FDA Raises Concerns With API Manufacturers

As quality issues have led to drug shortages, Donald Ashley, director of FDA’s Office of Compliance, raised several major concerns on Tuesday with the active pharmaceutical ingredient (API) industry, noting three trends related to the obfuscation of supply chain information, an increasing number of data integrity question marks and impurity concerns that have led to recalls.

On the obfuscation front, Ashley, speaking at the Association for Accessible Medicines’ conference in Bethesda, MD, noted that API companies sometimes fail to obtain and retain documents with the identity of the original manufacturer and certificate of analysis.

In addition, APIs, including opioids, are often distributed with inadequate certificates of analysis, which he said, “compromises supply chain accountability and traceability and may put consumers at risk.”

On data integrity, which often includes incomplete, inconsistent or inaccurate data, Ashley noted that of the warning letters issued to API manufacturers over the past four years, 73% have included including data integrity charges.

He also quoted from a warning letter sent to API manufacturer Lantech Pharmaceuticals in August, in which the firm admitted to “routinely deleting recovered solvents gas chromatography data older than three months permanently, without any backup.”

Ashley added: “Data integrity problems you can see are the tip of the iceberg,” noting that lapses often obscure other problems.

He also highlighted ICH’s Q7 guideline, which deals with the cGMPs for APIs, and which explains: “Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.”

On the impurities front, he also advised companies to consult ICH guidelines Q3A, Q3B(R2), Q3C, Q3D and M7(R1), as N-Nitrosodimethylamine (NDMA) and N-Nitrosodimethylamine (NDEA) have been found in a few different medicines. Recalls of the heartburn medicine ranitidine and the blood pressure medicine valsartan have occurred because of such impurities. However, FDA recently downplayed the levels of impurities in some ranitidine medicines, noting they “are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats.”

Outside the API concerns, Ashley noted that overall, the number of warning letters issued by FDA has increased between FY 2015 and 2019, although the agency has seen improvements in reducing the time between when an inspection ends and when a warning letter is issued, from a median of 11.6 months in 2015 to 6.5 months in 2019. He noted FDA is hoping to bring the time between inspection and issuance of the warning letter to six months by FY 2020.

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