---

---

---

April 8, 2021

Case #: 611316

WARNING LETTER

Dr. Koneru:

You registered your facility with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b]¹ on June 6, 2014, and most recently on November 16, 2020. From June 10, 2019 to July 18, 2019, an FDA investigator inspected your facility Exela Pharma Sciences, LLC located at 1245 Blowing Rock Blvd., Lenoir, NC 28645 and 1325 William White Place, Lenoir, NC 28645. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain provisions of the FDCA.

FDA issued a Form FDA 483 to your facility on July 18, 2019. FDA acknowledges receipt of your facility’s correspondence, dated August 8, 2019, June 9, 2020, and June 12, 2020. Based on this inspection, it appears you produced drugs that violate the FDCA.

A. Compounded Drug Products under the FDCA

Under section 503B(b) of the FDCA, a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.²

An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of section 503B of the FDCA [21 U.S.C. § 353b]. Outsourcing facilities must comply with other applicable provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.

In addition, for a compounded drug product to qualify for the exemptions under section 503B, it must be compounded in an outsourcing facility that is in compliance with the registration and reporting requirements in section 503B(b), including the requirement to submit adverse event reports to FDA “in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations)” (see section 503B(a)(1), (b)(5) of the FDCA [21 U.S.C. §353b(a)(1), (b)(5)]).

B. Failure to Meet the Conditions of Section 503B

During the inspection, the FDA investigator noted that drug products produced by your facility failed to meet the conditions of section 503B. Evidence collected indicates that your facility’s drug products were not compounded in an outsourcing facility that is in compliance with the requirements of section 503B(b) (see section 503B(a)(1) of the FDCA). In particular, your facility does not comply with section 503B(b)(5) of the FDCA, which as noted above, requires an outsourcing facility to submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).³ Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, at the time of the inspection, your documented procedures only covered “NDA/ANDA products” and makes no reference to the required adverse event submission process utilizing the Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG).

Because your compounded drug products have not met all of the conditions of section 503B, they are not eligible for the exemptions in that section from the FDA approval requirements of section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.

Specific violations are described below.

Unapproved New Drug Products

You do not have any FDA-approved applications on file for drug products that you compound.⁴ 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

You compound drug products that 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 causing them to be misbranded under section 502(f)(1) of the FDCA.⁵ The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. Further, 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 facility’s responses to the Form FDA 483.

You did not address certain issues related to the conditions of section 503B of the FDCA, for example: we have reviewed the Standard Operating Procedure (SOP) you submitted concerning adverse event reporting. We note that this SOP does not appear to adequately address adverse event reporting. For example, your SOP makes no reference to the required adverse event submission process utilizing the Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG).

As explained above, a facility must comply with adverse event reporting requirements (section 503B(b)(5) of the FDCA [21 U.S.C. §353b(b)(5)]) in order to qualify for the exemptions under section 503B. The SOP you have adopted does not comply with these requirements, because it provides inadequate instructions for reporting. Furthermore, your procedures for adverse event reporting must also comply with the requirements as specified in 21 C.F.R. 211.198.

Should you continue to compound and distribute drug products that do not meet the conditions of section 503B, the compounding and distribution of your drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the Drug Supply Chain Security Act requirements.

E. Conclusion

The issues cited in this letter are not intended to be an all-inclusive list of potential 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 the issues cited in this letter. Failure to promptly correct these violations may result in legal action, 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 the issues identified. Please include an explanation of each step being taken to prevent the recurrence, 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 address these issues within fifteen (15) working days, state the reason for the delay and the time within which you will finish addressing them.

Your written notification should refer to case # 611316.

Please electronically submit your reply, on company letterhead, to Rebecca Asente, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to John Diehl, Director, Compliance Branch, via john.diehl@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Ms. Asente 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

_________________________

1 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).

2 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 503B of the FDCA.

3 For more information, see FDA’s guidance, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” which can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM4341 88.pdf.

4 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) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.

5 Your compounded 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).