Skip To The Main Content
PDA News

PDA News

Proposed USP Chapter on Nonsterile Bioburden Long Overdue But Clarification Still Needed

by Karen Ginsbury, PCI Consulting | Aug 22, 2014
USP’s microbiology-related chapters continue to evolve and a new one is wending its way through the pharmacopoeial pathway. The new chapter, with a focus on nonsterile products, is unique and much needed.

USP’s microbiology-related chapters continue to evolve and a new one is wending its way through the pharmacopoeial pathway. The new chapter, with a focus on nonsterile products, is unique and much needed.

In 2013, the U.S. Pharmacopeial Convention (USP) published a draft general chapter on bioburden control of nonsterile products (1). A work of this nature, providing industry with some background and recommendations for strategies to control the environment in which nonsterile products are produced, is long overdue. Typically, companies have directed the majority of their resources to risk management of sterile—particularly aseptic—processing operations. Nonsterile manufacturing environments and processes tended to evolve from current practices rather than from a rigorous assessment of process and product requirements to control the introduction and propagation of microbes.

The USP has developed several general chapters in the area of microbiology over recent years, some with greater success and others with less. Chapter <1117>, Best Microbiology Laboratory Practices, is—together with the WHO Annex 2 on microbiological laboratories—one of the major resources for recommendations on appropriate practices in running a microbiology laboratory within a pharmaceutical company. On the other hand, <Chapter 1116>, Microbiological Evaluation of Clean Rooms and Other Controlled Environments (updated in 2012) came on top of the U.S. FDA’s aseptic processing guide (now somewhat outdated at ten years of age), EU’s Annex 1 on Manufacture of Sterile Products, plus PIC/S and ISO cleanroom guidances, seemingly superfluous at this point in time. The 2012 revision of this chapter to “Microbiological Control and Monitoring of Aseptic Processing Environment” added to the overall body of knowledge on cleanroom management with recommendations for monitoring microbial recovery rates rather than just looking at day-by-day numbers. This was a useful addition to the overall cleanroom management approach although other issues with the chapter’s content remain.

The proposed <1115> chapter on nonsterile products can undoubtedly provide valuable recommendations for industry regarding a microbial control strategy for products which have a defined bioburden requirement (microbial limit) but are not required to be sterile. In order to provide this value, the chapter needs to emphasize the challenge in maintaining a stated microbial limit, as opposed to maintaining sterility, which is an absolute state and maintained for as long as the package is integral. What the draft chapter fails to do—and, in fact to a large extent, creates the opposite impression—is illustrate the uniqueness of this challenge. Microbes are distinct in their phenomenal ability to survive under minimal nutrient conditions (e.g., to lay dormant and to proliferate at astounding rates). The chapter tells the reader it is inevitable that there will be pathogens in the production environment. The chapter, however, does not clarify that under appropriate circumstances, one of those pathogens could double itself every twenty minutes, resulting in 16 million (under ideal conditions) within an eight hour shift.

There are three major issues with the draft as published in Pharmacopeial Forum:

  1. The chapter exclusively warns against “excessive microbial controls” for nonsterile products as costly without added benefit. It neglects to mention the reverse scenario regarding the dangers of inadequate controls and the harm this could cause. The chapter gives the sole consideration for microbial control as “patient safety,” whereas in fact, the product itself, in addition to the process, may require microbial controls. Implementation of risk management over the past few years has shown clearly that when the sole focus is patient safety, processes and products continue to fail. If the intention is prevention, rather than detection and correction (which is far more wasteful and results in drug shortages), controls required to ensure appropriate processing conditions are essential. For example, some processes are inherently more susceptible to contamination (those using moist environments and temperatures convivial to microbial proliferation) than others, and therefore, require tighter controls. An initial read of the draft leaves the impression that very few measures are actually justified for nonsterile products. It seems unlikely that this is the message which the authors intended to convey.
  2. The chapter fails to consider the professional background of the reader, which is especially critical in the case of nonsterile products, where there may not even be a microbiologist on the company payroll. There is no explanation of the nature of the risks posed by microbes with respect to their unusual capacity for entry, survival and proliferation under minimal nutrient conditions. Without this background, and in light of the exhortations against “excessive controls” plus extensive, repeated statements about how human bodies can serve as incubators for microbes and that pathogens are always present in the production environment, a naïve reader might come to the conclusion that microbial risks posed by nonsterile products are negligible, thinking “we really should not be diverting resources to fix this minor issue.”
  3. The draft muddles the concept of risk management due to the manner in which it is written. For example, the chapter provides a list of product types with the (potential) risk, from high to low, that they pose for microbial contamination. There is no rationale for the grouping, which appears to contradict earlier statements such as:

“nonsterile products are administered to regions of the human body that are rich in microbial flora and have physical or immunological barriers to infection. Examples include the oral cavity, skin, nasopharynx, vagina, and rectum, which harbor a high and diverse viable microbial population.”

  1. Why then are vaginal suppositories higher on the list than topicals and aqueous oral liquids? Surely, risk management requires each company to perform their own assessment of their products and processes, looking at diverse factors and failure modes along with categorizing the risk based on identified controls. This is not addressed anywhere in the proposed chapter and there is a real danger that nonmicrobiologists may apply the recommendations blindly with little or no understanding of the underlying risks.

The draft chapter states that:

“When formulators evaluate the susceptibility of nonsterile pharmaceutical products to microbial hazards, considerations include whether the active ingredient has inherent antimicrobial activity, the microbiological content of excipients, inclusion of antimicrobial preservatives in the formulation, and water activity.”

Undoubtedly, before considering if the active has inherent antimicrobial activity, it would be prudent to look at whether the active, excipients or product formulation and production process have inherent ability to support and promote microbial proliferation.

In conclusion, the proposed chapter could, and should, be a valuable addition to the body of knowledge for manufacture and control of nonsterile products. Chapter <1115> should provide useful material for companies developing, maintaining and improving a microbial control strategy for these products. In order to achieve this goal, caution is needed in both the background material provided, the manner in which it is presented and the way in which risk management is described and approached. Consideration should be given to the readership, many of whom will not be experienced microbiologists. Some basic microbiological background is warranted, regarding the nature of microbial proliferation and the challenges in maintaining a defined bioburden as opposed to asepsis/sterility which is an absolute.

[Editor’s Note: There will be a session focused on objectionable organisms in nonsterile drugs at the PDA 9th Annual Global Conference on Pharmaceutical Microbiology, Monday, Oct. 20 at 1:15 p.m. In addition, Plenary Session 5 will cover microbiology-centric USP updates at 8:15 a.m. Oct. 22.]


  1. Bioburden Control of Nonsterile Drug Substances and Products. Pharmacopeial Forum 39 (2013)

About the Author

Karen Ginsbury is President and CEO of PCI, Pharmaceutical Consulting Israel Ltd., a company which provides services to the pharmaceutical, biotech and allied industries. She has designed, implemented and maintained company-wide compliance systems which have passed Israeli Ministry of Health, U.S. FDA and European inspections, working with both small start-ups and large pharma.