A Revised Aseptic Risk Assessment and Mitigation Methodology

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Aseptic processing is understood to be among the more complex processes in the pharmaceutical industry and one whose proper execution is essential to patient safety. One of the keys to success in aseptic processing is defining the operational details properly so that contamination risk can be minimized. Reduction of patient risk is understood to be the primary consideration, and it is intrinsically linked to managing contamination risk in products manufactured aseptically.

The past 100 years have witnessed an evolution of technologies for aseptic processing that have led to dramatically improved process capability. The evolution of practice was accomplished pragmatically, but without any formal consideration of risk.  The principles of aseptic processing developed and largely codified by FDA, the European Medicines Agency (EMA), the US Pharmacopeial Convention (USP), the Parenteral Drug Association (PDA), the International Society for Pharmaceutical Engineering (ISPE), and others evolved in a similar fashion, again without formalized risk assessment. Thus, aseptic processing practices as they exist today are the result of a series of predominantly subjective decisions about which design, practices, and measurements are most appropriate.

This absence of formal risk assessment began to change in 2004, when FDA issued an important document outlining its desire to encourage a more formal risk analysis-centered approach to CGMP compliance (1). Subsequent to that publication, the first attempts at development of risk assessment methodologies for aseptic processing were developed (2, 3). It was in this time frame that the authors first developed their risk assessment models (4, 5). These publications focused on the contamination risk associated with personnel activity, which arose from the universal understanding that it was the primary source of contamination, and hence risk, in aseptic processing activities (6). The first publication of the Akers-Agalloco (A&A) method (4) included a complex method for assessing aseptic risk and some activities that included too much redundancy in practice. The second publication (5) corrected these errors  and has been successfully used by several firms (7). To best use this risk method, the rationale provided in the original publication has to be combined with simpler calculations provided in the second publication. Based upon empirical data accrued over many years of practical experience in aseptic processing, the authors knew that, in application, it was possible to differentiate processes that had a comparatively high risk of product contamination from those that had the capacity to ensure lower contamination risk.  

Updates to the A&A method

In the years since the original publications, interactions with clients led to reconsideration of some of the core assumptions made in the earlier publications. There were many queries regarding the arbitrariness of the risk factors used in the interventional portion of the original work, and as explained in the following discussion, the authors replaced the subjective risk factors with a time-based scoring and changed the scoring methodology to use an inverse-square risk factor for proximity, which largely eliminates the authors’ personal bias in that part of the risk assessment.

In using their risk assessment methodology, the authors discovered that it was actually two independent risk-assessment methods combined into one larger and more complex tool. The first part of the original method was intervention based, while the second focused on process design. Each portion of the method can be used separately from the other, or they can be used together in series as originally published. The authors have had many more opportunities to use the individual components for assessing aseptic risk as compared to their combination. This article will explain how the submethods can be used separately. 

Intervention-focused method 

Because the accepted source of contamination in aseptic processing is personnel, it makes sense to develop a risk model that places human intervention at the very core. The authors had hypothesized that improvement of aseptic processing was primarily a matter of reducing reliance on gowned personnel in aseptic processing, in agreement with the suggestion of FDA’s Hank Avallone that “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” (6).  

The authors had learned from research using aseptic processing in cell-culture work that gowning and aerodynamic separation of humans from aseptic activities resulted in much lower contamination rates. Further research showed that humans were not merely “contaminated” as Avallone had thought, but were actually contamination generators. Published studies describe the rates at which humans who are gowned for aseptic work generate microbial and non-viable particulate contamination (8, 9). The rate of release of these contaminants into the environment depends on the types of gowning materials used as well as level of activity their work involved. The authors observed that ventilation played an essential role in removing the contamination emitted by the contamination generators (e.g., personnel) in aseptic cleanrooms. As advanced separative technologies came into wider use, the elimination of personnel had a profound impact on contamination rates, confirming that human-released contamination constitutes the greatest risk. 

The intervention aspect of the A&A method incorporates the concept of the human operator as a mobile contamination source directly with considerations of criticality, frequency, and proximity, which relate directly to human-derived microbial contamination in aseptic processing. Human activity is variable in aseptic processing whereas the design of the cleanroom and the operation of its ventilation system is effectively a constant. The following sections discuss these three variables. 

Criticality. The type of interventional manipulation being performed is linked to the contamination potential. Inherent interventions that are required parts of the aseptic process and cannot be easily eliminated must be designed to have the lowest risk contamination (10). Corrective interventions involving the removal of items from the operation have a greater level of risk because they vary substantially as to location and complexity. What the A&A method terms as critical interventions are corrective interventions of greater complexity that, in many cases, require the replacement of an item on the line. As such, they resemble the initial set-up of the line and represent the highest level of risk. A hierarchy of intervention risk associated with aseptic processing including some additional interventional categories is shown in Table I.

Table I. Aseptic interventions and contamination risk. CLICK TO ENLARGE.

Separate consideration of interventions as either inherent or corrective is necessary because the design approaches, execution details, risk mitigation means, and operational perspectives remain different. Inherent interventions require determination of a preferred methodology and training of personnel in their execution. Corrective interventions will always rely on operator expertise and aseptic technique because of their more variable nature. The goal of eliminating all corrective interventions, especially the critical correctives, remains, regardless of the ease with which some of the less invasive corrective actions might be undertaken.

The designation of interventions as either inherent or corrective, while useful in understanding their design and execution, is less useful in risk assessment. Consider that the replacement of environmental monitoring plates in an air sampler (an inherent intervention) is both more difficult and time consuming than removal of a single fallen vial using a pair of forceps (a corrective intervention). It seems logical to consider duration of the intervention (seconds within the critical zone) as a superior alternative to intervention type in the estimation of risk. A lengthy inherent intervention would thus be considered more risky than a simple corrective one. Time serves as a more definitive and less subjective means to assess the potential impact of an intervention compared to type of intervention. 

Frequency. The objective in all aseptic processes is to continuously reduce the frequency of interventions regardless of their type: inherent, corrective, or critical corrective. For example, the frequency of weight checks should be based upon the performance of the filling equipment and not an arbitrary time interval. If an intervention cannot be completely eliminated, reducing its frequency reduces the contamination risk. The “perfect” intervention is one that has been eliminated from the aseptic process (11). 

Proximity. The distance between where the intervention is performed and the nearest exposed sterile item affects risk. Logically, the shorter the distance between sterile items and the personnel performing the intervention, the greater the potential is for microbial transfer across that distance. An arbitrary distance scale was used in the initial A&A method for the sake of simplicity. William Whyte, an early proponent of formal aseptic risk assessment, suggested the use of the inverse-square rule for estimating the dispersion of microorganisms from a source (2, 3). This rule relies upon two assumptions: the existence of a point source of microorganisms that disseminates them much like a light bulb casts light and that microorganisms disseminated from that source would uniformly populate the surrounding environment. Although the inverse square rule is appropriate for gravity, energy, sound, and other physical phenomena, it should not be considered a wholly accurate model for microbial dispersion in an environment. Among the reasons for its limitations in this instance are:

• There is no “point” source for microorganisms in aseptic operations; they can be shed from any part of the operator’s gown or gloves.

• Aseptic processing is carried out in ISO 5 environments supplied with unidirectional air, which is specifically provided to suppress the distribution of microorganisms by air movement or dilution. However, other factors, including electrostatic charges, can alter the direction in which airborne contaminants move.

• Microorganisms have mass, and settling will occur even in the absence of air movement.

The use of the inverse square rule, even though it may not be precisely quantifiable, places greater weight than the original A&A method on interventional activities performed closer to exposed sterile materials. For this reason alone, the authors adapted the A&A method to incorporate this, albeit flawed, more objective means for considering the effect of distance in risk estimation. 

Evaluating interventional impact

The example shown in Table II explains how data gathered from observation of a filling line can be used in the evaluation of interventional impact on an aseptic filling process. For a meaningful assessment, at least one hour of the process should be monitored. Ideally, the assessment should extend to the full process duration. The time for execution of the various interventions is most accurately determined by recording it during each intervention; however, for interventions that are more frequent and similar in execution an average value based upon multiple observations could be used.

Table II. Click to Enlarge.

The raw score considers only the intervention contribution and ignores other elements. Normalization of the score by dividing by the number of units produced is employed to refine the assessment. The fewer units produced over the time period, the greater the contamination risk to any individual unit; a lower throughput is more likely to be associated with sterile items being exposed to contamination for a longer period of time with the process environment. When this calculation is made, the determined value is the intervention risk (IR). The goal in risk mitigation is to reduce the IR for the aseptic process.

Determination of the IR for an aseptic process can be used as a risk assessment tool without additional effort. The IR can be used in risk assessment and, ultimately, for risk mitigation in the following ways:

• Assessing of the performance of a filling line with different set-up personnel

• Assessing line performance with different operators or shifts 

• Assessing line performance with different combinations of components (i.e., stopper and vial)

• Assessing line performance over equipment life/length of the fill

• Assessing line performance with different formulations/fill volumes/operating speeds

• Identifying the “worst-case” selection of conditions and components for use in process simulations

• Supporting the process simulation as “worst-case” relative to routine production

• Evaluation of operator experience

• Evaluation of line performance in conjunction with changes in equipment, personnel, procedures, etc.

• Evaluation of performance changes with different lots of components.

Clearly, an intervention-focused risk assessment has a variety of uses. Importantly, the absence of subjectivity in the accumulation of the data used in the assessment eliminates the most common deficiency in other risk methods. The IR reported should be the same regardless of the observer. This feature is perhaps the method’s greatest value in that it eliminates bias in the assessment of risk.

Design-focused method

The other component of the initial A&A method was the design-focus element that provided for the assessment of aseptic manufacturing, aseptic filling (i.e., individually addressing aseptic set-up and filling), and lyophilization. The subcomponents differ, reflecting the unique elements of aseptic risk associated each of them. The risk factors in each of these were established with consideration of how the design choices influenced the extent of operator activity with sterile materials. As a consequence, this portion of the risk-assessment model can be used in isolation from the interventional element. 

Although many clients requested that manual aseptic filling be included in the A&A method, it is already included under the term aseptic compounding; this portion of the document is readily adapted to individual use. The aseptic compounding, filling, and lyophilization components of the method work independently of each other, and it is a simple matter to use only that portion of the design component risk method that is of interest. The authors agree conceptually with adding other aseptic processes to the design component of the risk method; lacking sufficient experience with these less common situations, however, the authors are loath to do so. The authors would encourage others to develop design-based risk assessments for aseptic process elements that the authors did not consider.  

Consideration of the risk associated with aseptic process design is not new. The evolution of aseptic processing from unclassified environments with minimally gowned personnel to present day isolation technology was the result of informal consideration of the contamination potential. The introduction of separative means, high-efficiency particulate air (HEPA) filters, full aseptic gowning, and automation to aseptic operations were a result of largely subjective evaluation of risk. In the design-focused portion of the A&A method, the authors ranked the various process and facility design elements according to the extent of human intervention required. This portion did not independently consider severity, frequency, or detectability, but rather developed an arbitrary risk ranking based upon what the authors believed was the least to most risky process or design feature.

In the initial publications, the authors included some examples based upon facilities both had visited; the authors’ clients, however, have afforded them substantially better opportunities to apply this risk tool. In one group exercise, teams of participants were asked to evaluate the risk associated with the filling of the same lyophilized product configuration in multiple facilities using the prevailing aseptic practices at various sites. The facilities chosen for the analysis were the smallest, oldest, newest, and largest that the firm operated. The calculations involved followed the design component of the simplified risk model from 2006 (5). The results of this exercise are presented in Table III.   

The results of this exercise revealed the utility of this form of risk assessment, with the following results:

• The filling risk contribution was essentially the same at all sites except the oldest site. After presenting their risk result, the team from the oldest site was able to review the aspects of their operations that raised their score by comparing their process/facility design to the other facilities.

• The lyophilization risk varied widely across the sites, and the practice/design of the newest site became a model for the remaining operations.

• Most importantly, the participants became aware that objective consideration of aseptic risk could reveal improvements to what were already considered fully compliant aseptic operations.

Conclusion

Over the past 10–15 years, there have been numerous risk assessment methods published. The majority of these entail some adaptation of failure mode and effects analysis (FMEA) or other subjective tools for risk assessment. The authors often encounter aseptic operations where aseptic process improvement opportunities are either not obvious or inherently limited. The firms operating these facilities fixate on the performance metrics they use, predominantly associated with environmental monitoring, without adequate consideration of the human impact. Environmental monitoring, process simulation, and sterility testing are largely inadequate for assessing the performance of contemporary aseptic operations (12). They rely on growth-based microbiological analysis which is limited statistically as well as analytically. The accepted limit of detection (LOD) of these methods is considered to be 10–100 colony forming units. These methods are being improperly credited with providing evidence of sterility assurance when in reality they are simply unable to provide useful information below their LOD. 

These methods also suffer from restricted sensitivity as they are unable to recover a number of potentially pathogenic organisms. As a result, the absence of contamination measured as no growth may be an illusion. It must be understood that in microbiology, zero recovery only means that nothing grew and never under any circumstances should it be considered proof of sterility. The authors believe that the A&A risk tools they have developed, and now refined, provide a more insightful means for evaluating and improving aseptic processing. 

There are two aspects of aseptic risk that are still troubling. First, too much is written and said about risk assessment and too little about risk mitigation. The purpose of understanding aseptic risk in the first place is to take action to reduce it. The knowledge that it has started to rain outside is useless, unless one makes the decision to open an umbrella. It’s not enough to measure risk: active steps need to be taken to minimize it. The more objective the means for assessing the risk, the more likely it will be to be able to determine what measures are best to mitigate that risk. Regardless of the risk level, actions must be taken to reduce it further despite any belief that the aseptic process it is already sufficiently safe. Continuous improvement should be the order of the day.     

The second concern is the continued use of microbiological analytical data to determine risk, establish “sterility assurance,” and “validate” processes. This industry has never come to grips with the reality that microbiological methods lack sensitivity. The methods have far higher LODs than prevailing standards and guidance documents imply, and they have substantial variability as well. Microbiology is a logarithmic science, and attempting to measure sterility using environmental monitoring is not just difficult; it is impossible. There are far better means of assessing process control and proactive steps that can be implemented to prevent contamination.  

It is easy to fall in love with an approach to cleanroom assessment that gives positive feedback, and in the authors’ experience, more than 99% of all environmental monitoring samples taken in ISO 5 environments don’t find contamination. This result is superficially reassuring until one realizes that given the LOD of the method, the one thing it doesn’t mean is that the environment is sterile. To those who aren’t microbiologists, using environmental monitoring or media fill data in an effort to assign a risk probability number or assert assurance of sterility seems logical, but it’s actually not. Despite the perceived lower LOD of some alternate methods, limitations in sampling mean that all environmental methods are inadequate. Sterility, or more correctly asepsis, cannot be tested in and thus can never be assumed to be present.   

References

1. FDA, Pharmaceutical CGMPS for the 21st Century–A Risk-based Approach (2004).
2. W. Whyte and T. Eaton, Eur. J. Parenteral and Pharmaceutical Sciences 9 (1) 16-23 (2004).
3. W. Whyte and T. Eaton, Eur. J. Parenteral and Pharmaceutical Sciences 9 (1) 11-15 (2004).
4. J. Agalloco and J. Akers, Pharm. Tech. 29 (11) 74-88 (2005).
5. J. Agalloco and J. Akers, Pharm. Tech. 30 (7) 60-76 (2006).
6. H. Avallone, J. Parenteral Sci. and Tech. 43 (1) 3-7 (1989).
7. H. Katayama et al., PDA J. Pharm. Sci. and Tech., 62 (4) 235-243 (2008).
8. B. Reinmuller, “Dispersion and Risk Assessment of Airborne Contaminants in Pharmaceutical Cleanrooms”, Royal Institute of Technology, Building Services Engineering, Bulletin 56 (2001).
9. W. Whyte, J. Parenteral Sci. and Tech. 39 (1) 51-60 (1985).
10. J. Agalloco and J. Akers, Pharm. Tech. 35 (4) 69-72 (2011).
11. J. Agalloco and J. Akers, Pharm. Tech. 31 (5) S8-11 (2007).
12. J. Agalloco and J. Akers, Pharm. Tech. 34 (3) Supplement, pp. S44-45 (2010), continued online. 

Article Details

Pharmaceutical Technology
Vol. 41, No. 11
November 2017
Pages: 32–39

Citation:

When referring to this article, please cite it as J. Agalloco and J. Akers, "A Revised Aseptic Risk Assessment and Mitigation Methodology," Pharmaceutical Technology 41 (11) 2017.

About the Authors

James P. Agalloco is president of Agalloco & Associates, P.O. Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, jagalloco@aol.com. He is also a member of Pharmaceutical Technology’s editorial advisory board. James Akers, PhD, is president of Akers Kennedy & Associates.