Kayla Lipcaman, ARL Bio Pharma Associate Microbiology Supervisor
Compounding pharmacies and outsourcing facilities must ensure that sterile compounded preparations are free from microbial contamination. To achieve this, they use aseptic processing. According to the United States Pharmacopeia (USP), aseptic processing is a method by which separate components (e.g., drugs, containers, or closures) are brought together under conditions that prevent microbial contamination.
A media fill, also known as a process simulation, is performed to evaluate the effectiveness of the aseptic process and the personnel's aseptic technique in preventing contamination.
The Food and Drug Administration (FDA) has established guidelines for performing media fills to validate aseptic operations. Media fills should be conducted during the initial qualification and at least twice a year, or as required, to maintain aseptic process control. Additionally, if there are significant changes to the facility, equipment, processes, or test methods, a new media fill must be performed to re-validate aseptic processing.
USP has also established standards for performing media fills as part of a competency test to assess personnel’s aseptic technique. A media fill is required before beginning to compound Category 1, 2, or 3 CSPs, and at predetermined intervals for each drug product category.
Media Fill Design
During a media fill, a microbiological growth medium that has previously or concurrently passed growth promotion testing is used in place of a drug product. The growth medium is exposed to the same contact surfaces and process conditions encountered during routine aseptic production, including:
- Equipment
- Container closure systems
- Critical environments
- Aseptic process manipulations
Media fills must closely simulate routine aseptic operations and be performed under worst-case, most challenging conditions, as required by USP and FDA guidance. The simulation should reflect actual production practices and batch sizes. Critical factors to consider include:
- Line speed
- Batch size
- Number and qualifications of personnel
- Routine and non-routine operational practices
Growth Media
The most common growth medium for media fills is Soybean Casein Digest Medium (SCDM), also known as Trypticase Soy Broth (TSB). Growth media may be obtained from a qualified commercial supplier or prepared in-house:
- If using a commercial supplier, a certificate of analysis (COA) must be obtained, according to the FDA and USP, to confirm that the media lot supports microbial growth. 503A pharmacies and 503B outsourcing facilities are required to qualify their suppliers.
- If preparing growth media in-house, each batch must undergo documented growth promotion testing in accordance with USP 71 Sterility Tests, prior to use in a media fill.
Incubation and Observation
After completion of the aseptic process simulation using growth media, the final sealed containers are incubated and observed under controlled conditions to detect potential microbial contamination.
The FDA recommends that incubation may be performed at:
- A single temperature range of either 20–25°C or 30–35°C; or,
- A two-stage incubation approach may be used, consisting of incubation at 20–25°C for a minimum of 7 days, followed by incubation at 30–35°C for an additional minimum of 7 days.
USP recommends incubation at 20–25°C for a minimum of 7 days, followed by incubation at 30–35°C for an additional minimum of 7 days.
Interpreting Test Results
If microbial growth is observed during or after the incubation period, the contaminated unit must be investigated. A microbial identification may be performed, as appropriate, to identify the organism to the genus and species levels and to support the investigation.
Compounding pharmacies and outsourcing facilities should interpret results to assess the risk of a CSP unit becoming contaminated during actual operations (e.g., start-up, sterile ingredient additions, aseptic connections, filling, and closing).
According to the FDA, the recommended criteria for assessing the state of aseptic processing control are as follows:
- When filling fewer than 5,000 units, no contaminated units should be detected. One contaminated unit is considered a cause for revalidation, following an investigation.
- When filling 5,000 to 10,000 units, one contaminated unit should result in an investigation, including consideration of a repeat media fill. Two contaminated units are considered a cause for revalidation, following investigation.
- When filling more than 10,000 units, one contaminated unit should result in an investigation. Two contaminated units are considered a cause for revalidation, following an investigation.
According to USP, the recommended criteria for assessing the state of personnel competency in aseptic technique are as follows:
- No contaminated units should be detected.
- Media fill failure constitutes an overall failure of aseptic manipulation competency.
Contact ARL Bio Pharma today for more information on media fills at info@arlok.com or 800-393-1595.
Resources:
- USP 797 Pharmaceutical Compounding—Sterile Preparations
- USP 1116 Microbiological Control and Monitoring of Aseptic Processing Environments
- USP 1211 Sterility Assurance
- FDA Guidance for Industry - Current Good Manufacturing Practice – Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act
- FDA Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice