REGULATORY UPDATE
Question 7: What happened to the endotoxins limit table in Appendix E of the 1987 Guidance?
The response explains the rational for withdrawal of the table of endotoxins limit that was Appendix E of the 1987 Guidance. Withdrawal of the Appendix E is a positive step as it forces users to refer to primary sources of information, including USP monographs. The response includes important recognition of the fact that the endotoxin limit in a USP monograph may not be appropriate for a particular product because the product strength or dosage regime differs from that used to calculate the limit in the USP monograph. Consequently, it is always prudent to verify endotoxin limits by calculating them using the maximum dosage stated in the package insert for the product.
Question 8: How can Quality by Design concepts support endotoxins limits?
The response emphasizes the importance of process control and the role of endotoxin testing of raw materials, product components and of in-process samples in assuring the quality of finished product. Also, preference for quantitative testing as opposed to over limit testing is indicated.
Question 9: When is the USP Chapter <151> Pyrogenicity Test (the rabbit pyrogen test) appropriate?
The response notes that for some products, a pyrogen test is specified in the USP monograph or may be necessary in cases in which a valid BET cannot be performed. The response also raises the possibility of contamination of products by non-endotoxin pyrogens. While this cannot be ruled out by endotoxin testing, actual cases of contamination by non-endotoxin pyrogens are rare. But for this fact, the BET would not have been accepted as an alternative to (or have largely replaced) the pyrogen test. (It is worth noting that some therapeutic agents are known pyrogens, such as interleukin-2.)
Question 10: How would an appropriate endotoxins limit be determined for a veterinary product that targets multiple species?
The response states: “For a veterinary product labeled for use in multiple species, the limit should be based on the maximum product dose used on the smallest species. If … the product may be used on juvenile and adult animals, the juvenile is considered the worst case”. The statement that the limit should be based on the maximum product dose used on the smallest species is surprising since it leaves open the potential for confusion if the maximum dose per unit mass is specified in the package insert (PI) for a larger species. In the event of such confusion, a conservative approach is to use the maximum dosage specified in the PI to determine endotoxin limit. This will result in the most stringent endotoxin limit, even if the limit is not based on the product dose for the smallest species – juvenile or otherwise.
Question 11: What are the endotoxins limits for medical devices?
In addition to the limits given in USP chapter <161> (which are 20 EU/ device and 2.15 EU/device respectively for devices that contact the cardiovascular or lymphatic system and for those that contact cerebrospinal fluid), the response also gives limits of 0.5 EU/mL and 0.06 EU/mL. These limits are linked to an extract volume of 40 mL, which is recommended in the next paragraph. It is not clear why an extract volume of 40 mL is given, even though provision for reduced or increased volumes is made to accommodate smaller or larger medical devices. The response states that the endotoxin limit can be adjusted if the extract volume is changed,
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but it does not mention that USP chapter <161> provides a formula for determining the endotoxin limit from any extract volume.
The response states, “For inhibition/enhancement testing, both the rinse/ extract solution and the device eluate/extract should be tested”. Thus, the guidance recommends that the solution to be used for extracting the device as well as the solution after extracting the device should be tested. The initial test of the solution will serve as a control in the event that the device extract gives a positive test result.
The response to Q11 states that more stringent limits should be applied to devices for which multiple units of the same device from one manufacturer are intended for use in a single procedure. The multiple units should meet the same endotoxins limit as a single device. This implies that the USP limit for a single device (e.g. 20 EU) should be divided by the maximum number of devices likely to be used in the single procedure. The resulting reduced limit would then be applied to each of the devices that are expected to be used together.
Question 12: What is the FDA’s expectation for regular screening of therapeutic drug products?
The response to this question indicates that FDA is encouraging endotoxin tests to be a sensitive as possible. This means testing at the highest product concentration as reasonably possible (i.e. as far from the MVD as possible). It seems clear that intent is to get as much information from the test as possible.
The response suggests testing at a dilution of 1:30 for a product for which the first dilution that does not interfere with the test is 1:20. This could result in interference problems if subsequent batches show slightly greater levels of interference. A more common recommendation in the industry is to test at a dilution of at least a twofold greater than that at which interference was overcome (unless that dilution exceeds the MVD). In the case of the example given, that would be 1:40.
Question 13: Are control standard endotoxins still acceptable for use in running bacterial endotoxins tests?
In the response to this question, the FDA provides a clear statement that use of appropriately calibrated CSE is encouraged.
Omitted Topics
In addition to the comments made on the Q&A document, it is notable that some topics that were addressed in the withdrawn 1987 and 1991 guidance documents are not included in the Q&A.
In the discussion on Question 6, it was noted the Q&A document does not address changing reagent manufacturer (while retaining the test method). This was included in the withdrawn guidelines.
The withdrawn 1987 FDA Guideline included a section on Initial Qualification of the Laboratory in the section on Drugs and Biological Products. It called for an assessment of the variability of the testing laboratory and for qualification of analysts. These are general GMP requirements and are not addressed specifically in the Q&A document. The USP BET chapter specifies verification of the performance of each lot of LAL reagent but it does not address qualification of laboratory and analysts.
Perhaps the most notable omission is the lack of any guidance on archived standard curves or the controls that should be used to verify their validity. There is now no mention of archived standard curves in any regulatory document, guidance or standard. The pharmacopeial BET chapters (USP,
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