ProRx, LLC — FDA Warning Letter Findings

The procedure outlined in your SOP #: ProSOP-B090, Rev. 00, appears contradictory. Step 7.1.4 within the SOP, states that the BSC (b)(4) . However, the instruction in step 7.1.5 states to turn off the blower prior to and during the sanitization of the BSC. You did not provide any scientific justification or data to support this practic e.

Your facility’s drug products, such as Vancomycin 25mg/ml 10ml, and Tobramycin 14mg/ml 10ml, did not include the following information on the container: 1) information to facilitate adverse event reporting: www.fda.gov/medwatch and 1-800-FDA-1088 and 2) directions for use, including, as appropriate, dosage and administration.

Your firm has never performed environmental monitoring in the ISO 5 area.

Your firm failed to establish an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

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.

Regarding the lack of a defined minimum pr…

Your firm used non-sterile wipes within the ISO 5 aseptic processing area.

Your firm’s ISO 5 BSC is powered off when not in use and during the cleaning and disinfection process prior to aseptic drug production. There is no assurance that contamination is not introduced when the BSC is powered off as it may allow for the influx of lesser quality air into a higher quality air area.

The supporting document you provided in your response does not adequately demonstrate that your cleanrooms were certified under dynamic conditions. For example, on page 8 of 12, the certification report indicates the room’s status as “At Rest” and the number of people in room is “ (b)(4) .” This does not appear to represent dynamic conditions at your facility. Review of the evidence collected during the inspection notes that your production process for sterile filling requires (b)(4) operators in the BSC during filling and capping.

Your facility’s drug products, such as Semaglutide 5mg/2ml (2.5mg/ml) 2ml, Tirzepatide 60mg/3ml (20mg/ml) 3ml, and Vancomycin 25mg/ml 10ml, did not include the following on the label: the statement “This is a compounded drug”; the name, address, and phone number of the applicable outsourcing facility; the established name of the drug; the dosage form; the statement “Office Use Only”; and a list of active and inactive ingredients, identified by established name and the quantity and proportion of each ingredient.

Your firm’s Pharmacist in Charge (PIC) was observed rapidly prodding a pile of sterilized rubber caps with forceps, in an attempt to dislodge them, inside of the ISO 5 Biosafety Cabinet (BSC), near uncapped filled vials of drug product intended to be sterile. This practice, moving quickly in a critical area, may disrupt airflow and increases the risk of bringing lesser quality air into the ISO 5 area.

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)).

Regarding your failure to establish a pest control program, you stated that you have instituted a formalized pest control policy and have signed a contract with (b)(4) to assist with (b)(4) monitoring of the perimeter of your facility and inside areas as needed. However, it appears your firm has not conducted any investigation to identify the root cause, specifically, where and how these insects enter the facility, or taken appropriate action to eliminate these points of ingress. Some of your corrective actions appear deficient…

Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).

An operator exposed their bare hands within the ISO 5 work area while donning gloves in preparation for aseptic production.

A flying insect was observed on the walls and ceilings of the ISO 7 Anteroom and on the door inside of the ISO 7 Buffer Room, approximately 10 feet from the ISO 5 BSC used for sterile drug processing. FDA investigators also noted CGMP violations at your facility, that caused your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example…

Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

The process outlined in your SOP #: ProSOP-B094 Rev.00, allows for the use of a sterile (b)(4) to cover unfilled sterile vials and directs operators to move the (b)(4) during filling. This practice puts the product at risk for contamination and may also disrupt unidirectional airflow to the exposed produc t.

The process outlined in your SOP #: ProSOP-B088, Rev. 00, instructs operators to don their (b)(4) of sterile gloves after donning not only their hair net, facemask, and shoe covers, but also the sterile garment using their bare hands. While the procedure requires your operator to wash and clean their hands with antiseptic before gowning, gowning with bare hands compromises the sterile garment and represents a contamination risk to your aseptic production environment. Additionally, your gowning procedure permits the reuse of gowning multiple times after entry and exit of the cleanroom within the same compounding day, which also represents a contamination ris k.

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

Regarding your media fills, we acknowledge your commitments described in your response, including that you have revised your media fill SOP and that, “Going forward, the size and scope of media fill will be (b)(4) .” However, to date, you have not submitted the revised media fill SOP, training records, or any other supporting documentation to demonstrate that the corrective actions were implemented. You have submitted two blank documents that appear to be your media fill batch record templates with no specific details reflecting the commitments written in your response. Moreover, your firm has provided no justification for failing to conduct an investigation and implement corrective and preventive actions (CAPA) related to your failed media fill. Any contaminated unit should be considered objectionable and investigated. Whenever contamination exists in a media fill batch, it should be considered indicative of a potential sterility assurance problem.

In your response, you stated that you, “purchased media that came with a valid Certificate of Analysis (COA)” and that “the COA lists all the organisms that the media supports.” Your response is not adequate as the media your firm uses is not a ready-to-use media; it comes in (b)(4) form that requires additional preparation at your facility before it can be used as intended. You did not commit to conducting growth promotion testing after media preparation to ensure that the media was prepared correctly prior to use. Growth promotion testing should be performed on all lots of prepared media.

Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).

Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition (21 CFR 211.56(a)).

Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)). Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been…

Your firm’s PIC put on gowning apparel in a way that may cause the gowning apparel to become contaminated. Specifically, your firm’s PIC was observed bending down on the floor, on their hands and knees, inside of the ISO 7 Anteroom. Your firm’s PIC then only sprayed their gloves with (b)(4) and proceeded to produce drug products intended to be sterile.

Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and 211.22(d)).

Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 area. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.

Regarding your Environmental Monitoring (EM) and Personnel Monitoring (PM), we acknowledge your commitment to include EM/PM for all your future batches and to also incubate your sampling plates at (b)(4) temperatures. However, you have not provided sufficient details regarding your planned corrective actions. In addition, you did not commit to revising the action level (" (b)(4) ") for viable surface sampling within the ISO 5 environment. Any microbial contamination within the ISO 5 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 the time period over which the contamination could have existed, as well as an evaluation of drug products that remain on the market that could be affected.

Your facility compounded drug products using a bulk drug substance from (b)(4) , which is not a registered establishment under section 510 of the FDCA.

In response to our concerns with your smoke studies, you provided a new smoke study conducted on August 13, 2024. However, this smoke study does not appear to be a simulation of operational conditions at your facility. For example, it does not include all materials and equipment your firm uses during production, such as IV bag setup and aseptic filling.

Your facility did not submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations). Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures for reporting adverse events (1) do not include a definition of what constitutes a “serious” and…

Your firm’s operator was observed filling drug product intended to be sterile in a manner that directly blocked first pass air over uncapped filled vials.