When Media Fills Miss the Mark

Media fills, or Aseptic Process Simulations (APS), are meant to show that a company’s aseptic process is under control. They are a key part of proving that sterile drugs are made in a clean and safe environment.

But more and more, inspectors are finding that these simulations don’t always reflect what really happens during production. When that happens, even a “successful” media fill may not count for much.

Over the past couple of years, regulators have made it very clear that if your media fills don’t match the real process, then your validation does not stand up.

A media fill is not just a box to tick. It must challenge the process and show that contamination can be kept out, even during difficult situations.

Simulating Sterile Operations Under Real Conditions.

What Does "Representative" Really Mean?

Inspectors are no longer accepting media fills that only represent ideal conditions. They expect simulations to reflect the actual manufacturing environment. That means:

• Using the same batch sizes you would for commercial production.

  
  

• Matching fill speeds and run durations to what really happens during manufacturing.

  
  

• Including common interventions, like component loading or line adjustments.

  
  

• Using actual operators who work on the production line.

  
  

If your APS only covers short runs or avoids tricky interventions, inspectors may say the validation is not complete.

It is not enough to do what’s easy or convenient. The simulation has to show how well the process handles real-world challenges.

The Problem with Cleaned-Up Simulations

One of the major inspection trends is media fills that are too clean or too safe.

In some cases, companies leave out interventions or do them in a way that is neater and less risky than usual. While this might make the media fill easier to pass, it does not prove that the process can keep products sterile under normal or difficult conditions.

For example, the FDA has issued warning letters where companies ran media fills that looked good on paper but didn’t include all the normal steps or challenges found in real production. The regulators pointed out that if a media fill avoids the real risks, it cannot truly test the aseptic process.

There have even been cases where certain steps were changed just for the simulation, like simplifying a manual addition that would normally be quite complex.

These shortcuts can lead to big problems, especially if the actual process is much more difficult to control.

Why Worst-Case Conditions Matter

Another common issue inspectors raise is the lack of worst-case scenarios in APS. These are situations where contamination is more likely, such as long run times, high fill volumes, or repeated operator interventions. Regulators now expect these to be part of the validation.

In several inspections, companies were cited for failing to simulate:

• The longest possible filling duration.

  
  

• The highest number of units filled.

  
  

• The performance of interventions by fully trained operators.

  
  

• Situations where gloves, tools, or parts had to be replaced mid-run.

  
  

By skipping these worst-case scenarios, companies miss the chance to show that their process can still perform well under pressure.

Inspectors are now asking companies to use real production data to design their APS. This includes things like downtime records, intervention logs, and previous EM trends. Guesswork is no longer enough.

Keeping Media Fills Real and Reliable

The goal of a media fill is not just to pass. It’s to give strong evidence that your process can prevent contamination during actual production. To do that, the simulation needs to include everything that could realistically go wrong.

This also means making sure your operators are involved in designing and performing the simulation. They know where the process is vulnerable, and their input helps ensure the simulation covers real risks.

Training should also reflect this thinking, operators need to understand that media fills are not just practice runs, but true tests of the entire aseptic system.

If It Doesn't Test the Limits, It Doesn't Prove Control

A media fill that avoids risk does not prove anything. Inspectors want to see that companies understand their process, including where it can fail, and that they are willing to test those points.

A good APS should be uncomfortable. It should challenge your assumptions and show that even in tough conditions, your controls still work.

If your media fills are simplified, outdated, or based on ideal situations only, it may be time to take another look.

A strong APS program reflects the real processes, pushes its limits, and builds confidence that the product is truly sterile every time.

If Your Media Fill is Too Easy, It's Not Doing It's Job

At Pharmalliance Consulting Ltd, we support manufacturers in building media fill programs that truly test their aseptic processes, not just validate the ideal.

We help teams design simulations that reflect real-world risks, incorporate meaningful interventions, and satisfy regulatory expectations for worst-case coverage.

Learn how our Contamination Control Excellence Program can help elevate your APS strategy: pharmalliance.ie/ccs-excellence.

Because when the stakes are sterility, your media fill should prove more than just paperwork.