The United States Food and Drug Administration (FDA)

By Global Compliance Seminar (LinkedInTwitter)

In a recent warning letter, the FDA has warned the drug manufacturer Emcure (Pharmaceuticals Ltd).

The following provides key observations made by the FDA inspectors and you are kindly recommended to review a full version of FDA warning letter.

It is noticeable that the FDA cited the term “falsification” six times in the warning letter.

Failure to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

  • Poor Aseptic Processing Techniques
  • Poor Sterilization Practices
  • Facility Design

Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

  • Unreliable Environmental and Personnel Monitoring
  • Inadequate Visual Inspection Program

Your firm lacked personnel monitoring data for aseptic operations on line (b)(4). Documents generated in the laboratory for personnel monitoring did not identify specific employees involved in filling operations.

According to your response, it was difficult to accurately locate plates corresponding to specific operators, because the plates were not uniquely identified. You indicated that operators were trained in aseptic practices; practices we observed were “deviations” that you “considered serious lapses by the facility management.” Furthermore, you acknowledged serious gaps “especially with respect to the suspected data integrity and falsification” in data generated in your environmental monitoring program.

Your response is inadequate. Despite your claim that your operators were appropriately trained, video recordings of your manufacturing operations clearly showed that your employees were not following proper aseptic techniques.

Failure to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

During our inspection, we observed multiple examples of incomplete, inaccurate, or falsified laboratory records.

a.    EM records for active air monitoring of the aseptic filling area reported samples as being collected when they were not actually collected, and some records documented purported EM results of zero colony forming units (CFU) even when the samples for which those results were reported were not actually collected. Contemporaneous video recordings that FDA reviewed during the inspection showed that such EM samples had not been collected, even though your laboratory records reported results for those samples. Our investigators observed your firm’s practice of falsifying EM results for samples that were not collected for multiple drugs, including (b)(4) injection USP lot (b)(4) and (b)(4) injection lot (b)(4).

Although your laboratory records for these products and lots indicated that you collected active air samples, the video we reviewed during the inspection demonstrated that operators did not actually collect the samples. During the inspection, your microbiologist confirmed that these EM samples were never collected. Additionally, two microbiologists informed the investigator that media plates were labeled and submitted for incubation as though they had been exposed to the environment. However, these media plates were never actually exposed to the environment. Your microbiologist indicated that this practice was routine and due to “work pressure.” Because the EM results for samples were falsely reported as having been collected and/or as having produced no CFU growth, you lack assurance that the injectable drugs your firm produced in this area were sterile at the end of the aseptic filling process.

b.    Our review of EM records from January 2014 through September 2014 found that no samples had exceeded the action levels for any of the (b)(4) filling lines in your (b)(4) plant, or for the filling line in Plant (b)(4). However, we observed 12 microbiological plates in the incubator showing EM results that required further action during our inspection of your laboratory.

These EM records provide critical data on environmental trends and whether environmental control is maintained during aseptic filling of a batch. Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination occurs.

In your response, you stated “there have been serious gaps in the management, oversight and execution of the environmental monitoring program, especially with respect to the suspected data integrity and falsification of data concerns.” Your response also indicated that you revised procedures, provided training, and reviewed documents from March 2013 to January 2015. Your investigation confirmed that EM samples were not collected and “the data was fraudulent.” You acknowledged these problems in your response and took some corrective actions. However, your response is inadequate because you have not demonstrated how you can ensure that EM records generated before the inspection were reliable and accurate, or how the falsification of some of your reported EM data may have affected the quality of your products.

We acknowledge your (b)(4) after the inspection, your management changes, and your engagement with consultants. However, your investigation was not extended to all systems and areas that may have been affected by your questionable practices. You have not provided data sufficient to demonstrate that all products released for distribution were manufactured with the appropriate environmental controls in place during aseptic filling operations.

Furthermore, data falsification and manipulation, and your reliance on incomplete records to release product to the market, are repeat violations. A February 2014 inspection of solid (b)(4) dosage operations at this same facility also reported data manipulation and falsification of test results generated by your firm, along with other deficient laboratory practices that also resulted in products being recalled from the U.S. market.

In your 2014 response, you made a similar commitment to hire a third party auditor to conduct a comprehensive audit of all laboratory electronic and hard copy data for tests conducted for all release and stability finished product. Our 2015 inspection found continuing practices of data falsification and manipulation at your facility, indicating that previous corrections were ineffective.

Last Updated: 2016-03-15

FDA Warned A Drug Manufacturer for Data Falsification