Extensive Warning Letter for Indian Manufacturer of Sterile Medicinal Products - Part 2

Serious violations of Good Manufacturing Practice in the manufacture of sterile products have been observed during a FDA inspection at the Indian manufacturer Emcure Pharmaceuticals Limited between January, 27th and February, 4th 2015. Warning Letters from the FDA always refer to the respective 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) - also see "New Extensive Warning Letter for Indian Manufacturer of Sterile Medicinal Products - Part 1, 21 CFR 211.160(b) and to 21 CFR 211.194(a).

The second part of this News closely examines the deficiencies with regard to 21 CFR 211.160(b).

"Your firm failed 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))"

Here, the deficiencies are divided into 2 groups:

  • Unreliable environmental and personnel monitoring
  • Poor visual controls

Unreliable environmental and personnel monitoring:

Considering the materials and requirements used for monitoring, the data obtained seem to be unreliable to the FDA. Here, three deficiencies have been listed in detail. For the FDA, the company's responses to these deficiencies weren't sufficient so that now further measures are expected from the company.

1. The inspector observed dried media plates in the incubator which were used for surface and personnel monitoring. 36 plates showed corresponding signs. The company has been instructed by the FDA to take further steps to determine whether the products manufactured under these conditions meet the microbiological limits. Moreover, the company shall explain how laboratory controls can be improved in the future to prevent use of unsuitable media.

2. The data from environmental monitoring in the filling areas didn't indicate the sampling location during filling. The SOP contained no information about the critical areas of filling. Instead, it was individual operators' decision to determine such locations themselves. As a response, the FDA expects the company to determine the sampling locations in the RABS and to improve the sampling procedures.

3. Personnel monitoring data were missing for operators in the aseptic area. The data generated in the laboratory for personnel monitoring didn't mention the operators' names.

Also the company's response according to which only employees trained in aseptic practices operate in aseptic matters was judged as unreliable. Watching the video recordings alone was sufficient to prove that the employees weren't following proper aseptic techniques.

It has also been noticed that many of these points have been laid down in a provision not taken into consideration by the personnel. The company has been decidedly reminded of its responsibility to have the production and quality management control the critical processes.

Inadequate visual inspection program:

Beside the poor monitoring program, the inadequate visual inspection program has also been criticised. In particular, the qualification and re-qualification of operators didn't specify the operators' ability to identify known product defects. It has also been criticised that visual inspection operators failed to correctly identify basic defects as described in the SOP. Moreover, the SOP doesn't contain any objective criteria to classify defects as critical or major. The company responded to these deficiencies with the announcement of a new qualification program for employees. Here, the FDA would have expected more than just the announcement - i.e. the revised program itself.

Finally, the FDA is expecting in the response to this Warning Letter a detailed summary of improvements of the visual inspection program, particularly the following elements:

  • The current training and the future training measures concerning visual inspection operators
  • Determining the effectiveness of the training measures taken
  • Setting the plan to improve defect classification
  • Setting the measures to be taken when a visual inspection operator isn't able to differentiate critical defects from major ones.
  • A statement from the company is expected regarding how to ensure that no batches with critical defects can be released to the market, given that the visual inspection program relied on subjective determinations of criticality by visual inspectors who were unable to correctly classify defects during the inspection.
  • The FDA is also expecting the results of a risk assessment of products which were visually inspected by unqualified employees.
  • Last but not least, measures should be taken to ensure that no patient has been / can be exposed to the products with critical defects.

The coming part 3 will be dedicated to the deficiencies with regard to laboratory records.

Source: FDA Warning Letter dated 03.03.2016 for Emcure Pharmaceuticals Limited

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