We appreciate the interest from Dr Spaide in our article “Avastin Doesn’t Blind People, People Blind People,” published in the February 2012 issue of the American Journal of Ophthalmology. We also are relieved to hear of Dr Spaide’s reported success with his technique for preparing bevacizumab for intravitreal injection. However, the recent outbreak of fungal meningitis from steroid injections prepared at a compounding pharmacy has brought increased scrutiny of these pharmacies and their compliance with United States Pharmacopeia (USP) chapter 797 (<797>) standards. In this reply, we address the points raised by Dr Spaide.
We acknowledge that USP <797> is interconnected with many other chapters in the USP and the National Formulary. In our article, we even referred to USP chapter 71 when discussing the sample size of our sterility testing procedures. However, it is unreasonable to devote a considerable portion of an article to a discussion of the “interconnectedness of this chapter to the hundreds of other chapters” when there is so much other useful information that must be conveyed with a limited number of words. In our article, we did mention that there have been other compounding practice guidelines aimed at ensuring quality control. Please see references 19, 20, and 21 of our article. As stated therein, compliance with these voluntary standards has been poor. USP <797> was created as an attempt to standardize proper compounding practices.
It is true that state boards have ultimate regulatory jurisdiction over pharmacy compounding. Some states have accepted USP <797> in their pharmacy rules and regulations, whereas others have passed hybrid or modified standards to regulate the practice. However, it is also true that appropriate oversight by states to ensure compliance with these rules and regulations has been called into question, as in the recent outbreak of fungal meningitis.
Our mention of the Mini-Spike Pin and the ISO 5 air quality environment when preparing intravitreal bevacizumab represents only 2 of many issues we discussed in the article. We also mentioned the major sections of USP <797>, the importance of double-checking compounding accuracy, avoiding multiple punctures of the single-use vial, syringe selection, sterility testing for extended storage, the controversy surrounding the use of a filter, keeping detailed accountability logs, and the selection of a compounding pharmacy. We are disappointed that Dr Spaide believes we “tidily summarize the extensive regulatory requirements” by mentioning the Mini-Spike and Class 5 air quality environment. We strongly disagree, and as mentioned in our article, an in-depth review of USP <797> was beyond the scope of the Perspective.
We firmly stand behind the recommendation to avoid the use of syringes with permanent or incorporated needles and do provide some evidence to support this position. There are both published and unpublished reports of needles that clogged when using these syringes for the preparation of bevacizumab for intravitreal injection. According to Joe Cabaleiro, Executive Director of the Pharmacy Compounding Accreditation Board, he is “aware of at least two anecdotal reports from compounding pharmacists about clogging of bevacizumab syringes for unknown reasons” (verbal communication, October 8, 2012). In addition to the clogging issue, we do not advocate this practice because the sterility of the needle is compromised, the needle may become slightly dulled, the needle will lose the silicone lubrication that coats the outside, and the risk of contamination increases when the single-use vial is penetrated multiple times or the metal crimp and rubber stopper are removed to draw up the drug. Moreover, we strongly advocate microbiologic testing of every batch before the syringes are used, and Dr Spaide should confirm that his compounding pharmacy follows this practice. The focus of our article was to establish accepted practices that are designed to ensure widespread public safety. Of course, someone with exquisite technique and working in the proper environment could pull individual doses as needed from the single-use vial, but this is not an acceptable practice. Keep in mind that the absence of reported problems from the compounding pharmacy does not mean that it is a good compounding practice. As we have witnessed over the past few years, practices at some state-regulated compounding pharmacies have demonstrated less than exquisite technique and working environments. When it comes to the compounding of bevacizumab, we must demand the highest standards for our patients and the techniques with the widest margin of safety.
Nowhere in our article did we state that the syringes should have a rubber stopper, but in fact we do use a sterile black rubber cap on the Luer-Slip fitting to seal our 1-mL polypropylene tuberculin syringes. Dr Spaide suggests that the use of a sterile rubber cap to seal the syringes may pose a problem because of “leaching components from stoppers.” His statement is irresponsible, and he provides little evidence of this claim except to cite 2 reports that are 22 and 27 years old regarding the use of unrelated rubber components and drugs. To the best of our knowledge, there have never been any reported problems of leaching components from the sterile rubber caps we use to repackage bevacizumab. Apparently, Dr Spaide is not aware that most injectable medications, including bevacizumab, ranibizumab, and aflibercept, come in vials with rubber stoppers.
Finally, we are very surprised that Dr Spaide believes that we ignored the significant potential for contamination caused by medications transferred from a vial to a syringe in a clinic. We have always recommended that bevacizumab syringes be prepared in a USP <797>-compliant compounding pharmacy. In fact, we actually mention in the closing paragraph that one advantage of bevacizumab is that the drug is “drawn into a syringe under strict aseptic conditions, whereas the syringe of ranibizumab routinely is prepared in the clinic without the benefit of a sterile environment.”