Mylan Pharmaceuticals Inc. made a hefty investment to improve Agila Specialties Pvt. Ltd. after its 2013 acquisition but despite the changes FDA has found numerous good manufacturing practice violations at three Agila plants in Bangalore, India.

On Aug. 6 FDA issued a 14-page warning letter to Mylan President Rajiv Malik citing deficiencies at the three sites, including use of gloves with cuts and tears in aseptic processing, inadequate laboratory controls, and failure to identify the source of gram-negative contamination.

The violations were found during FDA inspections of two plants, the Specialty Formulation Facility and the Sterile Product Division, in 2014, and an inspection of Agila’s Onco Therapies Limited facility in February 2015. The letter, signed by Thomas Cosgrove, director of the Office of Manufacturing Quality in the Center for Drug Evaluation and Research, was posted on the agency’s website Aug. 18.

Mylan announced the purchase of the Agila injectables business from Strides Shasun Ltd. in February 2013 and completed the acquisition in December of that year. In a February 2013 earnings call, CEO Heather Bresch noted that leadership was needed in the space “as some current market leaders are experiencing significant quality issues, resulting in supply disruptions and product shortages” Also see "Pharma Pursues Generic Injectables Quality Turnaround Opportunities" - Pink Sheet, 27 March, 2015..

Agila subsequently had its own quality issues as FDA issued a September 2013 warning letter to Strides citing violations at the Agila sterile manufacturing facility, many of which are also cited in the current letter ([A#28130915002]).

Since then Mylan has invested about $100 million in building infrastructure at Agila, hired consultants and replaced temporary employees with 200 new staff on the quality side ([A#28150306001]).

Production Had Been Halted At Three Plants

Following the February inspection, Mylan issued a March 27 statement to customers noting that it was continuing to take steps to integrate the Agila business and that as part of this process, it had made the “proactive decision to temporarily cease commercial production and distribution” at certain smaller Agila sites, including the Onco Therapies Limited (OTL) facility subject to inspection, the Beta Lactam Division (BLD), and Hosur.

“Several marketed and pipeline products on FDA drug shortages lists are manufactured at OTL and Hosur,” Mylan wrote. “Some of these are qualified and can be moved to another site. Mylan has advised FDA of the impacted products so that Mylan and the agency can coordinate to take appropriate actions to mitigate shortages.”

In its letter, FDA advised Mylan to inform CDER’s Drug Shortages staff immediately if it was considering a decision that could reduce the number of active pharmaceutical ingredients products produced by its manufacturing facility.

Mylan could not say how many products are manufactured at the plants cited by FDA. At the time of the acquisition, Agila had 61 FDA-approved ANDAs, 51 of which were commercialized, and 122 ANDAs pending at FDA.

FDA told Mylan that it may withhold approval of any new applications or supplements listing Mylan as the manufacturer until the agency confirms the company’s corrections and compliance with current good manufacturing practice. However, unlike other companies whose Indian facilities have been cited for GMP violations, FDA did not issue an import alert on Mylan’s sites.

Inadequate Microbial Testing, Poor Personnel Monitoring

In an Aug. 18 release, Mylan’s Bresch stated that since acquiring Agila, Mylan has been “taking extensive action to integrate the Agila business into Mylan’s One Quality Standard, and to ensure our leading position as a high quality, reliable source of injectables for the long term. As part of this ongoing process, we have a deep and unwavering commitment to quality everywhere we operate. We have been and will continue to work diligently to address all of the FDA’s observations and have made important progress.”

Among the violations found at the Onco Therapies facility in February, FDA said the company failed to follow written procedures to prevent microbiological contamination of drug products. For example, the agency said 15 gloves in one suite and four in another were “non-integral.” It said gloves used for aseptic processing had tears and pin holes and one glove had large cuts in two fingers. In addition, FDA said the company did not follow the proper procedures to test glove integrity and falsely represented results.

With regard to environmental monitoring, the agency said there were repeated out-of-action-level results from microbial testing but Mylan “did not examine the data for trends or take appropriate follow-up action.”

In addition, the agency said Mylan’s personnel monitoring is deficient. It cited a video in which FDA observed an operator was in contact with certain gloves without sanitizing his gloved hands and that the gloves were later worn for aseptic connections, purging filling needles, and interventions on the filling machine.

Further, FDA said that on video and in person, it observed employees with something (the substance was redacted from the letter) on their hands before environmental monitoring checks.

Compromised Lots May Have Been Released

The agency also stated that in response to the inspection, Mylan followed a product quality assessment protocol and found visible foreign particulate matter within examined lots. In March and April, Mylan voluntarily recalled seven lots of gemcitabine 200 mg/vial, gemcitabine 2 g, gemcitabine 1 g, carboplatin 10 mg/mL, methotrexate 25 mg/mL, and cytarabine 20 mg/mL and in June expanded the recall to an additional eight lots of gemcitabine and methotrexate. However, FDA said, other lots released into distribution may have been compromised by this manufacturing issue.

As for the two plants inspected in August to October 2014, FDA said the Specialty Formulation Facility did not document the actual number of aseptically filled units transferred to an unspecified location or the reasons media fills were rejected. The facility was cited for inadequate media fills and rejection of media fills units without justification in the September 2013 warning letter.

The agency also said the firm failed to identify the source of gram-negative Pseudomonas bacterial contamination it had identified during passive air sampling collected from a passageway in one ISO-7 suite, designed to meet the International Organization for Standardization 14644 standard for Class 7 cleanroom airborne particle limits.

At the Sterile Product Division, FDA said Mylan failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications. Among other things, the agency said it had observed that operators moving in and out of classified areas “were not slow and deliberate” during the set-up and filling of a batch and that it often saw operators bump into each other during filling operations.

The violations found at these three sites, together with other deficiencies found by FDA investigators, “raise questions about the ability of your current corporate quality system to achieve overall compliance with CGMP,” the letter states. “Furthermore, several violations are recurrent and long-standing.”

The agency added that even without the September 2013 letter, Mylan’s corporate quality system should have detected and corrected the violations without FDA intervention.

Mylan Hit With GMP Warning Letter Despite Quality Improvement Efforts

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