- Delivery Method:
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Recipient NameRobert A. Simpson
Recipient TitlePresident and CEO
- LeeSar, Inc.
2727 Winkler Avenue
Fort Myers, FL 33901-9358
- Issuing Office:
- Office of Pharmaceutical Quality
4040 N. Central Expressway, Suite 300
Dallas, TX 75204
February 18, 2020
Case # 544728
You originally registered 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 April 30, 2014. You registered again on November 11, 2016, and most recently on January 3, 2020.
From July 3, 2017, to July 12, 2017, FDA investigators inspected your facility, Leesar, Inc., located at 2727 Winkler Avenue, Fort Myers, Florida 33901-9358. During the inspection, the investigators observed that drug products you produced failed to meet the conditions under section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA. In addition, the investigators noted deficiencies in your practices for producing sterile drug products, which put patients at risk.
FDA issued a Form FDA 483 to your facility on July 12, 2017. FDA subsequently issued correspondence to you on December 5, 2017 and May 4, 2018. FDA acknowledges receipt of your facility’s response, dated August 1, 2017, and your subsequent submissions, dated August 31, 2017, September 29, 2017, October 27, 2107, November 30, 2017, December 11, 2017, December 30, 2017, March 30, 2018, May 21, 2018, September 28, 2018, and October 8, 2018.
Based on this inspection, it appears your facility is producing drugs that violate the FDCA.
A. Compounded Drugs 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 this section. Outsourcing facilities must comply with other 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 a report to FDA upon initially registering as an outsourcing facility, once in June of each year, and once in December of each year identifying the drug products compounded during the previous 6-month period (section 503B(b)(2) of the FDCA [21 U.S.C. §353b(b)(2)]) as well as 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)” (section 503B(b)(5) of the FDCA [21 U.S.C. §353b(b)(5)]).
B. Failure to Meet the Conditions of Section 503B
During the inspection, FDA investigators collected evidence indicating that drug products produced by your facility failed to meet the conditions of section 503B. For example, FDA noted that your facility failed to submit a complete report to FDA in June 2017, and again in December 2017, identifying the drug products that you compounded during the previous 6-month period.
In addition, evidence collected indicates 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. Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures do not adequately define what constitutes a serious adverse event and incorrectly advise employees to report adverse events using form FDA-3500B (used for volunteer reporting) instead of form FDA-3500A (for use by IND reporters, manufacturers, distributors, importers, and user facilities personnel).
Because your compounded drug products have not met all of the conditions in section 503B, they are not eligible for the exemptions under section 503B from the FDA approval requirements in 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.
C. Violations 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 section 502(f)(1) of the FDCA.3 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.
Failure to Report Drugs or Adverse Events
As noted above, your facility failed to submit a complete product report to FDA in June 2017, and again in December 2017, identifying the drug products that you compounded during the previous 6-month period (section 503B(b)(2) of the FDCA), and your facility does not comply with section 503B(b)(5) of the FDCA. The failure to report drugs or adverse events by an entity that is registered with FDA in accordance with section 503B(b) is a prohibited act under section 301(ccc)(3) of the FDCA [21 U.S.C. § 331(ccc)(3)].
D. Corrective Actions
We have reviewed your facility’s responses. While most of your proposed corrective actions appeared adequate, FDA still has the following concern:
Regarding issues related to the conditions of section 503B of the FDCA, we have reviewed the Standard Operating Procedure (SOP) you submitted, which “describes the responsibilities of LeeSar Inc. for managing, reporting and documenting adverse events from the time an adverse event is notified.” We note that this SOP does not appear to adequately address adverse event reporting.4 For example:
1) Your SOP indicates that employees should report Adverse Events using form FDA 3500B (used for volunteer reporting) instead of form FDA-3500A (for use by IND reporters, manufacturers, distributors, importers, and user facilities personnel);
2) Your SOP makes no references to the required adverse event submission process utilizing the Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG);
3) Your SOP does not outline the four data elements (Identifiable Patient, Identifiable Reporter, Suspect Drug Product, Serious Adverse Event) that should be collected;
4) Your SOP does not adequately define a serious adverse drug event consistent with the definition of serious adverse drug experience in section 310.305(b);
5) Your SOP does not include timelines for reporting adverse events;
6) Your SOP does not include information regarding follow-up reports or investigation procedures, and there is no timeline for investigating or providing a follow-up report of an adverse event;
7) Your SOP does not state how long adverse event records must be held.
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 incorrect and 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.
In addition, as explained above, 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 a report to FDA upon initially registering as an outsourcing facility, once in June of each year, and once in December of each year identifying the drug products compounded during the previous 6-month period (section 503B(b)(2) of the FDCA [21 U.S.C. §353b(b)(2)]).
Should you continue to compound and distribute drug products that do not meet the conditions of section 503B of the FDCA, 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.
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.
Furthermore, you stated that you are currently conducting feasibility assessments to determine how to perform dynamic airflow studies within the self-contained IV Station and that your firm will be conducting new airflow studies in static and dynamic conditions based on viabilities studies recommendations for the three IV Stations. Please provide a status update regarding these assessments.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps you have taken to correct the violations. Please include an explanation of each step being taken to prevent the recurrence of the 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 the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be completed.
Your written notification should refer to the Warning Letter Number above (Case # 544728).
Please electronically submit your reply, on company letterhead to: Mark Rivero, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to email@example.com.
If you have questions regarding the contents of this letter, please contact Mr. Rivero at 504-846-6103.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
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
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 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).
4 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/UCM434188.pdf.