Beyond Use Dating for TPN
Currently, TPN is made with a 9 day shelf life and thus delivered once a week to the patient. Such a Schedule impacts patients lives, their ability to travel, the way they prepare for natural disasters, and more. The United States Pharmacopeia or USP is the Organization in the US that sets the compounding standards for drugs; such as TPN. In 2012, USP made the decision to change the standards from what was previously a 17 day shelf life to 9 days due to an isolated compounding contamination incidence. The change was made without regard to data or a comprehensive study or more importantly patients were not consulted. The thought was patients don’t think this issue is important. That’s absolutely not true!!
In the month of November, we as patients, clinicians, and family members, can speak up, and can tell USP the impact this shortened shelf life, and thus delivery window has on our lives! We can tell USP this issue matters!!
Please go to tpnbeyondusedating.com, read the petition, and sign the petition asking USP to consider changing TPN Dating from 9 to 17 days!
My Letter of Support
To Whom It May Concern:
I am writing to pledge my support for the 503A Pharmacy Practicing Nutrition Support Clinicians (PNSP) Group petition to the USP 797 Committee. This petition asks the committee to consider extending the beyond use dating (BUD) for home parenteral nutrition form it’s current 9 day BUD to 17 days. As a clinician in the area of nutrition support, I support this petition for the following reasons.
Parenteral nutrition (PN) is commonly used in hospitals to provide supplemental or total nutrition support to patients who are unable to maintain nutritional status via the oral or enteral route.(Directors & the Clinical Guidelines Task, 2002; Mirtallo et al., 2004) Central venous access techniques were refined in the late 1960’s and long-term PN administration became a reality in the home setting.(Brandt et al., 2016) Although no registry data is required, it has been estimated that 33,000 individuals receive home parenteral nutrition (HPN) each year in the United States.(Winkler et al., 2016) Of these individuals, most (~80%) receive HPN for a short duration (less than 6 months). For those that require HPN for long-term or life-time nutrition support, HPN offers patients independence to live a more normal life outside the hospital. However, HPN is a high risk and complex therapy that requires expertise in managing and monitoring response to therapy to avoid both immediate and long-term health complications.(de Burgoa, Seidner, Hamilton, Stafford, & Steiger, 2006; Gillanders et al.)
In addition to the complexity of HPN, the physical obstacles of compounding, delivering, and storing HPN at home have a unique set of challenges that are posed upon pharmacies that specialize in providing HPN for their consumers.
It is essential that PN solutions be free of microbial contamination. The United States Pharmacopeia (USP) 797 recommends for a medium risk level, an expiration dating of < 30 hours for PN stored in a controlled room temperature and < 9 days for refrigerated samples.
In this letter, I aim to show that requiring an expiration dating of < 30hours for PN stored in a controlled room temperature and < 9 day for refrigerated samples should not be required for the following reasons: i.) All recent reported microbial contamination of parenteral products were not due to a lack of FDA regulations, but rather were due to major breaches of federal regulations. ii.) Allowing compounding pharmacies to provide internal data to support beyond use dating will allow individual pharmacies to self-regulate and determine appropriate BUD specific to their own compounding process and procedures and ultimately result in safer standards for patients. Iii.) Less frequent HPN deliveries may provide HPN patients greater freedom for travel, work, and social engagements, thereby leading to a greater sense of normalcy.
Microbial Contamination of Parenteral Products
Modifications in USP sterile product regulations were a direct result of contamination in parenteral products that lead to the implementation of stricter regulations. In September 2012, a New England Compounding Center (NECC) in Framingham, Massachusetts was linked to a meningitis outbreak that sickened over 800 individuals and resulted in the death of 64. As a result, the Centers for Disease Control and Prevention (CDC), in collaboration with state and local health departments and the Food and Drug Administration (FDA), began investigating a multistate outbreak of fungal meningitis and other infections among patients who had received contaminated steroid injections from NECC which was classified as a 503B compounding pharmacy. Such pharmacies are authorized to combine, mix, or alter ingredients to create specific formulations of drugs to clinics or physician offices who may, in turn dispense the medications. This is drug distribution versus dispensing for a specific patient as a 503A pharmacy. The safety concerns for compounding pharmacies led to increased government oversight and increased restrictions for all compounded products. The USP characterizes PN as medium risk pharmaceutical product and therefore requires a 7 day BUD when the compound is kept at 2-8 degree Celsius. This general guideline can be extended to a 9 day BUD with internal data to support sterility. Prior to the events in 2012 and the increased restrictions, pharmacies compounding TPN were allowed at least a 17-day beyond use date if this could be validated by internal data for sterility and stability. The standard of practice in Canada for TPN expiration dating has been 31 days for decades.(“Guidance for Industry: Pharmaceutical Qulity of Aqueous Solutions – Canada “)
While patient safety is of the utmost importance, the limited BUD for all pharmacies based on the hazardous practice of only one pharmacy is overly restrictive. This change in regulations has greatly impacted the dispensing and delivery of PN to patients.
Possibility of contamination
Although PN is categorized as a high-risk medication the high dextrose content and high osmolality in a typical PN solution is not conducive to the growth of microorganisms. When PN was inoculated with microorganisms to provide 10(1)-10(2) colony-forming units/ml (CFU/ml) of Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans and admixtures were stored at room temperature for 0, 6, 12, 24, 48, 72, and 96 hr, K. pneumoniae, E. coli, and P. aeruginosa were able to proliferate, but the growth of these organisms was retarded in conventional PN solutions as compared to peripheral parenteral nutrition (PPN) with a decreased dextrose concentration and osmolality. Proliferation of K. pneumoniae and E. coli was observed in both the PPN and PN, but P. aeruginosa grew well only in PPN. S. epidermidis was not able to grow in any admixtures tested; however, C. albicans grew well in all admixtures, but growth was slower in PN. The authors concluded, both PPN supported the growth of microorganisms significantly better than conventional TPN solutions, which as the solutions most common in home infusion.(D’Angio, Quercia, Treiber, McLaughlin, & Klimek, 1987)
Over the past few decades, the industry standard beyond use dating changed from 28 days to the now 9 day BUD. In order to validate sterility of HPN, a single pharmacy catering to HPN compounding conducted and internal study to determine microbial contamination. Lipid free HPN were prepared in a class 100-laminar-air flow hood in a clean room using an automated compounder (BAXA EM2400) by trained technicians. Solutions were then stored at controlled room temperature (22o + 5o C) or under refrigeration (2-8o C) for 28 days. At that time, they were filtered using the QuickTest system by QI medical. The samples were incubated at 37oC for 28 days and then examined. A clear solution was considered to be free of microbial contamination. Any cloudy samples were considered to be contaminated by microbes and were cultured. Eighty-seven HPN solutions were incubated at room temperature and 62 were incubated in refrigeration. Of those, none demonstrated microbial contamination. They investigated the microbial contamination in HPN solutions after storage for 28 days at both a controlled room temperature and under refrigeration. None of the samples were found to have microbial contamination.(Killmeier, Siepler, Diamantidis, & Nishikawa, 2006)
In addition to these data, others have examined microbial contamination in PN finding very low rates of contamination.(Dickson, Somani, Herrmann, & Abramowitz, 1993) Based on these results, it is tempting to suggest that these data confirm that all PN is free of microbial contamination under the storage conditions studied. However, the sample size is small and larger numbers are needed to provide a greater assurance of freedom from microbial contamination. In addition, these results do not apply to PN made using methods other than those described here, but do validate PN compounding
Healthcare related infections linked to TPN Contamination
Unfortunately, not all pharmacies share the same stellar record in preparing contamination free PN and this success is not standard across the board. Several striking cases of PN contamination have been reported in the medical literature and in public media. For example, Candida albicans was isolated in blood cultures of seven neonatal patients receiving PN. Diagnostic tests showed that the C. albicans isolates grown in the PN solution and from the patients’ blood cultures were clonally same strains, leading the investigators to believe that a C. albicans outbreak had occurred in the neonatal pediatric unit, due to contamination of TPN solution.(Guducuoglu et al., 2016)
In 2010, neonates treated with PN at the Pediatric Department of the University Medical Center Mainz had cultures positive for Enterobacter cloacae and Escherichia hermannii and these infections were linked to microbiological contamination of the amino acid solution used to prepare the PN solutions(Bhakdi, Kramer, Siegel, Jansen, & Exner, 2012)
In March 2011, five patients had blood cultures positive for Serratia marcescens and these infections were linked to PN. Upon further investigation, nineteen cases were identified and resulted in the deaths of nine patients. These infections were attributed to a compounding pharmacy that was compounding non-sterile amino acids due to a national shortage of commercially available amino acid preparations. Investigations discovered that this compounding pharmacy was negligent in following standards for sterile compounding(Gupta et al., 2014)
In a 2013 review, investigators found that between January 200 and just before the 2012 fungal meningitis outbreak, there were eleven reported outbreaks involving 207 patients and resulting in seventeen deaths. These events were related to compounding of corticosteroids, heparin flush solutions, cardioplegia solutions, intravenous magnesium sulfate, TPN, and fentanyl. Each of these adverse events were directly linked to lapses in the sterile compounding procedures that were mandated by the USP and FDA.(Staes, Jacobs, Mayer, & Allen, 2013)
HPN Patient Considerations
For HPN patients, following the current USP guidelines requires approximately weekly deliveries and an assurance that the HPN is refrigerated continuously. This strict
BUD can pose restrictions on the freedom and ease of travel for HPN patients. It may also affect patient work and social schedules having to be home to receive and refrigerate their HPN delivery, as it is not ideal for shipments of HPN to sit outside in extreme temperatures.
The goal of pharmacies is to provide safe and accurate HPN to patients in a manner that enhances the quality of life of patients. Winkler et al.,(Winkler et al., 2010) conducted interviews with 24 adults with short bowel syndrome on issues affecting their quality of life(Winkler et al., 2010). This study found that quality of life was affected by health, stamina, diarrhea, having an ostomy, and infusion schedule, but in all interviewees, there was a strong desire to achieve “normalcy” in life. Recent changes in BUD for HPN that have requiring increased shipping frequency have many potential impacts on the normalcy of HPN patient’s lives. Many patients will strive to be home to get the HPN shipment and unpack it so that it does not sit outside. This may cause patients to miss work, appointments, or social engagements. Additionally, a weekly delivery can hinder the freedom for consumers to travel. Even weekend or day trips may be impacted if they fall close to the delivery day. Having less frequent deliveries can have a very positive impact on the quality of life of patients. Additionally, weather events such as hurricanes, flooding, snow/ice storms may impact deliveries which could be anticipated and managed with longer BUD times.
Conclusions and Recommendations
The safety of HPN patients is the top priority of both pharmacies and governmental regulating bodies. The increasing strict regulations on HPN preparation were intended to enhance safety, but these new regulations do not have the rigorous scientific basis but are based on case reports of poor pharmacy management and oversight. Reports of parenteral product contamination have all been associated with non-compliance of regulatory standards and were not due to lack of sterility standards. While these new standards may have been intended to improve the lives of HPN patients, they have had a detrimental impact on the quality of life of patients by requiring more frequent deliveries, interruption of deliveries due to weather, and restrictions on travel.
Recommendations for practice would include: i.) allowing compounding pharmacies to provide internal data to support BUD and ii.) allow individual pharmacies to self-regulate and determine appropriate BUD specific to their own compounding process and procedures within the safe practices guidelines for the USP and ASPEN. Ultimately, this will benefit the patient who is the recipient of this valuable therapy. I greatly appreciate your time and consideration on this matter. If you would like to discuss this topic further, I would be happy to speak with you.
Emma M. Tillman, Pharm.D., Ph.D., BCNSP
Clinical Pharmacist Specialist – Pediatric Critical Care
Riley Hospital for Children, Indianapolis, IN