Over the past several years the FDA has issued Warning Letters to a number of aseptic processing facilities that have encountered difficulties with their management of air flow. While the management of airflow appears to be an easy area to manage within the Aseptic Processing Area (APA), the number of Warning Letters (Click Here) has suggested otherwise.
The “speed†in which a recent Form FDA 483 turned into a Warning Letter suggests that the FDA was quite concerned with what they observed within Sun Pharmaceutical Industries Ltd, India. Investigators from  the U.S. Food and Drug Administration (FDA) inspected their pharmaceutical manufacturing facility at Sun Pharmaceutical Industries Ltd., Halol-Baroda Highway, Halol, Gujarat between September 8-19, 2014, and following an exchange of letters, which found Sun Pharmaceutical’s actions insufficient, issued a Warning Letter (Click Here) on December 17, 2015.
The FDA reviewed the October 10, 2014, response in detail and found It lacking sufficient corrective actions. The FDA also acknowledged receipt of correspondence of December 12, 2014; February 10, 2015; and May 5, 2015. Please note that any additional information following an initial response may, or may not, be considered in the formation and issuance of a subsequent Warning Letter.
The Warning Letter included a number of Sections as part of Observation 1. They included:
- 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)).
COMMENT:
21 CFR 211.113(b) is the second of two sections within 21 CFR 211.113. 113(a) represents non-sterile drug products, while 113(b) references sterile drug products. The “following of appropriate written procedures†represent one mode in which 211.113 may be used. Â
- “You failed to perform adequate unidirectional airflow studies (smoke studies) under dynamic conditions to determine how the movement of air and personnel during aseptic operations could pose risks to product sterility. In addition, the studies indicate that your aseptic processing equipment is not properly designed. For example, an audit of your smoke studies found:
- Significant airflow turbulence, including air moving in an (b)(4)direction, in the laminar airflow (LAF) unit in which aseptic (b)(4) and tubing connections are made for the (b)(4) Also, the studies lacked dynamic simulation of this critical intervention.
- No dynamic smoke studies to demonstrate unidirectional airflow during the manual aseptic transfer of (b)(4)units into the (b)(4) used for transport to the (b)(4).
- Inadequate evaluation of airflow patterns in your stopper (b)(4) area, and turbulence around the stopper (b)(4).
- Lack of smoke studies during aseptic filling line setup activities.
- Operators (b)(4)open filled vials when adjusting the stopper (b)(4), which is a hazard to sterility assurance.
Without smoke study data to demonstrate unidirectional airflows over all aseptic operations and processing steps, you cannot show that your processes are designed to prevent microbiological contamination or provide adequate assurance of product sterility.â€
COMMENT:
Dynamic as opposed to static studies are critical within an APA to demonstrate the movement of air in the presence of personnel and filling and stoppering of vials. As noted in the Warning Letter, the results observed, even with their (Sun’s) rudimentary studies, suggest the APA equipment is not properly designed. The balance of the “bullets†noted above are self-explanatory. Â
“In your response to the FDA-483, you acknowledged the need for design improvements and new airflow studies. You also proposed to revise your smoke study protocol (b)(4) to cover all aseptic interventions and material movement, and to conduct smoke studies by November 15, 2014. Your firm has submitted neither a revised smoke test (b)(4), nor a satisfactory new smoke study.
In response to this letter, perform and send a video of new dynamic smoke studies that fully evaluate unidirectional airflow during your aseptic manufacturing operations, and a copy of your revised smoke test (b)(4). Also explain how your firm will be comprehensively evaluating the design of your aseptic processing operation, and describe any major equipment and facility upgrades that are planned.Â
COMMENT:
Promises to submit revised protocols and to conduct studies should always be followed with the utmost urgency. A failure to follow through, e.g., neither a revised smoke study…, nor a satisfactory new smoke study, was provided by the time of the issuance of this Warning Letter (December 17,2015).
Please note that several other Blogs will be forthcoming regarding this Warning Letter.
Leave a Reply