USP Microbial Examination of Non-Sterile Products

A road map to the world of non-sterile testing regulations

By James E.T. Gebo, technical representative, Laboratory Services, and Kimberly Kitch, laboratory technician, Microtest Laboratories Inc.

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Each product’s specifications are critical to assessing its microbial quality. In order to establish this limit, the intended use of the product needs to be considered as well as who the intended recipients will be. USP <1111>, Microbiological Attributes of Nonsterile Pharmaceutical Products, is a starting reference to establish a baseline criterion. However, a thorough risk assessment of each product should be conducted to determine if these criterion are adequate.

Sometimes additional objectionable pathogens should be considered. These are determined by how each product is manufactured, where the raw materials are sourced, the product’s intended use, and who the end-user will be. Is water associated with the cleaning of the system or used to make goods? Do the raw materials come from the America’s mid-west or a developing country? What is the intended use of the product? Will it be applied topically, orally, inhaled, etc.? What are the health hazards to the consumers? Are they immunocompromised? The aforementioned questions are only a few of countless considerations.

Objectionable organisms can come from an infinite number of sources. One critical area that can introduce objectionable organisms is the raw materials used in the product. Knowing the source of these components, location and physical source, will help in deciding if screening for additional organisms is necessary.
Materials sourced from regions that may not have adequate quality and environmental controls should be thoroughly examined for potential organisms that need to be screened for. Also, items that are sourced from animals or plants may harbor endogenous organisms that may be pathogenic to humans.

The production process can be a major source of contamination. Even with the best of controls, there will still be opportunities for contamination. Understanding your production process will help identify those potential vulnerabilities. Some steps of concern are those that involve compression and water. As these steps mix in-process material with outside resources there is a higher risk of contamination. Therefore, any contaminants present in these sources may be of concern. To aid in determining additional organisms of concern, an analysis of both the production process and environmental data can be beneficial.

Looking at infection trends and infection susceptibilities are also important when determining if additional objectionable organisms should be examined. Since your target recipient may be susceptible to certain infections, knowing who the product will be administered to is critical. It is important to note that not every infection will be of a concern. Infections would have to be examined along with the likelihood that your product will contain the pathogenic microorganism that could potentially cause such illnesses. Since some infections can only be transmitted via specific routes, the route of administration for each product should also be known.

When performing the product’s risk assessment, these are all questions that should be considered.

The intended recipient and the method of administration for each product are important factors when establishing the final acceptance criteria. Different recipient populations may require different acceptance criteria based on their ability to fight infection, age, and if any preexisting conditions exist. For example, if the product is used on neonates and infants, a more stringent criterion would likely apply because these groups have developing immune systems and are less capable of fighting infections. Likewise, if immunocompromised patients are the intended recipients, then a tighter criterion would also apply for the same reason. Other less obvious factors, such as preexisting diseases, wounds, or organ damage are important when establishing acceptance criteria. A thorough risk-based assessment should look at all of these factors when establishing the final acceptance criteria.



<61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests
<62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms
<1111> Microbiological Attributes of Nonsterile Pharmaceutical Products: Acceptance Criteria for Pharmaceutical Preparations and Substances For Pharmaceutical Use
<1227> Validation of Microbial Recovery From Pharmacopeial Articles

James Gebo is a Technical Services Representative at Microtest Laboratories. He has hands-on experience in regulatory microbiology and virology testing since 2004. He holds a B.S. in Biology, a Masters in Public Administration, and is a Registered Microbiologist (NRCM). To contact Gebo directly: 413-786-1680 or

Kimberly Kitch is a Laboratory Technician II at Microtest Laboratories. She has been employed by Microtest Laboratories since January, 2006 and has worked in a number of different areas, including but not limited to, Microbial Limits, Genetic Identification of Bacteria and Fungi, LAL/Biocompatibility, and Bioburden Testing. She holds an A.S. in Biology and intends to continue to pursue the field. To contact Kitch directly: 413-786-1680 or kkitch@microtest

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