By Crystal M. Booth, PSC Biotech
This is Part 2 of a two-part article on objectionable microorganisms in the nonsterile microbiology industry. Part 1 explained what an objectionable microorganism is and reviewed regulatory expectations for objectionable microorganisms in nonsterile pharmaceutical products. This part will discuss a risk-based approach to determining if a microorganism is objectionable for your particular application.
Is USP Compliance Enough?
In my opinion, the confusion over objectionable microorganism compliance for some companies is often initiated with the requirements of USP <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms. When speaking with random industry employees (including some at contract companies), they believe that they meet the requirements to be free from objectionable microorganisms if they comply with USP <61> and USP <62>. These companies appropriately utilize individual monographs and USP <1111> to determine the USP <61> and USP <62> specifications when needed. However, the following statements in USP <1111> are often overlooked: 1) “The list is not necessarily exhaustive, and for a given preparation it may be necessary to test for other microorganisms depending on the nature of the starting materials and the manufacturing process.” 2) “In addition to the microorganisms listed in Table 1, the significance of other microorganisms recovered should be evaluated…”.1 One reason for this oversight could be that USP <1111> was designed as a guidance chapter.
It is true that when a targeted specified microorganism is recovered while performing USP <62> tests, that specific microorganism is an objectionable microorganism. However, the assays and guidance listed in USP <61>, USP <62>, and USP <1111> are not intended to be an all-inclusive screen for every potential objectionable microorganism that must be evaluated.2 A comprehensive list of objectionable microorganisms does not exist. Furthermore, the objectionable status of a particular microorganism can change with different variables (e.g., route of administration). Consequently, a risk-based approach is the best method in determining if a microorganism is objectionable for a given application.
Considerations For Performing Risk Assessment Of Microorganisms
There are many acceptable methods to perform risk assessments. Some important points to consider include:
The main goal in performing a risk assessment is to have a scientifically sound justification that can be explained. One acceptable method is to utilize the failure mode effects analysis (FMEA) risk tool. When performing a FMEA, look at the severity, occurrence, and the ability to detect the occurrence (i.e., detection) to calculate a risk priority number (RPN). This RPN will help to determine any acceptable risks, unacceptable risks, and mitigations.
One of the first steps in performing a risk assessment is determining which recovered isolates will be screened and analyzed in order to establish their objectionable status. Will you analyze every microorganism? Will you analyze only the out-of-specification microorganisms or unique colonies?
PDA technical report 67 has a helpful risk analysis tool titled “Decision Matrix for Screening Objectionable Microorganisms.” Briefly, the diagram looks at the impact on the target patient population on the Y-axis. For example, are the patients at low, moderate, or high risk of becoming ill if they are exposed to the microorganism? On the X-axis, the diagram looks at the risk from the dosage type of the product. Depending on where the risks land on the chart, one can determine which microorganisms will require further evaluation. The evaluation range expands from only analyzing atypical or unique colony types to identifying all recovered colonies. In this way, every microorganism recovered in a nonsterile product test will not necessarily require evaluation; it is determined based on risk. This method is acceptable because the risks can be scientifically justified and explained. Another important note about the PDA technical report is that the authors also created and included a valuable “Objectionable Organism Decision Tree.”
Determining If A Recovered Isolate Is Objectionable
After deciding which microorganisms will be further analyzed, the next step is to perform identification of the isolate and verify the isolate is correctly identified.4 Once the identification is performed, a decision should be made as to whether the microorganism is an organism of concern. An organism of concern can be defined as “a bacterium, yeast, or mold that, due to its prominence in product recalls, infection outbreaks, nosocomial infections, and the clinical literature, results in a multifactor risk assessment to determine whether the microorganism is objectionable if it is present in a specific nonsterile product.”2 This analysis can be done by researching published literature.
During the literature research, items such as the characteristics of the microorganism, pathogenicity, and infective dose (e.g., correlated to the number of microorganisms recovered) should be examined. In addition, some microorganism names are changed over time. If a microorganism’s name has changed, historical names should also be investigated.3
Release decisions should not be based on one literature resource alone, as there is currently not one literary source that holds all of the answers to objectionable microorganisms. However, there are multiple valuable resources available to assist in making a scientifically based informed decision. Some of these resources include:
In addition to researching the microorganism, product specifics should be known. Information about the product should include:
Some of the information listed above is difficult for laboratory microbiologists to obtain on their own in order to make sound decisions.4 A qualified microbiologist should perform the risk assessment and, when necessary, additional staff members, such as a staff medical professional, managers, and quality assurance personnel, should be consulted.
Once all the information is obtained, it should be sorted, and a summary of the risk-based decision should be made. This information, along with the batch release decision, should be stored together in a secure location. The scientific rationale should be available, clearly written, and easy to explain during regulatory audits.
Although a comprehensive list of objectionable microorganisms does not exist, a company may find it beneficial to create a database on the objectionable status of microorganisms it has previously encountered and investigated. This data can serve as a template that can be adjusted in response to changes in the variables (e.g., different products or different lots of the same product). With good documentation and scientific rationale, properly leveraging previous work can help speed up the investigation.
In summary, an objectionable microorganism can adversely impact a nonsterile product, degrade product stability, or cause illness in a patient. Regulations require that nonsterile products be free of objectionable microorganisms. However, complying with USP <61> and USP <62> is not sufficient to prove nonsterile products are free of objectionable microorganisms.
While screening for objectionable microorganisms is a regulatory requirement, an all-inclusive list of objectionable microorganisms does not exist. The objectionable status of a particular microorganism can change based on variables, such as the route of administration, and it is up to the manufacturer to demonstrate that microorganisms present in nonsterile finished dosage forms are safe to release to the market.5 The most appropriate way to ensure compliance to the regulations is via risk assessment. The batch release decision based on the risk assessment and scientific rationale should be available, clearly written, and easy to explain during regulatory audits. In order to comply with regulatory expectations, the batch must: 1) pass specifications for USP <61> analysis, 2) pass specifications for USP <62> analysis, and 3) be “free from objectionable microorganisms.”
About The Author:
Crystal M. Booth, M.M., is a regional manager at PSC Biotech and has over 20 years of experience in pharmaceutical microbiology. She obtained her master’s degree in microbiology from North Carolina State University. Booth is a seasoned, award-winning technical writer and author of Method Development and Validation for the Pharmaceutical Microbiologist. During her career, she has worked in microbiology, consulting, quality assurance, CDMOs, R&D, and quality control laboratories. Booth has developed and validated numerous microbial methods and has worked with many different product types.