6.5 Reprocessing/Distribution of Material

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

When should a firm perform a sterility re-test? How should a microbiology laboratory handle deviations during sterility testing?

When should a firm perform a sterility re-test? How should a microbiology laboratory handle deviations during sterility testing?

Reference: 
1987 Guideline on Sterile Drug Product Produced by Aseptic Processing; 
USP 23, Section <71>, Sterility Tests; 
21 CFR 211.22, Responsibilities of quality control unit; 
211.192, Production record review;
211.160 General Requirements [Subpart I, Laboratory Controls]

The USP Sterility Test is limited in its ability to detect whether a batch contains contaminated units. Finding any unit that exhibits growth is a serious matter, and the subsequent investigation is generally quite involved and covers both the laboratory and production areas. The drug product lot fails the USP test requirement if any microbial growth is found and the test is not invalidated. The USP (Supplement 8) states that a firm should not perform a sterility re-test without evidence that the sterility test positive can be attributed to contamination introduced by the laboratory. Further, the 1987 Aseptic Guideline explains that a batch should not be released without clear documented evidence that the contamination occurred during testing.

It is difficult to justify invalidation of an initial sterility positive result. For example, the presence of any specific microorganism in both the test sample and the sterility testing environment would not alone rule out the aseptic manufacturing operation as the origin of the contamination. A comprehensive evaluation of manufacturing and testing operations, as well as multiple trending reports (e.g., long term trends at specific environmental monitoring locations) which can be revealing, would be consistent with section 211.192 of the CGMP regulations. Because of the low sensitivity of sterility testing, a finding of no growth during retesting should be afforded minimal weight relative to other parts of the investigation.

In summary, a high threshold of justification is needed for a decision to invalidate a sterility test positive result and perform re-testing. When investigations into the origin of the product's contamination are inconclusive, the decision to release or reject the batch should err on the side of patient safety. 

Per section 211.160 of the CGMP regulations, when deviations occur during sterility testing, they should be documented concurrent with the test, investigated, and remedied. As explained in the 1987 guideline, such deviations should be trended, with corrective measures taken in a timely manner. If any of these deviations may have compromised the integrity of the sterility test, it would be consistent with CGMP not to proceed with the test. For example, if asepsis is compromised during sample manipulation, then samples should not be incubated. Finally, it is important to note that an unreliable laboratory is an objectionable condition that underscores the need to err on the side of safety when investigating a sterility positive rather than risk overlooking a genuine production problem.

Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov; Tracy Roberts, HFD-325, 301-594-0098, e-mail: robertst@cder.fda.gov