Miriam E Tucker
January 15, 2018
Insulin vials and cartridges sold in pharmacies may not contain sufficient concentrations of insulin, new research finds.
The startling data, based on analysis of insulin vials randomly purchased in US pharmacies, were published online December 21 in the Journal of Diabetes Science and Technology by Alan W Carter, PharmD, of MRIGlobal and the University of Missouri–Kansas City, and Lutz Heinemann, PhD, of Science & Co, Düsseldorf, Germany.
Standards established by the US Pharmacopeia and Food and Drug Administration (FDA) require that insulin vials and cartridges contain a minimum of 95% intact insulin (95 U/mL).
In contrast, Drs Carter and Heinemann found that the average amount in 18 10-mL vials of NPH and regular insulin from the two major manufacturers, Novo Nordisk and Lilly, was just 40.2 U/mL, ranging from 13.9 to 94.2 U/mL. None met the 95-U/mL standard at the time of testing.
"Patients are paying high prices for insulin and should expect to receive insulin vials with adequate insulin content in return," the authors write.
Because insulin manufacturers must follow strict protocols, it is likely that the problem lies in the cold supply chain between the time the vials leave the manufacturing plant and arrive at the pharmacy, Dr Carter told Medscape Medical News.
"It's a safe assumption that companies comply with FDA rules. But what we have no control over is the pipeline that they go through once the manufacturer has them packaged and ready to go," he said, adding, "We want the company's help in figuring this out."
Dr Carter said that he and Dr Heinemann are working with the Diabetes Technology Society and trying to obtain funding to broaden this research to test larger samples and include insulin analogs and biosimilars.
Insulin Manufacturers Respond
In a statement, Novo Nordisk spokesman Ken Inchausti told Medscape Medical News, "We're committed to better understand these reported findings. Novo Nordisk has been producing human insulin for over 35 years and we take the quality of our medicines, and the safety of patients, seriously. We take significant measures to ensure that insulins manufactured at our facilities and shipped to our distributors meet the strict established concentration and temperature standards."
Novo Nordisk will "pursue discussions with the study authors as well as additional analysis on our insulin vials as appropriate. We're confident that the medicines that leave the Novo Nordisk distribution center are within specification for potency," Mr Inchausti added.
For its part, Lilly said in a statement, "Lilly is extremely confident in the quality of our insulins. Lilly uses robust global quality management systems and product control strategies to ensure we meet or exceed the high standards expected from our customers and global regulatory agencies. Lilly has controls and specifications at every stage of the manufacturing process — including validated testing of every batch that is distributed to the market."
The Lilly statement also points out that companies distributing insulin must hold a pharmaceutical distribution license issued by local government agencies in the United States. In addition, all wholesale distributors must have a Verified Accredited Wholesale Distributor certification that "ensures appropriate storage and distribution practices for pharmaceutical products."
Wide Variation Found Among Batches
The 18 vials used in the study represented 16 different insulin lots from the two manufacturers randomly purchased from five pharmacies supplied by three different wholesale sources. They included four vials of regular insulin and four vials of NPH insulin from one manufacturer and five vials of each insulin from the other. Expiration dates ranged from August 2018 to April 2019.
All vials were kept continuously refrigerated under monitored conditions (2–8°C) from time of purchase until analyzed on May 9, 2017.
The analysis was done using a mass spectrometry method developed for measuring insulin in plasma, and not — as the Lilly statement noted — using the standard FDA reference method for determining insulin drug product quantities. Those methods, they note, are published and publicly available in the US Pharmacopeia.
Indeed, Dr Carter said of their study method, "In theory it should work, but we don't know if it's the best method," adding efforts going forward with the Diabetes Technology Society will including developing a standardized method to extract product and conduct testing for intact insulin and other components that might have biological activity.
No association was found between insulin levels and country of origin, supply source, or cost. Among the lots of regular insulin, variance between four vials from one manufacturer was 14.5%, and between the five vials from the other was 5.1%.
Lot variation was greater for NPH insulin, at 10.9% and 38.9% for the 4 and 5 lots from the two manufacturers, respectively.
What Does it Mean Clinically?
Given the variability identified, one clinical implication is that patients should be advised to monitor very carefully when starting a new vial or cartridge of insulin and their doses should be adjusted for any changes in glycemic control, Dr Carter said.
And given that patients frequently experience deteriorations in glycemic control despite reporting no factors to account for it, the possibility of low insulin concentration should be considered as an explanation.
"If the patient says, 'I'm doing everything correctly,' it's possible their insulin is less potent. This is one additional variable...Clinicians have seen variability that can't be explained where a new vial just doesn't seem to work as well. It's anecdotal," he noted.
But this definitely needs further investigation before firm conclusions can be drawn, he cautioned.
"A solid study needs to be done...We don't want to panic anybody, but we want to make sure that we investigate thoroughly."
Dr Carter is a pharmacist manager for MRIGlobal and principal investigator for the National Institutes of Health – National Institute of Neurological Disorders and Stroke and National Center for Advancing Translational Sciences Drug Manufacturing Development Program contracts. Dr Heinemann is a consultant for a number of companies that develop novel diagnostic and therapeutic options for the treatment of patients with diabetes. He owns shares of Profil Germany and ProSciento.
SOURCE: January 15, 2018. J Diabetes Sci Technol. Published online December 21, 2017.