Delivery Method: VIA EMAIL CONFIRMED DELIVERY Product: Drugs Recipient:
Recipient Name
Evan Gilbert
Right Value Drug Stores, LLC dba Carie Boyd Pharmaceuticals
2501 W. Oak Street
Denton, TX 76201
United States
Issuing Office: Center for Drug Evaluation and Research (CDER)
United States
WARNING LETTER
WL # 694687
12/17/2024
Dear Mr. Gilbert:
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 July 3, 2019, and most recently on December 12, 2023. From May 28, 2024, to June 21, 2024, an FDA investigator inspected your facility, Right Value Drug Stores, LLC dba Carie Boyd Pharmaceuticals, located at 8400 Esters Blvd, Suite 190, Irving, TX 75063. During the inspection, the investigator noted 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 investigator noted serious deficiencies in your practices for producing drug products, which put patients at risk.
FDA issued a Form FDA 483 to your facility on June 21, 2024. FDA acknowledges receipt of your facility’s response, dated July 15, 2024. Based on this inspection, it appears you produced drug products 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.
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)]).
B. Failure to Meet the Conditions of Section 503B
During the inspection, the FDA investigator noted that drug products produced by your facility failed to meet the conditions of section 503B. For example, the investigator noted that some of your facility’s drug products, such as Ketoconazole 2% (b)(4) Cream, Testosterone Cypionate 200 mg/ml injections, and Testosterone Cypionate 200 mg/ml + Testosterone Propionate 10 mg/ml injections, did not include the following information on the label: The quantity or proportion of each inactive ingredient.
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 investigator 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 investigator observed:
1. 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. Specifically, your smoke studies demonstrated disruption in unidirectional airflow in your BSC hood 19-00133.
2. 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. Specifically, your firm’s media fill vial quantity per technician fails to reflect the most challenging conditions.
FDA investigator 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 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 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).
3. Your firm failed to clean and sterilize and process, where indicated by the nature of the drug, container closures to remove pyrogenic properties to assure they are suitable for their intended use (21 CFR 211.94(c)).
4. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
5. Your firm failed to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product (21 CFR 211.46(b)).
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.3 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.4 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. Some of your corrective actions appear adequate; however, we are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:
1. Regarding your firm’s failure to establish and follow adequate written procedures for cleaning and maintenance of equipment:
a. We acknowledge that your staff were re-trained on the Cleaning and (b)(4) of Glassware SOP. In your response, you stated you are working on a Glassware Hold Study; however, we are unable to review the adequacy of your response until your hold studies are completed and submitted for review.
2. Regarding your firm’s failure to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product:
a. You stated you are purchasing additional equipment to control environmental variables, such as temperature and humidity in your DEA Lockup area, however, we are unable to review the adequacy of your response until you submit further details about your proposed corrective actions (e.g., implementation time frame, equipment qualification and written procedures, etc.).
b. You stated that you intend to execute process validation for other product families stored in the Lockup area. However, details of your plan, such as the names of the other product families and how you plan to implement these validation protocols were not provided.
Some of your corrective actions appear deficient:
1. We acknowledge that on July 5, 2024, your firm re-executed smoke studies. Some of the smoke studies provided for review demonstrated non-unidirectional, recirculating airflow within the hood. For example, video 19-00133 Transfer of Vials into the Hood, (b)(4) currents were detected from time stamp 00:25 and could be identified throughout the video duration. Video 19-00133 EM Sampler Running and Filling of (b)(4) Vials, (b)(4) currents were identified from time stamp 12:07-12:17 and 13:20-14:54. In both videos, the disruption in airflow appeared to be in the far-right hand side of the BSC hood where empty vials were sitting. The ISO-5 area is critical because sterile drug products are exposed and therefore vulnerable to contamination. Your aseptic manufacturing process should be designed, and operations should be executed to minimize contamination hazards to your sterile drug product.
2. Regarding your Aseptic Process Simulations, batch records reveal that each operator is required to fill a minimum of (b)(4) units, however, during production an operator can fill up to (b)(4) units. Gowned personnel are the greatest source of microbial contamination in an aseptic process. Operators performing a media fill of less than their typical production volume and duration does not represent the worst-case challenge and stressful condition as it does not take into regard operator fatigue. Your firm failed to provide a robust media fill that mimics an operator’s actual production activity.
3. We acknowledge your initiation of deviations, DEV-2024-046 and DEV-2024-047 and investigation IR-2024-013 in relation to the power outage that occurred on 05/28/2024. However, utilizing visual inspection as your method in identifying the impact of humidity on your in-process pellets is inadequate. Your proposed method of visually inspecting pellets for “swelling” is not scientifically sound, nor data driven.
4. Regarding DEV-2023-073 and DEV-2023-074 o, we acknowledge your firm performed an investigation regarding the Total Airborne Particles exceeding the ISO 5 specifications on 12/20/2023 during the filling of Testosterone Cypionate/Testosterone Propionate 200/10 mg/ml with Miglyol R 812N, Lot(b)(4). However, upon reviewing the production Batch Record (b)(4), it was noted there were 26 major defects identified during the visual inspection, including dark particulates and filaments in vials. Despite those vials being removed, it appears no further investigation occurred.
5. Regarding the preparation of container closures to remove pyrogenic properties, your firm failed to adequately validate the (b)(4) process for your pellet vial caps and continued to use this process in the manufacturing of drug products. The process validation report, GS-2023-025 (dated 07/03/2023) cited multiple samples failing a (b)(4) in endotoxins. Your firm launched an investigation, IR-2023-036 (dated 09/06/2023) and it was concluded that the rinsing time needed to be increased and the process validation was to be repeated. It appears from your response and the documents provided, the process validation was never repeated. Additionally, your firm concluded the impact of endotoxin being present on a vial cap as low and stated in IR-2023-036, “there is minimal, if any, interaction/contact between the pellet within the vial and the cap,” and thus “there is no impact against any product which has or is being processed using caps that are processed by the current (b)(4) by rinsing procedure. There is no scientific basis for the justification of your claim.
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).
In addition, regarding observations related to the conditions of section 503B of the FDCA, your corrective actions appear adequate: you provided corrected labels that included the specific amounts of inactive ingredients or the quantity or proportion of each inactive ingredient.
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. A third party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.
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 (WL # 694687) 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 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.
4 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).
