Figure 3.1 very simply describes aseptic filling of a solid-dosage form into vials by two different but broadly similar technologies. In the first, the empty vials are depyrogenated in a double-door oven and loaded onto the filling machine; in the second, the empty vials are depyrogenated in a tunnel linked to the filling machine. Other than that, the processes are the same: rubber closures are sterilized in double-door autoclaves, the bulk sterile dosage form is brought into the filling room via an air-locked hatch, and personnel are required to enter the filling room to service and operate the processes.
£mpty Vials a
Autoclave Hatch Au
Figure 3.1. Simplified representation of aseptic filling of a solid dosage form into a vial.
For media fills, the placebo is substituted for the bulk sterile dosage form in exactly the same type of container. It is brought in through the hatch and taken and connected to the filling room and filled. TSB is then added to each vial. This may be done using an on-line liquid filler, which adds an extra aseptic stage to the filling process, or off-line. If the medium is added off-line, the time between filling the placebo and adding the medium becomes critical.
The filling process is then run as identically as possible in routine practice, with the following exceptions.
1. Any inert gas (e.g., CO2 or nitrogen) used to fill or sparge the vial headspace should be disconnected, or compressed air should be substituted for the gas. The principle of the use of placebos and culture media is to create conditions where there is the greatest possible likelihood of recovering any contaminants present. Most contaminants likely to be present in pharmaceutical manufacturing environments metabolise aerobically and the creation of anaerobic conditions in the headspace above the media would decrease the probability of recovering these aerobes.
2. The weight of placebo added to each vial need not necessarily be the same as the weight of the product. Typically they are identical for small fills. With larger fills it is not always usual practice to replicate the exact weight of the product, as long as the filling speed is adjusted to leave the vials open under the filling heads for the same time as they would be in routine filling. The principal reasons for doing this are in connection with media.
• The concentration of placebo in media must not be so high as to inhibit microbial growth. The smaller the weight of placebo present per vial, the easier this is to achieve. Polyethylene glycol is not inhibitory to microbial growth in TSB in concentrations of up to 100 g/l.
• Sterilization of microbiological media for media fills is a logistics problem faced by many microbiological QA laboratories. The greater the amounts of media required, the greater the problem. This can be minimized by using smaller amounts of media with smaller weights of placebo.
3. All contaminating events permitted in a specific process must be simulated in the time that the media fill is running, even though some may be infrequent events. Before media fills are run to validate a new process, and perhaps where there is little past experience of filling solid dosage forms, the operational Standard Operating Procedure (SOP) should be carefully scrutinized and the process "brainstormed" to prepare a list of potential contaminating events. This can be checked off during the media fill at the time they are simulated.
With existing processes, where personnel or wear and tear may have introduced informal changes to the process, it is sensible to repeat the "brainstorm" with the operational personnel periodically. Observe the operational process closely over several shifts, noting what happens and how often. Typical contaminating events include, but are not restricted to:
• Setup of the filling equipment prior to commencement of fill.
• Placebo-container changes. This is usually a manual process and each time it happens there is some risk of operator contamination.
• Replenishment of closures in the closure-hopper. This is also generally a manual process.
• Replenishment of vials in the vial-feed if this is a manual operation from a depyrogenating oven; this is not an issue with tunnel depyrogenation.
• Filling-machine adjustment at the beginning of the process and any adjustment that might be necessary in response to, for example, weight checks. These in-process machine adjustments must be simulated, even though they may not be necessary in the actual media fill.
• Filling machine stoppages.
• Removal of vials that have fallen over, etc.
• Off-loading of stoppers from autoclaves.
• Personnel shift changes and other occasions where personnel may leave or enter the filling room.
• Microbiological monitoring.
4. The most potent source of contamination in aseptic processes is personnel. It is important that any potentially contaminating event associated with manual intervention is addressed through each of the human variables. Each aseptic operator should be required to actually perform or simulate the performance of each potentially contaminating event in each media fill. In order to do this reasonably, it is customary to split human intervention potentially contaminating events into categories: "minor," "major and standard," or "critical, intermediate and standard." The choice of name for the categories is discretionary, but it is often regarded as unwise to speak to regulatory agencies using the term "minor" in relation to an aseptic intervention. It should be ensured that each aseptic operator performs all of those within the most serious category for each media fill. Less serious interventions need only be addressed by the "team," as distinct from each member of the team.
5. The media fill need not run over a complete shift, just long enough to fill a statistically significant minimum number of units. It needs to be enough to be able to simulate all of the potentially contaminating events, and to address the potential for contamination to build up over time.
The contents of each vial are only likely to be contaminated while the vial is open and its contents unprotected; this will be for a matter of seconds only in most aseptic processes. Irrespective of shift length, each vial is still only open for a few seconds. Admittedly there is a possibility of the concentration of contaminants increasing in a clean room over the time it is manned and operational, but this is addressed in routine liquid media fills at the end of a normal production run, with the personnel who have been working in the area. The only exception to this practice is for antibiotic filling, where it is important that all antibiotic traces are cleaned out of the filling equipment and the filling room before the placebo is filled. This is to prevent the antibiotics from inhibiting recovery of microorganisms in the medium. It is advisable to use personnel who have completed or are near the end of a shift on another filling line to simulate antibiotic filling, to simulate any "sloppiness" in aseptic technique that may arise from tiredness.
A more rigorous approach may be demanded to the validation of the time a sterile "setup" may be left on a filling machine, especially if filling is done on a campaign basis over more than one day. There are several possible approaches to this.
• Several thousand units may be filled with placebo and medium after startup. Unless the filling machine is sterilize-in-place (SlP)-equipped to point-of-fill, machine setup and aseptic assembly of presterilized product contact parts is surely one of the times of greatest contamination risk. Thereafter the machine may be "held sterile" for a period of hours or even days, and then several thousand more vials filled with media, with all interventions included or simulated. Thus the three major risks — setup, interventions and time-related factors — are all taken into account.
• Alternatively, several thousand units may be filled with placebo and medium after start-up, and then the machine may be "run dry", i.e., with no addition of placebo or TSB for as long as necessary, with operators freeing jams and simulating sample removal, as usual. The vials may then be filled with placebo and medium as before.
• The third alternative is for the machine to run placebo for the whole of the campaign length that is to be validated. Medium is, however, only filled for the first and last several thousand and after any serious interventions during the "placebo-only" period.
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