---

---

---

WARNING LETTER

July 24, 2020

Dear Mr. Igbinovia:

From February 25, 2019, to March 20, 2019, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, ACRX Specialty Pharmacy, Inc., located at 3200 Soaring Gulls Drive, Suite 101, Las Vegas, NV 89129. During the inspection, our 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. In addition, our investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.

Our investigator issued a Form FDA 483 to your firm on March 20, 2019. We acknowledge the receipt of your firm’s responses, dated April 5, 2019, and May 9, 2019. Additionally, we acknowledge your firm “ceased accepting orders designated as ‘Office Use’ with effect from March 11, 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, our investigator noted that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigator noted your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced. The non-patient specific prescriptions include, for example, glutathione 200mg/ml injection and tadalafil 40mg troche.

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

Our 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 poor practices during aseptic processing, including:

a. An operator preparing drug products while wearing gowning components and gloves that were potentially contaminated when he left the classified cleanroom to gather supplies from a non-classified area and returned to aseptic processing, without replacing his gowning and gloves.

b. An operator potentially contaminating a new bottle of sterile (b)(4), when the new bottle was opened and filled with the remaining quantity of a used bottle of sterile (b)(4) within the ISO 8 anteroom. Further, a container of sterile wipes was observed open for an extended amount of time on a cart inside the ISO 8 ante room and ISO 7 (b)(4) zone. The investigator observed the operator disinfect cleaning equipment/supplies that were transferred from the ISO 8 ante room into the ISO 7 (b)(4) room with said (b)(4) and cleaning wipes.

c. An operator holding the door open between the anteroom and the unclassified area for an extended period of time while he requested and gathered needed supplies.

2. 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.

3. 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. Our investigator 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 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)).

2. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

3. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).

4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

5. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)).

6. Your firm failed to conduct laboratory testing to determine whether each batch of drug product purporting to be sterile and pyrogen-free conforms to such requirements (21 CFR 211.167(a)).

7. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

8. Your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(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 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.² Accordingly, these ineligible drug products are misbranded under section 502(f)(1) of the FDCA. It is 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 your responses related to the insanitary conditions, some of your proposed corrective actions appear 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. You state that you have committed to ceasing the practice of holding the doors open between classified and unclassified spaces, and to perform regular pressure differential monitoring, but you did not provide supporting documentation of the correction (e.g., operator training or an updated procedure).

2. It remains unknown whether the post-inspection media fill simulates aseptic production operations under the worst-case, most-challenging and stressful conditions because documentation provided in your response did not address the same. For example, only (b)(4) milliliters of (b)(4) was used in your High-Risk Media Fill on 4/11/19. A media fill of only (b)(4) milliliters does not closely simulate typical aseptic production operations at your facility, such as the (b)(4) milliliters produced in routine production.

Regarding your responses related to the insanitary conditions, some of your corrective actions appear deficient. Specifically, your post-inspection smoke study did not simulate routine production. For example, the smoke study did not evaluate the (b)(4) sterilization of the product and the injection of that final drug product into finished product vials.

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 for receipt of a prescription for an identified individual patient prior to compounding and distributing drug products.

Regarding observations related to the conditions of section 503A of the FDCA, we acknowledge your letter to prescribers, dated April 5, 2019, which states that “Acrx Specialty Pharmacy ceased accepting orders designated as ‘Office Use’ with effect from March 11, 2019. All orders fulfilled at the pharmacy must be patient specific.”

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.³

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.

Send your written responses to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
19701 Fairchild Road
Irvine, CA 92612

Please identify your response with unique identifier 609518. Electronic responses may also be submitted to [email protected].

If you have questions regarding any issues in this letter, please contact LCDR Rumany Penn, Compliance Officer, at (562) 256-9280, or [email protected].

Sincerely,
/S/

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV

________________________

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).

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