US FDA Warns Syntec Pharma Against Sourcing APIs From Import-Alerted Suppliers
Executive Summary
Import alerts, warning letters failed to deter company from importing adulterated drug substances. Syntec also cited for cross-contamination, cleaning lapses.
A warning letter the US Food and Drug Administration published 3 August reflects the reality that it is possible for companies to import pharmaceuticals and their active ingredients into the US even from facilities that are listed on FDA import alerts.
The warning letter, issued on 6 July to Syntec Pharma Corp., Farmingdale, NY, provides a reminder that companies can get in trouble with the agency for such imports.
The warning letter stems from a 7-28 October 2020 inspection that raised serious concerns about cross-contamination risks, equipment cleaning failures and the lack of an effective quality unit.
But the warning letter also reflected an unusual degree of focus on sanctions against the company’s suppliers.
On its website, Syntec described itself as a US-based company that sources bulk drug substances for pharmaceutical companies and “various customers located in South and North America.”
The website lists APIs Syntec sells to pharmaceutical companies, compounding pharmacies and outsourcing facilities. Syntec offers to handle various registration and listing services for suppliers, and posts the fees on its website.
Banned Ingredients
When the FDA reviewed Syntec’s list of API suppliers, the agency found that three were subject to import alerts at the time Syntec imported their products.
Two were listed on import alert 66-40, the one for foreign facilities that failed to meet US drug good manufacturing practice requirements.
One was listed on import alert 99-32, the one for delaying, denying or limiting FDA inspections of foreign facilities.
Of the three, two had received FDA warning letters as well that explained why the agency considered the APIs they produced to be adulterated. Because Syntec had received adulterated APIs from them, it was in violation of the Food, Drug and Cosmetic Act.
Ineffective Import Alerts
The warning letter went through specific cases, noting, for example, that Syntec had obtained nitrofurantoin, pimobendane and estriol from import-alerted suppliers.
The warning letter did not explain how the APIs got through the border despite import alerts that say the agency “may detain” them because they are subject to refusal of admission.
It takes a court order to seize domestic drug products and active pharmaceutical ingredients to keep them off the US market, and the FDA rarely asks for such orders. However, it's up to the agency to decide whether it should add a foreign manufacturing facility to an import alert list, and it is a common occurrence that has generally been considered highly effective at protecting US patients from products of questionable quality.
Cytotoxic, Beta-Lactam Cross-Contamination Risks
The warning letter highlighted cross-contamination risks at Syntec’s facility, including of unacknowledged highly potent APIs.
The agency found unacceptable the solution Syntex proposed in its 4 December response to the FDA’s 28 October Form 483 report of inspectional observations.
The company suggested establishing separate storage shelves for cytotoxics and beta-lactams.
The agency made it clear that it would accept nothing less than a “completely and comprehensively” separate facility for beta-lactams, along with assurance of containment for potent compounds.
The agency noted that Syntec was storing lamustine and human chorionic gonadotropin at room temperature even though the manufacturers required refrigeration according to their certificates of analysis.
There were “personal food items” in the refrigerator where Syntec stored APIs and chemicals. Also in the storage room: weed killer, antifreeze and dry wall repair products.
Equipment Cleaning, Cleaning Validation Issues
The investigators found problems with equipment cleaning procedures as well.
Syntex failed to document whether it cleaned equipment after using it to repackage cytotoxic lomustine in April 2020.
The company used laundry detergent to clean the ventilation hood, utensils and balances instead of appropriate cleaning agents, and failed to perform cleaning validation studies.
The agency found inadequate Syntec’s response that the tools and equipment used were small and “visually clean before use,” leading the company to conclude that the risk of contamination “is exceedingly small.”
Quality Unit Effectiveness
The warning letter said there was not an effective quality unit at the site, and went on to detail some of the quality lapses behind that judgment.
For example, Syntex released super-potent lots of oxytocin after failing to establish the reliability of the API supplier’s analyses.
The company failed to make sure it had stability data that supported the retest or expiration dates it gave when it repackaged APIs.
The agency, which provided lists of tasks required to remediate the plant, acknowledged the company’s commitment to suspend drug manufacturing.