Purpose
To review the appropriate preparation of bevacizumab for intravitreal injection by compounding pharmacies with specific recommendations designed to prevent microbial contamination.
Design
Perspective.
Methods
A review and discussion of compounding issues with supporting literature, clinical experience, illustrations, and expert opinion.
Results
Closer examination of the events surrounding the recent clusters of infectious endophthalmitis cases occurring after the intravitreal injection of bevacizumab suggest that the vision loss is not the result of the drug or the injection technique, but rather of the compounding procedures used to prepare the syringes containing the bevacizumab. Noncompliance with recognized standards and poor aseptic technique are the most likely causes of these outbreaks. The key to preventing these catastrophic occurrences depends on the implementation of and strict adherence to United States Pharmacopoeia Chapter 797 requirements.
Conclusions
Recommendations arising from a root cause analysis of infectious endophthalmitis outbreaks should focus on the procedures used by pharmacies to compound bevacizumab. Microbial contamination of bevacizumab-containing syringes prepared from the same vial of drug can be avoided by using a single vial of bevacizumab for each eye or by following strict adherence to United States Pharmacopoeia Chapter 797 requirements when compounding a single vial of bevacizumab into multiple syringes.
After 6 years of intraocular bevacizumab (Avastin; Genentech/Roche, South San Francisco, California, USA) use in the United States, there have been several recent outbreaks of infectious and noninfectious endophthalmitis. Outbreaks have occurred in Nashville, both at a Veteran Affairs (VA) hospital and in the community, in Minneapolis, in Miami, and in Los Angeles at another VA hospital. In response to these outbreaks, the United States Food and Drug Administration (FDA) recently alerted healthcare professionals about the infection risk from repackaged bevacizumab prepared without using the proper aseptic technique. The use of intraocular bevacizumab also was prohibited temporarily within the entire VA healthcare system because of a concern surrounding compounded bevacizumab. After an investigation, the VA healthcare system is now permitting the use of intravitreal bevacizumab with restrictions: a single vial can be used only to inject 1 eye, just as a single vial of ranibizumab (Lucentis; Genentech/Roche) is used to inject 1 eye, thus avoiding the need for pharmacies to fractionate bevacizumab into multiple syringes.
By using a 100-mg vial of bevacizumab at a cost of $387.59 per eye, the VA healthcare system was able to eliminate the risk of contamination when repackaging bevacizumab and still was able save $994.62 when compared with the cost of $1382.21 for a single-use ranibizumab vial. It is this cost savings from the use of bevacizumab, along with the perception that bevacizumab and ranibizumab are similar with respect to safety and efficacy, that fuels the global off-label use of bevacizumab, although ranibizumab is the approved drug for the same indications. Among Medicare fee-for-service recipients, the cost savings is even greater, because Medicare allows a total reimbursement of approximately $50 for a single dose of bevacizumab compared with a reimbursement of approximately $2000 for a single dose of ranibizumab. The widespread use of off-label bevacizumab led to the bevacizumab-versus-ranibizumab trial known as the Comparison of Age-Related Macular Degeneration Treatments Trials, which confirmed the previously perceived similarities between ranibizumab and bevacizumab and reported a significant cost savings of $22 805 annually from the monthly use of bevacizumab.
Outside the United States, clustered outbreaks of inflammation and endophthalmitis have occurred as well, but they have received little media attention in the United States. In 2007 and 2008, an outbreak of inflammation and sterile endophthalmitis associated with a particular lot number of bevacizumab occurred in at least 105 Canadian patients. This outbreak was thought to be related to contaminants, most likely excess silicone oil residue and particulates, in the commercially available bevacizumab vials. A recent FDA report shows that particulate contaminants in commercially available bevacizumab continues to be a concern. In Japan, sterile endophthalmitis outbreaks were reported at 2 different institutions after patients were injected with bevacizumab. The syringes containing the bevacizumab were prepared by their respective institutional pharmacies, but it is unclear whether the 2 vials of drug were from the same lot. In Germany, a small outbreak of infectious endophthalmitis occurred in 2008. Five patients experienced significant inflammation and vision loss after being injected by a physician who fractionated a vial of bevacizumab in his office, rather than having it compounded by a pharmacy. In 2009, an outbreak occurred in Portugal, where a hospital pharmacy mistakenly aliquoted Velcade (bortezomib; Millennium Pharmaceuticals/Takeda, Cambridge, Massachusetts, USA) instead of bevacizumab into syringes. Six patients were injected, resulting in severe vision loss (Manuel Monteiro-Grillo, written communication, October 10, 2011). In Shanghai, China, a much larger outbreak of sterile endophthalmitis occurred in September 2010. Counterfeit bevacizumab had infiltrated the supply chain, and its injection into the eyes of at least 80 patients resulted in sterile endophthalmitis. In 2010, 2 cases of Serratia marcescens endophthalmitis after intravitreal bevacizumab were attributed to compounded bevacizumab prepared at a single university pharmacy.
These outbreaks of endophthalmitis can be divided into cases of microbial contamination and cases of sterile inflammation. Although there are several possible explanations for sterile inflammation, such as contaminants introduced at the time of manufacturing, improper storage and distribution of the bevacizumab, compounding errors leading to the injection of the wrong drug, and the introduction of counterfeit drug into the distribution network, the presence of microbiologic contaminants in the syringe can be explained only by improper procedures when compounding bevacizumab. The purpose of this perspective is to describe the appropriate method for fractionating bevacizumab into syringes for intravitreal injection, with specific recommendations to prevent the devastating complications arising from microbial contamination.
Compounding and Ophthalmology
Compounding drugs for physicians serves a vital function in medicine. Pharmacists routinely are asked to formulate sterile preparations, especially in ophthalmology, when suitable alternatives simply do not exist from pharmaceutical manufacturers because of incompatibilities of drug strength or composition, route of administration, or the need to eliminate potential allergens. However, there are potential serious pitfalls. In 2001, a well-publicized incident in California involved Serratia contamination of compounded betamethasone, resulting in the death of 3 patients who received epidural injections. Approximately 1 year later, fungal meningitis developed in 4 North Carolina residents after they received epidural injections of contaminated methylprednisolone that was prepared by a South Carolina compounding pharmacy. One of those patients died shortly after receiving the injection from a pain management clinic.
So, how do these events relate to ophthalmology? Because ophthalmologists depend on compounding pharmacies to prepare many medications that are not commercially available, changes that significantly impact compounding will affect ophthalmology. These and other incidents in which patients were harmed as a result of contaminated or improperly prepared compounded medications prompted the United States Pharmacopeia (USP) to develop meaningful, recognized, and enforceable quality assurance standards for all compounding pharmacies.
United States Pharmacopeia Standards
Before 2004, pharmacies had a long history of well-intended practice standards aimed at improving quality control when compounding sterile preparations. Unfortunately, compliance with these voluntary standards was poor. Consisting mostly of best practice recommendations, they were not enforceable by federal regulatory agencies such as the FDA. Limited resources and a variable commitment among states to regulate compounding also contributed to lax adherence with these advisory guidelines.
The FDA’s authority over compounding activities has been a topic of considerable debate in our judicial system over the years. Created by Congress in 1930, the FDA was established, in part, to protect public health by regulating manufactured pharmaceutical products. The agency was never created to oversee pharmacies or directly to enforce compliance with compounding procedures. Although federal legislation was passed in the 1990s to grant the FDA power to identify difficult-to-compound drug products and those for which compounding posed a potential threat to efficacy or patient safety, the Supreme Court in 2001 ruled this unconstitutional. The resulting dissolution of the FDA’s Pharmacy Compounding Advisory Committee contributed to breaches in the enforcement of quality standards for compounding pharmacies. As a result, the FDA focuses most of its efforts on entities that engage in large-scale manufacturing under the guise of pharmacy compounding. Since 1990, the FDA, along with the Centers for Disease Control and Prevention, has investigated more than 55 incidents of quality problems associated with compounded preparations, including failed sterility and potency testing, many of which have resulted in recalls, patient injury, and death.
The first official chapter dedicated to compounding was introduced in the 2004 issue of the United States Pharmacopeia National Formulary. The chapter is titled “Pharmaceutical Compounding—Sterile Preparations” and commonly is referred to as USP chapter 797 or just simply USP <797>. It is important to note that the numbering of this chapter (i.e., 797) was not chosen arbitrarily, and it was not by accident that the assigned value is less than 1000. The Federal Food, Drugs and Cosmetics Act of 1938 recognized USP National Formulary chapters that are numbered between 1 and 999 as official drugs standards, enforceable by the FDA. By assigning the number 797 to this chapter, the FDA intended to have the practice of compounding fall under its jurisdiction. The primary goal of USP <797> is to protect patients. The bulk of the chapter is dedicated to preventing contamination and to ensuring that finished preparations are sterile. However, the chapter also contains language and requirements for verification of compounding accuracy.
The first version of USP <797> provided a foundation for compounding drugs and raised the level of sterile drug compounding taking place in a wide variety of health care settings throughout the United States and the world. However, problems and criticisms arose. Some experts believed that the 2004 version of the chapter was based on very little scientific evidence. One of the most common complaints about the chapter was that it placed too much emphasis on environmental quality controls and not enough on personnel training and evaluation of aseptic technique. This argument was supported by a study showing the most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in which the drugs were compounded.
Publication of the second version of USP <797> was expected in 2007, but the expert committee commissioned to revise this dynamic document was inundated with comments from both the pharmaceutical industry and pharmacists. After careful consideration of all comments, the revised chapter was published finally in 2008. Environmental quality and control remains one of the most prominent sections of the chapter, but the current 2008 version focuses more on personnel training and technique verification.
United States Pharmacopeia Standards
Before 2004, pharmacies had a long history of well-intended practice standards aimed at improving quality control when compounding sterile preparations. Unfortunately, compliance with these voluntary standards was poor. Consisting mostly of best practice recommendations, they were not enforceable by federal regulatory agencies such as the FDA. Limited resources and a variable commitment among states to regulate compounding also contributed to lax adherence with these advisory guidelines.
The FDA’s authority over compounding activities has been a topic of considerable debate in our judicial system over the years. Created by Congress in 1930, the FDA was established, in part, to protect public health by regulating manufactured pharmaceutical products. The agency was never created to oversee pharmacies or directly to enforce compliance with compounding procedures. Although federal legislation was passed in the 1990s to grant the FDA power to identify difficult-to-compound drug products and those for which compounding posed a potential threat to efficacy or patient safety, the Supreme Court in 2001 ruled this unconstitutional. The resulting dissolution of the FDA’s Pharmacy Compounding Advisory Committee contributed to breaches in the enforcement of quality standards for compounding pharmacies. As a result, the FDA focuses most of its efforts on entities that engage in large-scale manufacturing under the guise of pharmacy compounding. Since 1990, the FDA, along with the Centers for Disease Control and Prevention, has investigated more than 55 incidents of quality problems associated with compounded preparations, including failed sterility and potency testing, many of which have resulted in recalls, patient injury, and death.
The first official chapter dedicated to compounding was introduced in the 2004 issue of the United States Pharmacopeia National Formulary. The chapter is titled “Pharmaceutical Compounding—Sterile Preparations” and commonly is referred to as USP chapter 797 or just simply USP <797>. It is important to note that the numbering of this chapter (i.e., 797) was not chosen arbitrarily, and it was not by accident that the assigned value is less than 1000. The Federal Food, Drugs and Cosmetics Act of 1938 recognized USP National Formulary chapters that are numbered between 1 and 999 as official drugs standards, enforceable by the FDA. By assigning the number 797 to this chapter, the FDA intended to have the practice of compounding fall under its jurisdiction. The primary goal of USP <797> is to protect patients. The bulk of the chapter is dedicated to preventing contamination and to ensuring that finished preparations are sterile. However, the chapter also contains language and requirements for verification of compounding accuracy.
The first version of USP <797> provided a foundation for compounding drugs and raised the level of sterile drug compounding taking place in a wide variety of health care settings throughout the United States and the world. However, problems and criticisms arose. Some experts believed that the 2004 version of the chapter was based on very little scientific evidence. One of the most common complaints about the chapter was that it placed too much emphasis on environmental quality controls and not enough on personnel training and evaluation of aseptic technique. This argument was supported by a study showing the most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in which the drugs were compounded.
Publication of the second version of USP <797> was expected in 2007, but the expert committee commissioned to revise this dynamic document was inundated with comments from both the pharmaceutical industry and pharmacists. After careful consideration of all comments, the revised chapter was published finally in 2008. Environmental quality and control remains one of the most prominent sections of the chapter, but the current 2008 version focuses more on personnel training and technique verification.
United States Pharmacopeia Chapter 797: Intravitreal Bevacizumab-Specific Recommendations
An in-depth review of USP <797> is beyond the scope of this paper. Table 1 provides a breakdown of the major sections in the chapter. In addition to the many compounding requirements detailed in the 61 pages of USP <797>, there are recommendations that have specific relevance to bevacizumab. Bevacizumab comes in a sterile solution 25 mg/mL (i.e., 1.25 mg/0.05 mL), so it does not need to be diluted, reconstituted, or altered in any way. The solution just needs to be transferred aseptically into sterile syringes before administration. What makes intravitreal bevacizumab so affordable is that the entire contents of a single-use vial can be fractionated into multiple syringes for extended storage and subsequent injection. During that process, there is always a risk of contaminating the drug, and there is also a risk that the wrong drug can be drawn into the syringe. The key to minimizing these risks is to have safeguards in place to prevent or mitigate harm to patients.
