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WARNING LETTER WL # 667414

September 20, 2023

Dear Mr. Moon:

From November 2, 2022, to November 30, 2022, U.S. Food and Drug Administration (FDA) investigators inspected your facility, Southern Tier Home Infusion, Inc. dba Pharmacy Innovations, located at 2936 West 17th Street, Erie, PA 16505. During the inspection, the investigators collected evidence indicating 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. 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 firm on November 30, 2022. FDA acknowledges receipt of your facility’s responses, dated January 19, 2023, and April 19, 2023. FDA also acknowledges your firm’s voluntary recall, initiated on December 22, 2022, of all sterile compounded products produced between October 2, 2022, and November 30, 2022. FDA further acknowledges that you ceased production of drug products intended or expected to be sterile inside the non-hazardous ISO 5 classified (b)(4) laminar air flow workbench (LAFW). 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 investigators collected evidence indicating that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigators noted that your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced, including Lidocaine/Tetracaine/Phenylephrine 20/4/2% Gel and Dutasteride 0.1% (1.5mL Vial) Injectable.

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 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. The ISO 5 and ISO 7 classified areas had difficult to clean, porous, particle-generating, and visibly dirty equipment or surfaces. FDA observed:
    a. Rust-like discoloration on a HEPA filter, (b)(4) plates, and the return vents; yellow residue on HEPA filters; holes in the wall; and a cracked plexiglass shield inside your ISO 5 classified (b)(4) LAFW.
    b. Dust and trash underneath work surface/deck in your ISO 5 classified biological safety cabinet.
    c. Rust-like discoloration on a HEPA filter diffuser in the ISO 7 classified anteroom.

2. You did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area. In June 2020, and between March and October 2022, your firm detected microbial contamination inside your ISO 5 classified critical areas but did not take appropriate steps to correct and prevent reoccurrence.

3. Your facility is designed and operated in a way that may permit the influx of lesser quality air into a higher quality air area in that you did not prevent the influx of unclassified air into your ISO 5 classified (b)(4) LAFW from the unclassified space above the ceiling and from the unclassified areas outside your cleanroom.

4. Your ISO 5 classified (b)(4) LAFW does not have adequate HEPA filter coverage, in that smoke studies revealed air turbulence, hood recertification studies demonstrated low air velocity, and (b)(4) was leaking from HEPA filters in both your ISO 5 and ISO 7 classified areas.

5. 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.

6. An operator touched product contact surfaces and aseptic connection points with their gloved hands, including the filling needle, the hub of the syringe, and the downstream end of the (b)(4).

7. An operator blocked first air by placing gloved hands directly over open sterile containers and performed aseptic manipulations by holding drug materials in (b)(4) orientation with airflow patterns, thereby preventing first air from protecting aseptic connections inside your ISO 5 classified critical areas.

8. An operator did not move in a slow and deliberate manner to prevent disruption of unidirectional airflow in the critical area during aseptic production, instead the operator moved so quickly that drug materials appear to have been inadvertently dropped back onto the workstation.

9. An operator allowed trash to accumulate on the front air intake grille of the ISO 5 classified Biological Safety Cabinet which potentially disrupted airflow patterns and thereby introduced contamination risks.

10. 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.

11. Your firm failed to use a sporicidal agent as part of your disinfection program on the plexiglass shield inside your (b)(4) ISO 5 classified LAFW.

12. Materials used to produce drug products intended to be sterile were exposed to lower than ISO 5 classified quality air, in that your firm’s sterilized ophthalmic ointment base was covered with unsecured (b)(4) and was exposed to lesser quality air in the unclassified area where the oven was located.

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.² 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.³ 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 also acknowledge your firm’s voluntary recall, initiated on December 22, 2022, of all drug products intended or expected to be sterile due to lack of sterility assurance. We further acknowledge you ceased all sterile compounding inside the non-hazardous ISO 5 classified (b)(4) LAFW.

Regarding your responses related to the insanitary conditions, some of your corrective actions appear 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. Your firm has not provided information about the new LAFW hoods that you have purchased to replace the ISO 5 classified (b)(4) LAFW, including but not limited to hood descriptions (such as hood model information and airflow orientation), photographic evidence, certifications, and information about how the new hoods will be cleaned, disinfected, and treated with sporicidal agents.
2. Poor aseptic practices (touching product contact surfaces and aseptic connection points, blocking first pass air, quick movements, and trash accumulation inside the ISO 5 classified critical areas) are a repeat observation from the 2017 FDA inspection, and you did not provide sufficient information about the educational materials used to retrain employees to give assurance that these poor aseptic practices will not reoccur. Additionally, you have not provided information about how you will retrain employees on proper aseptic practices in the newly purchased ISO 5 classified LAFW hoods.
3. Your firm has not addressed how you will ensure that your future smoke studies will adequately demonstrate air flow patterns, including but not limited to sufficient smoke production and angle perspectives which allow appropriate evaluation.

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

1. Regarding sealing the ceiling tiles, it is unclear if you are ensuring that the light fixtures are sealed in a manner that prevents ingress of lesser quality air from above the ceiling into the newly created ISO 7 area surrounding the new ISO 5 LAFW hoods.

2. Regarding your revised media fill procedures, you did not appear to consider fill volume (for example, (b)(4) vs. (b)(4) per unit) when determining the most difficult compounding processes. Further, the new media fill studies that you provided do not demonstrate the most challenging or stressful conditions that your operators perform at your facility. Finally, you have not indicated if operators will be restricted to the types of operations for which they have successfully completed a media fill.

3. Regarding your sterilized ointment base, you have not addressed how you will adequately protect it from contamination during transport from the (b)(4) ovens to the ISO 5 classified aseptic processing areas.

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.

As explained above, receipt of valid prescriptions for individually-identified patients is a condition of section 503A, which your firm failed to meet for a portion of the drug products you produced.

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.⁴

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 ma3terials, 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.

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 you have taken to address any violations, or you may inform us that you do not intend to resume production of drugs intended or expected to be sterile inside the non-hazardous cleanroom suite. If you intend to resume production of drugs intended or expected to be sterile inside the non-hazardous cleanroom suite in the future, please include an explanation of each step being taken to prevent the recurrence of any 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. In addition to taking appropriate corrective actions, you should notify this office fifteen (15) working days prior to resuming production of any drugs intended or expected to be sterile in the future.

Your written notification should refer to the Warning Letter number above #667414. Please send your electronic reply to Yvette Johnson, Compliance Officer at Yvette.Johnson@fda.hhs.gov and ORAPHARM1_RESPONSES@fda.hhs.gov

Sincerely,
/S/

Lisa Harlan
Program Division Director/ District Director
U.S. Food and Drug Administration
OPQO Division I / New Jersey District

cc: Richard B. Moon, Owner and President
Southern Tier Home Infusion, Inc. dba Pharmacy Innovations
2535 Johns Place
Jamestown, NY 14701
email:rmoon@pharmacyinnovations.net

Mark Wank, Chief Executive President
Southern Tier Home Infusion, Inc. dba Pharmacy Innovations
2535 Johns Place
Jamestown, NY 14701
Email:mwank@pharmacyinnovations.net

__________________________

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 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.

3 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).

4 In this letter we do not address whether your proposed corrective actions would resolve the CGMP violations noted above.