Regulatory Expectations For Objectionable Microorganisms In Nonsterile Pharmaceuticals

The topic of objectionable microorganisms is not new to the nonsterile microbiology industry. It has been around for several years and has triggered many warning letters. However, some companies still do not comply with the requirement that nonsterile products must be “free of objectionable organisms.”¹ This two-part article will discuss objectionable microorganisms recovered from nonsterile products. Part 1 will explain what an objectionable microorganism is and explore the regulatory expectations for objectionable microorganisms in nonsterile products. Part 2 will explain how to conduct risk assessments for objectionable microorganisms, and how to determine if a recovered isolate should be considered objectionable.

What Is An Objectionable Microorganism?

Microorganisms can be recovered from the environment, utility systems, raw materials, components, manufacturing equipment, in-process testing, or in the final product. But what makes one microorganism more abhorrent than another? An objectionable microorganism can be defined as a microorganism that can cause illness in the patient or that can adversely affect a nonsterile product.² This includes the potential to degrade a product’s stability.³

What Do The Regulations Say About Objectionable Microorganisms?

After being on the regulatory hot topic hit list for many years, there is still not an all-encompassing guideline or list of objectionable microorganisms. The simplified reason comes down to risk assessments. The expectation is that manufacturers have all of the variable information about their product and its intended use in order to make appropriate decisions regarding batch release.

There are many regulations and guidance documents available that discuss objectionable microorganisms. The following list of regulations and guidance documents is not intended to be an all-inclusive list.

• 21 CFR 211.84(d)(6): “Each lot of a component, drug product container, or closure with potential for microbial contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.”
• 21 CFR 211.113(a): “Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.”
• 21 CFR 211.165(b): “There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.”
• Parenteral Drug Association (PDA) Technical Report 67 – Exclusion of Objectionable Microorganisms from Nonsterile Pharmaceuticals, Medical Devices, and Cosmetics
• United States Pharmacopeia (USP) <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests
• USP <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms
• USP <1111> Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use
• USP <1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products
• Japanese Pharmacopeia (JP) 4.05 Microbiological Examination of Non-sterile Products
• European Pharmacopeia (EP) 2.6.12 Microbiological Examination of Non-sterile Products: Microbial Enumeration Tests
• EP 2.6.13 Microbiological Examination of Non-sterile Products: Tests for Specified Micro-organisms

In the list above, the USP, EP, and JP established global harmonization between chapters USP <61>, EP 2.6.12, and JP 4.05; as well as chapters USP <62>, EP 2.6.13, and JP 4.05. The tests described in these chapters are considered harmonized and equivalent.

What Happens When The FDA Finds Objectionable Microorganisms During Inspections?

Failure to properly adhere to the regulations and expectations may lead to regulatory observations. The FDA posts warning letters to its website (http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/). These warning letters can be reviewed in order to gain insight into the current regulatory expectations. This knowledge can be a powerful tool in preventing observations and remaining compliant.

By searching objectionable microorganism warning letters, it is evident that the regulation for nonsterile products to be free of objectionable microorganisms is taken seriously. For example, the following warning letter excerpts cite companies for this deficiency.

• Warning Letter Dated March 20, 2019: “Your firm failed to conduct appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms (21 CFR 211.165(b))…. You released multiple batches of these drug products without conducting tests to ensure they were free from objectionable microorganisms. It is essential that your drug products are produced in a manner that is suitable for their intended uses and that each batch is tested for conformance to appropriate microbial quality specifications. In your response, you provided examples of recently tested batches utilizing the USP method for microbial enumeration testing. Your response is inadequate because you did not provide your verification studies including data to show the suitability of the compendial method being used. Your response also failed to provide data to show that all previously released products, that remain on the U.S. market, were tested and found to meet your newly implemented USP microbial release specifications.”⁴ 
• Warning Letter Dated March 20, 2019: “Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a))…. Over multiple years, your firm obtained recurring test results for water used as a component of your drugs, as well as results for finished [redacted] drug products, outside of microbiological limits. This testing revealed extremely high levels of microbiological contamination, including results that were Too Numerous to Count (TNTC), and identified the presence of significant opportunistic pathogens in your drugs. Furthermore, your tests of retained samples and customer complaint bottles found objectionable microbiological contamination in already distributed lots…Significantly, you failed to take actions to prevent consumer exposure to marketed drug product lots known by your firm to contain microbiological contamination…. In addition to these total count failures, you identified objectionable microorganisms (such as Burkholderia multivorans) in multiple drug products but lacked investigations. You did not take effective actions to investigate root causes, and correct flaws, in your manufacturing operations and quality management systems to prevent recurrence of these serious quality failures. Ultimately, you did not ensure timely and effective corrective and preventative actions to prevent exposure of consumers to contaminated product. While you continued to obtain microbiological test results outside of acceptable limits on a recurring basis, you did not initiate recalls until the FDA identified these serious issues in our inspection and relayed safety concerns to you.”⁴
• Warning Letter Dated Aug. 29, 2018: “Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b))…. In addition, your firm did not have adequate test methods to detect objectionable microorganisms, including P. aeruginosa, E. coli, S. aureus, C. albicans, Clostridium sp., Salmonella sp., and bile-tolerant Gram-negative bacteria. These organisms are known to cause infections or produce toxins that can cause serious harm to patients. Also, although you tested for the presence of Clostridia, you did not incubate the inoculated sample under anaerobic conditions as is necessary to support the growth of Clostridia. Further, your firm also did not have all the necessary media, buffers, and environmental conditions needed to conduct microbiological testing.” ⁴

In Part 2 of this two-part article, we will explore objectionable microorganism risk assessment — and how to determine if a recovered isolate is objectionable.

References:

1. Code of Federal Regulations (CFR) Title 21. Accessed on March 25, 2019 at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm.
2. PDA (2014) PDA Technical Report No. 67: Exclusion of Objectionable Microorganisms from Nonsterile Pharmaceuticals, Medical Devices, and Cosmetics. PDA, Bethesda, MD.
3. Sutton, S. Ph.D. (2006) How to Determine if an Organism is “Objectionable”. The Microbiology Network. July, 2006. Assessed on March 25, 2019 at http://www.microbiol.org/resources/monographswhite-papers/how-to-determine-if-an-organism-is-objectionable/.
4. Food and Drug Administration (FDA) Warning Letters. Accessed on March 25, 2019 at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/.

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.