1Deviation, CAPA, and investigation
Related to the transfer of (b)(4) vials through an ISO (b)(4) area, your response is focused on potential long term corrective actions such as upgrading the (b)(4) to change the entire area to ISO (b)(4) , purchasing (b)(4) biosafety modules, or evaluating new (b)(4) to reduce or eliminate exposure to the ISO (b)(4) environment. However, your response did not address how you would ensure that other (b)(4) products are not exposed to worse than ISO (b)(4) quality air in the interim. In addition, you did not provide a copy of investigation 030325-02 as referenced in your response.
2Contamination control
Your response did not address microbial recoveries in the ISO (b)(4) areas of (b)(4) CFUs or less, including non-spore forming bacteria. Per your response, it appears that your firm’s action limit is greater than (b)(4) CFUs for all classified areas, including ISO (b)(4) areas. Please note that any microbial contamination in the ISO (b)(4) area is considered an insanitary condition. Any microbial contamination within the ISO (b)(4) area is a serious concern and upon recovery, your firm should immediately assess the impact on drug products produced. This assessment should include a thorough evaluation of how contamination could have entered this critical area, and over what period of time the contamination could have existed, as well as drug products that remain on the market that could be affected.
3Aseptic processing and sterility assurance
Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO (b)(4) area. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.
4Aseptic processing and sterility assurance
Your firm exposed drug products intended to be sterile to worse than ISO (b)(4) quality air.
5Environmental monitoring
Your firm failed to perform adequate routine environmental monitoring in the ISO (b)(4) area. Specifically, (b)(4) units are not monitored using meaningful environmental monitoring data to include surface, viable active air, or non-viable air samples inside the (b)(4) units. Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being adulterated. C. Corrective Actions We have reviewed your firm's responses to the Form FDA 483. Regarding your responses related to the insanitary conditions, the following corrective actions appear deficient…
6Aseptic processing and sterility assurance
Your firm failed to sterilize (b)(4) by routine sterilization cycles and protect from contamination by sterilizing (b)(4) on (b)(4) air lines/vents.
7Aseptic processing and sterility assurance
You state that your firm “will commit to assessing and improving the current media fill program to include loading and unloading trays of media filled vials in the (b)(4) .” However, your response did not address how you would ensure that (b)(4) products have appropriate media fills in the interim to ensure the processes are aseptic. Furthermore, your response did not state that you would cease or pause (b)(4) products you produce until adequate corrections are made.
8Environmental monitoring
With regard to your TriMix Gel product you state that “Even though the product [Trimix Gel] has been discontinued, an investigation 030325-01 has been opened that includes a review of customer complaints, adverse events, and environmental monitoring for the Trimix Gel product…” However, you did not provide a copy of investigation 030325-01 as referenced in your response.
9Aseptic processing and sterility assurance
Your media fills were not performed under the most challenging or stressful conditions. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility.
10Aseptic processing and sterility assurance
Your firm did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO (b)(4) aseptic processing area.
11Aseptic processing and sterility assurance
You acknowledged in your response that your firm does currently utilize a sterilization process for the (b)(4) . Generally speaking, (b)(4) and (b)(4) are considered adequate methods for (b)(4) sterilization. We note it is difficult to demonstrate sterilization of a (b)(4) by chemical treatment, that is (b)(4) , such as sporicidal agents on (b)(4) surfaces. You further stated that “We have opened an investigation 030325-06 for observation. A risk assessment of the current…
12Aseptic processing and sterility assurance
You state that your firm’s new “smoke studies will include simulations that capture worst‐case, dynamic conditions on the video, along with interventions common to the processes employed in the facility during aseptic compounding in the ISO (b)(4) BSC hoods.” However, you have not provided any new smoke studies or protocols for new smoke studies. With respect to previously deficient smoke studies, you further state that your firm “opened investigation 030325‐04 for the observation and if there are any potential product quality concerns.” However, you did not provide a copy of investigation 030325‐04 as referenced in your response. Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether drug products you compound meet the conditions of section 503A, including the condition on receipt of a prescription for an identified individual patient prior to compounding and distributing drug products. D.
