When every drop counts: what CDMO clients with rare or expensive APIs should expect from the fill-finish process
Sterile fill-finish is the critical final step of injectable drug production, ensuring patient safety by preventing microbial, bacterial, and particulate contamination in medications that enter the bloodstream directly. While fill-finish is a vital step in the production of these therapies, drug product loss is unfortunately inherent to the process. Filtering and filling an injectable drug in traditional filling lines at an aseptic fill-finish CDMO can result in the loss of more than a liter of drug product for a single batch. Given that just one liter of a high-value drug product can be valued at over $1 million, and that many other high-value drugs are difficult to produce or have long production lead times, this level of product loss is far from ideal. For many clients, a single dose is worth thousands of dollars.
So, why does this loss occur in aseptic fill-finish, and how can a CDMO overcome material constraints to preserve as much drug product as possible for clients with rare or expensive APIs? This article will detail where product is lost in sterile filtration and filling, changes a CDMO can make to the process to increase the final product yield, and what to look for in a CDMO when producing a rare or expensive product.
Why is drug product loss inherent to sterile fill-finish?
GMP production of a drug product involves a few steps. The first step is the formulation and sterile filtration of the bulk drug product. Though the exact process depends on the specific product, formulation typically involves thawing, mixing, and sterile filtering.
Sterile filtration is the greatest source of product loss. This results from a combination of product left over in the mixing vessel, product trapped in the tubing between sterile filters, and product retained by the sterilizing filters.
After formulation and filtration, the remaining drug product loss comes from sterile filling. A line purge, which involves dispensing a set volume of drug product solution through each fill needle, is necessary to ensure there is no air in the filling line. Next, a CDMO must perform weight checks at certain intervals to verify that dispensed volumes are consistent across the batch. In many cases, these are destructive weight checks which result in further product loss. Finally, there is also drug product lost within the tubing used for filling. If air gets trapped in the tubing at the end of a fill, the CDMO must end the fill early and lose any drug product that is left in the fill line assembly.
If all this loss is inherent to the fill-finish process, is it possible to overcome, especially when the client can’t afford to lose any more of their expensive or rare API than is absolutely necessary? Luckily for such clients, it is possible to modify the fill-finish process to reduce loss and overcome material constraints.
How to overcome material constraints for expensive APIs when performing sterile filtration
By understanding where drug product is lost during the sterile filtration step, a CDMO can implement practices to reduce that loss.
While a CDMO cannot eliminate mixing vessels from formulation, they can reduce drug product loss by filtering into a presterilized bioprocess bag (biobag) instead of a mixing vessel. By draining from the bottom, biobags allow all the drug product to be removed. In contrast, draining from a mixing vessel through a dip tube often introduces air into the siphon line, which can prematurely end the fill.
To prevent line loss from the tubing, a CDMO can simply reduce the length of the tubing as much as possible. Reducing the inner diameter of the tubing can also increase product yield but may slow down the process and increase pressure on the system.
Finally, selecting fewer and smaller filters will result in smaller hold-up volumes within the filter. Smaller filters increase filtration time, so the filter size must be carefully selected to fit the process.
How to overcome material constraints for expensive APIs during sterile filling
A CDMO can also implement practices to increase yield by understanding where drug product is lost in filling.
Just as it does in filtration, reducing the length of tubing where possible will reduce line losses from filling significantly without adding any risk to the drug product. CDMOs can also reduce the inner diameter of tubing, but as in filtration, the size should be optimized to limit stress on the system and prevent the filling time from increasing too much. Reducing line purge requirements can also reduce drug product loss.
The next strategy is to perform non-destructive weight checks instead of destructive weight checks. There are two ways that this is commonly done at a CDMO. The first is to measure the mass of the empty container and subtract from it the mass of the filled container. The second way involves measuring the number of water molecules in the container via radio waves and comparing this against a standard to calculate the volume of the solution. If a CDMO cannot offer non-destructive weight checks, it’s possible to reduce waste by performing fewer destructive weight checks instead. This strategy does come with the risk that weight checks fall out of an acceptable range before a correction can be made.
Finally, product yield can be increased by lifting the bulk drug product container at the end of the fill. This helps prevent air bubbles from entering the drug product solution, as they rise toward the mixing bag rather than traveling through the tubing and into the fill needle.
For a deeper look into reducing loss in fill-finish, watch our webinar on this topic: Reducing loss in fill finish for high-value drug products.
What matters most when outsourcing fill-finish for rare or high-value APIs?
For clients whose drug product costs upwards of $1 million per liter, selecting the wrong fill-finish CDMO can lead to significant financial losses. Partnering with a CDMO experienced in higher-yield filling can save thousands of dollars and, more importantly, milliliters of precious drug solution. Companies considering a CDMO partnership should select a manufacturer that will work with them to develop a process that minimizes as much product loss as possible. At the right CDMO, with the right product, and with all mitigation strategies in place, drug product loss can be mitigated to 50 – 75 mL for a one liter fill.
Another green flag is a manufacturer with an innovative approach to increasing drug product yield. A next-generation strategy for reducing drug product loss—beyond the methods discussed in this article—is to further minimize the amount of tubing used during the fill process, as demonstrated by the low-loss filling process at Sharp Sterile Manufacturing. In this approach, the vessel containing the drug product is connected directly to the filling needle, nearly eliminating tubing from the system. This can be accomplished by removing the pump from the process, though doing so requires an alternative method to ensure accurate drug product dispensing.
Peristaltic and piston pumps, commonly used in sterile filling, use suction to pull the solution in and mechanical force to push it out. In a pump-free setup, suction is unnecessary; instead, a force is needed to push the drug product out of the fill needle. This can be achieved by pressurizing the filling vessel to a low pressure (~1 psi) with sterile gas, to provide the necessary force to push the product out.
By removing the pump and eliminating several feet of tubing, the low-loss fill process at Sharp Sterile Manufacturing limits loss to less than 30 mL per lot. This innovative, isolator-based filling system uses only three inches of tubing to connect the fill vessel to the actuator and fill needle and is ideal for rare or expensive APIs.
Ultimately, selecting a fill-finish partner with the right expertise, technology, and processes to protect every drop of product can make the difference between preserving valuable API and losing irreplaceable material. Advanced approaches can dramatically reduce waste and ensure that even the smallest quantities are fully utilized. By prioritizing a CDMO that focuses on yield optimization at every step, sponsors can maximize their material efficiency, reduce costs, and safeguard the value of their rare or high-value APIs.
