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

The author provides a history of the information chapter USP ‹1211› "Sterilization and Sterility Assurance of Compendial Articles," from the early 1900s to the current version.
May 01, 2009

In 1900, the eighth revision of the United States Pharmacopeia (USP) was recast from its traditional focus of how to make medicines to the role it would eventually take as a book that describes the safe making of medicines. The US Pharmacopeial Convention resolved to "append assay processes to as many of the potent drugs and preparations made therefrom as may be found possible, provided that the processes of assay are reasonably simple and lead to fairly uniform results in different hands" (1). This publication was followed shortly by the Federal Food and Drugs Act of 1906, which elevated the position of USP and increased its authority dramatically. It was against this background that the first informational chapter about sterilization appeared.

The original chapter. The original chapter on sterilization appeared in USP IX, which became official in September 1916 (2). Although this chapter was sparse on technical detail, it provided a background discussing the need to sterilize various medicines, containers, and stoppers with recommendations as to how to achieve this sterilization. Part of this early emphasis stems from USP's focus at that time on the practicing pharmacist and the need to put procedures in place that were accessible to the practitioner (1).

Bear in mind, that this chapter was published more than 20 years before the passage of the Food Drug & Cosmetic (FD&C) Act of 1938, which gave the US Food and Drug Administration the authority to require proof of a product's safety before marketing, and almost 50 years before the first good manufacturing practice (GMP) was finalized (3–5). As an aside, the importance of sterilization and sterility assurance continues to be a grave issue to this day. It was the 1972 Devonport incident involving lax control of a sterilization process and the resultant damage that drove modern concepts of sterility assurance as an operational imperative (6, 7).

The 1947 revision. The 1916 informational chapter was extensively revised in 1947 (and increased in length by approximately sevenfold) to provide a great more detail about many types of sterilization methods, several of which are no longer in use (8). This version provided information about what would probably be called "compendial conditions" for sterilization by dry heat (>1 h at >170 °C), for "steam under pressure" (115.5 °C for 30 min, 121.5 °C for 20 min, or 126.5 °C for 15 min), and for "free-flowing steam." This last technique was used in a series of exposures to kill vegetative cells with respites to allow spore germination before repeated exposure to steam. Also known as tyndallization, this method of sterilization is no longer recommended (9). The informational chapter also included a discussion of "fractional moist-heat sterilization at low temperatures" (inspissation), in which the medicine is heated at 60–80 °C for 4–7 days, as well as a discussion of sterilization by boiling in an oil bath. Interesting methods all, although on the whole this author is glad that validation and demonstration of efficacy has become the expectation. This 1947 chapter has some specific recommendations for sterilization by filtration and aseptic processing (along with a direction that the label is to state "Prepared by Aseptic Manipulation").

Revisions in the 1960s. The title of the chapter was changed back to "Sterilization" for USP XVI (10). This version was a complete rewrite of the chapter. It included a special note that while the "fractional sterilization" methods might work well for bacterial growth media, it is not appropriate for pharmaceutical preparations because spores may not germinate in them (not mentioned is the issue of metabolic byproducts created by the germinating spores if the process works).