REGULATORY UPDATE
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individual units gives more information about variability between samples. That information is lost when units are pooled for testing.
The issues addressed in the recent BET version and in the FDA’s Q&A guidance document do not fundamentally change the way endotoxin testing should be performed.
and the batch size. A minimum of three units, representing the beginning, middle, and end, should be tested from a lot”. The wording in the current guidance emphasizes the justification of an appropriate sampling technique and states that the sampling plan should be dynamic. This might result in the need for an increased level of testing compared to those based on the former document. The numbers of samples might be reduced once sufficient data has been collected to demonstrate that a process is under control. There is no mention in the response to Question 1 of sampling from the beginning, middle and end of a production run. However, this is included in the response to Question 4.
Question 2: When is retesting appropriate?
Prior to publication of the guidance, FDA speakers had stated at meetings that the outdated provisions for retesting in the former guidance documents was a principle reason for their withdrawal. The withdrawn documents were written before the Barr decision of 1993 and before the Out of Specification (OOS) Guidance was issued by FDA in 2006. They were inconsistent with the OOS guidance and current FDA thinking. The response to Question 2 agrees with and refers to the 2006 OOS Guidance document.
Question 3: Is sample storage and handling important?
Sample storage and handling is a point about which FDA has shown consistent concern for over 20 years (for example see Guilfoyle et al. [6]). This issue is important. Sample stability is also mentioned in the response to question 4 in the discussion of medical device extracts.
Question 4: Can finished product samples for analysis of bacterial endotoxins be pooled into a composite sample prior to analysis?
The response allows for pooling of products provided that the MVD for the sample pool (and, by logical extension, the endotoxin limit for the sample pool) is reduced proportionately. This is not a new point. The issue of pooling of drug products has been raised at meetings by FDA speakers for many years and it has appeared in the handouts of presentations. This is the first time it has appeared in a guidance document. FDA suggests pooling no more than three units and refers to testing representative finished product containers from the beginning, middle, and end of the production run. It is noted here that when vials/containers of drug product are tested individually there is no need to reduce the MVD. Also, testing
12 American Pharmaceutical Review | Endotoxin Supplement 2013
For medical devices, the guidance refers to the standards ISO 10993-1 and ISO 10993-12 for rinsing/eluting and sampling techniques. The response to the question does not refer to USP Chapter <161>, Transfusion and Infusion Assemblies and Similar Medical Devices [2]. This USP chapter calls for pooling up to 10 medical device extracts and gives a formula for calculating the endotoxin limit for the extract pool. USP chapter <161> does not require adjusting the MVD (or the endotoxin limit) to account for pooling because that has been accounted for in the endotoxin limit of 20 EU/device. This is not stated in the USP chapter of the guidance document but it is explained clearly in the standard ANSI/AAMI ST72:2011 [5] in Annex A, item A.8.
Question 5: May a firm use alternative assays to those in the USP for a compendial article?
The response regarding alternate (i.e. non-compendial) methods states that such methods and/or procedures may be used if they provide advantages in accuracy, sensitivity, precision, selectivity, or adaptability to automation or computerized data reduction, and in other special circumstances. It makes clear that (1) such methods should be appropriately validated and (2) if a difference appears or in the event of a dispute, the final decision is made based upon the USP compendial gel-clot method unless otherwise indicated in the monograph for the product being tested.
As examples of alternative assays that require validation as alternate methods, the recombinant Factor C assay and the Monocyte Activation Test (MAT) are cited.
Question 6: What is the best process for transitioning from one alternate bacterial endotoxins test (BET) method to another?
The response to the question makes clear that firms should carefully consider the validation requirements for a method change. Consequently, it would be prudent to document the rationale for the approach taken to the validation, including whether or not to adopt the suggestion to test field samples. It suggests that comparing the two tests (the current test and the proposed new method) to verify the equivalence of the new method. In addition, it states that the sensitivity of the new method can be evaluated on spiked product samples. The response is not explicit whether “spiked product samples” refers to spiking of undiluted product or to spiking of product at the test dilution, as is typically done to prepare positive product controls.
It is a little surprising that the USP chapter <1225>, “Validation of Compendial Procedures” is referenced. Chapter <1225> describes the requirements for validation of procedures that are included in the USP (i.e. Compendial Procedures). The methods at issue in this question and answer are those that are included in the USP BET chapter and are therefore validated compendial procedures. A more appropriate reference would be chapter <1226> “Verification of Compendial Procedures” (which does refer to chapter <1225>).
There is no mention of the testing required to support changing to reagent from a different manufacturer (without a change of test method). Thus, it is left to the firm to appropriately validate and document the change. A reagent transfer protocol is available from Associates of Cape Cod, Inc., that can assist with this process.
Finally, the response gives useful information on the expectations for reporting such changes to FDA.
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