Dr. Robert Mello Reports on Draft of FDA Endotoxin Q&A at PMF Conference

November 7th, 2011

Dr. Robert Mello (FDA/CDER) presented the current draft of FDA’s effort to replace the 1987 Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-product Endotoxin Test for Human Parenteral Drugs, Biological Products, and Medical Devices withdrawn July 12, 2011.   This presentation was made at the PMF 2011 Bacterial Endotoxin Summit being held in New Brunswick, NJ.

This Q&A document will be published in this Q&A format to speed its release over that required for a full-fledged guidance document (as described by Dr. Mello a Level I document takes longer to be released through the regulatory system).  Participants in this effort at FDA include CDER (OPS/NDMS, OPS/OGD andOC/DMPQ), CBER/OVRR/DPQ, CVM, CDRH and ORA (NE Regional Lab and PHIL-DO).  This is, therefore, a document with wide consensus throughout the agency.    The Q&A is a level II document – clarification rather than any new policy, and although this is a “final form” which in due time (when finalized) will be published in the Federal Register, the agency will maintain an open docket for comments.

From the draft introduction:

“This guidance provides recommendations for biologic, drug, and device firms on FDA’s current thinking concerning the testing recommendations and acceptance criteria in…”
  • USP<85>  Bacterial Endotoxins Test
  • USP<161> Transfusion and Infusion Assemblies and Similar Medical Devices
  • AAMI ST72:2002 Bacterial Endotoxins—Test Methodologies, Routine Monitoring, and Alternatives to Batch Testing
“These three documents describe the fundamental principles of the gel clot, photometric, and kinetic test methods and recommend that appropriate components and finished products be tested for the presence of pyrogens and endotoxins.”
Organized in a series of questions, the topics addressed in this document include (with a brief -and highly unoffical- summary of answer as presented):
  1. How do I establish a sampling plan for in-process testing and finished product release?
    Start with maximal coverage in this dynamic plan, adjust downward with experience (notify FDA of changes)
  2. When is retesting appropriate?
    It depends – all testing records must be retained and reported but review USP <85> for some guidance.  Further:     “All testing procedures, including those for retesting within the above limits should be specified in advance in written standard operating procedures approved by the firm’s quality control unit.”
  3. Is sample storage and handling important?
    Yes – firms should have data to support written practice
  4. Can finished product samples be pooled into a composite sample prior to analysis?
    Yes, but there are some important restrictions based on manufacturing and product characteristics.    If done for small volume parenterals it is important to adjust MVD to reflect pooling dilution.
  5. What is the best process for transitioning from one bacterial endotoxins test (BET) method to another?
    This is a bit involved in the guidance, but generally follows USP <1225> and needs FDA involvment either through a Prior Approval Supplement (existing product) or Prior Approval Supplement-Comparability Protocol (CP) (approval of a general method for transitioning).  The changes in individual products are presented to FDA then as a CBE (change being effected).
  6. May a firm use alternative assays to those in the USP for a compendial article?
    Yes, but it must be validated (USP <1225>) and in the event of a conflict the USP method serves as the referee test.
  7. What happened to the endotoxins limit table in Appendix E of the 1987 LAL Guidance?
    It is out-of-date.   “The appropriate way to establish the endotoxins limit is to use the calculation methods provided in the USP or AAMI standards.”
  8. How can endotoxins limits support Quality by Design concepts?
    This section provides some very useful information on the establishment of raw material and in-process specifications.  Trending is encouraged.
  9. When is the USP Chapter <151> Pyrogenicity Test (the rabbit pyrogen test) appropriate?
    Generally, when required by monograph, although some consideration should be given to the potential for contamination of the product by non-endotoxin pyrogenic material.
  10. How would an appropriate endotoxins limit be determined for a product that targets multiple species?
    “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…”
  11. What are the endotoxins limits for medical devices?
    These are basically described in USP Chapter <161> Transfusion and Infusion Assemblies and Similar Medical Devices and ISO 11979-8, Ophthalmic Implants, Intraocular Lenses, Supplemental Information Sheet, although devices associated with the eyes are a special case and need to be considered as such.  It is advised to consult the medical division for additional information on established these limits.
  12. What is the FDA’s expectation for regular screening of therapeutic drug products?
    It should be done at the most concentrated form that does not have interference in the test from the product formulation.
  13. Are control standard endotoxins (CSEs) still acceptable for use in running BETs?
    Yes – so long as they “are suitably calibrated to the international reference endotoxins standard.”

In summary then, Dr. Mello provided a preview of the soon-to-be-released Q&A on bacterial endotoxin testing by FDA.  This presentation was given to the 2011 PMF Bacterial Summit, moderated by Karen McCullough and presented by PMF, a not-for-profit scientific and educational associate.   Other speakers at this conference include such notables in the bacterial endotoxin field as

  • Ron Berzofsky, Ph.D. Wako Chemicals USA
  • Alan Baines, Lonza
  • Mick Dawson, Ph.D., Associates of Cape Cod
  • John Dubczak, Charles River Laboratories
  • Dennis Guilfoyle, Ph.D., FDA ORA
  • Amy Karren, W.L. Gore and Associates
  • Karen McCullough, MMI Consulting
The PMF presents directed conferences and workshops to the microbiology community on topics of interest.  These conferences present the most recent information from a regulatory and scientific perspective from international experts in the industry.
This summary is provided for information only and should not be used as regulatory guidance.  The PMF, Microbiology Network, or any affiliated institution or individual is not responsible for decisions and actions taken by others after reading this posting.  This summary is prepared by the author and should not be assumed to be the work of any employee or associate of FDA.
Scott Sutton, Ph.D.

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