- Delivery Method:
- VIA UPS
Recipient NameRobert L. Crocker
Recipient TitleOwner and Pharmacist in Charge
- Farmville Discount Drug, Inc. DBA Best Value Drug
3708 N. Main Street
Farmville, NC 27828-1499
- Issuing Office:
- Office of Pharmaceutical Quality Operations, Division II
4040 N. Central Expressway, Suite 300
Dallas, TX 75204
July 9, 2019
Case # 574044
From November 13, 2017, to November 17, 2017, U.S. Food and Drug Administration (FDA) investigators inspected your facility, Farmville Discount Drug, Inc., dba Best Value Drug, at 3708 N. Main Street, Farmville, North Carolina 27828. During the inspection, the investigators 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 investigators 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 November 17, 2017, and November 20, 2017, respectively. FDA acknowledges receipt of your facility’s responses, dated December 8, 2017, March 27, 2018, and April 5, 2018. 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 practices (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)]. Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A.
In addition, for a compounded drug product to qualify for the exemptions under section 503A, bulk drug substances used to compound it must: (I) comply with the standards of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, if a monograph exists, and the USP chapter on pharmacy compounding; (II) if such a monograph does not exist, be components of drugs approved by the Secretary; or (III) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, appear on a list developed by the Secretary through regulation (“503A bulks list”) (section 503A(b)(1)(A)(i) of the FDCA).
B. Failure to Meet the Conditions of Section 503A
During the inspection, the FDA investigators noted that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigators noted:
- Your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced.
- Your firm compounded drug products using Colloidal Silver. Drug products compounded using Colloidal Silver are not eligible for the exemptions provided by section 503A(a), because Colloidal Silver is not the subject of an applicable USP or NF monograph, is not a component of an FDA-approved human drug, and does not appear on the 503A bulks list.
Therefore, you compounded drug products that do not meet the conditions of section 503A and are not eligible for the exemptions in that section from 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 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 [21 U.S.C. § 351(a)(2)(A)]. For example:
1. Your firm produced Colloidal Silver, an aqueous-based solution for oral inhalation with non-pharmaceutical grade (b)(4) in an unclassified environment.
2. Poor aseptic practices were observed. These included a technician blocking first pass air with his gloved hands in an ISO 5 area while producing products intended to be sterile; a technician retrieving materials and supplies from the ISO 7 area and then returning to the ISO 5 area to continue aseptic processing without first changing or sanitizing gloves; a technician contacting the edge of the ISO-5 work surface while wearing a non-sterile gown; and a technician manipulating the outer portion of a sterile glove with his bare hand prior to producing drugs intended to be sterile.
3. Your firm used a non-sterile cleaning agent as well as non-sterile cleaning wipes in the ISO 5 aseptic processing area.
4. 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.
5. Your facility design was not adequate for sterile drug production as it may have allowed unclassified air from the surrounding environment into the cleanroom. Specifically, the ISO 7 “Sterile Compounding Room” was constructed with two metal vents, which connect to the unclassified area. Our investigators observed a gap between the ISO 7 “Sterile Compounding Room” and the unclassified area where “hook-and-loop” fasteners used to attach the flexible walls had become detached. In addition, a (b)(4) was being used to transfer components, drug product containers and closures, from the unclassified area directly into the ISO 7 “Sterile Compounding Room.”
Furthermore, the manufacture of drug products ineligible for the exemptions in section 503A is subject to FDA’s CGMP regulations, Title 21, Code of Federal Regulations (CFR), parts 210 and 211. The manufacture of the bulk drug substance colloidal silver is subject to statutory CGMP requirements in section 501(a)(2)(B) of the FDCA. The FDA investigators observed significant CGMP violations at your facility, causing those drugs to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations of CGMP regulations included, for example, your firm’s failure 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)).
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.
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. Accordingly, these ineligible drug products are misbranded under section 502(f)(1) 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.
Regarding the insanitary conditions observations in the Form FDA 483, some of your corrective actions appear to be adequate. However, we cannot fully evaluate the adequacy of the following corrective actions described in your response because you did not include sufficient information or supporting documentation:
1. Your December 8, 2017, response indicates that your firm uses commercially prepared (b)(4) in non-sterile compounding. However, you did not provide evidence to demonstrate that the (b)(4) you utilize in non-sterile drug production meets, at minimum, the specifications of (b)(4). In addition, it is the Agency’s policy that any action limit over (b)(4) for a (b)(4) is unacceptable (see inspection guide at (b)(4)).
2. Your December 8, 2017, response states, “We have also ordered sterile gowns for use whenever our personnel are required to lean or reach into the ISO 5 hood.” It is not clear during what circumstances operators would be required to lean into the ISO 5 hood, and whether the sterile gowns will be adequate to prevent exposed skin on the face and neck of operators from entering the ISO 5 hood.
3. Documentation (i.e., product labels, invoices, cleaning logs) was not provided to demonstrate that the wipes and disinfectants currently used in the ISO 5 area are sterile.
4. You did not provide a description of how smoke studies were performed to simulate dynamic conditions, or alternatively, provide the video discussed in your response.
5. We have reviewed the documentation provided by your firm which describes the completion of modifications to your cleanroom walls, vents, and (b)(4). FDA intends to further review all supporting documentation, as well as the physical changes made to your cleanroom, during a future inspection.
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 on receipt of a prescription for an identified individual patient prior to compounding and distributing drug products.
We noted during the inspection, the FDA investigators observed that you produce, using a generator, the bulk drug substance colloidal silver for production of inhalation solutions. FDA has noted in the past that “[t]here are serious and complicating aspects to many of the diseases…silver ingredients purport to treat or prevent.” See 21 CFR 310.548. Please be advised that FDA has received numerous reports of serious adverse events associated with colloidal silver and is unaware of any adequate and well-controlled studies to support the use of this drug for any disease or condition.
We acknowledge your letter dated November 16, 2017, in which you state your firm “will not manufacture, compound or sell Colloidal Silver Solutions.” You further noted that on November 15, 2017, your firm “…destroyed all Colloidal Silver Solutions in and on the premises…” and on November 16, 2017, …all Colloidal silver generators ((b)(4)) were removed from the Premises….”
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 sterile 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 the Warning Letter Number above (Case # 570944). Please electronically submit your signed reply on your firm’s letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at firstname.lastname@example.org and email@example.com.
If you have questions regarding the contents of this letter, you may contact Mr. Thao Ta, Compliance Officer, via phone at 214-253-5217 or e-mail at firstname.lastname@example.org.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
 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.
 On June 9, 2016, FDA issued a final guidance titled, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act. This guidance describes FDA’s interim regulatory policy for State-licensed pharmacies, Federal facilities, and licensed physicians that compound human drug products using bulk drug substances that do not otherwise meet the conditions of section 503A(b)(1)(A)(i) while the 503A bulks list is being developed. Specifically, the guidance sets out the conditions under which FDA does not intend to take action against a State-licensed pharmacy, Federal facility, or licensed physician for compounding a drug product using a bulk drug substance that is not the subject of an applicable USP or NF monograph or a component of an FDA-approved drug, until the substance is identified in a final rule as included or not included on the 503A bulks list. These conditions include that the substance may be eligible for inclusion on the 503A bulks list, was nominated with adequate support for FDA to evaluate it, and has not been identified by FDA as a substance that appears to present significant safety risks pending further evaluation. Colloidal silver was nominated for inclusion on the 503A bulks list. It was not nominated with adequate support for FDA to evaluate the substance. For additional information, see the guidance at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469120.pdf.
 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).
 In this letter we do not address whether your proposed corrective actions would resolve the CGMP violations noted above.