Microbial Solutions
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Jon Kallay
Are You Confident Your Non-Sterile Products are Safe?
Updated FDA guidelines for non-sterile manufacturing outline how to pro-actively monitor your materials and facility to save yourself the expense and notoriety of non-sterile product recalls
The FDA released a 27-page guidance describing microbial risks to non-sterile products. The document recommends strategies to identify contamination risks, track microflora, and control the environment. While these products do not need to be sterile, manufacturers must be confident their Quality Risk Management (QRM) approach minimizes opportunity for microbes to spoil their products and harm their customers.
Charles River Laboratories, Microbial Solutions Accugenix® identification services can help with the testing of non-sterile products! Here is a summary of the guidance’s references to tracking accurate microbial identifications.
To most professional quality microbiologists, the document content is familiar.
- Water, raw materials, equipment, and personnel are common sources of microbes in the manufacturing area.
- Controls should be in place to limit contamination.
- Monitoring is necessary to ensure controls are effective
- Risk to product, and the extent of necessary process control and monitoring practices, depends on the microorganisms identified and product make-up.
How do the FDA guidelines for non-sterile manufacturing speak to identifying contaminating organisms in non-sterile products?
The body of the FDA guidelines for non-sterile manufacturing references the importance in obtaining microbial identifications for non-sterile products. The topic is addressed in these four instances:
- Starting in Line 366: “Manufacturers should periodically identify microorganisms present in the manufacturing facility which might lead to contamination of the NSD (Non-sterile Drug) and ensure that their controls effectively mitigate the impact of these microorganisms on their NSD.” This example highlights the need to understand your manufacturing environment. Organisms found in the air, water, or equipment one day could show up in product the next day. Routinely monitoring for and identifying these environmental organisms gives you a head start on remediation activities. If the organisms ultimately show up in your non-sterile product, you know exactly where to clean to prevent recurrence.
- Starting in Line 394, the guidance has conditions for Microbial Release testing, which include: “Specified organism testing and identification program to identify other objectionable microorganisms”. Specified organism testing, as outlined in USP chapter <62>, selects for recovery of certain objectionable organisms like E. coli and Salmonella. If those organisms are present in the product, the test should recover them. However, general microbial enumeration tests can recover a variety of microorganisms. Many of those may also be objectionable for the integrity and safety of your specific non-sterile product and customer group. It is essential to understand objectionable organisms are not limited to those listed in chapter 62. Each individual identification must be assessed for product impact.
- Starting in Line 508, on unusual non-sterile product formulations: “This example demonstrates that more rigorous identification and assessment of the bioburden in these products is critical to understand product hazard . . . These methods should differentiate and identify objectionable microorganisms.” This reference builds on the idea brought up in line 394. Here, the document emphasizes the broad scope of microorganisms that could be objectionable for unusual product formulations
- Line 566, on testing for Burkholderia “There can be difficulties detecting and correctly identifying and classifying BCC (Refs. 1, 15) and, consideration of the diverse phenotypes exhibited by BCC members is essential for recovery method development.” The document takes for granted that organism identifications will be accurate. However, this line highlights the need for specialized identification procedures, like Accugenix ProSeq, to differentiate closely related species. Different Burkholderia strains pose varying levels of risk to your non-sterile product. You want to ensure you can detect and identify your strains of concern.
Key Takeaways from the FDA’s New Non-sterile Guidance
The FDA has released Microbiological Quality Considerations in Non-Sterile Drug Manufacturing, providing non-sterile drug (NSD) manufacturers with recommendations to help assess the risk of contamination with objectionable microorganisms. We did a deep-dive on it.
Watch it on-demand
What can you learn about poor examples of environmental monitoring for non-sterile products?
The Appendix to this guidance document includes nine case studies. All case studies touched on significant microbial contamination of non-sterile products. Most events resulted in product recalls. In two cases, the events discuss the importance of routine environmental monitoring for non-sterile products and identification of microbes at a manufacturing site.
Case 2
In Case 2, the FDA guidelines for non-sterile manufacturing discusses two separate E. coli contamination events for non-sterile products. Each event resulted in recalls of over 10,000 distributed units. Neither manufacturer was able to identify the root cause of their event.
With no direct link of the contaminating organism to a specific source, all non-sterile processes are suspect. Lots of good, and likely expensive, corrective actions came out of these events. To name a few: new processes for cleaning and storing equipment, updated quality assurance procedures, and employee training. These extensive actions were taken because there was no specific remediation focus.
It appears as if the contamination has not repeated at those sites. However, not knowing the source of the organism leaves a lingering feeling that it could return at any time.
Case 8
In Case 8, fungal contamination led to the recall of 45 lots of anti-diabetic medication. This medicine is marketed to a patient population with a known risk of serious infections. With good identifications and trending, the site found an excipient material contained the same organisms as the final product. Further trending at the excipient manufacturer determined the drying process trapped seasonal fungal isolates. Unfortunately, these investigation findings occurred after product made it to the market.
Work with Charles River
If you pro-actively monitor your materials and facility, you can save yourself the expense and notoriety of product recalls. These FDA guidelines for non-sterile manufacturing will help you determine where and how to monitor your non-sterile products. Charles River, with services like FunITS Fungal Identification and Accugenix Tracking and Trending Software, can help with the rest.
