The Need for Reform in Compounding Laws
The article below appeared on the Institute for Safe Medicine Practice(ISMP) website. It addresses the Alabama Total Parenteral Nutrition (TPN) bags that were contaminated, infected 19 patients and resulted in 9 patients' deaths. The article addresses the lack of enforcement of laws, regulations and pharmacy board standards relating to compounding. For example, any sterile activity should be undertaken with great care and in compliance with the United States Pharmacopeia (USP) Chapter 797, Pharmaceutical Compounding: Sterile Preparations. The National Association of Boards of Pharmacy (NABP) has incorporated the 797 requirement into its Model State Pharmacy Act and Model Rules. As the article points out the NABP does not have authority to enforce its recommendations. State boards of pharmacy, who could enforce such laws, vary as to their position on 797. Some states have adopted the entire chapter into laws, regulations or board policies and procedures, some have incorporated only portions of 797, and some have not taken any action and do not require compliance with 797. Another point made in the article is that most state boards have insufficient funding to send experienced and trained inspectors to pharmacy operations to ensure compliance with 797. Deaths such as those resulting in Francks, ApotheCure, and the Alabama case, show that change in enforcement of compounding standards needs to occur before anymore deaths occur. The question is how to best implement the reforms needed.
Last week, the Alabama Department of Public Health (ADPH) reported an ongoing investigation of an outbreak of Serratia marcescens bacteremia associated with contaminated total parenteral nutrition (TPN) bags in six Alabama hospitals.(1-4) The outbreak was identified after two of the six hospitals reported an unusual number of cases of Serratia marcescens bacteremia to the ADPH and the Centers for Disease Control and Prevention (CDC). An investigation was immediately started.
A total of 19 patients from six hospitals were adversely affected after receiving the contaminated TPN. The CDC determined that all six hospitals had received TPN produced by a single compounding pharmacy, Meds IV. Nine of the 19 affected patients have died, although the CDC has not confirmed that the deaths were directly caused by the contaminated TPN.(3) Meds IV was notified about the contaminated TPN and is fully cooperating with the investigation.
To date, the investigation has uncovered traces of Serratia marcescens in the compounding room at Meds IV, although genetic testing will be required to determine whether the organisms found in the pharmacy caused the TPN contamination. Health officials also reported that seven newborns received TPN supplements from Meds IV in March, along with 41 adults. While 19 of those 41 adults got sick, none of the babies became ill.(4) Thus, the investigation is focusing on differences between compounding TPN for adults vs. neonates.
At this time, Meds IV has discontinued all production and has recalled all of its compounded preparations.
USP Chapter <797>
Any type of sterile compounding activities must be undertaken with great care and in compliance with the United States Pharmacopeia (USP) Chapter <797>, Pharmaceutical Compounding: Sterile Preparations. It is tragic events like this that compelled USP to first establish <797>, which was initially published in 2004 and revised in June 2008. Chapter <797> describes a network of systems and processes “to prevent patient harm and fatality from microbial contamination (nonsterility), excessive bacterial endotoxins, large content errors in the strength of correct ingredients, and incorrect ingredients in compounded sterile preparations (CSPs).”(5)
Increased use of compounding pharmacies for sterile preparations
In the past, most sterile compounding was completed in-house in hospital pharmacies. However, this trend has shifted over the years,(6-7) particularly after the 2008 revision of <797>, as many pharmacies found it difficult to meet all the requirements of the standard. A recent (1st quarter of 2011) survey conducted by Pharmacy Purchasing & Products showed that 66% of pharmacies outsource at least some portion of their sterile compounding. Reliance on compounding pharmacies has continued to rise due to an unprecedented escalation in shortages of parenteral drugs, including recent shortages of vitamins, electrolytes, and other pharmaceutical components of TPN.
From a safety perspective, it makes sense to outsource the compounding of CSPs. It is difficult and costly for hospitals to comply with all of the <797> standard if they prepare just a few parenteral CSPs each day. As a general rule, compounding pharmacies that prepare large quantities of CSPs may be better equipped to employ, enforce, and monitor ongoing compliance with all of the <797> standard. But should hospitals be wary of using a compounding pharmacy in light of this latest infection outbreak?
While it’s true that contamination of CSPs from a compounding pharmacy can result in large and serious outbreaks, ISMP believes the use of compounding pharmacies should not be summarily dismissed as a result of this tragic outbreak. However, we must state unequivocally that the real issue to be learned from this event is that better oversight and licensing and/or registration requirements for compounding pharmacies are required.
Enforcement of <797>
Compounding pharmacies frequently prepare very complex CSPs, many with high-alert medications intended for parenteral administration. Jay Mirtallo, A.S.P.E.N. president elect, noted in a March 30, 2011 press release on this latest infection outbreak (www.nutritioncare.org/Index.aspx?id=6174) that, “Parenteral nutrition by nature is one of the most complex sterile preparations to prepare, relying on a specific order of mixture as well as method of preparation to assure sterility, compatibility, and stability.” Thus, one might expect the Food and Drug Administration (FDA) to subject compounding pharmacies to the same strict current good manufacturing practices (cGMPs) that are routine for drug manufacturers. Or one might expect all state boards of pharmacy to hold compounding pharmacies accountable for meeting the <797> standard in its entirety. However, there is often little or no required regulatory or licensing/registration oversight of compounding pharmacies to ensure and enforce compliance with <797>.
Chapter <797> is enforceable by the FDA; the agency clearly has the authority to inspect pharmacies and enforce the standard in the interest of public health.(5) However, FDA defers to the individual states to regulate the practice of pharmacy and to perform inspections.5 In the 1970s, the National Coordinating Committee on Large Volume Parenterals (NCCLVP) of USP emerged to ensure high quality CSPs. But with the dissolution of this group in the 1980s, FDA turned to the profession of pharmacy to address problems with sterile preparation. Since the early 1990s, FDA has been aware of multiple problems with compounded preparations that have resulted in recalls, patient injuries, and deaths.(5) However, when we communicated with the FDA recently to discuss this event, no one could clearly articulate how the agency regulates compounding pharmacies.
The National Association of Boards of Pharmacy (NABP) has incorporated the <797> requirement into its Model State Pharmacy Act and Model Rules, noting that, “The board’s Good Compounding Practices Applicable to State Licensed Pharmacies, and the current USP-NF chapters on compounding and sterile pharmaceutical preparations” are to be adhered to by compounding pharmacies and pharmacists.(6) However, the Model Rules or requirements of the Model State Pharmacy Act are only enforced to the extent that they are adopted by individual states, as the NABP does not have authority to enforce its recommendations.
Individual state boards of pharmacy vary in regard to the position taken with respect to <797>. Some states have adopted the chapter in its entirety, but most have chosen to incorporate only portions of <797> into laws, regulations, or board policies and procedures.(5) Some states have taken no action and do not require compliance with <797>. In addition, most state boards have insufficient funding to send experienced and trained surveyors to actually inspect pharmacy operations to ensure compliance with <797>.
While The Joint Commission (TJC) requires organizations to comply with portions of <797> that are similar to its standards, TJC views <797> as a best practice and expects organizations to review best practices for the purpose of improving systems (MM.08.01.01). Thus, surveyors may expect an improvement plan based on <797>, but it is left to the accredited organization as to what they need to improve. TJC expects organizations to comply with <797> in states that require such compliance. However, most surveyors have not been adequately trained regarding <797> and would simply ask to see the latest state inspection results.
Lessons learned: Need for future oversight
As we move forward and learn from the most recent outbreak, we are calling upon all state boards of pharmacy to expect compounding pharmacies to comply with all aspects of <797>, and to survey these pharmacies regularly to enforce compliance. To do this, state pharmacy boards must be provided with additional resources to adequately train and deploy surveyors to assess compliance. Today, many pharmacy boards are ill equipped to take on this responsibility; without additional resources, the assignment of responsibility will not result in improved oversight. The pharmacy boards that choose a limited set of criteria from the <797> standard for enforcement in their states are ill-advised regarding its benefit to public safety; partial compliance will not even partially protect patients from the risk of infection from contaminated CSPs. The <797> standard is not set out as an incremental improvement plan; it’s a bundle that must be implemented in its entirety and on an ongoing basis to be effective. Each of the state boards of pharmacy must demand and expect their licensees to comply with <797>.
We are calling upon FDA to work collaboratively with the state boards of pharmacy to provide them with the necessary support and training to survey compounding pharmacies for compliance with <797>. Further, we believe compounding pharmacies that distribute sizeable quantities (to be defined by FDA) of preparations, and those operating interstate, should be registered with FDA and subject to periodic inspections. We also encourage FDA to move forward with plans to publish guidances on Good Pharmacy Compounding Practices for Sterile Drug Products, and Outsourcer Pharmacy Operations Compliance Policy Guide (www.ismp.org/sc?k=ucm079647), to clearly articulate requirements for registration with FDA, periodic inspections, support available to the state boards of pharmacy, and expectations regarding the state boards’ role in regulating compounding pharmacies.
We are calling upon TJC to consistently survey compliance with applicable parts of the <797> standard as it relates to the type of CSPs being prepared in accredited facilities in all states.
We are calling upon all pharmacies and pharmacists/technicians who compound sterile preparations, regardless of where they work, to know and comply with <797> to the fullest extent possible. Pharmacy staff should use commercially available ready-to-use products when available, or start with sterile products whenever possible if preparing CSPs. This applies to the smallest hospitals up to the largest compounding pharmacies. We also recommend establishing an internal quality surveillance and review team to regularly monitor compounded preparations, the environment, compounding equipment, and personnel for compliance with key aspects of <797>, much like an internal peer-review process. An April 2011 supplement to Pharmacy Purchasing & Products on the state of pharmacy compounding is an excellent resource to help guide the surveillance and improvement process.(8) Any problems uncovered during surveillance require immediate stoppage of compounding, investigation, corrective action, and revalidation before resumption of activities. All pharmacy staff have a moral and legal obligation to compound preparations using the least risky processes while adhering to the highest standards possible.
We don’t have all the details about this recent outbreak, but a crucially important lesson we can take away from this tragedy is that we all need to make improvements based on the outcome of this investigation. Unfortunately, there are too many in healthcare who feel that, if it hasn’t happened to them, the adverse experiences of others do not apply. If investigation into this event uncovers some aspect (e.g., frequency of testing staff samples and environmental samples) of compounding that was overlooked in either the <797> standard or in staff practices, then let’s learn from it, incorporate necessary changes, and provide leadership and oversight to assure our patients are kept safe.
ISMP thanks Eric S. Kastango, MBA, RPh, FASHP, CEO of ClinicalIQ, for his contribution to this article.
1) US Food and Drug Administration (FDA). Meds IV pharmacy, IV compounded products recall: outbreak of Serratia marcescens bacteremia in Alabama hospitals. March 30, 2011. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249099.htm
2) US Food and Drug Administration (FDA). CDC and ADPH investigate outbreak at Alabama hospitals; products recalled. March 29, 2011. www.fda.gov/Safety/Recalls/ucm249068.htm
3) Watkins T. Contaminated IV solution suspected in 9 patient deaths in Alabama. CNN Health. March 29, 2011. www.cnn.com/2011/HEALTH/03/29/alabama.hospitals.deaths/index.html?hpt=T2
4) Wolfson H. Investigators piecing together tainted IV puzzle after deaths in Alabama hospitals. The Birmingham News. April 3, 2011. http://blog.al.com/spotnews/2011/04/investigators_piecing_together.html
5) American Society of Health-System Pharmacists (ASHP). The ASHP discussion guide on USP Chapter <797> for compounding sterile preparations. www.ashp.org/s_ashp/docs/files/DiscGuide797-2008.pdf
6) National Association of Boards of Pharmacy. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. Mount Prospect, IL. August 2007.
7) Seres D, Sacks GS, Pederssen CA, Johnson D, et al. Parenteral nutrition safe practices: results of the 2003 American Society for Parenteral and Enteral Nutrition Survey. J Parenteral and Enteral Nutrition. 2006;30(3):259-65.
8) Pharmacy Purchasing & Products (PP&P). 2011 state of pharmacy compounding; PP&P’s 4th annual national survey. April 2011.