Baxter Shares Perspective on Sevoflurane Safety

Francois Lebel, MD; Andrew Watkins

Regarding sevoflurane formulations contains a number of inaccuracies that prompt me to respond on behalf of Baxter Healthcare Corporation.

The chemical instability of sevoflurane in the presence of strong Lewis acids has played a role in a number of corrective action incidents since the introduction of the product in the early to mid 1990s. Specific lots of Abbott’s Ultane product have been recalled on 2 occasions because of Lewis acid mediated degradation occurring in the bottled drug product.

Both of these incidents were attributed to contamination of the bulk sevoflurane drug product with strong Lewis acids by contact with improperly cleaned or maintained shipping containers, followed by a cascading degradation reaction of sevoflurane in which the glass container in which the product was marketed played a major role. In response to these incidents, Abbott Laboratories took 2 actions: an increase of water content to reduce the rate of reaction of sevoflurane with any strong Lewis acids that might be present, and perhaps more importantly, an elimination of the glass container that served as the source of the Lewis acids that drove the runaway degradation reaction observed in contaminated lots.

Lewis acid mediated degradation has also been implicated in the more recent reports of interaction of sevoflurane with the Penlon Sigma Delta vaporizer.2 In this case, the source of the strong Lewis acids initiating degradation was found not to be the drug product but the vaporizer itself.

The Penlon Sigma Delta sevoflurane vaporizer has been distributed by Abbott Laboratories, and more recently by Baxter, for use by purchasers of the respective companies’ sevoflurane products. Following the identification of the incompatibility between sevoflurane and the Penlon Sigma Delta vaporizer, Baxter has removed all Penlon Sigma Delta vaporizers distributed to its customers from service, and has endeavored to inform all purchasers of Baxter sevoflurane, known to be in possession of Penlon Sigma Delta vaporizers not provided by Baxter, of this incompatibility.*

Dr. Kharasch’s discussion of the Penlon Sigma Delta vaporizer creates the impression that degradation only occurs with low-water sevoflurane.

Laboratory tests on the Penlon Sigma Delta vaporizer with Abbott’s Ultane sevoflurane have been provided to Baxter and to a number of regulatory authorities around the world.3 These results show that all sevoflurane products tested undergo some level of degradation in Penlon Sigma Delta vaporizers, and although Abbott’s Ultane product degrades more slowly under the test conditions, it does degrade. Dr. Kharasch wrote a letter interpreting the results of such tests that was provided to regulatory authorities, in which he concludes that, “There was lesser, but apparent, degradation of Abbott sevoflurane” in Penlon vaporizers. We can only conclude that the role of water in the stability of sevoflurane in a vaporizer, and its fate during the administration of anesthesia, is incompletely understood.

In addition, Dr. Kharasch cites information regarding the identification of “potential Lewis acids (metal oxides)” on commercial vaporizers, and implies that this should be a cause of great worry and “vigilance” for the practitioner of anesthesia. He fails to note that 2 of the vaporizers within which hundreds of square centimeters of “potential Lewis acids” are exposed to the sevoflurane liquid and vapor (the GE/Datex-Ohmeda Tec 7 and the Draeger Vapor 2000) have been shown by Abbott’s own testing to be completely compatible with all sevoflurane formulations, regardless of water content, with no degradation detected under accelerated study conditions. The reference to all metal surfaces in vaporizers as “potential Lewis acids,” regardless of their demonstrated compatibility with sevoflurane of both high and low water content, would seem to be a generalization with limited scientific basis.

It is unfortunate that a widely distributed commercial sevoflurane vaporizer has been found to include materials of construction that are incompatible with sevoflurane, and that this finding was made only after many such units had been put into service around the world. We agree that vigilance, in preventing the exposure of the chemically fragile sevoflurane molecule tmo chemically incompatible materials, is prudent. Proper evaluation of the compatibility of vaporizers with sevoflurane under conditions of actual use and elimination of drug contact with materials capable of initiating the degradation of sevoflurane is, in the end, the only “safe” approach to the use of this popular and effective anesthetic.


* Baxter has been informed by Penion that the Penion Sigma Delta Sevoflurane vaporizer was redesigned in October 2006 and is designed for use with Sevoflurane, meeting the USP and European Pharmacopoeia standards, available in the market at that date. Baxter has not performed tests on the Penion Sigma Delta vaporizers produced after that date.

Francois Lebel, MD
Vice-President, Global Medical and Clinical Affairs Baxter Healthcare, Medication Delivery

 

References

  1. Kharasch ED. Sevoflurane: the challenges of safe formulation. APSF Newsletter 2007;48(4):55.
  2. Penlon Sigma Delta Sevoflurane vaporizer. Available at http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2025389&ssTargetNodeId=967. Accessed November 8, 2007.
  3. Documents on File, Baxter Healthcare Corporation.

Penlon Clarifies Vaporizer Modifications

Thank you for the opportunity to reply to the item written by Francois Lebel.

The Penlon Sigma Delta vaporizer was launched in 2001 and was designed for use with Sevoflurane formulations available at that time.

The recent communications from Dr Kharasch and Dr Lebel require some clarification. The Penlon Sigma Delta vaporizers they discuss were re-designed in October 2006 to eliminate the issues with potential of degradation. The vaporizer is now produced with a plastic (PTFE) coated internal surface and all potential for Lewis acid production has been removed. The vaporizer is now designed specifically for use with all Sevoflurane formulations meeting either USP or European Pharmacopoeia specifications regardless of formulation, wet or dry. I hope this provides clarification.

Andrew Watkins
Director of Development, Quality, and Regulatory Affairs
Penlon Ltd.