attention and opportunities for reduction are often explored with greater energy. Bulk filling, in particular, can often be a very manual process with basic tubing losses leading to practical limitations and unrecoverable volumes being tolerated as a result.
Manual, single-use bulk filling solutions are common and are often dependent upon operator expertise, operator insight, and techniques not easy to capture in standard operating procedures (SOPs) to manage losses. Filling systems often use complex designs with poor physical support adding undesirable variables to the process and avoidable risk. Systems that are designed to minimize product losses and are supported by automated platforms to achieve this reproducibly, both enhance recovery and minimize risk associated with the extensive manual manipulation at a critical point in the manufacturing process.
So, while bulk filling is one of the less sexy unit operations within the production of drug substance, it remains critical to productivity and deserves greater attention.