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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2020 13 standardization of inherent and corrective inter- ventional procedures. Where each intervention is performed in a near identical manner, participa- tion can be largely replaced by close procedural conformance to the intervention procedures. It's the intervention procedures that must be repli- cated, and in doing so, the individual operator's identity is less important. The operators must all be gown qualified, proficient in aseptic technique, and compliant with the details of all permitted interventions. It's the interventional procedures that matter. The interventions, regardless of type, must be defined in detail, rehearsed extensively, and practiced consistently. Duration of process simulation A common concern in process simulation is the duration of the fill. Global regulators have ex- pressed the desire that media fills be equal to or greater in duration/size than the production pro- cess they represent. The expressed rationale is that the level of performance will slowly degrade over time (i.e., staff performance and/or the abil- ity to maintain environmental conditions over the course of a lengthy aseptic operation). Addressing this concern for personnel is straightforward; per- sonnel present during media fills should be present for the same duration used in routine production. This addresses operator fatigue. The expected decay in environmental condi- tions over time has been evaluated, and there is no evidence that environmental conditions within aseptic suites degrade over the course of produc- tion activities (19). In addition, it is increasingly common for firms producing very large batches (or even campaigns) to conduct media fills after the completion of production, with no intermedi- ate cleaning or decontamination. Industry perfor- mance with these (and all other media fills) is gen- erally outstanding, which further supports the lack of microbial build-up in aseptic environments over lengthy periods in a properly designed facility (20). Accountability Another aspect of media fills that has gained vis- ibility is the expectation of 100% accountability of filled units. The author's first experience with this occurred some years ago when the number of units inspected (and found free of contamination) was approximately 20 units more than the number in- dicated as having been placed into incubation. The discrepancy was caused by an assumption that the boxes used to hold the vials held exactly the same number of units, when in fact the number in each varied slightly both above and below the expected value. Alerted, we placed greater emphasis on ac- countability during media fills and established that the accountability results for medial fills should match that of production batches of comparable size. Since that time, there have been reports of FDA 483 observations in which any discrepancy in the accountability forces an assumption of positive results and an expectation for failure of the media fill. Recalling the experience with too many vials, the author finds the position taken in the FDA's observations to be "guilty until proven innocent." Manual activities In addition, there have been reports of FDA 483 observations that effectively eliminate the inclu- sion of all manual activity in relation to the manu- facture of aseptically filled products. This prohibi- tion would extend to loading/unloading of freeze dryers, sampling of product, aseptic formulation