INDIAN MFG FACILITIES RECEIVE WARNING LETTER FOR PROBLEMS ASSOIATED WITH THE ASEPTIC PROCESSING AREA (APA) (102215)

The U.S. Food and Drug Administration (FDA) inspected the following two pharmaceutical manufacturing facilities:

1. August 25-29, 2014: Sandoz Private Limited, MIDC Plot Nos. 8-A/2 & 8-B, TTC Industrial Area, Kalwe Block, Village Dinghe, Navi Mumbai 400 708, Maharashtra, India (Kalwe facility)
2. August 12-28, 2014: Sandoz Private Limited, Plot Nos. D31 & D32, MIDC, TTC Industrial Area, Turbhe, Thane-Belapur Road, Navi Mumbai 400 705 Maharashtra, India (Turbhe facility)

At both sites, the FDA identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.

The following Blog includes only the Turbhe facility and focuses upon the Indian Mfg Facilities Aseptic Processing Area (APA). 

We (the FDA) are aware of your plan to shut down and/or divest the Turbhe facility. Nevertheless, because several CGMP violations at the Turbhe facility relate to aseptic process controls, and are similar to violations cited in Warning Letter 320-12-05 issued to Novartis International AG on November 18, 2011, we note the following violations at this site.

1.  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)).

You failed to perform adequate unidirectional airflow studies (smoke studies) on the aseptic filling line used to produce sterile finished drug products.  Portions of a videotaped smoke study reviewed by the investigator did not adequately document airflow patterns during manual interventions.  In some instances, airflow patterns could not be observed and evaluated.  Insufficient smoke and poor camera angles made it impossible to determine unidirectional airflow.

COMMENT 

Unidirectional airflow studies, i.e., smoke studies have become a standard element of what the FDA desires to review when they visit an APA. As noted, airflow patterns during manual interventions need to be reviewed and evaluated. Where the FDA finds insufficient evidence based on their observations, they will request the firm to repeat these studies and submit the information to them. Interestingly, the Compliance Officer for this Warning Letter has been on the forefront of those auditing APA and reviewing smoke studies. Please visit the following Blogs (Click Here) to view similar 483s and Warning Letters. 

1. Your firm failed to establish procedures to remove units following interventions, periodic adjustments, set-up, and end of fill.  Furthermore, your firm rejected units with intact container/closure systems from media fills without written justification or explanation.

According to the SFDF/MF/12/07 media fill batch record (filling end date July 3, 2012), 359 media-filled vials were rejected after interventions due to machine set-up and periodic adjustments, and after the end of the filling process.  None of these vials were incubated as part of the media fill.

According to the SFDF/MF/14/01 media fill batch record (filling end date May 13, 2014), 177 media-filled vials were rejected after interventions due to machine set-up and periodic adjustments, and after the end of the filling process.  None of these vials were incubated as part of the media fill.

COMMENT 

Procedures should be in place and followed for units removed following interventions, periodic adjustments, set-up and end of fill. In addition, rejected vials with intact container/closure systems involved in media fills should only be removed with written justification or explanation. In addition, incubation of the vials should have been completed. Please visit FDA’s Guidance for Industry Aseptic Processing (September 2004) (Click Here)  to learn more. 

2. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

You have inadequate scientific justification for your environmental monitoring sampling plans in manufacturing areas for aseptically-filled injectable drug products.  This includes the locations of viable airborne particulate sampling, settle plates, and contact surface monitoring.

We acknowledge your SOP/CB/QC/510, “Microbiological Monitoring of Air, Surfaces and Personnel in Production Area.” You used a chart contained in this SOP to justify your choice of environmental sampling locations.  However, you did not supply data to support your current locations.  In addition, neither your environmental monitoring procedures nor your sampling records clearly identify where environmental monitoring samples are taken.

COMMENT 

ICH Q9 Risk Management (Click Here) should be observed when developing data to clearly identify where environmental monitoring samples are to be taken. When developing environmental sampling locations, it becomes necessary to sample more than the minimum to establish that the best locations are being used for sampling purposes.