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FDA Issues New Warning Letters to API Repackers

The Food and Drug Administration (FDA) recently issued warning letters to three repackers of Active Pharmaceutical Ingredients (API) for alleged violations of Current Good Manufacturing Practice (CGMP) requirements. The FDA’s issuance of these warning letters, along with statements made in a press release dated July 2, 2019, indicate that the FDA is increasing its oversight of the global supply chain for pharmaceuticals and active pharmaceutical ingredients, and issuing warning letters based on violations of guidance document provisions.

The press release states that as the pharmaceutical supply chain becomes increasingly complex and globalized, the FDA is making it a priority to identify and prevent any potential supply chain weaknesses, including inspecting and exercising oversight over API repackers. The FDA stated that repackers must follow all quality standards pertaining to them, which the Agency is interpreting to include those laid out in the FDA Guidances for Industry “Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients” (FDA Guidance) and “Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients – Questions and Answers” (FDA Questions and Answers). The FDA also stated that it will continue to inspect and take action as appropriate against repackers, particularly repackers in the opioid API supply chain.

Notably, in each of the warning letters, the FDA cited violations of FDA guidance documents, rather than statutes or regulations. For example, each warning letter states that a certificate of analysis must contain information about the original API manufacturer based on FDA Guidance and the FDA Questions and Answers. However, in the FDA Guidance, the Agency says that certificates of analysis ‘should’ show the name, address and telephone number of the original manufacturer, but an alternative approach may be used if such approach satisfies the requirements of the applicable statutes. The FDA Guidances represent the Agency’s current thinking on a given topic but are not binding on the FDA or the public. Nevertheless, in the warning letters, the FDA is asserting that the FDA Guidance recommendations constitute requirements.

Examples of some of the recent warning letters include:

  • A repacker received a warning letter alleging CGMP violations, including the company’s failure to maintain complete traceability of API throughout the supply chain, including failing to obtain and retain documents with the identity of the original manufacturer and Certificates of Analysis (COA) from the original manufacturer. The company also distributed API, including opioids, to its customers, without complete certificates of analysis.
  • In a warning letter to another repacker, the company was cited for failing to conform with CGMPs, including failing to thoroughly investigate complaints regarding sub-potent API, failure to adequately review batch records for completeness and accuracy (for example, failing to detect discrepancies in bottle counts or deviations in manufacturing processes), and failing to perform cleaning validation studies to show that cleaning procedures for non-dedicated production equipment are sufficient to prevent potential cross-contamination between repackaged active pharmaceutical ingredients – including highly potent drugs such as opioids, testosterone, progesterone, and estrogen. The repacker also allegedly failed to provide adequate certificates of analysis for active pharmaceutical ingredients by not providing all quality and regulatory information received from the API manufacturer to customers, including the name and address of the original API manufacturers, and failing to include copies of the original batch certificate.
  • The FDA issued a warning letter to a company engaged in the preparation of repackaged opioid APIs. The company allegedly failed to provide the names and addresses of the original API manufacturer in the certificates of analysis provided to customers, and failed to adequately investigate to determine the root causes of and identify corrective action for CGMP deviations, including cracked bottles and repackaged opioids.

Additionally, two of the companies received warning letters addressing their repackaging glycerin, which the FDA considers a potential health hazard when contaminated with diethylene glycol (DEG). The FDA stated that lapses in supply chain oversight, including incomplete information on the certificates of analysis, is considered a factor with allowed for glycerin drugs to be contaminated with DEG in the past.

As the FDA increases its oversight and scrutiny of repackers and the global pharmaceutical supply chain generally, repackers must understand the applicable regulatory requirements and must be prepared to respond to the FDA oversight and inspections. Frier Levitt routinely reviews and counsels repackers on these issues. Contact Frier Levitt today to speak to an attorney.