New Extensive Warning Letter for Indian Manufacturer of Sterile Medicinal Products - Part 1

Recommendation

18/19 June 2024
Copenhagen, Denmark

Environmental Monitoring
Compliant and Reasonable

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), 21 CFR 211.160(b) and to 21 CFR 211.194(a).

The first part of this News closely examines the deficiencies regarding 21 CFR 211.113(b).

"Your firm failed 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))"

Here, the deficiencies are divided into 3 groups: 

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

Poor Aseptic Processing Practices:
On the inspector's part, a number of negative observations have been listed:

• An employee placed a cup on the floor of an ISO 7 area to collect water. When setting up the filling line of the ISO 5 area, employees used that water to wet the mechanical assembly in the piston drive. 
• Machine operators crawled on the floor on their hands and knees under the filling line. 
• An operator directed vials to the machine with his hand located directly above. 
• When setting up, an employee moved an un-bagged sterilised tool directly from the ISO 7 to the ISO 5 area. 
• During unloading in the ISO 7 area, an operator dropped a sterilised lid from a container onto the floor. He then picked it up and placed it back on the container. 
• Before performing aseptic filling activities in the filling room during aseptic setup, operators wore goggles on their foreheads and exposed skin. 
• Operators opened machines to adjust or remove vials with bare hands. 
• Operators carried unprotected sterilised material from an ISO 5 to an ISO 7 area and then to the mobile Laminar Air Flow area.

In addition, it has been noticed that all these elements had been regulated but not executed by the staff.
 
Poor Sterilization Practices:
The validation report referred to a loading pattern for the RABS. According to the inspector's observation, the operators didn't follow it.

Facility Design:
Two aspects have been primarily criticised by the inspector. An employee crawled under a filling line to access an area where he performed other critical operations. Besides, the inspector wasn't delighted by the point regarding collected water from the bottom of a filling machine to lubricate equipment!

When answering to the inspection report (with regard to the deficiencies list on the Form 483), the FDA would have expected an evaluation of all available videos to identify all batches that could be affected by poor aseptic practices and associated risks. As response to this Warning Letter, the FDA now expects following actions to be taken by the company:

• List of all batches manufactured from November 2014 to the end of the inspection 
• Independent third party's evaluation of the recordings 
• Detailed action plan describing the revisions of the procedures, content of employee training and how video recordings are evaluated and by whom

The coming part 2 will be dedicated to the deficiencies with regard to environmental and personnel monitoring.

Source: FDA Warning Letter dated 03.03.2016 for Encure Pharmaceutical Limited