What happens when patients who receive a trusted treatment start experiencing adverse reactions? And what can be done to help prevent it from reoccurring? USP standards serve as part of a robust safety network that manufacturers and regulatory agencies can rely on to help ensure the quality of drug products.
Recently, physicians became concerned when they saw a sharp increase in patients complaining of symptoms associated with allergic reactions - flushing, itching, hives, shortness of breath, decreased blood pressure, and increased heart rate - after receiving injections of the antibiotic, gentamicin. One fatality was reported in connection with the treatment. As regulatory agencies and healthcare professionals scrambled to identify the cause, countries including Canada, the United Kingdom and Australia recalled batches of gentamicin and issued regulatory warnings1-3.
Gentamicin is an antibiotic usually administered by injection for serious bacterial infections when other treatments may not be effective4. Investigations into the reports of adverse reactions revealed that humans weren’t the only species experiencing problems with gentamicin injections. Since 2015, at least 154 adverse drug reactions (ADRs) were reported in horses that received gentamicin injections and resulted in at least nine deaths5. The cause was eventually identified: elevated histamine levels. Histamines are part of the body’s immune system and trigger allergic responses, including the symptoms described by the patients who received the gentamicin injections. Some batches of gentamicin had histamine levels 7-fold higher than the threshold at which this adverse event (i.e., allergic response symptoms) start to appear. But what caused the elevated histamine levels?
Part of the gentamicin manufacturing process involves growing gentamicin-producing bacteria in a nutrient-rich growth medium that includes peptone, an ingredient derived from fish. The elevated histamine levels in the gentamicin were linked to poor-quality fish peptone, caused by improper handling and storage conditions. Since gentamicin isn’t the only antibiotic that uses fish peptone in its manufacturing process, other antibiotics might also contain elevated histamine levels that could lead to adverse reactions in patients.
Whether it’s antibiotics or other drug products, the processes in pharmaceutical manufacturing are complex, with a myriad of steps before a drug product reaches a patient. The more numerous the steps and the more complex the process, the more opportunities there are for something to go wrong and quality to be compromised.
Rigorous quality control and quality assurance programs help pharmaceutical manufacturers and regulatory agencies ensure the quality of drug products. USP documentary and physical reference standards are components of these programs for assessing the quality of pharmaceutical processes and products. Documentary (aka compendial) standards define testing methods, specifications and acceptance criteria for evaluating the identity, purity, quality and strength of a drug product. Documentary standards are often complemented with corresponding physical reference standards that can serve as benchmarks against which to measure the attributes of the drug products being tested.
For 200 years, USP has helped protect public health with standards for the identity, purity, quality and strength of medicines. Throughout its history, USP has worked with experts from the pharmaceutical industry, academia, regulatory agencies and other organizations around the world who volunteer their time to collaborate in the development of USP quality standards. These experts are part of the entire standards development process from ideation through approval and release.
Monitoring and controlling residual levels of histamine will reduce the possibility of a repetition of the adverse reactions due to elevated histamine levels described above. USP is currently working on a public documentary standard with validated methods to quantitate histamine in antibiotics. The first entry will be a method for testing histamine in gentamicin sulfate and test methods for other antibiotics will be added to the general chapter when they become available.
Recognizing that other residual impurities may remain in finished dosage forms that are produced using fermentation processes, USP is actively seeking input from stakeholders to identify and participate in the development of standards for such impurities. Anyone interested in contributing to these efforts is asked to contact Dr. Ying Han at firstname.lastname@example.org.
USP’s standards development also includes a public vetting period when stakeholders can provide input on proposed documentary standards. The standard for quantitation of histamines in gentamicin sulfate is expected to be available for public comment in the USP Pharmacopeial Forum (PF) in July 2020. All interested parties are invited to review and comment on proposed standards currently in PF and check back periodically to review and comment on additional proposed standards. The Expert Committee responsible for developing USP standards takes into consideration all insights, questions and recommendations to help ensure that the final standard is as robust as possible to ensure drug quality and protect public health.
- Recall: potential for allergic reactions due to higher than expected amounts of histamine., (Therapeutics Goods Administration, Symonston, Australia, 2017).
- Gentamicin Injection USP (10 mg/ml and 40 mg/ml): potential for adverse reactions with 12 lots contaminated with histamine. (Health Canada, Ottawa, Ontario, Canada, 2018).
- Gentamicin: potential for histamine-related adverse drug reactions with some batches., (Medicines and Health Care Regulatory Agency, London, United Kingdom., 2017).
- O’Grady, M., Schlumbohm, W. CVMP assessment report regarding the request for an opinion under Article 30(3) of Regulation (EC) No. 726/2004. For veterinary medicinal products containing gentamicin for parenteral administration to horses. (European Medicines Agency, 2018)