Examining Ingredient Substitution in the Opioid Pharmaceutical Supply Chain: Findings from CDER’s Product Survey
The rapid growth of the sale of illicit, chemically synthesized fentanyl, fentanyl analogs, and methamphetamines has raised the need for enhanced approaches to protect public health. Securing the supply chain for approved medications, including opioids, remains a top priority for FDA under the Overdose Prevention Framework. To aid this goal, FDA worked to further develop our surveillance and enforcement efforts to search for potential adulteration within the supply chain of FDA-regulated products.
Specifically, CDER’s Office of Compliance developed a multi-year opioid product quality survey designed to uncover impurities or substitutions of illegal, unsafe substances in place of the intended active pharmaceutical ingredient (API) in certain products. During this survey, FDA tested multiple FDA-regulated opioid drugs, ingredients used to make opioid drugs, products used to reverse opioid overdoses, and products used in the treatment of opioid addiction. FDA found no evidence of illegal substitution in any of the ingredients and products tested.
The agency will continue to test additional products as part of ongoing regulatory oversight efforts.
The aggressive search for potential substitution led to FDA laboratory scientists in CDER’s Office of Pharmaceutical Quality’s Office of Testing and Research developing and validating a highly sensitive test method to analyze various opioids for potential substitution. The test method also makes it possible to isolate, identify, and quantify unknown impurities identified during the analysis.
Using this method, FDA tested APIs, including those produced by primary manufacturers and repackagers of APIs, intended for products marketed in the US, and finished drug products intended for the US market.
CDER, in collaboration with the FDA Office of Regulatory Affairs, collected and tested:
- APIs used to make buprenorphine, fentanyl, hydrocodone, hydromorphone, morphine, nalbuphine, sufentanil, and tramadol. All 90+ samples tested met FDA specifications for API content and did not show signs of substitution.
- Acetaminophen/hydrocodone, acetaminophen/oxycodone, tramadol, oxycodone, fentanyl, buprenorphine, methadone, naloxone, naltrexone, opium tinctures, and morphine sulfate finished dosage forms. The 70+ drug samples tested did not show signs of substitution and met applicable specifications for API content.
- Injectable opioid products compounded from API at 503B outsourcing facilities, specifically morphine sulfate, hydromorphone chloride, hydromorphone hydrochloride, and fentanyl citrate. All 15+ drug product samples met FDA specifications for API content and did not show signs of substitution.
Various testing results are posted on FDA’s Drug Quality Sampling and Testing Programs.