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March 11, 2020

Case # 605569

WARNING LETTER

Mr. Rabbani:

From July 2, 2018, to July 13, 2018, U.S. Food and Drug Administration (FDA) investigators inspected your facility, Pharmcore Inc., dba Hallandale Pharmacy at 1109 East Hallandale Beach Boulevard, Hallandale, Florida 33009. 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. The investigators noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.

FDA issued a Form FDA 483 to your firm on July 13, 2018. FDA acknowledges receipt of your facility’s response, dated August 3, 2018. We also acknowledge your voluntary recall, initiated on August 2, 2018, of aseptically processed drug products produced between July 28, 2017, through June 1, 2018, that were within expiry due to a lack of sterility assurance. FDA further acknowledges that your facility ceased sterile compounding on July 6, 2018, at your Hallandale, Florida facility, and began sterile compounding operations in August 2018 at your new facility, located at 2666 Southwest 36th Street, Fort Lauderdale, Florida 33312.

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 collected evidence indicating that your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced, including prescription (b)(6) for Benzocaine/Lidocaine/Tetracaine Cream and prescription (b)(6) for Trimix 5ML Vial.

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 collected evidence indicating 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. Your facility is designed and operated in a way that permits the influx of lesser quality air into areas of higher quality air. Specifically:

a. Power is turned off to the entire sterile suite during cleaning operations. This includes the power to the ISO-5 areas (i.e., biological safety cabinet [BSC] and (b)(4) areas). Our investigators observed that the (b)(4) walls of the sterile suite appeared to become concave while the power was turned off, which suggests a loss of positive pressure. Moreover, after power was restored to the sterile suite and the ISO-5 areas, your firm lacked controls to verify the air quality of each ISO classified area prior to beginning sterile drug operations.
b. Three (3) holes were observed in the (b)(4) walls of the ISO-7 non-hazardous area, which separate the sterile suite from the unclassified area.
c. An unsealed hole was observed in the ISO-5 BSC located in the ISO-7 non-hazardous room in the sterile suite.

2. Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within ISO 5 areas. Therefore, your drug products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination. Specifically, non-unidirectional airflow was documented in the May 2018 certification report for the ISO-5 area used for (b)(4) and your firm lacked recent smoke studies to refute this finding.

3. Your facility is not maintained in a state of control. Specifically:
a. Visible debris and stains were observed within the ISO-5 BSC located in the ISO-7 non-hazardous room of the sterile suite.
b. Apparent rust was observed on exterior surfaces of the ISO-5 BSC located in the ISO-7 non-hazardous room in the sterile suite.
c. Apparent rust was observed on several surfaces of the stainless-steel prep table in the ISO-7 non-hazardous room in the sterile suite; and on the floor in the ISO-7 non-hazardous room in the sterile suite.
d. Visible debris was observed on the tops of the sliding doors within the sterile suite.
e. Dirt was observed on the ceiling HEPA filter covers in the ISO-7 non-hazardous room in the sterile suite.

4. Cleaning equipment was not maintained in good repair. Specifically, fraying was observed on mop heads used to clean the sterile suite. Moreover, at least one mop head was constructed of particle generating material.

5. 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.

Furthermore, the manufacture of the ineligible drug products is subject to FDA’s CGMP regulations, Title 21, Code of Federal Regulations (CFR), parts 210 and 211. The FDA investigators observed significant CGMP violations at your facility, causing the ineligible drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations included, for example:

1. Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)).

2. Your firm failed 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)).

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 also 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

FDA acknowledges receipt of your facility’s response, dated August 3, 2018. We also acknowledge your voluntary recall, initiated on August 2, 2018, of aseptically processed drug products produced between July 28, 2017, through June 1, 2018, that were within expiry due to a lack of sterility assurance. FDA further acknowledges that your facility ceased sterile compounding on July 6, 2018, at your Hallandale, Florida facility, and began sterile compounding operations in August 2018 at your new facility, located at 2666 Southwest 36th Street, Building A, Fort Lauderdale, Florida 33312.

Regarding your response related to the insanitary condition observations, 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. For example:

1. Your response to FDA 483 Observation 2 stated that your firm moved to a new facility with a new sterile suite that is “fully contained.” However, the response did not discuss the design of your new cleanroom to include a facility diagram or information on the materials used to construct the walls and ceilings. Moreover, your letter did not specify the controls that will be used to prevent the influx of lower quality air into areas of higher quality air. Further, your response did not describe the controls that will be used to maintain your facility in a state of good repair (i.e., no visible dirt or debris within production areas or on equipment).

2. Your response to FDA 483 Observations 1 and 2 did not indicate whether power (i.e. electricity) will remain on during cleaning operations of the ISO-5 areas (i.e., biological safety cabinets/hoods [BSC/hoods], (b)(4) areas) and the cleanroom suite. Moreover, the response did not specify how cleaning equipment (i.e. mops, mops heads) will be evaluated for debris and residue prior to use within your cleanroom suite.

3. Your response to FDA 483 Observation 5 did not include copies of certification reports, smoke study videos, or other documents which demonstrate unidirectional airflow within ISO-5 areas and the air quality of the ISO-5 areas. Moreover, your letter did not include documentation showing the quality of the air within the cleanroom suite.

4. Your response to FDA 483 Observation 2-part 7 stated that cleaning procedures for equipment used in the “disinfecting process” were updated. However, the response did not indicate whether your firm continues to use “(b)(4)” to apply a sporicidal agent to surfaces during the disinfecting process. Moreover, your response did not identify the sporicidal agent that will be used in the ISO 5 areas as well as the new cleanroom. It is requested that you provide information on the sporicidal agent used to include the concentration of the sporicidal agent; the contact time of the sporicidal agent; the frequency that the sporicidal agent will be applied; and how the sporicidal agent will be applied to surfaces.

5. Your response to FDA 483 Observation 1-part 2e, and 483 Observation 2-part 2 states that media fills are conducted under “worst-case” scenarios. However, review of media fill documents collected during our 2018 inspection found that 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.

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.

Regarding the conditions of section 503A of the FDCA, 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 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.

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 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 fifteen (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 # 605569). Please electronically submit your signed reply on your firm’s letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at [email protected] and [email protected].

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 [email protected].

Sincerely,
/S/

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

cc:
Medhat Mettias, R.Ph, Pharmacist in charge
Pharmcore, Inc.
dba Hallandale Pharmacy
2666 Southwest 36th Street
Fort Lauderdale, Florida 33312

Renee Alsobrook, Chief
Department of Business and Professional Regulation
Division of Drugs, Devices and Cosmetics
Compliance and Enforcement
2601 Blair Stone Road
Tallahassee, Florida 32399-1047
 

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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 Act, [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) [21 U.S.C. 321(p)] of the FDCA 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.