USP <1211>: The Compendial Informational Chapter on Sterility Assurance - Pharmaceutical Technology

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USP <1211>: The Compendial Informational Chapter on Sterility Assurance
The author provides a history of the information chapter USP 91211: "Sterilization and Sterility Assurance of Compendial Articles," from the early 1900s to the current version.

Pharmaceutical Technology

These changes were intended to be a short-term correction to eliminate the more glaring concerns in ‹1211›. However, there was significant comment from the field in this proposal. The chapter was thought to need reorganization to keep the focus within individual sections on process, equipment, and product more tightly directed. The chapter as a whole needed closer conformance to existing consensus standards in terms of moist heat under pressure, dry heat, and aseptic processes. As with many documents about sterilization, readers felt that clarification of ambiguous terms was needed as well as a clarification of definitions. There was also strong sentiment that the sterility test should not be discussed at all in this chapter because it is a separate chapter in its own right. Finally, there was a request for more detail about the use of isolators for aseptic processing.

Clearly, this version did not help clarify the situation. Therefore, no further action was taken, and this version did not become official. A proposal for a partial rewrite is expected in Pharmacopeial Forum before summer 2009. This rewrite will remove obviously incorrect information about sterilization and bring the chapter in line with the current sterility test chapter. This revision will therefore address the most egregious points of the current chapter ‹1211›.

On a longer timeframe, serious changes to the organization of the chapter are under consideration. Among the changes being discussed are an increased focus on concepts and principles of quality control for sterile articles, an expanded discussion of process equipment capability, and operational abilities within the established parameters as well as information about other aspects of process validation.

The different methods of sterilization may be removed to different (new) chapters; specifically,
  • Chemical sterilization: The chapter may include discussions on aldehydes, oxidizers, halides, acids, and bases.
  • Dry-heat depyrogenation: This method will be described as predominantly used for glass and stainless-steel items that can withstand the applied temperatures (usually in the >200–300 C range). This chapter will be used with a planned endotoxin monograph that has been drafted.
  • Sterilization by filtration: This chapter will be a complete revision from the current text in ‹1211› to bring it more in line with current thought on filtration validation.
  • Gas sterilization: This chapter is envisioned as applicable to single-phase gaseous processes only and uses ethylene oxide sterilization as a model for all the systems. The chapter will probably describe two different validation approaches: the traditional half-cycle method and a bracketing method. Gases expected to be included are ethylene oxide, ozone and chlorine dioxide. These systems will be described as differing from vapor systems in that condensation is not a consideration.
  • Dry-heat sterilization: A distinction will be made between dry-heat sterilization and depyrogenation because of major process differences. This chapter will most likely identify Bacillus atrophaeus spores as an appropriate biological indicator for sterilization by dry heat and define a temperature range for effective cycles while citing the mathematical correlation between physical data and microbiocidal activity.
  • Radiation sterilization: Methods to be included in this chapter will be gamma rays, electron beams, and the minor contributors (i.e., x-rays, microwaves, and visible light). These processes have the potential to damage the product but provide precise parameters, and dose-setting and dose-substantiation procedures can be used to validate the radiation dose required to achieve sterility assurance level.
  • Steam sterilization: This chapter may be separated into two parts (steam and terminal sterilization) to allow for differences, and greater clarity, or remain in one chapter that will list the "overkill approach" as the method of choice. This chapter will also stress the importance of clearly recognizing processes where over-processing is not a concern from those processes where over-processing can damage the product.
  • Vapor sterilization: This chapter will be intended for condensing vapor systems (gas and liquid phases present simultaneously) such as hydrogen peroxide and peracetic acid systems. The presence of multiple phases that are present simultaneously complicates concentration determination at the point of sterilization, thereby making D-value determination problematic. The approaches for validation will be described as a hybrid of the liquid- and gas-sterilization methods. Two validation strategies will be presented: the traditional half-cycle method and the bracketing method.


USP has had the opportunity to contribute to sterility assurance since the early 1900s. The ability of USP to assemble experts and allow them to propose guidance on the basis of their experience and knowledge is a unique strength of the compendium in its role as a safeguard of the public's health. That the actions taken by the committee will change over time as our knowledge increases and the pharmaceutical and pharmacy industries change should not be a surprise.Indeed, this flexibility is a particular and planned strength of the USP system of "continuous improvement." As with many other chapters, evidence from the development of USP ‹1211› suggests that this process works best with a motivated committee and an industry engaged in the process.


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