Canadian Company Chided in Warning Letter for Releasing Out-of-Specification Products

Canadian pharmaceutical manufacturer Jubilant HollisterStier General Partnership has been hit with a warning letter from US regulators, which allege that the company's Quebec facility exhibited "significant violations" of current good manufacturing practices during an inspection made of the facility last year, including known deficiencies that went uncorrected for as long as two years.

The company, a contract manufacturer, bills itself as being able to manufacture sterile injectable, solid and semi-solid dosage forms. Its Quebec facility reportedly manufactures sterile injectables, ophthalmic and otic solutions, ointments, creams and liquids.

CAPA Failures

FDA's 20 February 2013 letter references a 19-26 March 2012 inspection made by regulators with FDA's Center for Drug Evaluation and Research (CDER).

While there, investigators said they found that the company had "failed to perform an investigation for the failure" of one of its injectable products, which reportedly failed to meet in-process pH requirements, which was later confirmed by the company's quality control team. Another-or perhaps the same injectable product-failed to meet particle in-process acceptance criteria, but this was accepted as an acceptable part of the process.

Under CGMP regulations, companies are supposed to take an active approach toward addressing out-of-process products, finding the root cause of the problem, analyzing it, and putting into place new processes meant to prevent them from occurring. This is referred to more generally as Corrective and Preventive Action, or CAPA, which includes a root cause analysis (RCA).

But Jubilant having out-of-specification results isn't necessarily unusual. Companies experience such matters all the time. But FDA said Jubilant's response to those issues set it apart from most other companies, and not in a good way.

"Our investigator found that you do not determine and implement corrective and preventive actions (CAPAs) in a timely manner to prevent recurrence of manufacturing deviations," FDA wrote. "For example, the inspection noted that some CAPAs remained open for approximately 500-700 days (one was open for 761 days) without implementation of corrections."

In a response to FDA, the company reportedly said that such CAPA actions had been undertaken and the causes identified, but FDA said its response missed the broader point: "Why Jubilant had not completed these CAPAs in a timely manner to prevent repetition of manufacturing problems."

"We are concerned that your response corrects the FDA 483 observation, but does not provide for a systematic and sustainable correction to ensure timely and effective CAPAs," the agency wrote. FDA added that it was still awaiting a "brief summary" explaining this delay.

Other Alleged Deficiencies

Other reported deficiencies were concerning to FDA as well, it said. In another instance, the company relied solely on visual inspection-not more rigorous laboratory-based testing-to test for conformance to specifications. Even still, the company "released multiple lots of finished [product] despite the failure of these lots of meet acceptance criteria during 100% visual inspection," regulators wrote. Those lots exhibited "major defects," possibly including glass particles or other foreign material.

In another instance, the facility experienced a power failure, which raised the storage temperature of a product by more than 30 degrees Celsius. Despite removing most of the batch from distribution, some were still allowed to be released-a decision FDA said had not been explained.

Unsurprisingly, FDA also noted that the company's visual-based inspection methods did not ensure that drug products were produced to a consistent identity, strength, quality or purity. Regulators noted a number of lots that had been released despite high percentages of "major defect rejection rates" in individual products exceeding allowable levels, which often indicates broader failures in the lot.

"We are concerned, however, with your risk assessment, which suggests that the failure of these products to meet acceptance criteria for defects during the 100% inspection has no bearing on the quality of the released units," FDA added.

Focus has reached out to Jubilant for comment and will update this space if we hear back.