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  1. Warning Letters

WARNING LETTER

ProRx, LLC MARCS-CMS 696742 —

Delivery Method:
Via Electronic Mail - Delivery and Read Receipt Requested
Product:
Drugs
Recipient:
Recipient Name
Pardeep K. Gupta
ProRx, LLC

619 Jeffers Circle
Exton, PA 19341-2540
United States

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

WARNING LETTER
WL # 696742

12/20/24

Dear Mr. Gupta:

You registered your facility with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b]1 on April 27, 2022, and most recently on November 22, 2024. From July 15, 2024, to August 2, 2024, FDA investigators inspected your facility, ProRx, LLC, located at 619 Jeffers Circle, Exton, Pennsylvania 19341. During the inspection, the investigators collected evidence that drug products you produced failed to meet the conditions of section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain provisions of the FDCA. In addition, the investigators noted serious deficiencies in your practices for producing drug products intended or expected to be sterile, which put patients at risk.

FDA issued a Form FDA 483 to your facility on August 2, 2024. FDA acknowledges receipt of your facility’s responses, dated August 7, 2024, August 23, 2024, and September 18, 2024. FDA acknowledges that your firm ceased sterile drug production as of August 7, 2024, and notified FDA, on November 11, 2024, of an intent to resume sterile drug production. FDA also acknowledges that on August 22, 2024, your firm initiated a voluntary recall of drug products intended or expected to be sterile, within expiry, due to lack of sterility assurance. Based on this inspection, it appears you produced drugs that violate the FDCA.

A. Compounded Drug Products under the FDCA

Under section 503B(b) of the FDCA, a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.2

An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Outsourcing facilities must comply with other applicable provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.

In addition, for a drug product compounded using bulk drug substances to qualify for exemptions under section 503B, each bulk drug substance used to compound a drug product must be manufactured by an establishment that is registered under section 510 of the FDCA [21 U.S.C § 360] (section 503B(a)(2)(C) of the FDCA [21 U.S.C. § 353b(a)(2)(C)]).

In addition, for a compounded drug product to qualify for the exemptions under section 503B, the labeling of the drug must include certain information (section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]).

Furthermore, for a compounded drug product to qualify for the exemptions under section 503B, it must be compounded in an outsourcing facility that is in compliance with the registration and reporting requirements in section 503B(b), including the requirement to 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)” (section 503B(a)(1), (b)(5) of the FDCA [21 U.S.C. § 353b(a)(1), (b)(5)]).

B. Failure to Meet the Conditions of Section 503B

During the inspection, FDA investigators noted that drug products produced by your facility failed to meet the conditions of section 503B. For example, the investigators collected evidence that:

1. 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.

2. 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.

3. 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.

4. 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 “unexpected” adverse event (21 CFR 310.305(b)); (2) do not include a requirement to report each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible, but in no case later than 15 calendar days of initial receipt of the information (21 CFR 310.305(c)(1)(i)); (3) do not include a requirement to promptly investigate and submit a follow-up report regarding a serious, unexpected adverse event within 15 calendar days of receipt of new information or as requested by FDA (21 CFR 310.305(c)(2)); (4) do not include a requirement that the firm investigate four data elements when an adverse event report is received – Identifiable Patient, Identifiable Reporter, Suspect Drug Product, Serious Adverse Event (21 CFR 310.305(d)); and (5) do not provide that adverse events should be reported utilizing FDA’s Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG) (21 CFR 310.305(e)).3

Because your compounded drug products have not met all of the conditions of section 503B, they are not eligible for the exemptions in that section from the FDA approval requirements of section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.

Specific violations are described below.

C. Violations of the FDCA

Adulterated Drug Products

FDA investigators noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example, the investigators observed that:

1. 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.

2. 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.

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

4. 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.

5. 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.

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

7. 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.

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

9. 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.

10. 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:

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)).

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

3. 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)).

4. 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).

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

6. 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)).

7. 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)).

8. 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).

9. 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)).

10. 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 established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a revised draft guidance, Current Good Manufacturing Practice — Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.

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.

Unapproved New Drug Products

You do not have any FDA-approved applications on file for drug products that you compound.4 Under sections 505(a) and 301(d) of the FDCA [21 U.S.C. §§ 331(d)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug. Marketing of these products, or other applicable products, without an approved application violates these provisions of the FDCA.

Misbranded Drug Products

You compound drug products that are intended for conditions not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses causing them to be misbranded under section 502(f)(1) of the FDCA.5 The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. Further, it is also a prohibited act under section 301(k) of the FDCA 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 misbranded.

D. Corrective Actions

We have reviewed your facility’s responses to the Form FDA 483. FDA acknowledges that your firm ceased sterile drug production as of August 7, 2024, and notified FDA, on November 11, 2024, of an intent to resume sterile drug production. FDA also acknowledges your voluntary recall, on August 22, 2024, of drug products intended or expected to be sterile, within expiry, due to lack of sterility assurance.

We are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:

1. 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.

2. 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:

1. 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 product.

2. The process outlined in your SOP #: ProSOP-B088, Rev. 00, instructs operators to don their (b)(4) pair 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 risk.

3. 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 practice.

4. 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.

5. 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.

6. 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) colonies”) 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.

7. 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.

8. Regarding the lack of a defined minimum pressure differential between classified and non-classified spaces, you stated that you have revised your SOP to define the pressure differential from the ISO 7 space to the non-classified area to (b)(4). However, you did not provide scientific justification for utilizing this specification. A positive pressure differential of at least 0.04-0.06 inches of water gauge (10-15 Pascals (Pa)) should be maintained between adjacent rooms of differing classification (with doors closed).

9. Regarding our concerns noted with your visual inspection program, we acknowledge you established a written procedure for your visual inspection process, SOP #: ProSOP-B069, Rev. 00. However, your SOP lacks key procedures and processes required for a visual inspection program. For example, there was no mention of 100% inspection, Acceptance Quality Limit (AQL) inspection, operator qualification, classification of defects, or the testing environment. Additionally, there is no scientific justification for how your PIC is going to assess, “the integrity and quality of the preparation” with respect to your new SOP stating to notify the PIC if there was a discrepancy observed during visual inspection and the PIC will, “decide on the integrity and quality of the preparation.”

10. Regarding your failure to perform a disinfectant efficacy study, your responses focus on purchasing ready to use pharmaceutical grade germicidal detergents, disinfectants, and (b)(4) sporicidal solutions and a commitment to use them per the manufacturer’s instructions. While your firm may rely on this information when initially determining the effectiveness of agents used to clean and disinfect, your firm still needs to conduct an evaluation of the suitability and efficacy of the cleaning agents and cleaning methods with applicable work surfaces within your facility.

11. Your responses related to your equipment qualification studies are not adequate. For example, you did not perform an adequate load study on any of the listed units within this observation. All the units were tested via a mapping study on “empty shelves.” You did not test these units under the load comparable to that expected during routine production. There was no information describing the different type of materials (e.g., vials, caps, rubber stoppers) that were loaded inside these units to represent routine production. You did not establish any preventative maintenance requirements for any of the equipment listed within this observation with the exception of the (b)(4) unit. You did not provide any scientific justification for your statement that these units, that are used for testing and storage of your sterile drug products, are all “maintenance free except when poor temperature control is observed” then an investigation will be open and “rectified by appropriate repair.”

In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you produce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b).]

Regarding observations related to the conditions of section 503B of the FDCA, your corrective actions appear deficient:

1. The information that you submitted, including the SOP for Product Labeling and the Label Template, does not adequately address the labeling deficiencies. Specifically, the label template does not provide for a list of active ingredients, identified by established name and the quantity or proportion of each ingredient.

2. Your revised documented procedures for reporting adverse events do not adequately address adverse event reporting. For example:

  a. Your procedures do not adequately define what constitutes a “serious” and “unexpected” adverse event;
  b. Your procedures do not include a requirement to report each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible, but in no case later than 15 calendar days of initial receipt of the information;
  c. Your procedures do not include a requirement to promptly investigate and submit a follow-up report regarding a serious, unexpected adverse event within 15 calendar days of receipt of new information or as requested by FDA;
  d. Your procedures do not include a requirement that the firm investigate four data elements when an adverse event report is received – Identifiable Patient, Identifiable Reporter, Suspect Drug Product, Serious Adverse Event; and
  e. Your procedures do not provide that adverse events should be reported utilizing the Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG).

Furthermore, you have not addressed the compounding of drug products using bulk drug substances manufactured by establishments which are not registered establishments under section 510 of the FDCA.

Should you continue to compound and distribute drug products that do not meet the conditions of section 503B, the compounding and distribution of your drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the Drug Supply Chain Security Act requirements.

FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. In particular, this review should assess your aseptic processing operations and CGMP compliance. A third-party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

E. Conclusion

The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.

You should take prompt action to address any violations. Failure to adequately address any violations may result in legal action without further notice, including, without limitation, seizure and injunction.

Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to address any violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. This letter notifies you of our concerns and provides you an opportunity to address them. If you believe your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot completely address this matter within fifteen (15) working days, state the reason for the delay and the time within which you will do so.

Your response and any questions regarding the contents of this letter should be sent to compoundinginspections@fda.hhs.gov. In your response, refer to the Warning Letter Number above (#696742) and include a subject line that clearly identifies the submission as a Response to Warning Letter.

Sincerely,
/S/

F. Gail Bormel, JD, RPh
Director
Office of Compounding Quality and Compliance
Office of Compliance
Center for Drug Evaluation and Research

_____________________

1 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).

2 We remind you that there are conditions, other than those discussed in this letter, that must be satisfied to qualify for the exemptions in section 503B of the FDCA.

3 For more information, see, FDA’s guidance, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” which can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434188.pdf.

4 The specific products made by your firm are drugs within the meaning of section 201(g) of the FDCA [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases and/or because they are intended to affect the structure or any function of the body. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.

5 Your compounded drug products are not exempted from the requirements of section 502(f)(1) of the FDCA by regulations issued by the FDA (see, e.g., 21 CFR 201.115).

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