REGULATORY UPDATE
been eliminated. It should be noted that USP chapter <161> “Transfusion and Infusion Assemblies and Similar Medical Devices” [2] refers to the BET chapter for testing of medical device extracts. The removal of references to extracts from the BET chapter does not change this or mean that it is not appropriate to test medical device extracts using the method described in the BET.
3. Change from “Standard Regression Curve” to “Standard Curve”
In the DETERMINATION OF MAXIMUM VALID DILUTION (MVD) section, under the sub-heading Concentration of Sample Solution, the word “regression” has been deleted from the reference to the “standard regression curve for the Turbidimetric Technique or Chromogenic Technique”. The deletion of “regression” has no impact on the meaning or intent of the sentence.
4. Correction of Units for the Endotoxin Limits for Radiopharmaceuticals
In footnote number 2, which explains endotoxin limits for different categories of product, in the section on radiopharmaceutical products, the units EU have been added to read “For radiopharmaceutical products not administered intrathecally, the endotoxin limit is calculated as 175 EU/V…. For intrathecally administered radiopharmaceuticals, the endotoxin limit is obtained by the formula 14 EU/V.”
The insertion of “EU” in the formula for calculating endotoxin limits for radiopharmaceutical products means that the resulting limit will have units of “EU/mL”. The change corrects the units, which otherwise work out as just “/mL”.
5. Simplification of the Endotoxin Limit for Products Administered per Square Meter of Body Surface Area
Also in footnote number 2, in the section on formulations (usually anticancer products) administered on a per square meter of body surface, the definition of K in the formula for calculating the endotoxin limit has been changed from “K = 2.5 USP-EU/kg and M is the (maximum dose/m2 dose/m2
/hour x 1.80 m2 ”.
)/70 Kg” to “K = 100 EU/m2
and submissions to regulatory agencies unless desired. There is no risk to public health resulting from leaving in place a slightly more stringent limit than that which is required by the recent change.
6. Requirement to Repeat the Test for Interfering Factors for the Gel- Clot Technique
In section on the GEL-CLOT TECHNIQUE, under the sub-heading Test for Interfering Factors, a requirement has been added to repeat the test for interfering factors when any condition changes that is likely to influence the result of the test.
The requirement brings the section on the GEL-CLOT TECHNIQUE into agreement with the section on PHOTOMETRIC QUANTITATIVE TECHNIQUES, which states under the sub-heading Preparatory Testing “Validation for the test method is required when conditions that are likely to influence the test result change”. (Validation includes verification (1) of the criteria for the standard curve and (2) that the sample solution does not interfere with the test.)
FDA Guidance for Industry “Pyrogen and Endotoxins Testing: Questions and Answers” 2012
In June of 2012, the FDA released the long awaited question and answer (Q&A) guidance document on pyrogen and endotoxin testing [4], almost exactly a year after the withdrawal of the former guidance documents (the 1987 “Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test For Human and Animal Parenteral Drugs, Biological Products and Medical Devices” and the 1991 “Interim Guidance for Human and Veterinary Drug Products and Biologicals: Kinetic LAL Techniques”).
Comments and M is the maximum
If the values and formulae given in the BET chapter prior to the recent change are used to calculate K per square meter basis, a value of 97 EU/ m2 is obtained. The change to the footnote rounds this value to 100 EU/m2
.
This change results in slight increase in product specific endotoxin limits and MVDs, but is still almost half the value that obtained prior to the interim revision announcement that became effective in April of 2011 [3]).
This change has a number of advantages:
1. The value of K is a round number that incorporates the corrections for the surface area of a “typical” 70 kg person.
2. The calculation of the endotoxin limit is greatly simplified, which reduces the opportunity for error.
3. The structure of the formula is now similar to that for radiopharmaceuticals (and to that for medical device extracts given in USP chapter <161>, Transfusion and Infusion Assemblies and Similar Medical Devices [2]).
4. The value of K is now expressed in the same units as the dose of the product, which is analogous to the value of K for drugs administered per kg body weight.
As the endotoxin limit for a product calculated using a value of K of 100 EU/ m2
is slightly less stringent that that calculated using the previous value of K of 2.5 EU/Kg, it should not be necessary to change the limits in procedures
11
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Introduction The title and the Introduction section to the guidance make clear that the scope of the guidance includes the pyrogen test. One of the questions addresses when it is appropriate to use the pyrogen test. However, the Introduction states that the document does not cover the breadth of endotoxin and pyrogen testing. It focuses on specific issues that may be subject to misinterpretation and are not covered in compendial procedures or in currently available guidance documents.
The guidance refers to the USP Chapter <85> BET, the USP Chapter <161>, Transfusion and Infusion Assemblies and Similar Medical Devices [2], and the AAMI/ANSI standard ST72:2002/R2010 (the current version of which is ST72 2011 [5]). It states that these three documents describe the fundamental principles of the gel clot, photometric, and kinetic test methods, and that a thorough understanding of these documents is expected.
Background
The Background section does not mention the Interim Guidance document of 1991. The Interim Guidance was specific to testing of drugs and biological products by turbidimetric and chromogenic methods. It was withdrawn at the same time as the 1987 Guidance.
Question 1: How do I establish a sampling plan for in-process testing and finished product release?
The 1987 Guideline on the Limulus amebocyte Lysate Test, (which was withdrawn in 2011), stated: “Sampling technique selected and the number of units to be tested should be based on the manufacturing procedures
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