Dipti V. Patel
31818 US Highway 19 N
Palm Harbor, FL 34684-3713
4040 N. Central Expressway, Suite 300
Dallas, TX 75204
July 29, 2019
Case # 587148
From October 15, 2018, to October 25, 2018, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, Promise Pharmacy, LLC, located at 31818 US Highway 19 N, Palm Harbor, Florida 34684-3713. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353a] for exemption from certain provisions of the FDCA. The investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.
FDA issued a Form FDA 483 and an amended Form FDA 483 to your firm on October 25, 2018, and November 12, 2018, respectively. FDA acknowledges receipt of your facility’s response on November 14, 2018, revised on November 19, 2018, as well as your subsequent correspondence. Additionally, we acknowledge your actions, on October 22, 2018, to voluntarily recall prednisolone and gatifloxacin ophthalmic solutions due to small particulates floating in the solutions, and on December 13, 2018, to voluntarily recall all non-hazardous drug products intended to be sterile within expiry due to lack of sterility assurance. We also acknowledge that you voluntarily ceased sterile operations in your non-hazardous cleanroom on November 14, 2018, and November 19, 2018, and resumed sterile operations in your non-hazardous cleanroom on January 2, 2019.
Based on this inspection, it appears that you produced drug products that violate the FDCA.
A. Compounded Drug Products Under the FDCA
Section 503A of the FDCA describes the conditions under which human drug products compounded by a licensed pharmacist in a State licensed pharmacy or a Federal facility, or a licensed physician, qualify for exemptions from three sections of the FDCA: compliance with current good manufacturing practice (CGMP) (section 501(a)(2)(B)); labeling with adequate directions for use (section 502(f)(1)); and FDA approval prior to marketing (section 505) [21 U.S.C. §§ 351(a)(2)(B), 352(f)(1) and 355(a)].1 Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A.
B. Failure to Meet the Conditions of Section 503A
During the inspection, the FDA investigator noted that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigator noted that your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced.
Therefore, you compounded drug products that do not meet the conditions of section 503A and are not eligible for the exemptions in that section, including the FDA approval requirement of section 505 of the FDCA, the requirement under section 502(f)(1) of the FDCA that labeling bear adequate directions for use, and the requirement of compliance with CGMP under section 501(a)(2)(B) of the FDCA. In the remainder of this letter, we refer to your drug products that do not qualify for exemptions under section 503A as the “ineligible drug products.”
Specific violations are described below.
C. Violations of the FDCA
Adulterated Drug Products
The 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:
1. The investigator observed the presence of particulates in multiple bottles of prednisolone and gatifloxacin ophthalmic solution. Fifteen (15) bottles from the same lot had already been dispensed and distributed.
2. Your firm’s non-hazardous cleanroom was inadequate for the production of sterile drug products. In addition, the investigator observed a (b)(4) within the cleanroom that was partially located under a light fixture that did not have a HEPA filter.
3. The investigator observed poor practices during aseptic processing, including an operator blocking first pass HEPA filtered air during production and an operator not wearing a beard cover while in the cleanroom. In addition, an operator did not move slowly and deliberately in the ISO 5 environment when transferring partially stoppered vials from the work area to the (b)(4).
Our investigator noted that your firm released and distributed several drug products in which the strength exceeded the label claim. For example, your firm released and distributed injectable bremelanotide (20mg), which was determined to have 114.3% the amount of bremelanotide listed on the label. Under section 501(c) of the FDCA [21 U.S.C. § 351(c)], a drug is adulterated if it is unrecognized in an official compendium and its strength differs from, or its quality or purity falls below, that which it purports or is represented to possess. The strength of your injectable bremelanotide differed from and exceeded the labeled amount of bremelanotide the product was purported to possess, causing it to be adulterated under section 501(c) of the FDCA.
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 the ineligible drug products that you compounded. 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
The ineligible drug products you compounded 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.2 Accordingly, these ineligible drug products are misbranded under section 502(f)(1) of the FDCA. The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. 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 firm’s responses to the Form FDA 483. We acknowledge your decisions to voluntarily cease sterile operations in your non-hazardous cleanroom on November 14, 2018, and November 19, 2018. We acknowledge your voluntary recall of Lot [email protected] of Prednisolone and Gatifloxacin Ophthalmic Solution 1%/0.5% sterile 3ml vials on October 22, 2018. We also acknowledge your December 18, 2018, recall of all drugs products intended to be sterile produced in your firm’s non-hazardous cleanroom, which were dispensed from June 13, 2018, to December 13, 2018.
Regarding your responses related to the insanitary conditions, some of your corrective actions appear to be adequate. However, we cannot fully evaluate the adequacy of the following corrective actions described in your responses because you did not include sufficient information or supporting documentation:
1. Regarding the observation of particulates in multiple bottles of prednisolone and gatifloxacin ophthalmic solution, we have reviewed your revised SOP 615.2 “Visual Inspection of Drug Product.” However, you did not provide documentation that your staff has been trained on the revised SOP. We acknowledge your statement that your firm has ceased production of this product while you make “(b)(4)” and confirm that “(b)(4).” To date, we have not received an update regarding the adjustments made for this drug product. Your firm should ensure that all ophthalmic solutions you produce are essentially free from particles and have a pH level suitable for administration in the eye.
2. We have reviewed your updates related to your non-hazardous cleanroom, including the video titled, “Smoke Study for Hood to (b)(4).” We are unable to fully evaluate the transfer from the hood to the (b)(4) as the amount of smoke present was not sufficient to visualize (b)(4) airflow. Your firm should ensure this transfer occurs under ISO 5 (b)(4) air flow in order to prevent contamination.
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 of receipt of a prescription for an identified individual patient prior to compounding and distributing drug products.
Should you continue to compound and distribute drug products that do not meet the conditions of section 503A, the compounding and distribution of such drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the drug CGMP regulations. Before doing so, you must comply with the requirements of section 505 and 502(f)(1) and fully implement corrections that meet the minimum requirements of the CGMP regulations.
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)].
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 aseptic drug manufacturing expertise should assist you in conducting this comprehensive evaluation.
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 the violations identified above 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 correct the violations cited in this letter. Failure to promptly correct these 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 correct violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction.
Your written notification should refer to Case # 587148.
Please electronically submit your reply on company letterhead to Dayna I. Martinez, Compliance Officer, at [email protected] In addition, please submit a signed copy of your response to [email protected] and [email protected]
If you have questions regarding the contents of this letter, you may contact Ms. Dayna I. Martinez via (787) 729-8608 or [email protected]
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II
Renee Alsobrook, Chief, Compliance and Enforcement
Division of Drugs, Devices and Cosmetics
Department of Business and Professional Regulation
2601 Blair Stone Road
Tallahassee, Florida 32399-1047
1 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 503A of the FDCA.
2 Your ineligible 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).