New FDA Q&As on Endotoxin Testing

In the recent past, many questions have come up and been discussed in the field of endotoxin and pyrogen testing, both on the European and US side. We reported in many news about topics such as masking (Question and Answers to Endotoxin Masking and Low Endotoxin Recovery (LER)), alternative test methods (  Endotoxin and Pyrogen Testing - Challenges for Biotechnological and Biopharmaceutical Products ), suitability of different test systems (Endotoxins and Pyrogens - Which test to be used?) and more (e.g. FDA publishes Guidance for Setting Endotoxin Limits During Development of Investigational Oncology Drugs and Biological Products) . There have also been many new developments on the regulatory side, i.e. in pharmacopoeias or other guidance documents, especially in Europe (for example: The End for the Rabbit Test ). But also in the US these topics are controversially discussed. The FDA has just published a draft guidance "Questions and Answers on Quality Related Controlled Correspondence" which, among other topics, also contains new questions and answers on the subject of endotoxin. In section 4 Microbiology the following Q&As are included:

Question 1:  How should a bacterial endotoxins test acceptance criterion be determined for the finished drug product?

"The finished drug product bacterial endotoxins test acceptance criterion should be determined based on the maximum dose that can be delivered within one hour as interpreted from the package insert. Special considerations can include:

  • Additional doses that may be administered after the initial dose,
  • Maintenance doses administered after an initial bolus dose,
  • Incremental dose increases, and
  • For anesthetics or other drugs for which repeat doses are administered until a desired clinical outcome is achieved, the maximum number of potential doses at the minimum specified time interval between doses that could be administered in a one-hour period.

The USP General Chapter Bacterial Endotoxins Test recommended maximum endotoxin exposure is NMT 5 EU/kg (interpreted as within 1 hour) for most drugs based on an average patient weight of 70 kg. For drugs administered to pediatric patients, consult the WHO-CDC growth charts for average weight at the youngest patient age for the proposed generic drug.
For drug products administered topically on a body surface area basis, the recommended  maximum endotoxins exposure is 100 EU per square meter.
For drug products administered intrathecally (or epidurally due to risk of inadvertent intrathecal administration), the maximum recommended exposure is 0.2 EU/kg (in 1 hour).
Please note that USP monographs may contain historical bacterial endotoxins test acceptance criteria that may not reflect the maximum dose that can be interpreted from the current drugpackage insert of the RLD. The proposed endotoxin limit for a proposed generic product should be based on dosing in the current RLD package insert. If the calculated limit is higher than the USP monograph limit, we recommend that applicants submit a controlled correspondence to  confirm acceptability with the Agency prior to submission of the ANDA."

Question 2:  Is it acceptable to omit bacterial endotoxin limits in the proposed specification for a topical ophthalmic drug product

"Topical ophthalmic drug products are generally not required to be tested for bacterial endotoxins. Therefore, the finished product release and stability specifications for topical ophthalmic  products are not required to include testing for bacterial endotoxins unless the labeling indicates  that the product is nonpyrogenic. However, if the labeling for a topical ophthalmic product  includes directions for use on an abraded eye and/or use during surgery, a bacterial endotoxin specification for the drug product may be appropriate.

Please note that this answer is specific to this question and does not address other ophthalmic drug products, dosage forms, or combination products that include an ophthalmic drug product  component."

You can find the complete Q&A document, which also covers a whole range of other interesting topics, at: "Questions and Answers on Quality Related Controlled Correspondence, Guidance for Industry"

In this context, please note the ECA Endotoxin and Pyrogen Testing Conference, which will take place live online on 25/26 November as part of PharmaLab 2021.

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