Sustainable Media Program for the Pharmaceutical Industry, Part I: Simple and Straightforward Information and Tips

Would your media program pass the test? The FDA inspection test, that is. In this new blog series, ProPharma Group’s Simona Gherman breaks down the FDA regulatory requirements for a successful media program. This article will be limited to media programs covering sterile drug products and biological products that are manufactured using aseptic processes. Also noteworthy is that if you provide pharmaceuticals or biologics outside of the United States, you should adhere to the most stringent of regulatory requirements to ensure appropriate media fill coverage for all countries in which you distribute.

Part I of this two-part series will focus on background information. What do you need to know about the media fills prior to starting your Media Program or prior to improving your Media Program?

Why have a Media Program in the first place, and what does it prove?

Guidance gives us an insight to the Agency’s current thinking. However, the Code of Federal Regulation (CFR) is the codification of general and permanent rules and regulations (sometimes called “administrative laws”). The short answer to “why” is that it is the law, but let’s take a closer look.

A Media Program, also referred to as media fills, media runs or Process Simulation Testing (PST), helps you achieve three goals:

1. Aid in verifying sterility assurance (equipment, facility, personnel)
2. Confirm microbial contamination mitigation
3. Demonstrate facility and processes are in a state of process control

The media fill process shall mimic the routine product filling process, and that includes all critical process/manufacturing steps (from equipment set-up through product sealing). All aspects of cGMP shall be adhered to for media fills as they are for routine manufacturing. This includes:

• Building and Facilities (supporting areas, clean rooms, air filtration, design)
• Personnel availability in all areas, including laboratories (training, qualification, monitoring)
• Components, materials, and containers/closures (preparation, storage, inspection)
• Time limitations (expiry, hold times)
• Validation (equipment qualification, processing, product, filtration, sterilization)
• Documentation (batch records, procedures)
• Laboratory controls (environmental monitoring, microbial, bioburden, methods, particulate monitoring)
• Sterility (microbial controls, sampling, incubation, investigation)

As with any Validation activity these days, one media run is considered inconclusive but three is also no longer the magic number. The frequency of media fills, the size of the media fills, and the number of media fills conducted (specifically for the initial media fill on any filling line) shall be statistically appropriate and significant. At a minimum, here are some general industry practices with regard to media programs:

• Initial Qualification media: a statistically significant number of runs are conducted for initial media runs. The magic number used to be 3.
• Requalification medias: one media fill conducted every 6 months across all shifts.
• If different processes occur at one facility, different media fills may be required to cover all types of processes at the above mentioned frequency.
• Selecting a worst case process to conduct a media run may cover all other processes. This will have to be justified, documented, and approved by the organization, including Quality. As an example, if both lyophilized (freeze-dried) and non-lyophilized (liquid) products are manufactured in the same facility, then running a media using freeze drying processes will cover a liquid process if justified appropriately.
• Terminal sterilization processes do not require media fills if justified and documented appropriately
• Medias shall also challenge the maximum running time (fill duration), the maximum and minimum filling speeds, and the maximum number of personnel and interventions in the suite and involved in the process. The duration, speeds, quantities, etc. shall represent worst case manufacturing scenarios.
• The fill size (number of components utilized during a media fill) shall, at a minimum, be equal to the process batch size it is representing.

Media fills shall use clear containers (amber or opaque containers may be substituted with clear containers of the same shape, size, etc.) – clear containers aid in inspection. If substitution to a clear container is not possible, an inspection method different than a visual inspection method shall be utilized.

All media-filled containers shall be inspected (100% - all intact units). Include damaged containers in incubation process. A note indicating damage and possible turbidity shall suffice as an explanation without the need for a formal deviation. By including damaged components in the entirety of the media fill process, this represents what could occur during product manufacturing and what could be released to the market.

Once manufacturing activities are completed, the media filled vials are transported to incubators. Prior to incubation, each vial shall be swirled and/or inverted to ensure media contact on all surfaces of the vial. Incubation of the media vials shall occur at both 20-25°C and 30-35°C. Vials shall be in each incubator a minimum of 7 days. During the media incubation process, the vials should never be outside of incubation temperatures. That means that all inspection shall occur in the incubators.

And finally, at the completion of each media run, all documents (protocols, batch records, data, deviations and final reports, as appropriate) shall be included in a final and approved package and maintained per the appropriate retention policy of each facility.

cGMPs

The items listed above are all good and fine for establishing or maintaining an adequate media program. However, you will not have successful media program results if cGMPs are not followed. Information outlined in both the CFR and Guidance for Industry shall be adhered to or taken into consideration during not only media fills, but all aseptic processing activities.

Staying well-informed and in tune with the regulatory recommendations and requirements while maintaining a clean and effective process will ensure a successful and sustainable media program.

In Part II of this series, we will discuss the “how”, focusing on what you need, in various stages of media fills, to be successful.

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