Note: The opinions expressed in this blog are those of the author and should not be interpreted as the positions or policies of USP or any other organization.
The compendial Sterility Test first appeared in recognizable form in the British Pharmacopeia in 1932 and then in the USP in 1935 as a direct response to a clear need for a recognized test to check for pharmaceutical product sterility. Since this time, the design of the test has remained fundamentally unchanged although there has been refinements in the actual test design ending with its international harmonization in 2003. What we call the “Sterility Test” is more appropriate titled “Sterility Tests” in the compendia as the chapter includes two distinct types of testing, one utilizing membrane filtration and the second a direct transfer of the medicine into recovery media for recovery. The concerns discussed below apply to both test designs.
To address the obvious concern first – the compendial Sterility Tests are not actually capable of “proving” product sterility. The destructive nature of the tests (after testing the samples there is nothing left to sell) limits the sample size to a portion of the batch only – we can truly only “prove” that portion actually tested to be sterile. The sample size limitation means that we must follow strict guidelines as to the volume per unit and number of units product tested. These limitations are described in Tables 2 and 3 of the compendial chapter.
A second area of practical limitation to the tests is that we can only recover contamination that is capable of growth under the test incubation conditions of media type, incubation temperature and incubation duration.
A final area of limitation to the compendial sterility tests involves the potential presence, in many medications, of antimicrobial properties. These properties may be retained during filtration or carried over during direct transfer of the product to recovery media. The adequacy of the recovery method must therefore be demonstrated and this procedure is described in the compendial tests as a Method Suitability test.
The test limitations have resulted in the realization that the best assurance of product sterility is in the manufacturing or compounding process controls, rather than in testing the finished medication. While the discussion of process controls, sterilization validation (or alternately process simulation studies for aseptic processes) and facility/personnel control is fascinating it is one for another blog. Let’s not forget that the compendial Sterility Tests have some real value.
The compendial sterility test does allow for identification of some compromised batches of products and so is useful in that regard. However, in my opinion, the main value of the compendial sterility test is that it is well-defined. That is to say that if someone claims to have tested that material in compliance with the test, everyone involved knows exactly what was done. However, to retain this value it is critical to conduct the test precisely in compliance with the compendia. This compliance requires adherence to the critical design features of the test:
- Adequate sample volume tested as described in Table 2 and 3 of the compendial test.
- Adequate demonstration of Method Suitability for that volume
- Correct media used
The test requires the use of both the aerobic recovery medium Soybean Casein Digest Broth (SCDB) and the anaerobic recovery medium Fluid Thioglycollate Medium (FTM)
- Correct incubation temperatures used
The SCDB to be incubated at 20-25oC and the FTM at 30-35oC
- The media incubations to be conducted for at least 14 days before completion of a passing test
The test can, of course, fail much sooner. There is also a provision for a subculture of the incubated media if the product renders the recovery medium turbid that extends this minimal period.
If these 5 basic conditions are not met, then the test cannot be claimed to be compliant with the compendial sterility test.
For those interested in hearing more there will be a webinar upcoming on this topic with some discussion of the impact of the compendial sterility test on the current compounding pharmacy situation. The webinar will be on October 31 at 2 pm (eastern). Registration for this webinar is $299 and available here.
Sutton, S. 2011. The Sterility Tests. IN: Rapid Sterility Testing J. Moldenhauer (ed) PDA/DHI Publ pp. 7-28
Sutton, S. 2010 “The Compendial Sterility Tests”; IN Pharmaceutical Dosage Forms: Parenteral Medications, Third Edition Volume 2: Facility Design, Sterilization and Processing Sandeep Nema and John D. Ludwig, (ed) Informa Healthcare.
Moldenhauer, J and SVW Sutton. 2004 Towards an Improved Sterility Test. PDA J Pharm Sci Tech 58(6):284-286
Dabbah, R, J. Knapp, and S Sutton. 2001. The Role of USP In the Assessment of Microbiological Quality of Pharmaceuticals. Pharm Technol. July 2001 pp. 54-60
Sutton, SVW, et al. 2001. Activities of the USP Microbiology Subcommittee of Revision During the 1995-2000 Revision Cycle PDA J Pharm Sci Tech. 55(1):33-48
Sutton, SVW et al. 2005. Activities of the USP Analytical Microbiology Expert Committee During the 2000-2005 Revision Cycle. PDA J Pharm Sci Tech. 59(3):157-176.
Sutton, S. & R. Tirumalai. 2011. Activities of the USP Microbiology and Sterility Assurance Expert Committee During the 2005-2010 Revision Cycle. Amer Pharm Rev. pp. 12-30