Carolina Infusion — FDA Warning Letter Findings

You stated in your response that the revised endotoxin test procedure includes the use of single use containers. However, although the revised SOP # 9.170 Version Number 2.0, Serial Dilution for Intrathecal Endotoxin Testing , mentions the use of (b)(4) tubes within the document, it does not indicate that the tubes are single use containers. In addition, you did not provide any supporting training documentation showing your staff were trained on this new procedure, and know how to correctly operate the (b)(4) equipment, or interpret the endotoxin report from the (b)(4) equipment.

Your facility design allowed the influx of poor-quality air into a higher classified area.

You have not addressed the lack of established endotoxin limit for your sterile intrathecal finished drug products. The acceptability of the new endotoxin results tested on 08/17/2022 submitted for evaluation cannot be fully determined because no endotoxin limit or calculation of the endotoxin limit for the intrathecal finished drug products associated with these samples were provided for evaluation.

Your firm did not address the concerns associated with the lack of endotoxin control during the production process and then release of intrathecal drug products when the (b)(4) equipment is not available for testing. Without endotoxin controls (such as endotoxin data on CoAs for bulk drug substances and other components, finished product endotoxin testing, etc.), there are no assurances that intrathecal drug products are safe for their intended use.

Your ISO-5 classified areas were not certified under dynamic conditions. 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 certification reports for your (b)(4) ISO 5 hoods did not indicate that they were performed under dynamic conditions which is different from the certification reports for your “compounding room (b)(4) that stated, “Tested Under Dynamic Cond.” In addition, you state that “we do not load the hood with items not intended for that specific prescription,”. It is unclear how you define “dynamic condition” and under what dynamic conditions the hoods are certified. Your SOP…

Your firm produced drug products with materials that had not been verified to assure that they did not contribute endotoxin contamination that may be objectionable given the product’s intended use.

You stated in your response that your certification vendor, (b)(4) , acknowledged that there were errors associated with the differential pressure reporting in the initial (b)(4) report (Report # (b)(4) , dated 2/23/2022) submitted to the firm and the report was changed. However, you did not provide the revised report for review, and therefore, we cannot evaluate the changes made to the initial (b)(4) report or its adequacy.

The new endotoxin results tested on 08/17/2022 provided by your firm did not include or address the finished drug products for intrathecal use that are combination of two or more APIs which your firm also produces. Regarding your responses related to the insanitary conditions, the following corrective actions appear deficient…

You stated in your response that you “will be using (b)(4) in the formulation of these non-sterile compounds.” This would be effective September 1, 2022. However, you did not provide any supporting documentation such as invoices showing the proof of purchase or training documentation for staff pertaining to the use of (b)(4) in non-sterile drug production.

You stated that “no growth was observed after swabbing and (b)(4) plating” post cleaning of the anteroom with “ (b)(4) ” and cleaning of the sink within the room with (b)(4) upon learning of the actionable growth observed in the February 2022 environmental sampling performed by (b)(4) . However, you did not provide any supporting evidence such as cleaning logs or subsequent environmental sampling data for evaluation. In addition, your firm’s recent (b)(4) report performed on August 30, 2022, indicates that “microbiological analysis (viable count)” was performed. However, the report provided as part of the response did not include the results of the viable count from this sampling date. You did not address certain observations related to insanitary conditions, for example…

Your response to inadequate pressure differentials in the sterile compounding cleanroom conveyed that the only way the differential pressure “could possibly go below (b)(4) ” is “if the door had not been shut and the door cracked open.” If this is accurate, then your firm’s monitoring system for differential pressures failed to adequately detect a drop in differential pressure and provide real time notification, therefore, putting the cleanroom (certified as ISO 6 where ISO 5 hoods are located, and sterile products including intrathecals are produced) at risk for potential influx of poor-quality air to enter the cleanroom undetected.

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.

Your firm used non-pharmaceutical grade components in the formulation of non-sterile drug products.

You stated in your response that you revised the endotoxin testing SOP 9.170, Version Number 2.0, Serial Dilution for Intrathecal Endotoxin Testing and that your firm “does not pool different finished compounded intrathecal compounded drug products into one unit.” However, this statement or information of not pooling different intrathecal finished drug products during endotoxin testing is not included in the revised SOP provided. In addition, you did not provide any supporting training documentation showing your staff were trained on this new procedure.

You stated in your response that your access hallway “is not neutral, it is positive pressure with an ISO 6 classification.” However, the supporting evidence provided by your firm contradicts this statement because the hallway certification report dated June 21, 2022, has the hallway as “Work Area Pressure: Neutral, Neutral to All Rooms.” Your response also stated that the hallway is classified as an ISO 6 and “since the rooms are also ISO 6, upon opening the door to any of the rooms, there is neutral pressure because all rooms and hallway are ISO-6. Therefore, no contaminants can come in or out of the room.” You provided no evidence, such as testing data or reports, to support that the facility design would prevent contamination, specifically, in the sterile compounding cleanroom where ISO 5 hoods are located, and sterile production occurs. In addition, your response further states “anti-room is a positive pressure room, and the hallway is not neutral” but you provided no evidence, such as a certification report, to prove this claim.

Review of your prescription batch records show that you produce more complex preparations during sterile drug production than what your firm demonstrated using the media fill kit from (b)(4) . For example: a. Your firm performs more complex filling procedure such as producing and filling directly into patient specific syringes as the final container closure and filling a higher number of units than what was demonstrated using the media fill kit from (b)(4) . b. Your firm also performs more complex compounding procedure including the use of nonsterile stock solutions with 90 days and 180 days beyond use date (BUD). The hold time for the non-sterile stock solution in this more complex procedure was not considered in your firm’s current media fill procedure.