FDA Warns Repackers Distributing Pharmaceutical Ingredients with Manufacturing Quality Standard Violations

The U.S. Food and Drug Administration (FDA) has issued warning letters to three repackers of active pharmaceutical ingredients (API), B&B Pharmaceuticals, Inc., Asclemed USA, doing business as Enovachem and Spectrum Laboratory Products, Inc., for significant violations of current good manufacturing practice (CGMP) requirements.

"Repackers play a role in the pharmaceutical supply chain, and some distribute bulk API to drug manufacturers and pharmacy compounders. The U.S. drug supply chain remains one of the safest in the world, yet because of the various players and increased globalization, it has become increasingly complex. The FDA remains vigilant in our inspections and oversight of the supply chain and as part of this effort, we inspect API repackers to help identify and prevent any weaknesses in the legitimate supply chain – this is especially important within the context of the opioid crisis for those who handle opioids," said Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research. "The supply chain issues we have found in the API repacking industry broadly pose a real threat to the public health and we're calling on them to address these issues as quickly as possible. For patient safety and supply chain transparency, repackers must follow all quality standards pertaining to them – including clearly identifying the original manufacturer of the drugs, such as opioids, to their customers who use them to make the finished drugs patients take every day. This information is vitally important to ensure the drugs patients take meet high quality standards that patients deserve."

Generally, API repackers take bulk API (usually in powder form) from the container in which it was distributed by the original manufacturer and place it into a different container without further manipulation of the drug and distribute it to drug manufacturers, compounding pharmacies or outsourcing facilities. Improper repackaging or lack of supply chain oversight of API can cause serious vulnerabilities in the supply chain and may lead to adverse events in patients.

The warning letter issued to B&B Pharmaceuticals describes failures to conform to CGMPs, including failure to thoroughly investigate complaints regarding sub-potent API. The repacker also failed to conduct cleaning validation studies to demonstrate that their cleaning procedures for non-dedicated production equipment are adequate to prevent potential cross-contamination between repackaged API, including highly potent drugs such as testosterone, progesterone, estrogen and opioids. The repacker also failed to provide adequate certificates of analysis for API, by not including critical information about the quality and sourcing of drugs and their components. Omitting this vital information from a certificate of analysis compromises supply chain accountability and traceability and may put consumers at risk.

The warning letter issued to Enovachem notes, among other violations, failure to maintain traceability of the API throughout the supply chain, specifically warning that the company failed to obtain and retain documents with the identity of the original manufacturer and certificates of analysis from the original manufacturer. The company also distributed API, including opioids, to its customers with incomplete certificates of analysis, which compromises supply chain accountability and traceability and may put consumers at risk. The customers included compounding pharmacies which use the API for prescription compounding.

The FDA issued a warning letter to Spectrum for significant deviations from CGMPs. Spectrum repackages various opioid APIs but did not provide complete information in its certificates of analysis provided to its customers, including compounding pharmacies. Spectrum failed to properly investigate and resolve critical CGMP deviations, including cracked bottles of repackaged opioids, among other violations.

The Spectrum and Enovachem warning letters also state these companies list glycerin among the products they repackage. In 2007, the FDA issued final guidance intended to alert pharmaceutical manufacturers, pharmacy compounders, repackers, and suppliers to the potential public health hazard of glycerin contaminated with diethylene glycol (DEG), a poison which may be deadly to patients. Lapses in supply chain oversight, including incomplete information on certificates of analysis, was one of the factors that allowed contaminated drugs to enter the supply chain in the past.

The FDA has requested responses from each repacker within 15 working days. The warning letters also state that failure to correct violations may result in legal action without further notice, including, without limitation, seizure, and injunction.

Additionally, the FDA has issued separate warning letters to other API repackers for similar violations, including Vipor Chemicals Private Ltd., Lumis Global Pharmaceuticals Co. Ltd., Sal Pharma, Huron Pharmaceuticals, Inc. and Fagron, Inc., and added Lumis Global Pharmaceuticals Co. Ltd. and Sal Pharma to import alerts, including 66-40 for failure to meeting CGMPs, to keep their API from ultimately reaching U.S. patients. The agency has also issued alerts about safety issues with repackaged porcine thyroid API and baclofen API.

The FDA will continue to inspect and take action as appropriate against repackers, particularly those in the opioid API supply chain.

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