Extensive Warning Letter for Indian Manufacturer of Sterile Medicinal Products - Part 3

In the course of an FDA inspection at the Indian Manufacturer Emcure Pharmaceuticals Limited between January 27 and February 4, 2015, serious violations of Good Manufacturing Practice in the manufacture of sterile products were criticized. FDA Warning Letters always refer to corresponding paragraphs from 21 CFR Part 211. The 7-page Warning Letter addressed to the Indian company focussed on major deviations with regard to 21 CFR 211.113(b), 21 CFR 211.160(b) and to 21 CFR 211.194(a).

This third part of the news closely examines the deficiencies with regard to 21 CFR 211.194(a).

"Your firm failed to ensure that laboratory records included complete data derived from all test necessary to assure compliance with established specifications and standards (21 CFR 211.194(a))"

The FDA investigator criticized a variety of incomplete, inaccurate or falsified laboratory records.

1. Environmental monitoring records for active air monitoring of the aseptic filling area; samples were reported when they had not actually been collected. Some records in laboratory protocols showed "0 CFU" although no samples had been collected. The FDA investigator was able to prove this by means of several video recordings.

2. Media plates were labeled and submitted for incubation even though they had never been exposed to the environment. This practice was referred to as routine due to heavy workload.

3. The review of environmental monitoring records from January through September 2014 revealed that no samples had exceeded the action levels for any of the filling lines. However, the investigator observed 12 microbiological plates in the incubator showing results that would have required further action.

The company admitted to this fraudulent practice. They responded that they would revise their procedures, train their staff and also review the documents from March 2013 to January 2015. However, their reply was not sufficient for the FDA, as there was no assessment of the falsifications with regard to the quality of the produced batches.

Furthermore, they criticized the company's documentation practice giving specific examples.

1. A media fill batch documented "checked by" operations performed by an employee who was not present at the facility. In addition to that, during this media fill, a QA employee signed "checked by" for observing an intervention when he was not even in the filling room during this intervention.

2. Cleaning and disinfection of the filling machine was not completed before the filling of a specific batch. However, cleaning and disinfection records were created although the video recordings did not show that.

3. An employee performed in-process weight checks during a filling operation taking place at 13:30, but this activity was not documented until 14:15. In addition, another weight check operation performed had not been documented at all on the record when reviewed by the inspector.

Evaluation: The serious GMP violations and the proven document falsifications identified by the investigator during the inspection led to severe consequences for the company. Until all deviations have been corrected, FDA has suspended approval of all their products. FDA expects a plan from the company listing the corrections of these violations within 15 working days. This should list in detail amongst others the following:

1. A comprehensive evaluation of the extent of the inaccurate data including a detailed action plan.

2. A comprehensive risk assessment of the observed failures with regards to the quality of the drugs produced to date. 

3. A management strategy for the firm that includes the details of their CAPA measures, such as contacting their customers, recalling drugs and additional tests. In addition, they should list further measures, such as revising procedures, implementing new controls, personnel training etc. pp. in order to prevent the recurrence of CGMP violations.

Source: FDA Warning Letter for Emcure Pharmaceuticals Limited dated 3.3.2016

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