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Monday, March 13, 2017



1.     Test Performance
1.1 The process simulation test should follow as closely as possible the routine aseptic manufacturing process and include all critical subsequent manufacturing steps. All equipment should remain the same wherever practicable as for the routine process. Appropriate combinations of container size and opening as well as speed of the processing line should be used (preferably at the extremes).

1.2 The process simulation test should represent a “worst case” situation and include all manipulations and interventions likely to be represented during a shift.

1.3               Worst case conditions are often thought to be the largest container with the widest mouth as it is exposed longer to the environment. However, there are exceptions to this and one of them is small ampoules run at the highest speed as the ampoules may be unstable and cause frequent jams thus necessitating frequent operator intervention.

1.4               The fill volume of the containers should be sufficient to enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth.

1.5               If batches smaller than 3000 units are produced, the minimum number of containers used for the process simulation should be equal to that of the commercial batch size.

1.6               Simulation tests should be performed on different days and hours during the week and not only at the beginning of a work day.

1.7               If the same process is conducted in a separate clean room, this should also be validated.

1.8               In order to find the possible source of contamination it may be a good advise to video tape the aseptic fill and also number the individual vials or segregate vials in chronological order during incubation.

2.       Selection of Growth Medium

2.1 The criteria for the selection of growth medium include: low selectivity, clarity, medium concentration and filterability.
2.2 Low Selectivity: The medium selected should be capable of supporting a wide range of microorganisms, which might reasonably be encountered and be based also on the in house flora (e.g. isolates from monitoring etc.).
3.0 Media used in the evaluation must pass a growth promotion test. The control organisms used should include those relevant strains of test micro-organisms identified by relevant Pharmacopoeias as being suitable for use in the growth promotion test.

5.1       Growth promotion tests should demonstrate that the medium supports recovery and growth of low numbers of microorganisms, i.e. 10-100 CFU/unit or less.

5.2          Growth promotion testing of the media used in simulation studies should be carried out on completion of the incubation period to demonstrate the ability of the media to sustain growth if contamination is present. Growth should be demonstrated within 5 days at the same incubation temperature as used during the simulation test performance.

5.3              Clarity: The medium should be clear to allow for ease in observing turbidity.
5.4       Medium Concentration: Recommendations of the supplier should be followed unless alternative concentrations are validated to deliver equal results.

5.5             Filterability: If a filter is used in the aseptic manufacturing process, the medium should be capable of being filtered through the same grade as used in production.

6.       Incubation Conditions

6.1     It is generally accepted to incubate at 20-25°C for a minimum of 7 days followed immediately, or after a first reading, by incubation at 30-35°C for a total minimum incubation time of 14 days. Other incubation schedules should be based on supporting validation data.

6.2               Prior to incubation the containers with the microbiological growth medium should be inverted or otherwise manipulated to ensure that all surfaces, included the internal surface of the closure, are thoroughly wetted by the medium. The containers should not be completely filled with medium in order to provide sufficient oxygen for the growth of obligate aerobes. Similarly, containers should not be overlaid with inert gases even though the product may be (see also general comment in Chapter 3.1).

6.3               The microorganisms present in the containers of the simulation test should be identified to genus but preferably species level to aid determination of the possible sources of the contamination.

7.       Reading of the Test
7.1               When inspecting the containers they should be compared to a known sterile container for comparison as some microbial growth shows up as a faint haze which is difficult to detect unless there is a control container to compare against. Personnel should be trained for this task.

8.       Test Frequency

8.1               The manufacturer based on his individual circumstances should ultimately decide if more or more frequent tests are required than requested in this chapter.

8.2               It should be distinguished between “start-up” and “on-going” simulation tests.

8.3               A “start-up” simulation test consists of three consecutive satisfactory simulation tests per shift and should be carried out before routine manufacturing can start.

8.4               “Start–up” simulation tests are performed for example for new processes, new equipment or after critical changes of processes, equipment or environment as for example significant personnel changes (a new shift), modifications in equipment directly in contact with the product or modifications in the HVAC system.

8.5               An “on-going” simulation test consists of one satisfactory simulation test per shift and is mainly performed for the periodic monitoring of aseptic conditions during routine manufacturing but also for example after less critical changes of processes, equipment or environment or if processing lines stand idle for more than 6 months.

8.6               “On-going” simulation tests should be performed with each shift of each process line at least twice per year under the condition that there were no changes in the normal production procedures and no action limits were exceeded.
8.7               Exceeding an action level demands a re-validation. Depending on the result of the follow-up investigation this re-validation may require the inclusion of one to three satisfactory process simulation tests.


9.1               After the incubation period of the media-filled containers they are visually examined for microbial growth. Contaminated containers should be examined for evidence of container/closure damage which might compromise the integrity of the packaging system. Damaged containers should not be included as failures (positives) when evaluating results.

9.2               The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply:  

·         When filling fewer than 5000 units, no contaminated units should be detected.
·         When filling 5,000 to 10,000 units:

a.        One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill;
b.      Two (2) contaminated units are considered cause for revalidation, following investigation.

·         When filling more than 10,000 units:
a.        One (1) contaminated unit should result in an investigation;
b.       Two (2) contaminated units are considered cause for revalidation, following investigation.

9.3           For any run size, intermittent incidents of microbial contamination may be indicative of low-level contamination that should be investigated. Investigation of gross failures should include the potential impact on the sterility assurance of batches manufactured since the last successful media fill.

9.4      All contaminating microorganisms whether or not an alert or action limit has been exceeded should be identified to at least genus and preferably species where practicable to determine the possible source of contamination.

9.5      If a process simulation test fails then due account should be taken of products filled between the last successful test and the test failure. Recording of any deviations during the simulation test is important to trace later on the exact cause and to evaluate the consequences. The investigation should identify batches that could be affected during this time period and the disposition of the affected batches should be re-assessed.

Author: Mahender Nagaraju
Source: PIC/S Guidelines
GMP News, GMP guidelines, GMP Violations, GMP warnings, GMP Trends. A Public Health Global News Portal. (This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed/ experts experiences sharing.) Disclaimer: The Logos/Images & content posted here are belongs to respective to Authority / owners of firm. The Article posted under public health importance news. Please ensure the guideline as per Regulatory agencies.


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