Aseptic Fill/Finish – Step by Step

Edition 4, April 2024.

This is the first in a series of newsletters providing more detail on the Aseptic Fill/Finish process.? I’ll start with a general overview today, and further explore each topic in future editions. ?

Aseptic Fill/Finish Process in a GMP World

1.?????? Primary Package – Make it clean & Make it Sterile!

Whether you’re filling a vial, ampoule, syringe, or cartridge the initial steps to make the container safe for pharmaceutical product all have the same goal. You must create a particle free, bacteria free container to house the product. (I use the word “free” here loosely, there is a ton of science that goes into the requirements, we’ll get specific in later editions.)? This is not just true for the container, but also the closure system – stopper, plunger, cap, etc.? Each container type has a different process and will vary.?

For a bulk container process, a washing machine is needed to remove particles from the inside and outside of the container.? The containers are then brought to high temperature as part of a depyrogentation process. This is typically achieved in either an oven or tunnel using dry heat. Although many refer to it as a sterilization process, the depyrogenation process goes a bit further, for now I’ll use them interchangeably - more on this later.

In recent years many pharmaceutical companies have decided they don’t want to be in the business of cleaning and sterilizing containers, so they’ve opted for Ready to Use (RTU) containers - pre-cleaned and sterilized containers direct from the supplier. ?These are especially useful for smaller production batches, and difficult to prepare containers like syringes.? The number of manufacturers choosing RTU containers will continue to trend upwards as suppliers are able to scale.

2.?????? Aseptic Environment – Barrier System, Bio Decontamination, Clean Laminar Air, Environmental Monitoring, and the Human System

The filling of pharmaceutical products for injection requires them to be filled in a Grade A / ISO 5 area.? This sets a limit on airborne particulate, including specific requirements around airborne viable microorganisms.? It takes a significant system designed to work in unison to create and maintain the Aseptic filling zone.

• The cleanroom – Air filtration & Conditioning, Airlock entryways, etc
• The Barrier system (Isolator or RABS)
• The Bio-decontamination system
• Clean, Laminar Air System – air filtration, conditioning, and laminarization
• Environmental Monitoring System – viable and non-viable sampling devices.
• The Human System - Cleaning Processes, Gowning Procedures & Aseptic Technique

3.?????? Fill the Primary Package with Pharmaceutical Drug Substance

Now that we have the right container, and the right environment, it’s time to finally fill the product for the final package.? This process starts with the bulk Drug Substance, usually in a mobile tank, bag, or piped directly from the formulation area.? The drug substance is often filtered and pumped into an intermediate container – bag or tank. The intermediate container has a smaller volume, and the fill level is tightly controlled to ensure the head pressure of the product does not affect the pumping/filling process.

There are different types of pumps used in the pharma industry, most commonly used are peristaltic pumps and piston pumps.? The peristaltic pumps are often preferred because they allow the manufacturer to utilize a Single-Use Fill Path. This is a specifically designed set of intermediate bag, tubing, and needles usually pre-assembled and sterilized. This set is used only for one batch of product then disposed – this removes a number of cleaning steps, and also removes any chance of cross contamination.

The product is pumped into the container at a precise speed and volume. Product specifics play a role in pump type, tubing, needle size & type selection.? Check weighing is usually used to confirm the filling process is under precise control – this can be done statistically by sampling 1 or 2 percent, or by weighing 100% of the containers before and after filling.

4.?????? Close the container – Stopper, Plunger, and Cap Application.

After the product is filled into the container you must close the container to ensure the product remains contaminate free once it leaves the Aseptic zone and makes its way to the patient. ?Vials, syringes and cartridges use a polymer stopper or plunger to create a seal around the container.? The vial stopper is placed into the vial opening – this can be done by a pick and place robotic system, or a stoppering wheel.? The plunger is inserted into the syringe – usually through a mechanical stoppering system or vacuum stoppering.? Vials utilize an aluminum cap to hold the seal in place against the container opening.? Cartridges are unique as they have two open ends, one receives a plunger like a syringe, while the other receives an aluminum cap with an integrated seal – similar to a vial. Ampoules are also unique, as they utilize flame sealing to close the glass opening.

Now that the container is filled, sealed and closed it will leave the Aseptic zone for further processing – visual inspection, labeling, secondary packaging, etc.? I’ll see you here in May for deeper dive into Aseptic Fill/Finish!

In the Rearview…

March – in like a lion and out like a lamb – apparently true for business too.? The beginning of the year we’ve had many new inquiries, most at early investigative stages.? The last week or two it’s slowed down, but this finally gives me time to prepare for Interphex!

Looking Ahead

In just a week I’ll be in Manhattan for INTERPHEX Global .? This is one of the biggest shows of the year for the pharma industry in North America.? I’m looking forward to having project discussions, seeing customers face to face, and a nice steak dinner.

See you there!

-Mike Kerbaugh

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