Where Drug Product is Lost in Fill Finish and How to Limit It

Sterile filling is an important step in injectable drug product manufacturing for products that cannot withstand terminal sterilization. Unfortunately, drug product loss is inherent to fill finish. This is concerning for high-value drugs where the active pharmaceutical ingredient (API) is expensive, difficult to produce, or has long production lead times. Some drug products that we have filled at BSM were valued over $1 Million for a single liter of drug product. For fills, like these, each additional vial, syringe, or cartridge that is filled can save a client thousands of dollars.

Most fill finish CMOs predict at least a liter of drug product to be lost during the filtration and filling process. In in this post, we will discuss where product is lost during the process, how these losses can be limited, and a new sterile filling process to limit loss to less than 30 mL.

Want a deeper understanding of how to reduce drug product loss? Download our white paper:

Minimizing volume losses in small-scale aseptic fill finish for high-value drug products

Where is product lost during sterile filtration?

First, where is product lost? Sterile filtration is the greatest source of product loss, and there are three main culprits:

Product leftover in the mixing vessel

There is no such thing as a perfect transfer. Your drug product will either be thawed and mixed or formulated in a mixing vessel and then sterilized via filtration into a second vessel. Product will inherently be lost on the walls of the vessel the product is filtered from. If special care is taken to remove all product, expect to lose at least 3 mL to product leftover in the mixing vessel. If care is not taken to fully empty the vessel, you can expect to lose closer to 10 – 15 mL of product.

Line Losses

Lines losses in sterile filling is the product that is lost in the tubing. Line losses can be significant, especially during sterile filtration because product becomes trapped in the tubing between and after the sterile filters. Although product after the filter can be recovered, product in between filters will remain stuck. Volumes will vary, but you can expect to lose at the very least, 5 mL, and more realistically 15 – 20 mL for 1L of drug product that is filtered.

Filter Hold Up

Sterilizing filters will retain a significant amount of solution. The amount retained will vary by filter, but for a typical filter used to sterilize one liter of drug product, about 12 mL of holdup per filter is expected. Since most fills only require two filters, this is a total loss of 24 mL.

Figure 1. Hold up volume between filters before (top), during (middle), and after (bottom) filtration. A significant volume of solution becomes trapped between filter membranes after filtration.

Where is product lost during filling?

Product loss is also expected during filling. There are three main sources of loss:

Line Purge

Before the fill is started, the fill line assembly (the tubing that feeds the fill needle with drug product) must be supplied with drug product solution and be free of air. This is done by drawing solution through the tubing and dispensing a set volume of solution from each fill needle that’s used. This is called a “line purge,” and the volume collected is set by the CMO based on what they believe to be appropriate to ensure all air is removed from the filling line. Expect at least 10 mL per filling line to be collected.

Weight checks

Fill volumes must remain consistent across the entire filled batch. To verify that dispense volumes are consistent, the CMO will perform weight checks. Most weight checks use a destructive method of measurement whereby a single filled unit is consumed for each weight check performed. It’s standard practice to also perform several weight checks at the start of filling to ensure that the set dispense volume is accurate and within the acceptable range. Weight checks are then performed every 50 -150 units to bracket filled units and ensure the dispensed volume isn’t falling out of range. A final weight check is performed on the last vial, syringe, or cartridge that’s filled. The amount of product that is lost is directly proportional to the number of weight checks performed and the target fill volume. If we assume 1,000 units are filled with 1 mL of drug product each and weight checks are performed every 100 units, then you can expect to lose at least 13 mL of drug product (3 beginning weight checks, nine performed every 100 units filled, and one last weight check).

Line Loss

As mentioned above, line loss is the product leftover in the tubing, or in this case, the fill line assembly. The amount of tubing used varies widely based on the CMO and their filling line. Some may require 70 feet worth of tubing and others only a few feet.

Ideally, filling ends when the CMO runs out of product to fill, but if air becomes trapped in the fill line near the end of a fill, then filling made be called off early. If the CMO does not watch for bubbles entering the line near the end of the fill (and work to prevent or remove these), then this can cause out-of-spec weight checks, end a fill, and lead to a significant amount of unused product left in the fill line assembly.

How to reduce product loss during sterile filtration

Now that we know the sources of product loss, we can discuss how mitigate their effect. There are several practices that can be implemented to reduce drug product loss during sterile filtration:

Use bioprocess bags over mixing vessels

While the vessel that you formulate in and filter from will likely remain a mixing vessel for practical purposes, the vessel that drug product is filtered into should be a presterilized bioprocess bag (biobag) where appropriate. Many clients opt for these flexible bags when product loss is a concern, because they are much easier to empty completely during filling. Biobags are drained from the bottom of the container and effectively remove all drug product. Mixing vessels, on the other hand, require a dip tube to siphon drug product from the container, and these have a hard time removing product at the end of the fill without drawing in air with it (which can prematurely end a fill).

Figure 2. A spinner flask (left) vs. a biobag (right) at the end of a fill. Air bubbles will be caught in the fill line before all the solution is drained from the flask, prematurely ending the fill. Biobags (right), on the other hand, will drain nearly all its contents before air is introduced into the fill line. This increases the number of units in a fill.

Reduce the length and ID of tubing

A simple solution to cut down line losses without affecting filtration is to reduce the length of tubing where possible. Reducing the inner diameter (ID) of tubing is another method to reduce product loss, however, this will slow down filtration and add stress to the system, so your CMO should optimize your tubing ID to reduce volume loss without adversely affecting your filtration.

Use fewer and smaller filters

The greatest amount of product loss is between filter membranes. Any product remaining between filters is unrecoverable. The best way to reduce this loss is to use the fewest number of filters possible. All filters should undergo integrity testing after filtration and before filling to ensure the filters pass before product is filled into its final container.

In addition to using fewer filters, smaller filters that have smaller hold-up volumes can be used to reduce product loss. However, filters do have a limit to the volume of product it can filter and using smaller filters will increase filtration time. The size of the filter should be optimized for your project to reduce product loss without adversely affecting your process.

How to reduce product loss during filling

Drug product loss can also be mitigated in sterile filling. Some methods to reduce loss are to:

Reduce the length and ID of tubing

As mentioned above, reducing the length of tubing where possible will reduce line losses significantly without adding any risk to the process. Reducing the ID of tubing can also be performed to reduce product loss, but it should be optimized to also allow for reasonable filling times and to limit the amount of stress placed on the system.

Figure 3. Tubing with a larger ID and larger length (top left), tubing with a smaller ID and larger length (top right), tubing with a smaller length and larger ID (bottom left), and tubing with a smaller ID and smaller length (bottom right). Decreasing tubing length and ID will reduce the volume of drug product remaining in the tubing. This will reduce product lost in the line.

Reduce line purge requirements

If your CMO is confident that they can reduce the line purge requirement and remove all air in the line, then this is a simple, low-risk solution to reduce drug product loss.

Perform non-destructive weight checks

There are two methods of performing non-destructive weight checks (see figure 4). If a non-destructive weight check method is offered at your CMO, then these should be performed in place of destructive weight checks.

Figure 4. Non-destructive vs. destructive weight check methods.

Perform fewer destructive weight checks

If your CMO does not offer non-destructive weight checks, then you may be able to reduce waste by decreasing the frequency that weight checks are performed. For example, performing a weight check every 150 filled units instead of every 100 can save three filled units across a 1,000 unit fill (see figure 5). However, this does increase the risk that weight checks fall out of an acceptable range before a correction can be made. If the weight checks do fall out of range, this can lead to significantly more product lost. Your CMO should balance this risk with reducing product loss.

Figure 5. Number of units consumed to perform a destructive weight check in a 1,000-unit fill when performed every 100 units (left) vs. every 150 units (right). Performing fewer destructive weight checks can help reduce drug product loss.

Lift the bulk drug product at the end of a fill

An easy, low-risk solution to extending a fill is to lift the bulk drug product that your CMO is filling from at the end of a fill. When the volume nears the end of a fill, it’s easy for air to be siphoned into the fill assembly. If bubbles become trapped in the fill assembly near the end of a fill, then the fill is typically ended, leaving the remaining solution in the line and in the bulk drug product vessel to waste. By lifting the bulk drug product, you encourage any air to rise back up into the vessel rather than be pulled into the fill assembly where they can become trapped and end a fill. This will ensure that as much drug product is used to produce units in your fill.

Figure 6. Bulk drug product solution not lifted vs. lifted. Lifting the bulk drug product near the end of the fill helps draw air back out the line and potentially extends the fill.

Other methods to reduce drug product loss

There are two other high-risk methods that can be implemented to reduce loss during sterile filtration:

  • Filtering on the line
  • Performing a filter blow down

Because of the risk associated with these processes, we suggest you do not implement these strategies. Although they are not described here, they are covered in our white paper.

A new way of sterile filling to reduce product loss even further

You can make modifications to a typical sterile fill process to mitigate product loss, but it can only go so far. At the right CMO, with the right product, and with all mitigation strategies in place, product loss can be mitigated to 50 – 75 mL for one liter of drug product filled.

We recently developed and validated a new sterile fill process, at Berkshire Sterile Manufacturing, designed to reduce loss even further. In this new process, we removed the pump and shortened tubing lengths to just a few inches long. Our low loss fill process uses low pressure and a highly accurate actuator to set the fill volume. There is no hand-pipetting involved. The process is entirely isolator-based to offer the best sterility assurance. And, product loss is limited to less than 30 mL. We are actively working on modifications to limit loss even further to less than 5 mL.


Volume losses are unavoidable in fill finish, but they can be minimized to very low volumes. For companies looking to fill a small number of units of a high-value drug product, there are several practices that can be implemented to maximize the number of units in your drug production, during the filtration and filling process and through proper planning. Seeking out a CMO that actively implements these practices and has experience in low volume and low loss drug product filling is key to keeping product loss to a minimum.

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