In response to the national outbreak of fungal meningitis, all eyes have been focused on compounding pharmacies and ways to better monitor their compliance with USP Chapter <797> to prevent contamination of compounded sterile preparations (CSPs). Or, in the case of large-scale compounding operations that are licensed as pharmacies and registered as a manufacturer with the FDA, monitoring compliance with current good manufacturing practices (c-GMPs) would be appropriate. Indeed, a crucial lesson to be learned from this tragic event is one we covered in our last newsletter when we called for enhanced regulatory oversight and inspection of compounding pharmacies. However, we don’t want to lose sight of the fact that the outbreak should also serve as a wake-up call to all healthcare providers who compound medications in any setting to examine their own sterile compounding procedures and confirm that all dispensing activities are within the scope of their license. We also hope the outbreak will be viewed as a watershed event that drives much needed improvement in sterile compounding education in academic settings, training or certification programs, and continuous on-the-job training and monitoring for pharmacists and pharmacy technicians. Additionally, we are asking healthcare providers that use CSPs to seriously consider whether they have an ethical and legal obligation to inform end users that many preparations are essentially not approved by FDA and thus have inherent risks, especially if these medications are prepared from non-sterile ingredients. Further discussion on these topics follows, along with a short survey to share your viewpoints on these important issues.
Internal Sterile Compounding Practices
Pharmacists and technicians who carry out sterile compounding in any setting, including hospitals, should acknowledge that similar types of environmental and procedural breaches that led to the national outbreak of meningitis could happen in their pharmacies. In fact, a 2011 study showed an overall contamination rate from fingertip testing of 18.2%, which resulted in a 5.1% contamination rate of the compounded items.(1) Not surprisingly, a 2012 national survey suggests that progress in compliance with USP Chapter <797> has been very slow, even nonexistent for some aspects of the standard, since its inception in 2008.(2) According to the study authors, the outstanding compliance issues appear to be related to convincing the pharmacy and/or leadership that consistent and dependable employee work practices are the single most important factor in ensuring safe sterile compounding. Too many facilities are waiting needlessly for physical upgrades or a new clean room before making fundamental changes in staff work practices and workflow.
Additionally, staff can develop a false sense of security when they are in full compounding garb, and forget that their subsequent movements and contact with the compounding materials can impact the sterility of the end products.(3) Further, healthcare providers may not recognize that some healthcare-associated infections (HAIs) can be a result of contaminated CSPs. They may have a robust surveillance system to detect HAIs, but they infrequently investigate the possibility of a contaminated CSP as a potential source of infection. Hopefully, the recent meningitis outbreak will raise awareness of the risks associated with CSPs and correct lenient attitudes toward internal compliance with, and monitoring of, proper aseptic practices as defined by USP Chapter <797>. It should also compel a frank assessment of compliance to these standards in all areas where sterile compounding occurs. Tools are readily available to assist with assessment and training on the American Society of Health-System Pharmacists website (www.ashp.org) and the CriticalPoint website (www.criticalpoint.info/home). If external resources are desired for assistance, ISMP has also partnered with Clinical IQ, LLC, to conduct onsite assessments and support training for USP Chapter <797> compliance.
Sterile Compounding Training
Many pharmacy schools and educational programs for pharmacists and technicians lack appropriate “hands-on” training in aseptic technique and sterile compounding. A study regarding the extent of didactic and laboratory instruction on sterile compounding in US pharmacy schools found that the content varied widely, and only 13% of pharmacy school deans felt that their students had been adequately trained in sterile compounding prior to graduation.(4) If not in pharmacy schools, where do pharmacists first learn about sterile compounding? Given this large gap in education, many pharmacists may not even recognize that they lack such skills and may not be qualified to properly teach sterile compounding to technicians, assess basic competencies, and monitor compliance with proper aseptic techniques.(3)
Last year, Larry Trissel, 2011 recipient of the ISMP Lifetime Achievement Award, brought up this concern during his acceptance speech. He emphasized that, in the rush to revolutionize pharmacy and move it into a more clinical realm, traditional pharmacy elements of value and need have been abandoned. For one, he said, “New pharmacy graduates have been shortchanged regarding needed traditional skills in pharmaceutical mathematics, pharmaceutical compounding and preparation, and the basics of pharmaceutical chemistry and clinical pharmaceutics. From repeated episodes of contamination of supposedly sterile preparations…patients have repeatedly been injured and killed because of the inadequacy of this traditional drug knowledge in practice.” Trissel also noted that pharmacy students used to be frequent sources of new clinical pharmaceutics research under the guidance of academic mentors; but today, few schools and their students conduct laboratory research.
It is our hope that the meningitis outbreak will serve as an impetus for the Accreditation Council for Pharmacy Education (ACPE), the American Association of Colleges of Pharmacy (AACP), and others to reexamine how we train pharmacists and pharmacy technicians to carry out sterile compounding, particularly given the current trend to expand the role of pharmacy technicians in both sterile compounding and compliance monitoring.
Disclosure and Informed Consent
Compounding sterile preparations may represent an unnecessary risk if FDA-approved products are already available from a drug manufacturer or if the requested dosage or concentration can be standardized to allow use of commercial products. However, there are times when individualized CSPs are needed, particularly during critical drug shortages or for special populations to achieve desired therapeutic results. Still, increased risk enters the picture when a compounding pharmacy acts as a manufacturer using non-sterile drug powder, when the contents or formulation do not match FDA-approved counterparts, or when the preparation may have been produced absent c-GMPs used by manufacturers.(5) Thus, despite the benefits, CSPs may also carry potential risks given that their exact clinical properties have not undergone rigorous testing and FDA approval, nor has the compounding process undergone intensive state or federal inspection. Considering the heightened risk of potentially life-threatening errors and contamination during compounding, you may have conditions that warrant disclosure to those prescribing and administering the CSPs and to patients who receive the compounded medications.
In the wake of the meningitis outbreak, physicians have, in fact, reported questions from patients who are worried about the safety of their medications, especially injectables.(6) Do healthcare providers have an ethical and legal responsibility to disclose to patients the source of high-risk compounded preparations, particularly if they are purchased from an outsourced vendor that is not FDA-registered? If so, who would disclose the information, and would written consent be necessary before administration? While some physicians order compounded preparations directly from external compounding pharmacies, others simply prescribe the compounded medication and leave it up to the pharmacy or office staff to secure it from a reputable source. Thus, they may not know that a CSP has been compounded from non-sterile ingredients or by an external pharmacy. Do pharmacists purchasing and dispensing these CSPs have an ethical and legal obligation to disclose the CSPs’ source(s) to prescribers, particularly when using an external compounding pharmacy?
Recent discussions with a medical ethicist and an attorney who is representing victims of the meningitis outbreak provided some insight into these questions. According to the ethicist, disclosure is required when providing care beyond what one would typically consider “ordinary care” and/or when conditions are such that the provider has reason to believe there could be an adverse outcome. For example, a physician who prescribes a CSP that has been compounded internally and for which he or she has no reason to doubt its integrity, might not need to disclose it (although a risk-benefit discussion may be necessary to discuss the adverse effects of the active ingredients, such as chemotherapy). However, given the recent meningitis outbreak and prior events with preparations from external compounding pharmacies, it may be prudent to advise patients regarding the source of externally compounded preparations, to disclose that these are not FDA-approved, and to discuss the benefits and risks, including possible adverse effects. The ethicist also points out what seems obvious—all patients who have received a medication or preparation that has subsequently been identified as problematic must be contacted and advised of the risk.
According to the attorney handling the meningitis cases, each prescriber and facility where the contaminated injections occurred is equally culpable along with the compounding source if patients experience a related adverse event. Thus, the New England Compounding Center, the healthcare facilities where the patients received the injections, and the prescribers who injected the drugs are all defendants in the meningitis cases (www.ismp.org/sc?id=125). The attorney believes that informed consent was required in these cases because the compounding pharmacy had a “checkered past” that could have been identified by the defendants had they used due diligence to investigate the source of the preparations. Thus, disclosure is dependent on the information obtained during a due diligence investigation of the compounding source prior to administering the drug. The results of such an investigation and the issue of disclosure need to be brought to the medical staff (via a pharmacy & therapeutics committee) for a decision regarding whether to use the product in the hospital and whether disclosure is required. This also protects the pharmacy from being required to make a unilateral decision.
Your Viewpoint Requested
We are very interested in learning your viewpoints on these difficult issues, particularly monitoring internal compliance with USP <797>, training and competency verification of USP <797>, and disclosing the source of unapproved CSPs and their inherent risks. Please take a few minutes to complete the short survey on page 4 and submit your responses by December 14 to: www.surveymonkey.com/s/ISMP-CSPs. We will provide the aggregate results in a future issue.
1) Frandzel S. Hand and glove hygiene keys to safe compounding. Pharmacy Practice News. March 2012. Accessed on Oct. 29 at: www.ismp.org/sc?id=123.
2) Douglass K, Kastango ES, Cantor P. The 2012 USP <797> compliance survey: measuring progress. Pharmacy Purchasing & Products. 2012;9(10):4. Accessed on Oct. 29 at: www.ismp.org/sc?id=123.
3) Simmons H. The importance of proper aseptic technique. Pharmacy Purchasing & Products. 2007;4(4):2,4. Accessed on Oct. 29 at: www.ismp.org/sc?id=124.
4) Hellums M, Alverson SP, Monk-Tutor MR. Instruction on compounded sterile preparations at US schools of pharmacy. Am J Health Syst Pharm. 2007;64(21):2,267-74.
5) Lam C. Pharmacy compounding-regulatory issues. Perkins D, Richmond F, editors. Accessed on Oct. 29 at: www.ismp.org/sc?id=120.
6) O’Reilly KB. Meningitis outbreak tests physician trust in compounding pharmacies. American Medical News (amednews.com). October 29, 2012. Accessed on Oct. 29 at: www.ismp.org/sc?id=121.