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June 6, 2023

Case #: 659051

WARNING LETTER

Dear Mr. Sims:

From October 3, 2022, to October 13, 2022, U.S. Food and Drug Administration (FDA) investigators inspected your facility, Pharmacy Plus, Inc., dba Vital Care Compounder, located at 115 S. 40th Avenue, Hattiesburg, MS 39402. During the inspection, 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 firm on October 13, 2022. FDA acknowledges receipt of your facility’s response, dated October 31, 2022. We also acknowledge that on October 7, 2022, your firm initiated a recall of drug products intended to be sterile that were within expiry due to a lack of sterility assurance. 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)].

B. 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. For example, the investigators noted that:

1. Your firm did not take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area.

2. Your laminar airflow hood contained difficult to clean, particle-generating and visibly dirty equipment or surfaces.

3. Your firm used non-sterile pads and wipers within the ISO 5 aseptic processing area.

4. An operator used a non-sterile tool on, and manually contacted, the inner surface of the container or closure for sterile drug products.

5. An operator placed their gloved hands outside the ISO 5 work area to retrieve supplies without sanitizing their gloved hands before re-entry into the ISO 5 hood.

6. Your firm produced hazardous drugs without providing adequate segregation, cleaning of work surfaces, and cleaning of utensils to prevent cross- contamination.

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 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.

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.

C. Corrective Actions

We have reviewed your firm’s response to the Form FDA 483. We acknowledge your recall of multiple lots of drug products on October 7, 2022.

Regarding your response related to the insanitary conditions, 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. Regarding Observation 4, in which your laminar airflow hood contained difficult to clean, particle-generating and visibly dirty equipment or surfaces, we acknowledge your response within which you stated that you will remove it; however, you did not provide supporting documentation which demonstrates that the laminar airflow hood has been removed.

2. Regarding Observation 5 in which an operator was observed using non-sterile pads and wipes within the ISO 5 aseptic processing area, your response stated that you ordered sterile cleaning pads for use within the ISO 5; however, the data sheet provided with your response appears to be for sterile mop heads, rather than for sterile cleaning pads. In addition, your response stated that you trained your operators, “to be cognizant of packaging to assure that all wipes, pads, cleaners, and wands used within the ISO 5 classified areas are sterile, lint-free, or non-shedding;” however, training records were not submitted for review. The use of non-sterile wipes within the ISO 5 is a repeat observation from both the 2019 and 2016 inspections.

3. Regarding Observation 6 in which an operator used a non-sterile tool on, and manually contacted, the inner surface of the container or closure for sterile drug products, your response stated that (b)(4) forceps were purchased for handling sterile container and closures; however, you did not provide sufficient documentation, such as a purchase invoice and/or a package insert, for review. In addition, your response stated that your operators were trained on the requirement and use of sterile tools to contact the container closure of sterile drug products; however, you did not provide documentation, such as training records, for review.

4. Regarding Observation 7, in which an operator placed their gloved hands outside the ISO 5 work area to retrieve supplies without sanitizing their gloved hands before re-entry into the ISO 5 hood, your response stated that you re-assessed and re-trained staff on the frequency required for disinfecting and changing gloves during sterile compounding; however, you did not provide documentation such as training records, for review.

5. Regarding Observation 10, in which your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 area, your response stated that future smoke studies would closely mimic production (dynamic) operations, including using the representative equipment and materials used during aseptic processing; however, documentation such as a description of the conditions at the time of the smoke studies or a video copy (if available or performed) of the smoke studies to show that these studies have been and will be conducted under dynamic conditions, training records, and a revised standard operating procedure (SOP) were not provided for review. In addition, it is unclear whether your ISO 5 laminar flow hood(s) have been assessed per the revised SOP.

Regarding your response related to the insanitary conditions, the following corrective actions appear deficient:

1. We acknowledge your Form FDA 483 response which seeks to address actionable microbial contamination within your ISO 5 classified aseptic processing areas. During the inspection, your firm’s leadership attributed the out- of-specification (OOS) environmental monitoring (EM) results to an error by your certification company, without providing a scientific rationale to support that conclusion. We acknowledge the revision of your Environmental Monitoring for Viable Microbial Counts and Particulates SOP to include cessation of compounding (if active air sampling yields OOS results) and recall of drug products within expiry; however, the SOP does not include additional information about the determination of the root-cause of an excursion. Given that subsequent EM results yielded fungal contamination at other locations within your controlled areas, a root-cause for the route(s) of contamination should be assessed and corrective actions performed. In addition, the revised SOP indicates that a “(b)(4) clean…with (b)(4) different cleaners” should be performed if active air sampling yields an OOS EM result; however, the SOP does not specify which cleaners will be used nor the frequency, and, therefore, there is no assurance that the cleaners are suitable for remediation of the contamination identified.

2. We acknowledge your commitments to prevent cross-contamination during drug production. Your response does not address the frequency of cleaning (i.e., between each batch), nor does it address the potential for cross-contamination via operator gloves, gowning, and other routes, and how to mitigate them. In addition, your response does not address the appropriate washing of equipment and/or materials used during compounding. Furthermore, your response indicates that your firm will use a dedicated (b)(4) hood and equipment for hazardous compounding; however, you did not provide documentation demonstrating that this requirement was incorporated into your SOP(s), nor did you provide corresponding training records. Therefore, we remain concerned that hazardous, sensitizing, or highly potent drug product residue may be introduced into subsequent products compounded in your pharmacy.

3. We acknowledge that you created a new High Risk Media Fill SOP. The Form FDA 483 observation indicates that a critical aseptic processing step was not assessed during your prior media fill challenge. Specifically, the transfer of the beaker containing sterile product from the (b)(4) to the ISO 5 laminar flow hood was not evaluated. Your revised media fill SOP does not appear to replicate this process. Furthermore, the observation noted that your firm does not perform an assessment of the variety of container closures used during aseptic production. Your revised SOP only lists vials for the media fill, and does not include other container closures, such as droptainers. Lastly, your firm did not have sufficient space to incubate all the media fill units, and your response did not address this matter.

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.

FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. 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.

D. 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 written notification should refer to case 659051.

Please electronically submit your reply, on company letterhead, to Rebecca Asente, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov and Rebecca.asente@fda.hhs.gov. In addition, please submit a signed copy of your response to Ronda Loyd-Jones, Director, Compliance Branch, at Ronda.Loyd-Jones@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Rebecca Asente, Compliance Officer, via (504) 846-6104 or Rebecca.asente@fda.hhs.gov.

Sincerely,
/S/
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II