Risk-Based Microbial Assessment Tool (R-MAT): A Novel Approach to Assessing Environmental and Critical Utilities Excursions

Abstract

When it comes to environmental and critical utilities monitoring, industry agrees that robust investigation and corrective actions are needed following recovery of objectionable organisms.¹ However, objectionable organisms make up only a small portion of the flora that are commonly recovered in a controlled facility and the required actions and response to excursions of this nature should be carefully evaluated to avoid the inevitable time and money associated with costly investigations. In 2006, when ICH Q9 was first published, the opportunity to define risks and risk levels according to our own product and processes presented itself.² The principles of quality risk management provided the industry with sound methodologies to assess, control, review and communicate the risks most critical to our products. Overtime, the adoption of risk-based methods for the assessment of our risks has become more critical as both a means to evaluate our products/processes and patient impact but also as a means of demonstrating to the health authorities that industry has a comprehensive understanding of their processes and is appropriately positioned to make risk-based decisions. Despite the opportunity to employ risk management, some firms are still struggling with using risk-based methods particularly when it comes to environmental monitoring and critical utilities excursions. This article describes the Risk-based Microbial Assessment Tool which can assist in both determining the appropriate actions for addressing excursions and assist the organization in developing a proactive means of preventing excursions.

Introduction

Risk-based Microbial Assessment Tool (R-MAT) is a method for identifying the level of risk associated with microbial recovery. The use of a risk-based approach ensures that each excursion is evaluated consistently, enables the creation of action plans that are commensurate with the level of identified risk, and facilitates communication with leadership.

R-MAT employs the ICH Q9 definition of risk “the combination of the likelihood of occurrence of harm and the severity of that harm”² and is applicable to excursions stemming from both environmental and critical utilities monitoring. In line with the principles of quality risk management, scientific knowledge serves as a critical input into the risk tool and the proper execution of this risk based approach as part of the quality risk management process ensures that the level of effort, formality and documentation is commensurate with the level of risk.

R-MAT finds its foundation in the Epidemiological Triad used by the Centers for Disease Control and Prevention (CDC) to assess the spread of infectious diseases. In the CDC’s methodology, three components are considered in evaluating disease-causing pathogens: Agent (the disease-causing organism), Host (the person or population with the disease), and Environmental Factors (place in which the host and agent interact).³ The challenges faced when evaluating disease proliferation and dissemination are markedly similar to those encountered when evaluating microbial contamination in non-sterile manufacturing. Both disciplines share a constant struggle to develop appropriate, practical, and effective means to control or prevent harm. While epidemiologists evaluate the agent, host, and environmental factors, practitioners in the pharmaceutical industry focus on the, Patient, Product and Facility when performing investigations. The interplay of these three factors can be illustrated through the Microbial Impact Triangle (Figure 1). Using this relationship, we can answer the following risk questions:

• Can the recovered organism be introduced and perpetuated in our manufacturing facilities?
• Can the recovered organism contaminate our product stream thereby impacting patient safety?

Figure 1. The Microbial Impact Triangle

Risk-Based Approaches

As regulators encourage the industry to demonstrate process knowledge using risk-based approaches, the opportunity to leverage the principles of risk management for consistent decision making are more abundant than ever. The R-MAT approach outlined in this article off ers a method to evaluate microbial excursions to ensure that the level of eff ort, formality and documentation associated with the excursion is appropriately and consistently assessed. In order to take appropriate action and to prevent future contamination events, microbial excursions must be rigorously assessed to identify the root cause, construct corrective and preventive action, and facilitate the identification of trends.

Risk-Based Microbial Assessment Tool: The Method

Step One: Assess the Organisms Identified

Trained microbiologists at the facility conduct the first step in this assessment. The organisms recovered to determine the following:

• Type and size of organism
• Natural habitat
• Ubiquity in the outside environment
• Pathogenicity of the organism
• Growth requirements and parameters (e.g., media type, temperature, gas requirements, humidity requirements, length of incubation)
• Potential routes of entry (e.g., raw materials, environment, personnel, water, gasses)

Step Two: Conduct a Vulnerability Assessment

The vulnerability assessment is a two-part process. First the frequency of organism recovery must be determined, using trended microbial data. Table 1 provides example criteria that may be used to rank the relative level of organism collection frequency.

Table 1. Example Frequency Criteria

The second step in performing the vulnerability assessment is to evaluate the level of control within the facility or utility. Controls available to the site such as disinfectant eff ectiveness tests, periodic utility sanitization eff orts, environmental qualification studies, facility design (e.g. room gradation, HEPA filtration, pressure diff erentials), gowning, validation reports, bioburden data, could also be layered onto these criteria to ensure that controls are comprehensively captured. Table 2 outlines example criteria for the Level of Control.

Table 2. Example Level of Control Criteria

After the frequency of collection and the level of control are identified, the vulnerability score is assigned using a risk matrix (Figure 2). The score is determined by finding the intersection of the individual rankings. For example, if the organism collected was identified as having an Average frequency rate and a Medium level of control the vulnerability score would be “V2”.

Figure 2. Matrix for determining Vulnerability Score

It is important to consider carefully the ‘level of control’ from two perspectives: documented evidence (e.g., procedures and protocols that define the control intended to be in place) and demonstrated eff ectiveness (e.g., continued evidence that the controls in place are performing as intended). If during the assessment you have selected a collection frequency of ‘likely’ and pair that with a ‘high’ level of control, the level of evidence to support this combination should be substantial. In a scenario such as this, it will be critical to determine exactly what controls failed and allowed the excursion to occur. In this type of scenario it is important to evaluate the eff ectiveness of the controls that are currently in place and identify exactly where the layers of protection failed. One way to assess the eff ectiveness of the controls is by conducting a bowtie risk assessment. The bowtie is a risk assessment tool that outlines a hazard or loss of control as the central event and considers all potential causes and consequences of the event. Additionally, preventative barriers and protective barriers are described in order to fully evaluate all of the layers of protection applicable. No barrier or control is perfect and there can be holes in any control that is developed. The use of R-MAT may reveal that a control described for a particular organism is not as robust as originally perceived either because the control is lacking in ability or because the reliability of the control is not as robust as intended.

The vulnerability score serves as a surrogate for the likelihood component of the risk equation. The other element of the risk equation, severity, is evaluated next.

Step Three: Evaluate the Severity

Severity is a measure of the possible consequences of a hazard.² The criteria listed in Table 3 evaluate the potential loss of control based upon where in the facility the organism was collected from the least critical areas to the most critical areas.

Table 3. Example Severity Criteria

Step Four: Determine Risk Level and Required Actions

The overall risk level is determined by finding the intersection of the vulnerability score and the severity score in Figure 3.0. Table 4 outlined below provides suggestions actions to take based on the risk level identified.

Figure 3. Matrix for Determining Overall Risk Level

Table 4. R-MAT Action Table

Step Five: Document the Assessment

Complete and comprehensive documentation of the assessment and associated events is the final step. Documentation of the assessment should include:

• The organism overview as described in step one which will outline the organisms recovered
• Trended environmental monitoring/critical utilities data or other historical data inputs used to justify the frequency of collection ranking.
• Procedures and/or protocols that provide evidence of the level of control ranking.
• Justification identified for the severity level.

Assembling a Cross-Functional Team

As with all risk tools, the R-MAT described herein should be performed by a multi-disciplinary team, rather than a single individual. This community of experts will ensure that microbial assessments are conducted in a consistent manner, calibrating each contributing expert’s understanding of the relative risk and sanctioned decision-making framework to align science, quality, and regulation. By providing this community with the R-MAT to drive the process, consistent decisionmaking becomes simpler. Suggested members of the cross-function team include but are not limited to Quality Control Microbiology, Quality Assurance, Manufacturing, Facilities and Engineering, Validation and Leadership.

Quality Control Microbiology

Due to the nature of the data required for assessment, QC Microbiologists should serve as the foundation of the community. A critical function of the microbiologists is to educate the team members regarding the organisms collected. The QC group supplies the community with environmental and critical utilities monitoring data. This data is used to review current and historical environmental monitoring and critical utilities data to identified trends. It is best to present this data to the team using graphical representations and include maps of the locations where excursions occurred to provide context to the team. Microbiologists should identify and review the organisms recovered and provide organism background to the team such as; where and when the organism was recovered, if the same organisms have been recovered in additional or adjacent areas of the facility, and common sources of the organism (e.g., soil, water, skin). Additionally, it is essential that any formal risk assessment tool (e.g., HACCP) used to define the monitoring program be reassessed at the time of the excursion, to determine if there is an increase in the frequency of a hazard or if a new hazard has been identified. Reviewing and updating this risk assessment is known as “risk review” in ICH Q9. When evaluating inputs into the living risk assessment, the QC or designated group should arrange for a walk thru of the facility. Walking down the facility with all team members can shed light on new hazards and provide the team with additional information about the equipment, materials, and operations occurring in the various areas of manufacturing.

Manufacturing

Representatives from the manufacturing or operations side of the business also provide critical inputs to the community. When selecting individuals from manufacturing, it is important to identify those individuals who have a strong understanding of each process step, the critical quality attributes associated with the product at each process step and who understand the connection between the critical quality attributes and their associated critical process parameters.

Facilities and Engineering

The facilities and engineering groups should be prepared to educate the cross functional team regarding equipment such as utilities and production equipment and provide background relative to the historical performance of equipment and the impact that equipment plays on product quality (e.g., calibration, maintenance).

Validation

Involvement of the validation group will provide the team with an understanding of the critical process parameters and critical quality attributes of the systems under assessment. With access to validation protocols and knowledge of system performance and history, the validation groups can bring a level of process knowledge to the team to assist in understanding the impact of an excursion on the process.

Leadership

It is important for the team to have a sponsor within the organization that not only supports the mission of the community but also actively advocates for the team by supporting their decisions and provides them with the adequate resources to take action and qualified personnel to perform the tasks identified by the team.

Conclusion

The use of risk-based strategies is only one element that can assist in assessing microbial excursions - it is the blending of this effort with the use of cross-functional team that allows for a comprehensive assessment of microbial excursions. This combination of strengths will lead to stronger knowledge sharing and ultimately knowledge management throughout your firm and fosters a consistent and focused strategy for investigating excursions. Many organizations are still handling their EM program from a reactive perspective - investigating and closing excursions as they come. Overtime, using the R-MAT approach, the organization can move to a more proactive assessment and begin to hone in on the elements that prevent excursions from occurring.

References

1. General Chapter <111> Microbiological Quality of Nonsterile Pharmaceutical Products. USP 37- NF 32; U.S. Pharmacopeia: 2014. www.usp.org.
2. ICH Quality Guideline Q9: Quality Risk Management; International Conference on Harmonization: 2006. www.ich.org (accessed July 18, 2014).
3. Centers for Disease Control and Prevention (CDC). Principles of Epidemiology in Public Health Practice information page. Available at: https://www.cdc.gov/ophss/csels/dsepd/ ss1978/lesson1/section8.html

Author Biography

Amanda Bishop McFarland, M.S. is a Quality Risk Management and Microbiology Consultant with Valsource, LLC with over 15 years industry experience. She specializes in the creation and implementation of Risk Management programs and in developing custom risk-based strategies for use in Quality Systems (i.e., microbiology, auditing, validation). She has a Bachelors of Science (Entomology) and a Masters of Science in Mycology both from the University of Florida. Amanda is an active member of the Parenteral Drug Association (PDA), a faculty member of the PDA’s Quality Risk Management courses and co-lead of the PDA’s Quality Risk Management Interest Group.