The FDA Center for Devices and Radiological Health (CDRH) is warning manufacturers of drug-device combination products of the potential for nitrosamine impurities, which are classified as probable carcinogens associated with forms of cancer.
The FDA did not name specific devices or kinds of devices that could be at risk in the letter it sent to manufacturers last week.
The agency said a nitrosamine drug substance-related impurity, 1-methyl-4-nitrosopiperazine, has been detected in certain CDRH-led combination products containing the drug rifampin (also known as rifampicin). Potential sources of nitrosamine impurities include the drug or manufacturing processes for the finished combination products.
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Some catheters — like certain central venous catheters, endoscopic ventricular catheters and catheters used in hydrocephalus shunt systems — are impregnated with rifampin and/or other antimicrobials to reduce the incidence of catheter-related bloodstream infections.
The drug is also used in absorbable antibacterial envelopes for cardiac implants like implantable cardioverter defibrillators (ICDs) and neuro implants such as spinal cord neuromodulators and stimulators for the vagus nerve sacral nerve and deep brain stimulation.
As another example, Boston Scientific’s InhibiZone Antibiotic Surface Treatment uses impregnated rifampin (and minocycline) for the device manufacturer’s AMS 700 Penile Implants. (But again, those products were not specifically named as at risk of nitrosamine impurities by the FDA.)
Nitrosamine exposure above acceptable levels over long periods of time could elevate the risk of cancer.
CDRH is involved in ongoing investigations into the root cause and scope of nitrosamine impurities in CDRH-led combination products, but said in the letter it was not aware of any adverse events associated with nitrosamine exposure from the products. The agency is working with manufacturers to understand potential causes of nitrosamine formation and evaluate the potential use of interim or alternative limits for certain products.
Manufacturers are responsible for identifying potential nitrosamine impurities originating from pharmaceutical components and evaluating nitrosamines that could arise from manufacturing processes, according to the FDA.
Manufacturers are also responsible for developing and employing analytical methods to detect and minimize nitrosamines and assess patient exposure.
The warning advised manufacturers to evaluate pathways where nitrosamines could be introduced during manufacturing, assembly, sterilization or storage of the finished product. Raw materials, manufacturing aids, packaging, sterilization processes, storage conditions and other factors could produce additional or new nitrosamines, the FDA said.
If manufacturers identify potential nitrosamine risks, the FDA recommends assessing whether daily acceptable nitrosamine intake limits are exceeded. If limits are exceeded, or could potentially be exceeded, the agency recommends contacting the CDRH.
Rifampin is an FDA-approved antibiotic for treating tuberculosis and patients with asymptomatic Neisseria meningitidis, a meningococcal disease, in the nasopharynx. It’s also used off-label to treat leprosy, severe gram-positive bacterial infections such as osteomyelitis, endocarditis, anthrax and brain abscesses, and specific gram-negative organisms.
