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James E. Akers is the president of Akers Kennedy & Associates, PO Box 22562, Kansas City, MO 64113, firstname.lastname@example.org.
James P. Agalloco is the president of Agalloco & Associates, P.O. Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, email@example.com. He is also a member of Pharmaceutical Technology’s editorial advisory board.
The authors revisit their previous effort to refine the terms that describe interventions and to dispel confusion that arose after the original article was published.
In 2007, the authors published an article on interventions in aseptic processing to bring attention to the contamination risk associated with human workers in cleanrooms (1). The authors made the salient point that interventions are associated with contamination risk and should be avoided. In fact, as the authors previously suggested, no intervention is safe or risk-free, and the perfect intervention is the one that isn't necessary. Interventions should be avoided at all times because each one exposes the product, and ultimately the patient, to increased risk.
The authors' original effort was concise and sorely needed at the time, but hindsight reveals that it was incomplete. This article reflects the authors' recognition that more needs to be said about this important subject. As consultants, the authors are in almost daily conversations about aseptic processing, and interventions often are directly or indirectly central to the topic of discussion. For example, discussions regarding environmental-monitoring issues often relate to personnel and interventions just as those about media-fill contamination or product-testing issues do.
The current article does not reflect a change in the authors' original position with respect to interventions. It is, rather, an attempt to clarify how that position should be understood within the industry. The authors also will elucidate how interventions should be defined and managed. The authors hope that this expanded discussion leads to a pragmatic consideration of risk assessment and management, hence more efficient and effective quality-improvement programs, as well as better standard-setting and regulation.
Inherent and corrective interventions
The authors' first effort defined interventions as either routine or nonroutine. The intervening years have provided reason to establish more definitive categories than before. Two major categories still are appropriate, but they should be defined somewhat differently. The previous paper stated that routine interventions were predominantly inherent and that nonroutine interventions were largely corrective. The distinction appeared to be sufficiently clear, but were chagrined to find that some individuals and firms misunderstood or ignored the distinction. For example, at least one particular corrective intervention was considered routine because it had to be performed frequently during the execution of a batch.* This interpretation violates the principle that no intervention is safe, and it is disturbing to note that an intervention was tolerated as an acceptable activity largely because of the frequency with which it had to be performed. This misinterpretation denies the very concern that the authors wished to highlight: that interventions are inherently risky and the goal should be to reduce their number. To dispel confusion, this article will restate the author's perspectives with respect to interventions in aseptic processing. Also, the benign acceptance of frequent mechanical problems or component feed difficulties is cause for concern. Experience has taught us that interventions that produce line stoppages are avoidable. Under continuous process improvement, ongoing efficiency problems should be resolved for commercial as well as contamination-risk reasons.
Inherent interventions. Inherent interventions are operator-performed activities that are an integral part of the process without which the process can either not occur or cannot be adequately controlled. Examples of inherent interventions are: the initial setup of the aseptic process (which is a series of manual interventions to make the equipment ready for use); product and package resupply; monitoring of process operation (i.e., weight or volume checks and in-process environmental sampling); recordkeeping; and any other activity whose execution is needed to keep the process running.
The frequency of inherent interventions is largely fixed by external factors and not subject to significant variation once initially established. The frequency of their execution may be defined in procedures or by operational requirements. The following inherent interventions are a required part of every aseptic process because their absence would prevent its execution:
Inherent interventions are also an integral part of every process simulation and occur at essentially the same rate during a filling process as they would for a product lot with the same container components. Some firms increase the frequency of environmental monitoring during process simulations, but it is safe to say that the execution rate for inherent interventions in a process simulation is nearly the same as that experienced during a product fill for the same container-closure system.**
The setup of the aseptic processing line entails the assembly and positioning of sterilized product-contact parts on the filling machine or line. Containers and closures are introduced and fed through the equipment, and adjustments are made as necessary to ensure reliability of operation. Product material (liquid or powder) is then connected to or introduced into the equipment, and initial weight or volume settings are established. The setup is essentially one lengthy inherent intervention from beginning to end. The intensity of the necessary activities is such that setup represents the greatest potential risk of contamination.
Corrective interventions. Corrective interventions are operator-performed activities required because of a fault or difficulty in the execution of the process. These interventions are necessary to address problems with equipment, materials, or procedures that require action to return the process to proper operation. Typical reasons for corrective interventions include container breakage, component misfeed, product leak, weight or volume adjustments, and equipment malfunction that interrupts operations.
The need for corrective interventions during an aseptic operation can vary substantially and can be affected by factors largely within the firm's control. In an ideal world (e.g., one with perfect equipment, materials, components, and procedures), it is conceivable that an aseptic process could be executed without the need for a single corrective intervention. Although this situation might not seem possible, it is reality for a substantial number of aseptic processing systems that use advanced technologies. However, even with less technology, the goal should always be to minimize the incidence of interventions. Corrective interventions are the result of one or more of the following causes:
At the present time, the incidence rate of corrective interventions can be expected to vary. Differences in the product, container, and closure can influence the need for interventions. When a line requires extensive adjustment during the set-up (i.e., inherent interventions), its operating performance likely will vary, even when the materials are unchanged, and the need for corrective intervention will also vary. Our industry should be seeking to reduce corrective intervention rates (actually interventions of all kinds) with the goal of completely eliminating them.† The Akers–Agalloco method provides a means for reviewing interventions with respect to their frequency, proximity, and criticality, and provides guidance for the development of criteria that can evaluate their impact (2, 3).
Three subcategories of corrective interventions warrant further discussion. Critical interventions are manual activities that involve repeating a portion of the initial setup. The risks associated with manipulating sterilized product-contact parts must be considered comparable to those associated with initial setup. Given the nature of the tasks required, an extensive clearance of the processing environment is generally required. The only factor that would not require clearance would be the use of separative technologies to mitigate the risk associated with critical interventions.
During the execution of an aseptic process, a situation may call for a heroic intervention, one that entails an inordinate amount of risk. The first inclination of many operating personnel may be to perform the intervention regardless of the associated risk. Caution is in order when the intervention requires activities likely to result in contamination. As a general rule, certain activities should never be permitted in conjunction with an aseptic process because they violate the principles of aseptic technique.
The execution of an aseptic process may require a new intervention, one that has not been considered previously (see the following section). Before proceeding with a new intervention, its consequences should be evaluated. The decision to proceed with a new intervention should be made by supervision and evaluated in the release decision. Again, unusually intrusive new interventions could be allowed in processes that use separative technologies such as isolators. In such cases, provided isolator integrity is retained, the risk of contamination caused by humans is negligible.
The importance of interventions in aseptic processing requires a degree of structure to be established to ensure that practices are consistent across the organization. The authors recommend that the following sequence of activities be used to accomplish this.
1. Conduct an informal poll of the entire aseptic processing staff about the interventions they perform. This poll should ask about inherent and corrective interventions for all processing lines. Surprising as it might seem, the list of interventions will differ from individual to individual.
2. The interventions should be categorized as inherent or corrective for each line, process, or configuration. Each list should be reviewed in detail because some of the identified interventions may represent an inordinate contamination risk. Production, quality, and microbiology experts should determine which interventions should be retained as acceptable practice for that process. Heroic interventions should be avoided.
3. In conjunction with the aseptic operators, the interventions should be defined with adequate detail to ensure that all personnel can execute them in a nearly identical manner (see sidebar, "Intervention procedures"). Technically competent individuals should evaluate the individual intervention procedures to minimize their contamination potential. The procedure should specify the number or location of any components or filled containers to be removed from the line. The extent of the line clearance should vary with the location and severity of the intervention. For example, if an unfilled vial falls over on the line without breaking, its removal may be sufficient to return the line to full operation.†† Were an unstoppered, filled vial to break and spill, the extent of the necessary line clearance and interventional activity would increase.
4. Once a preferred approach for executing an intervention has been chosen, it should be incorporated into an SOP. Procedures for corrective interventions must allow for flexibility to address their variability.
5. The aseptic operators should be trained in the various intervention procedures they are expected to perform. Videos of execution and sequential photographs of the interventions can be beneficial in this effort.
6. The batch records for production lots should maintain a record of each corrective intervention performed. These records should support the frequency of corrective interventions during process simulation. Inherent interventions already are defined by other procedures for operation and monitoring of the process, so recording their execution in the lot record may not be necessary.
7. When the need for a new intervention arises, the supervisory decision may be not to proceed with the new intervention. In these circumstances, a lot-termination procedure can help secure product materials.
Sterility by design
The authors's article titled "The Myth Called 'Sterility'" reviewed the current controls for aseptic processing (4). In that article, the authors stated that the existing controls for assessing aseptic processing performance are largely inadequate to ensure the sterility of the materials being produced. Although industry might not understand it fully, reliance on sampling and monitoring is no longer adequate. In fact, some unscientific compliance approaches imply that sterility can be monitored, validated, or tested into a process.
The capabilities of modern aseptic processing exceed the ability of the current measurement tools. The authors previously outlined the components of aseptic operations that should be considered to attain sterility. The description of these components focused on design considerations that minimized or eliminated the need for operator intervention. The concepts embodied in that article are perhaps most directly applicable to the design of new aseptic processing facilities, or to equipment or component selection. Nevertheless, the article includes the following recommendations that can be applied without significant capital investment:
Sterility—or, more accurately, microbiological safety suitable for injectable medicines—is accomplished through design more than any other means. Excessive tolerance of interventions, whether inherent or corrective, amounts to settling for an inferior design. Given the negative outcomes that can result from interventions, the goal must be to minimize them. Facility, equipment, and procedures must be designed, specified, and defined with that intent.
The authors' vision of the future is one in which advanced aseptic processing is universal and direct human interaction with sterile materials never occurs (5–8). Until these systems are universal, the need for aseptic interventions will persist, and firms should organize their interventional activities to mitigate the risk of contamination. The authors maintain that interventions should be avoided at all times. It is instructive to remember Hank Avallone's important lesson: "It is useful to assume that the operator is always contaminated while operating in the aseptic area. If the procedures are viewed from this perspective, those practices which are exposing the product to contamination are more easily identified" (9).
James Agalloco* is president of Agalloco & Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, firstname.lastname@example.org. He also is a member of Pharmaceutical Technology's editorial advisory board. James Akers is president of Akers Kennedy & Associates.
*To whom all correspondence should be addressed.
1. J. Agalloco and J. Akers, "Aseptic Processing" supplement to Pharm. Technol. 31 (5), s8–s11 (2007).
2. J. Agalloco and J. Akers, Pharm. Technol. 29 (11), 74–88 (2005).
3. J. Agalloco and J. Akers, Pharm. Technol. 30 (7), 60–76 (2006).
4. J. Agalloco and J. Akers, "Bioprocessing and Sterile Manufacturing" supplement to Pharm. Technol. 34 (3), s44–s45 (2010).
5. J. Akers, J. Agalloco, and R. Madsen, Pharm. Manuf. 4 (2), 25–27 (2006).
6. J. Agalloco and J. Akers, "Aseptic Processing" supplement to Pharm. Technol. 29 (3), s16–s23 (2005).
7. J. Agalloco, J. Akers, and R. Madsen, "The Future of Parenteral Manufacturing," in Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 3, S. Nema and J. Ludwig, Eds. (InformaUSA, New York, 3rd ed., 2010).
8. J. Agalloco and J. Akers, "Future of Aseptic Processing," in Advanced Aseptic Processing Technology, J. Agalloco and J. Akers, Eds. (InformaUSA, New York, 2010).
9. H. Avallone, J. Parenter. Sci. Technol. 43 (1), 3–7 (1989).
*While helping to revise the Parenteral Drug Association's Technical Report (TR) 22, "Process Simulation for Aseptically Filled Products," the authors learned that other task-force members had had similar experiences. The revised TR has a similar perspective on interventions as this article does. The authors provide here a more complete understanding of the problem that resulted from the slightly vague terminology used in their 2007 effort.
**Please note that the text indicates the same rate of intervention, not the same number of interventions.
†Much like the goal for the amount of contamination in aseptic processing simulations, the goal for the number of interventions also should be zero.
††Mandating the removal of a specific number or segment of additional units in the execution of all corrective interventions increases the risk of contamination if that removal requires increased access to the critical zone.