USP intends to revise the Chapters on Microbiological Control of Non-sterile Medicinal Products

Often, aseptically manufactured medicinal products are given more attention by industry and authorities, especially during phases of revision of the authoritative guideline, Annex 1 of the EU GMP Guideline. However, non-sterile pharmaceutical products are also expected to produce a therapeutic effect for the patient with a minimum of undesirable adverse effects. To ensure the greatest patient safety, they are expected to be free of pathogenic microorganisms. Especially as microbiological contamination may also affect the physicochemical properties and therapeutic value of the product. The USP has published a number of compendia on the microbiological quality of non-sterile medicinal products. However, as the USP writes in its Stimuli article in PF48(2): "The chapters of the compendia on the microbiological quality of non-sterile products place too much emphasis on testing finished products, which may result in less attention being paid to the means necessary to actually protect products and patients from microbial contamination. This article discusses possible revisions to refine both process recommendations and microbiological testing expectations to improve patient safety. This includes adding or revising content that provides guidance for general microbial control of non-sterile products."


Looking at the US FDA's requirements for current good manufacturing practice (cGMP), the following expectation can be found: "Appropriate written procedures shall be established and followed that are designed to prevent undesirable microorganisms in medicinal products that are not required to be sterile" (US Food and Drug Administration. Current good manufacturing practice for finished pharmaceuticals. 2021. 21 CFR §211.113. Accessed November 8, 2021.)

This can be interpreted to mean that the regulatory authorities require procedures and tests to minimise the risk of the presence of undesirable micro-organisms and thus to exclude the associated negative consequences as far as possible. In reality, this can be particularly difficult with non-sterile products because, as the name suggests, they are not sterile. They may contain microorganisms, but the type and quantity should be such that there is no risk to the product or the patient. The requirement to contain as few potentially harmful microorganisms as possible poses particular challenges for manufacturers, as this property cannot be ensured by testing the end product due to the limited statistical samples and limited microbiological tests.


Historically, the USP first published recommendations for microbial control of non-sterile products in 1994 - the Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use <1111> As part of revisions and with the harmonisation in the EP and JP, this led to the development and first publication in 2006 of the USP chapters "Microbiological Examination of Non-Sterile Products: Tests for Specified Microorganisms <62> and <1111> which came into force in 2009. The aim was to ensure that, in non-sterile medicinal products and active substances, certain test procedures are used to exclude the presence of selected critical microorganisms that pose a risk to the product and the patient.

The USP describes the problem at that time as follows today: "The emphasis on testing finished medicinal products has probably led to less attention being paid to the means necessary to protect products and thus patients from microbial contamination. The expectation in pharmacopoeias to include selected representative strains depending on the route of administration of the drug is also misleading as it implies that other microorganisms are not relevant."

With the growing awareness that patient safety cannot be ensured by testing finished medicinal products alone, other chapters followed over the years, e.g. to develop an information chapter on environmental monitoring in non-sterile manufacturing. As the development and lessons learned progressed, the focus of the chapter shifted to facility design, system and equipment design, and operational practices that collectively enable control of the microbial content of non-sterile products and pharmaceutical excipients and APIs, culminating in the chapter on Bioburden Control of Non-sterile Drug Substances and Products <1115> in 2015.

What the future may hold

In order to continue the development of the chapters for microbiological control of non-sterile medicinal products, the USP Expert Committee is considering revising the following eligible chapters or creating additional information:

  • Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use <1111>
  • Bioburden Control of Non-sterile Drug Substances and Products <1115>
  • Microbiological Best Laboratory Practices <1117>
  • Microbial Characterization, Identification, and Strain Typing <1113>
  • Recovered Microorganism Decision Tree
  • Microbial Risk Identification/Assessment

With the current publication, the USP aims to inform stakeholders of the overall scope and nature of the expected changes and encourages them to comment before the Expert Committee begins its work in depth.

For further information, please visit the USP website and log in for access at Refining Microbiological Control and Testing for Nonsterile Products.

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