Regulatory Focus™ > News Articles > Rare Multi-Facility Warning Letter Slams Manufacturer, Says Concerns Extend to All Plants

Rare Multi-Facility Warning Letter Slams Manufacturer, Says Concerns Extend to All Plants

Posted 20 March 2013 | By Alexander Gaffney, RAC

A Warning Letter sent by the US Food and Drug Administration (FDA) to generic manufacturing company Apotex, Inc. cites a number of "serious" current good manufacturing practice deficiencies found at two manufacturing sites maintained by the company-a rarity among FDA Warning Letters.

The 21 February 2013 letter references a 13-24 August inspection of two Canada-based facilities operated by the company.

Facility One: Toronto

At the first facility, FDA claimed the company failed to adequately conduct required studies, such as "smoke studies" to assess airflow patterns for the aseptic filling line used in the production of at least one injectable product. In one instance, "turbulent airflow" was witnessed in a filling line, hinting at a compromised line that could jeopardize the sterility of the injectable products. Those concerns went uninvestigated, FDA found. Apotex said in a response to FDA that it has since conducted smoke study testing, which FDA is in the process of confirming.

In another incident, FDA said it found that Apotex had not established maximum holding times for vials, "used in media fills prior to incubation." In some cases, vials were filled for nearly a week before being moved to an incubator due to space constraints. FDA expressed concerns that this could lead to the growth of microorganisms that would not otherwise grow during incubation.

Inspectors also said they found evidence that the company had released some products that had unexplained discrepancies or failures-a repeat observation from a prior inspection. FDA cited an instance when one of the company's operators had noted critical defects in several tablets. Despite the company tolerating zero defects per batch at that particular step, the product was still released.

Several similar incidents were also alleged, and FDA said it was most concerned that the company "did not identify the true root causes of the various deficiencies," which resulted in the problems recurring or having the potential to recur.

"We remain concerned about the lots affected by this practice and released into distribution; your response did not provide information to show that a thorough investigation to determine the cause of each unexplained discrepancy or failure to meet specifications had been conducted," FDA wrote.

Inspectors also raised concerns about process validation. In one notable and alarming incident portrayed in the warning letter, an Apotex employee reported that the microbiological activity of an environmental monitoring plate was zero. Upon checking, the FDA inspector found at least one colony forming unit (CFU) present on the plate, later confirmed by testing.

The company's response to this incident was alarming on multiple levels, FDA said.

"Your firm did not take further action to investigate and determine the impact of inaccurate reporting of your microbiological plate readings on the release of your batches," it explained. "The failure to document positive results for a microbial plate that was confirmed as containing microbial growth raises concerns about the accurate reporting of results in your records. Accurate and reliable microbial data management is essential to support the reliability of your aseptic manufacturing of finished drug products intended for distribution in the United States."

Facility Two: Ontario

The company's Ontario facility did not fare much better than its Toronto facility, with FDA inspectors finding many of the same CGMP deficiencies.

For example, inspectors said unexplained batch failures went uninvestigated, including an injectable product that failed sterility testing. Other batches from the same lot were not recalled-a point likely not lost upon FDA inspectors who have been grappling in recent months with contaminated injectable drugs compounded at pharmacies throughout the US.

Incubation concerns were also raised at the second facility. In a novel observation, FDA said it found that the company "failed to record and maintain the raw data to support [its] conclusions regarding the effectiveness" of a solution product it manufactured. Instead of reporting the actual observed colony count for each plate, the company instead recorded test results for each time point.

Global Concerns

Some of the concerns raised at the second facility were, like the first, repeat observations from earlier inspections at a related (but different) plant, also in Ontario.

"The evidence suggests that Apotex has failed to implement adequate global and sustainable corrective and preventive actions, and that it continues to manufacture and distribute pharmaceutical product without upholding its legal obligation to comply with CGMP," FDA said, using unusually blunt language.

"FDA's inspections continue to find repeated deficiencies in your quality systems," regulators continued. "We highly recommend that appropriate resources be used to conduct a thorough retrospective evaluation of past deficiencies and that appropriate permanent changes be implemented to ensure that your corporation manufactures pharmaceutical products using a sustainable quality platform in all your facilities.  Fundamental to this responsibility is your assurance of timely investigation and resolution of the issues, prevention of distribution of defective product, and implementation of an effective quality management system across all facets of your pharmaceutical manufacturing operations."

Until deficiencies are remedied, FDA said it "may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer."

The company was recently the subject of an import alert on its products, which was only lifted in May 2011. At the time, the company said it was "pleased the FDA has recognized the enhancements to our global quality systems," and would immediately resume shipments to US markets.

If FDA's Warning Letter is any indication, those same global quality systems may be back in the sights of regulators.

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


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