The aseptic process simulation (or media fill test) has been a compliance expectation for aseptic processing operations since the 1980s. Industry guidance from the Parenteral Drug Association (PDA), Pharmaceutical and Healthcare Sciences Society (PHSS), International Standards Organization (ISO), Food and Drug Administration (FDA), European Medicines Agency (EMA) and Pharmaceutical Inspection Cooperation/Scheme [PIC/S] regulatory outlines have endeavored to establish the “what” and “how” of their execution. The PDA’s latest guidance outlined the subject in a comprehensive manner addressing all of the major elements of the simulation design and execution.7 It might be expected that given the extent of the available content, that no controversies or confusion would exist regarding process simulations. Unfortunately, that is not the case. There are a number of areas where interpreting the published information and applying it in the real world has proven to be problematic.
Anaerobic Media Fills
The sterility test uses two media, Soybean-Casein Digest Medium (SCDM) and Fluid Thioglycollate Medium (FTM), to mimic the potential growth conditions present in the human anatomy. Early guidance documents on process simulation indicated that both media were to be used in evaluating an aseptic process. More recent guidance has largely eliminated FTM from consideration recognizing that true anaerobic conditions cannot be attained in the vast majority of conventional aseptic filling operations — even those with inert gas purges and/or lyophilization. Anaerobic conditions (oxygen levels NMT 0.2%) can only be attained in isolator systems with a total inert gas environment. For all other installations, SCDM should be the only media used, and oxygen should be substituted for inert gas. This approach will detect facultative anaerobes, which are the only microbes capable of growth in FTM.
Standard practice in the design of process simulation is to bracket the vial sizes normally processed on an individual filling line. Thus, a filling line used for 1, 2, 3, 5, 6, 10, 12 and 15 mL would ordinarily use the 1 and 15 mL vials in the simulation. Consider, however, that several of the containers might differ only in height, thus the 3 mL vial might have a higher center of gravity than either the 1 or 2 mL containers and be more susceptible to tipping over requiring added human intervention. Its inclusion in the media fill program design is essential to support the added activity necessary. The smaller 1 mL vial might present its own set of unique difficulties and also warrant inclusion. The preferred approach would include both the 1 and 3 mL vials representing the lower end of the range. Size alone should not dictate the simulation design.
As noted, the selection of process simulation test components is commonly driven by container size. Handling considerations have recently been given mention to ensure that those components requiring added handling for proper feeding are considered. In order to make such a determination, data must be gathered on the performance of components on the filling line. Filling batch records should require the collection of intervention data in a manner that allows for the identification of those components that cause the highest frequency of corrective interventions on the filling line. This must extend to both containers and closures, and perhaps their combination to ensure that the program design incorporates the materials that create the need for greater operator intervention.
The core concerns in all manned aseptic processes are the activities performed by the operators. As the gowned operators are universally acknowledged to be the predominant source of microbial contamination in the entire activity, it stands to reason that everything the operator comes into contact with is placed at risk. There are three categories of operator activity in aseptic processing:
- set-up — the preparation of the line from individually sterilized components
- inherent interventions — the activities required to operate the line, i.e., component replenishment, environmental monitoring, etc.
- corrective interventions — the steps taken in response to a system failure, i.e., vial breakage, stopper jam, etc. 10,11,12
There are important considerations to be taken in each of these areas that would benefit from clarification. The specifics of each activity should be reviewed from a microbial contamination potential, operator safety and cGMP conformance perspective to provide a “best practice” approach to their execution.
The task of assembling/positioning and adjusting the individual sterilized filling parts should be considered a specialized and singular inherent intervention. Its execution by an experienced operator is the first aseptic step in the process and often entails extensive interaction with sterilized materials. The steps taken to ready the line for use should be detailed and the operator proficient in the entire sequence. The last portion of the set-up includes: introduction of container/closures; confirmation of their proper feed through the line; adjustment of fill weights/volumes, closure placement/seal force; and removal of the set-up units. Preference should be given in equipment design and selection to filling equipment that simplifies any aspect of the set-up to reduce the interventional activity. Environmental monitoring should be performed during the set-up, and personnel monitoring upon completion.