Persistent Non-Compliance Leads to a Consent Decree

Persistent: (adj): existing for a long or longer than usual time or continuously

Non-compliance (noun): failure or refusal to comply with something (such as a rule or regulation): a state of not being in compliance

(Both definitions are taken from Merriam-Webster.com.)

Put these two words together in the pharma world and the combination creates a recipe for potential harm to patients and serious legal action, with the pharma company exhibiting this behavior likely to receive an FDA warning letter and possibly become the defendant in a suit filed by the U.S. Department of Justice (DOJ).

Specifically, what happens when a pharma company fails to have adequate procedures to prevent cross-contamination of equipment, fails to reject drug lots using a contaminated ingredient, and fails to fully investigate the root cause of such contamination? And what happens when these failures are discovered repeatedly during inspections, even after the company has been warned to correct them?

[Related: For more from author Jerry Chapman, click here to access additional insights from him involving the contamination risks of cloth wipes.]

At the 2022 PDA/FDA Joint Regulatory Conference in mid-September in Washington, D.C., FDA CDER Office of Compliance Director Donald Ashley presented a case study that traced the inspection and compliance history of Morton Grove, where those issues occurred. Morton Grove is an Illinois-based drug manufacturer that makes both over-the-counter and generic drugs and is owned by Mumbai, India-based Wockhardt.

“We had inspected the firm several times over the years,” Ashley noted, “but things took a turn for the worse,” when an early 2016 inspection found violations related to:

• Inadequate investigations for out-of-specification results
• Repeating tests until a passing result was found
• Inadequate process validation “which was probably an underlying root cause source of a lot of the other problems that they were experiencing”
• Widespread multiple concerns with data integrity

FDA issued a warning letter to the firm citing these violations in February 2017.

The letter also cites concerns the agency had with senior management’s oversight and approach to quality issues–not just at the Morton Grove facility, but also at other facilities owned by Wockhardt.

To say the least, the firm had an extremely poor quality culture resulting in no small part from poor leadership by senior management

Not surprising given the well-known mantra that “quality culture is pervasive”. 

On inspection, FDA personnel observed that the firm was conducting investigations of quality-related problems, “but they were doing it outside of the quality unit, specifically, so investigations would not be covered by the quality unit procedures,” Ashley asserted.

He said the owner of the company had a pattern of running poor quality manufacturing sites–sites that had received FDA warning letters and import alerts for similar CGMP violations, including for data integrity, and in particular for poor investigations into failing results.

“To say the least, the firm had an extremely poor quality culture resulting in no small part from poor leadership by senior management,” the CDER compliance director said.

Here is an excerpt from the warning letter:

“At this time, seven Wockhardt facilities (including Morton Grove) are considered out of compliance with CGMP. These repeated failures at multiple sites demonstrate your company’s inadequate oversight and control over the manufacture of drugs.

“In your responses to the various actions listed above, including during multiple meetings with FDA, you have repeatedly discussed and promised corporate-wide corrective actions. Yet, when FDA inspects or returns to other Wockhardt facilities, similar violations are shown to persist.

“Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems and processes, and ultimately, the products manufactured, conform to FDA requirements.”

The letter listed repeat violations and deviations at multiple sites owned by Wockhardt, including an overview of which sites had previously received a warning letter or been placed on U.S. Import Alert (Figure 1).

 

FIGURE 1 | Excerpt from FDA Warning Letter to Morton Grove February 2017

Subsequent to the 2017 warning letter, FDA reinspected the Morton Grove facility twice, once in 2019 and then again in 2021, and the data integrity issues “just got worse” Ashley stressed. “So, even after we had alerted the site to our concerns over data integrity in the 2017 warning letter, upon reinspection, we found that backdating of microbial test results was actually condoned by the facility management. That, for us, really called into question the validity of any of the test results at the site.”

Also discovered was evidence of serious cleaning deficiencies as well as microbial contamination of drugs.

Ashley provided photographic examples of the observations that agency investigators reported upon reinspection (Figure 2). The photo on the left shows the inside of a piece of equipment that had been marked clean, however, “you can easily see the drug residue on those product contact services, so the material could have readily transferred and contaminated the next batch made with that equipment,” he pointed out.

 

FIGURE 2 | What FDA Found on Re-Inspection

“And on the right, you can see rust and chipped paint on a motor that was directly above an opening in a tank, and so that allowed the rust to fall directly into the tank and contaminate the drugs.”

Given the lab testing integrity issues seen previously, the agency was concerned that testing would not find these contamination events had they occurred.

Due to the widespread and escalating quality concerns that were identified at the facility, FDA worked with DOJ to seek relief through the courts.

In August 2022, an Illinois federal judge approved a consent decree of permanent injunction. It states, in part, “the negotiated consent decree entered by the court permanently enjoins the defendants from violating the FDCA, and requires, among other things, that the defendants stop manufacturing, processing, labeling, holding, or distributing adulterated drugs. Further, the defendants must destroy all drugs in the facility, except for those that are medically necessary.”

As for the other sites that were mentioned in the warning letter to Morton Grove, all but one of those remain on import alert or are no longer in the U.S. supply chain, Ashley reported.

To access the site profile for Morton Grove Pharmaceuticals in Redica Systems, click here. When evaluating a potential GMP partner, it is critical to perform due diligence, including reviewing a site or organization’s enforcement history. If you want to learn more about how Redica Systems can help you monitor your GMP partners, contact us to schedule a walkthrough of the platform.