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


This version includes a greatly expanded section about filtration and aseptic manufacturing, including an emphasis on the control of the fill environment. A strong suggestion is included to the pharmacist and operators to perform aseptic manipulations under hoods or shields in an area protected from visitors. A new section was added to the chapter on the need to monitor the environment, with settle plates and media fills recommended. Finally, the chapter states that making sure the janitorial staff cleans the area after the shift. leaving a full overnight period before the next day's fill, is considered very important. This chapter was rewritten for USP XVII (11). Although most changes were editorial, specific instructions for types of sterilization methodologies were included as separate sections and new methods–sterilization by ethylene oxide and sterilization by irradiation–were included for the first time.

Revision of 1970s. The chapter "Sterilization" was amended again for USP XVIII (12). In addition to extensive editorial changes, two important new sections were added. The first section dealt with biological indicators and the need for appropriate selection of the indicator (one for heat may not be a suitable species for irradiation) as well as the need for competent manufacture of the indicator itself to maintain its relevant properties (e.g., heat resistance or similar property). The second new section dealt with the sterility test. The opening paragraph of this section is so entertaining that I have to share it:

The significance to be attached to a demonstration by test that a drug or device has been rendered sterile is determined largely by the extent of the control exerted during the manufacturing and sterilization processes. The object of the sterilization process is to make the article safe for use, but the tests may be expected to reveal only that living organisms have been removed or destroyed to the extent where they no longer multiply in appropriate culture media under favorable conditions. Interpretations of the results of sterility tests must allow for the possibility that the degree of contamination is of a low order of magnitude. Confidence in the results of the tests with respect to a given lot of articles is based upon knowledge that the lot has been subjected to a sterilization procedure of proven effectiveness. Where feasible, the effectiveness of the process should be demonstrated each time it is carried out by including marked, intentionally contaminated controls, or indicators, which are examined under the conditions of the tests.

This passage is somewhat ironic because speakers to this day insist that USP created a flawed test for sterility that should have been fixed long ago. Although this argument is undoubtedly true, this test was first entered in the British Pharmacopoeia of 1930, then in USP of 1932 with no significant improvements in the intervening 77 years. One would think someone would have come up with a better assay by this time.

The 1970 version of the USP chapter provides some instruction about change control (not in those terms, of course) and the need to control the sterility test environment. Although no one can doubt the importance of some guidance about how to perform and interpret the sterility test, the inclusion of this information in the chapter would create difficulties lasting to the present. The 1970 revision of the chapter continued and expanded somewhat the discussion of aseptic processing with monitoring by settle plates and media fills that was introduced in 1960.

The version of the chapter that appeared in USP XIX (13) reintroduces the major section about sterilization methods, establishes biological indicators as a major section, and creates a major section entitled "Sterility Testing of Lots." The sections contain a great deal of detail. For example, the biological indicators section provides a method to confirm heat lethality of the spores. In addition, the section "Sterility Testing of Lots" contains recommendations about the media to be used, sample plans, and number of units to be tested. The particulars described in the chapter "Sterilization" were not necessarily in agreement with the contemporary referee chapter "Sterility Tests" (14).

Revision of 1980s. The chapter was further revised for USP XX (15). The major organizational scheme from 1975 remains, but much of the detail has been removed. In particular, the section on biological indicators now uses the parameter of "D-value" to describe the desired heat resistance of the different spores, and the section about sterility testing has been toned down dramatically and is no longer conflicting with the "Sterility Tests" chapter. In addition, this version clearly states that ‹71› "Sterility Tests" is the official referee test. For those interested in the history of the sterility test chapter, USP XX included the first mention of "First Retest" and "Second Retest" in the then 48-year-old test (16). It should also be noted that USP XX is the first volume that uses the chapter numbering system where "Sterilization" carries the chapter number ‹1211›.


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