Producing non-terminally sterilized parenteral products requires strict microbiological controls to mitigate potential contamination in highly controlled environments. A holistic Sterility Assurance program is the combination of all facility and process controls, practices, and procedures that ensure, with a high degree of confidence, that products are free of microbial contamination. One of most fundamental measures of Sterility Assurance program effectiveness is Environmental Monitoring (EM). Although there is not a direct correlation between EM data and product quality, it is a representative measure of holistic environmental contamination control and capability representative of multiple mechanism within a site’s Microbiological Control Strategy.
Environmental Monitoring Performance Qualification
It is critically important to assess the processing environment to determine those areas that have the highest risk of microbiologi- cal ingress. This will develop a deep understanding of the interplay of inherent facility/process contamination risks and mitigations. Understanding these risks informs the sterility assurance program and enables development of a robust EM program to measure per- formance. Environmental Monitoring Performance Qualification (EMPQ) provides documented evidence that an area is capable of meeting specified levels for the proposed classification. This quali- fication activity is an overall assessment of the design and environ- mental controls (e.g., HVAC, gowning, disinfectants, behaviors, etc.) of a facility. The EMPQ should evaluate the facility along with asso- ciated equipment (sterile and non-sterile) and processes within the area. This activity allows the selection of routine sampling sites for on-going facility environmental monitoring. The routine sites should be determined based on risk assessment and include the following:
- proximity to sterile components, equipment and/or product
- duration of equipment exposure
- personnel movement
- duration of personnel exposure and
- cleanability.
Execution of an appropriately designed EMPQ will inform the routine EM program such that it is robust and representative.
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Risk Assessment Tool
Risk Assessment is a systematic process of evaluating the potential risks that may be involved in an activity or undertaking. There are many types of Risk Assessment/Analysis tools (e.g., failure mode and effects analysis (FMEA), fishbone, process mapping, flow chart, etc.) available for use for the biopharmaceutical industry. Any of these tools are acceptable for evaluating risk. As stated earlier, the EMPQ is an evaluation for microbiological and particulate levels within the facility being qualified. Therefore, an assessment should provide an appropriate structure to evaluate microbiological or particulate generation and/or ingress into the area. This risk assessment tool allows the assessor a systematic approach to evaluate an area for microbiological and particle hazard ingress.
Risk Factor and Ranking
Risk factor identification is a systematic use of information or data to identify hazards the assessor will consider while executing the risk assessment. These factors allow the assessor to evaluate the environment for risk of hazardous ingress. The environment is assessed related to exposure to sterile components, equipment, and product as it relates to proximity and the duration of the exposure. Personnel activity is then evaluated, as personnel are the number one source of microbiological contamination, along with the duration of the activity. Cleanability of the environment including equipment in the area will allow the assessor to determine the appropriateness of the area or equipment cleanroom construction. Airflow Pattern Testing (AFPT) is another critical factor that informs development of the EMPQ but is not directly assessed as part of this risk assessment.
Ranking of the risk factors are critical, as these allow the assessor to systematically rank risk associated with the area and/or process(es) during the assessment. These rankings are comprised of numerical and qualitative values. Both numerical and qualitative values are aligned to provide the assessor a consistent risk ranking process, see Table 1. Along with providing numerical and qualitative values for the risk factors, each must have clearly defined descriptions for each factor that will be evaluated, see Tables 2-6. The descriptions allow the assessor to consistently assess the area while executing the Hazard Analysis Critical Control Points (HACCP) analysis.
Risk Assessment and Analysis
Defining risk factors and rankings ensures consistent execution of the EMPQ risk assessment process. First, the assessor will need up-to-date drawings for the facility to be assessed. Next, the assessor will delineate the facility into grids based upon area classification. These grids are as follows: Grade A 1m2, Grade B 2m2, Grade C 3m2 and Grade D 4m2, see Figure 1. The assessor will number each grid from higher classification (Grade A) to lower classification (Grade D). The assessor then develops a cross-functional team (Quality, Engineering, Operations) to perform the risk assessment.
The cross-functional team will then evaluate each grid spatially and document numerical risk ranking for each risk factor. The risk analysis is documented as the cross-functional team moves through the facility grid. In addition to establishing the grid and numerical risk factor rankings, the assessor documents the following: 1) classification,2) grid activity 3) risk score and 4) rational for risk factor rankings (see Table 7 for an example). The cross-functional team will ensure the activity for each grid is clearly documented, along with the associated risk rankings. The overall risk score is calculated by multiplying the risk factor rankings. The risk score provides the overall risk associated to the grid. It is imperative that clear rationale is provided for each risk ranking for the associated risk factors. Documentation of all appropriate data and rationale, that led the cross-functional team risk ranking, is critical to ensure transparent communication of the risk assessment outcome to facility stakeholders. The assessor then communicates, through document review and approval, the outcome of the risk assessment to all facility stakeholders.
Risk Acceptance Criteria
The acceptance criteria for the assessment program is based on all possible combinations (i.e., combinatorics) of risk factor rankings within the three risk groupings (Low, Medium or High). The acceptance criteria were developed for the equal distribution of qualitative risk rankings based on the total number of possible calculated risk rankings. There are 21 distinct scores that can be obtained from the 243 possible combinations derived from FIVE factors when rated 1, 2, or 3. Table 8 provides the 21 possible scores with how many combinations (“Count” in Table 8) each score can be obtained from (the counts will add to 243). The 33% quantile is 12 and the 67% quantile is 36, which are the demarcations for low and high risk, respectively.
After completion of the risk assessment, the assessor determines the overall risk using the acceptance criteria discussed previously to determine overall risk (‘Low’, ‘Medium’ or ‘High’) for each grid within an individual room. This allows the EMPQ assessor to determine appropriate distribution of environmental monitoring sampling sites, based upon risk, within the facility. EMPQ results along with the risk assessment will drive final selection of routine EM sampling sites, which facilitates evaluating if a manufacturing space remains in a state of microbiological and particle control throughout production.
Summary
There are many ways to execute risk analysis of controlled and classified areas within a manufacturing facility. This is an example of a robust integrated HACCP approach to understanding contamination risk within production areas. Evaluating the environment in this manner will allow the user to identify locations with the greatest potential for microbial and particulate contamination and enables risk- based selection for EMPQ sampling locations. Ultimately, this process ensures robust detectability of the potential hazards that exist in the routine production environment and activities, and in turn generates meaningful data relating to environmental state-of-control during routine operations. Use of this risk analysis builds an EM Program built on a foundation of scientific rationale and excellence.