FDA Cites Data Integrity Concerns at Mylan, Product Quality Issues at Indoco

FDA cites data-integrity concerns at Mylan, product quality issues at Indoco

Two months prior to inspecting Divi’s Labs and Hetero Labs in India, FDA investigator Massoud Motamed inspected a finished dosage form (FDF) facility of Mylan Laboratories in Nashik (India) from September 5-14, 2016.

This week, the facility was issued a warning letter by the FDA after data integrity concerns emerged from the site. PharmaCompass has also obtained a copy of the Form 483 issued to Mylan from FDAZilla.com.

The warning letter to Mylan only reiterates the conclusion PharmaCompass had drawn from FDA’s observations at Divi’s (READ: Divi’s inspection reveals FDA’s shifting focus beyond audit trails).

The chromatography systems at Mylan had their audit trails enabled. However, Mylan’s quality unit failed to monitor and investigate error signals that indicated loss or deletion of original cGMP analytical data.

The quality unit failed to review or investigate the audit trail for tests which included the message, “deleted result set”, or instances where the audit trail displayed the message “Project Integrity Failed”.

The “Project Integrity Failed” message indicates that injections were missing from the results of analytical testing. The review of the data package, for a specific case, showed that the initials run was missing from the analysis and Mylan’s quality unit did not investigate the incident.

Mylan invalidated OOS results without sufficient probe

During a thorough review of Mylan’s Quality Control systems, Motamed uncovered that Mylan had invalidated 101 out of 139 (about 72 percent) out-of-specification (OOS) results without sufficiently investigating the root cause of initial failure.

While Mylan attributed the problem to “analytical bias” in its laboratory processes, the FDA said there was a failure (on part of Mylan) in determining how the analytical errors could be eliminated or mitigated in the future.

The FDA investigator said numerous laboratory incidents were attributed to power interruptions, connectivity problems (disconnection of the Ethernet or power cord), and instrument malfunctions. The frequency of these events and the lack of comprehensive investigation into the problems (on part of Mylan) to correct them and prevent their recurrence was also a cause of concern.

Mylan’s frequent invalidation of initial failures without an assignable cause and the decision to exclude a large proportion of this information from its trend reports which monitored OOS investigations was also highlighted, especially as it was a repeat observation from a previous FDA inspection conducted in March 2015.

Four key messages in FDA’s Form 483, issued to Mylan

PharmaCompass was able to lay its hands on the Form 483, which includes many messages that were missing in the warning letter issued to Mylan. Here are the highlights of the Form 483:

— The analysis (i.e. GMP testing) of drug products undertaken by Mylan was done prior to ensuring the validity of the methods of GMP testing.

— Mylan validated laboratory methods which did not provide consistent and reliable test results.

— Mylan’s visual inspection system failed to identify chipped or broken tablets. Thereby, it failed to ensure product quality. This is a repeat observation from a previous inspection (conducted in March 2015).

— A white residue was found on the equipment which was considered to be clean by Mylan. This was an area of concern at other sites too, that had been inspected by Motamed.

At Indoco, FDA cites 1,500 complaints of leaking sterile solution bottles

While there was no specific product quality concern highlighted at Mylan, this wasn’t the case at Indoco Remedies. In a previous (2011) FDA inspection at Indoco, the regulator had cited 17 product complaints for leakage or crusty residue in the drug product.

In the warning letter issued to Indoco’s facility located in Goa (India), the FDA mentioned that the firm received numerous (approximately 1,500) consumer complaints related to leaking, empty, and under-filled sterile solution bottles between January 2012 and August 2016.

Indoco’s investigation indicated that this persistent critical quality defect was due to a filling machine issue and these defects were not easily detected. In some cases, the cracks did not appear immediately. Rather, the cracks developed days later in the finished units.

Although Indoco had been working on remedying the problem since 2013, they continued to receive a large number of complaints. It was unclear to the FDA if the latest actions had adequately addressed the causes of these recurring problems.

While Indoco did implement a leak testing of finished units at the end of processing, the FDA raised concerns over how this test would detect leaks that emerged after several days.

The FDA also questioned the practice where Indoco proposed “an action level threshold for initiating investigations that is based on the number of complaints received per batch”. The warning letter states that the criteria should be the criticality of the product complaint rather than the number.

Indoco, which acts as a contract manufacturer to various drug products, also failed to notify its customers, although numerous complaints had been received for multiple lots pertaining to defects like leaking, empty, and under-filled bottles.

Indoco’s failure to appropriately notify its customers of the quality problems may have delayed their customer’s ability to take important actions to ensure the quality, safety, and efficacy of its product.

Our view

While the observations at Indoco highlight concerns related to over a thousand product quality complaints, the Mylan warning letter indicates an emerging trend the industry should be aware of — that the focus of regulatory inspections is moving beyond audit trails

Inspections are no longer about companies not having enabled the audit trails on computerized systems that are used for high performance liquid chromatography and gas chromatography.

Recent FDA observations indicate a thorough review of the information captured by the audit trails and an increased focus on batches which were out-of-specification (OOS).

Investigators matter

The FDA inspector at Mylan inspected Divi’s Labs, which was placed on an Import Alert, and his observations also led to warning letters being issued to Interquim in Spain as well as to CTX Life Sciences and Pan Drugs in India.

While organizations cannot choose the investigator who will inspect their facility, they can ensure that the areas of focus for Motamed get addressed adequately.

FDA and EU regulators once again don’t agree on the state of compliance

In a statement to Regulatory Focus, Mylan said “production at its Nashik site “continues uninterrupted” and the company does not anticipate any supply issues related to any products currently being manufactured at the site as the Nashik site has a good standing with other global regulators, including UK's MHRA, which inspected the site after the FDA inspection and granted it a GMP certificate.”

READ: FDA and EU differ on cGMP standards at the same facilities: How will they mutually recognize inspections?

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“ The article is based on the information available in public and which the author believes to be true. The author is not disseminating any information, which the author believes or knows, is confidential or in conflict with the privacy of any person. The views expressed or information supplied through this article is mere opinion and observation of the author. The author does not intend to defame, insult or, cause loss or damage to anyone, in any manner, through this article.”

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