Trissel Had It Right: Re-Emphasis on Pharmaceutics Testing Needed
This is an exciting time of year for ISMP, when our organization selects the ISMP Cheers Awards winners and prepares to honor them at our annual Cheers Awards dinner and gala. It’s a time of contemplation for us regarding both the challenges and successes associated with medication safety that have been encountered and achieved throughout the year. It’s also a time of reflection about our previous award recipients and the exemplary work they have accomplished to improve medication safety.
One of this year’s most daunting challenges is the issue ISMP, the US Food and Drug Administration (FDA), and BD brought to light about reduced potency of oral or parenteral liquid medications repackaged and stored in certain lots of 1 mL, 3 mL, 5 mL, 10 mL, 20 mL, and 30 mL BD syringes. Given this dilemma, our thoughts went immediately to a previous Cheers Lifetime Achievement Award recipient, Lawrence A. Trissel, BS Pharm, FASHP, and his stirring acceptance speech regarding the adverse impact of what he perceived to be a national de-emphasis on clinical pharmaceutics testing over the past 25 years.
This is the very type of pharmaceutics testing that was needed to identify the recent problem impacting potency. Yet, very few facilities and schools of pharmacy are set up to test products in syringes. Thankfully, several hospitals that were converting to robotic syringe production sent samples for external laboratory testing and reported the potency problem to ISMP and BD. While we can’t say with confidence that the potency issue would have been detected sooner if ongoing pharmaceutics testing had been occurring at previous frequencies, it is certainly possible given that the hospitals identified the problem serendipitously.
Furthermore, without stability testing, the potency issue calls into question what hospitals have been doing for years to improve medication safety—preparing patient-specific, unit dose, prefilled syringes in the pharmacy in advance of anticipated use, or obtaining prepared syringes from outsourcers. Such efforts provide an irreplaceable safety net by dispensing injectable and oral liquid medications in ready-to-use containers. Nevertheless, it appears that we have sometimes administered subpotent medications to patients when utilizing pharmacy-prepared syringes.
ISMP first drew attention to the loss of drug potency with certain medications prepared in advance in BD syringes in our July 30 newsletter and then again in our August 27 issue. BD issued letters about the problem to syringe customers dated July 31 and September 1, and FDA issued Alerts on August 19 and September 8. Potency is defined as the concentration of the drug, or how much drug is in the preparation. The US Pharmacopeial Convention (USP) has established that the acceptable range of potency for an active pharmaceutical ingredient preparation is typically ± 10%, or within the range between 90% and 110%. In this case, decreased potency below an acceptable range was reported when fentaNYL, rocuronium, neostigmine, morphine, midazolam, methadone, atropine, HYDROmorphone, cisatracurium, and remifentanil were stored in certain general purpose BD syringes. The decrease in potency is caused by an interaction between the drug and the rubber stopper used in certain syringe lots. It turns out, general purpose syringes from any manufacturer were never cleared by FDA for use as a closed container storage system for all drug products, and the suitability of these syringes for that purpose has now been called into question.
The fix to this problem is not an easy one. An abrupt withdrawal from use of general purpose syringes for preparation and repackaging of medications would result in an increased risk to patients and a disruption in the healthcare system. Yet, we have heard that some nurses are now being asked to prepare medications in a syringe (oral or parenteral) for immediate use to prevent a potential loss of potency. Breaches in aseptic technique, erroneous selection of diluent type and amount, dose measurement inaccuracies, and unlabeled syringes in patient care units could lead to contamination and medication errors.
To validate potency and beyond-use dating for medications drawn up in syringes, testing would be needed over the period of time intended to store the product in the syringe. However, this type of clinical pharmaceutics testing has significantly declined in the last 25 years, with little or no support from pharmacy schools and research foundations today.
De-emphasis on clinical pharmaceutics
At the 2011 ISMP Cheers Awards dinner, Mr. Trissel pointed out a serious problem: other than minimal pre-market testing by product manufacturers, fewer and fewer studies on drug storage, potency, stability, compatibility, and beyond-use dating are being conducted in the US. Trissel noted, “Over the last 20 or 25 years, this entire area of study and research has undergone a transformation in the US, withering into near non-existence.” Without ongoing studies, key product information that could promote safer pharmaceutical preparation and reduce the risk of medication errors is becoming quite scarce.
Trissel shared his observation that the transformation of pharmacy education and practice into a clinical profession was crucial, and that we should all applaud the increased clinical roles that pharmacists now play, and the positive impact on patient safety that it can represent. But he went on to say that, in the rush to revolutionize the future of pharmacy, traditional pharmacy elements of value and need have been abandoned.
Trissel noted that the changes that were envisioned while moving pharmacy into a more clinical role were not intended to shortchange pharmacy graduates, yet students are no longer taught the basics of pharmaceutical chemistry and clinical pharmaceutics. Nor was the transition to a more clinical role intended to eliminate drug stability, potency, and compatibility research, but in the US, that has indeed been an outcome. Trissel said, “Pharmacy students, including PharmD candidates, used to be frequent sources of new clinical pharmaceutics research, especially under the guidance of academic mentors. Unfortunately, few pharmacy schools and their students conduct laboratory research projects anymore.” At the largest pharmacy meeting in the world in 2011, Trissel pointed out that there were only three poster presentations on drug stability, potency, and compatibility. Virtually no support for this kind of laboratory research has come from the research foundations of major pharmacy organizations, even though the immediate applicability of the information to the clinical setting is well recognized. “Apparently, drug stability, potency, and compatibility research has not been deemed sufficiently worthy of their support,” said Trissel.
If you doubt the impact that this de-emphasis of clinical pharmaceutics has had, consider the amount of new research studies published to support the clinical care of patients. In 1991 and 1992 there were 245 newly published clinical pharmaceutics research articles incorporated into the 7th edition of Trissel’s Handbook on Injectable Drugs. Most of the studies came from US researchers in academia, pharmacy practice, and pharmacy students performing laboratory-based research. Twenty years later, Trissel noted that the 17th edition of the Handbook on Injectable Drugs (his last before retiring) incorporated less than 45 new research articles, most from foreign researchers. In the last 20 years, there has been more than an 80% decline in new research studies of drug stability, potency, and compatibility.
Trissel believes clinical pharmaceutics research is viewed by much of the present day pharmacy profession as an activity outside of the profession. He said, “In past decades, things were very different. This kind of laboratory-based research was considered of value to patient care by the pharmacy profession. But now, the changes in pharmacy education and practice have led to the point that drug stability, potency, and compatibility research is just about dead. It is not as if the pharmacy profession in the US has ‘dropped the ball’; it is as if the team abandoned the field and walked away.”
Trissel concluded his acceptance speech by challenging the audience: “Whose job is it to protect patients from harm from drug instabilities and incompatibilities and other aspects of clinical pharmaceutics? Nurses and physicians? Not likely. Drug companies or the FDA? Even less likely. If not pharmacists, the self-declared drug experts, then who? If the pharmacy profession in the US abandons it, what does that say about pharmacy schools, pharmacy professional institutions and associations, and pharmacy practitioners?”
ISMP agrees that drug stability, potency, and compatibility testing is important to patient care and safety, and that a way needs to be found for traditional concepts and skills, including clinical pharmaceutics and testing, to be reintroduced and re-emphasized in pharmacy education and practice before these skills are lost. We hope the pharmacy community and others will help spark interest again in clinical pharmaceutics and testing among pharmacy students and practitioners, and promote graduate work in pharmaceutics to reinforce the importance and relevance of this research to clinical care needs and safety.
In the case of decreased potency of medications prepared in syringes in advance, we worry about taking a huge step back in safety if parenteral and oral liquid medications cannot be dispensed in ready-to-use, prefilled, labeled syringes. But we also worry about patients who may be receiving subpotent medication doses, leading to adverse outcomes such as uncontrolled pain or an overdose when the dose is titrated up after the patient receives a subpotent opioid but subsequently receives a fully potent opioid.
The loss of potency of medications stored in syringes is a serious problem, and the best solution is currently a conundrum. The answer is not to abandon the use of prefilled syringes, nor is it to ask patients to bear the brunt of subpotent medications. For now, we can only advise organizations to try to limit drug exposure in plastic syringes by using them as promptly as possible after preparation in the pharmacy, and to make sure staff are aware of the problem and know to report unexpected changes in drug effectiveness, such as a sudden loss of pain control. We also urge everyone in healthcare to watch for updates on this important issue.