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Recipient NameCraig E. Else
- IntegraDose Compounding Services LLC
719 Kasota Ave SE
Minneapolis, MN 55414-2842
- Issuing Office:
- Division of Pharmaceutical Quality Operations III
May 6, 2020
Case #: 592187
Dear Mr. Else:
You 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 May 8, 2018, and most recently on November 21, 2019. On September 10, 2018, to September 19, 2018, an FDA investigator inspected your facility, IntegraDose Compounding Services, LLC located at 719 Kasota Ave SE, Minneapolis, MN 55414. During the inspection, the investigator collected evidence indicating 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. In addition, the investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.
FDA issued a Form FDA 483 to your facility on September 19, 2018. FDA acknowledges receipt of your facility’s responses, dated October 9, 2018, and April 1, 2019. 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 this section. 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, the labeling of the drug must include certain information (section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)])
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)” (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, the FDA investigator collected evidence indicating that drug products produced by your facility failed to meet the conditions of section 503B. For example, FDA noted some of your facility’s drug products did not include the following information on the label: a list of active and inactive ingredients, identified by established name and the quantity or proportion of each ingredient (section 503B(a)(10)(A)(iii)(X) of the FDCA).
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 do not include timelines for reporting adverse events to FDA.
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.
C. Violations of the FDCA
Adulterated Drug Products
The FDA 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. During the production of Phenylephrine Hydrochloride on September 11, 2018, the investigator observed your technician leaning into the ISO-5 hood with her elbows and forearms touching the working surface inside the ISO-5 area.
2. 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.
3. 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.
The FDA investigator also noted CGMP violations at your facility that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
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)).
Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a revised draft guidance, Current Good Manufacturing Practice — Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.
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
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.3 Further, 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 Adverse Events
As noted above, your facility does not comply with section 503B(b)(5) of the FDCA. The failure to report 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 to the Form FDA 483, dated October 9, 2018, and April 1, 2019. Some of your corrective actions appear adequate. However, we are unable to fully evaluate the following corrective actions due to lack of sufficient information or adequate supporting documentation:
1. In response to Observation 1 of the Form FDA 483, you revised your SOP PQ5130 OOS Investigation. However, you did not provide:
a. A complete CAPA 201725 report (referenced in CAPA 2018010) that is used to track the “designed experiment” for “sample preparation and analysis variation evaluations”, as shown in CAPA 2018010, page 5 of 52.
b. A method validation report for Hydromorphone HCl. Protocol 2018-0734 appeared to show that all test results exceeded the specification ((b)(4)%) while the target results should be within specification.
c. A description of the CGMP-related roles and responsibilities between your firm and your contract testing laboratory during an OOS investigation.
2. In response to Observation 2 of the Form FDA 483, you revised SOP PQ-5190 Process Media Fill Testing, provided copies of the master batch records, and executed Syringe Media Fill batch record. However, you did not provide:
a. Your justification to conduct a media fill at a minimum of (b)(4)-- (b)(4) for the syringe production process and (b)(4) for the bag production process. It is unclear whether the syringe or bag production process is the most challenging process at your firm.
b. A sufficient executed syringe media fill batch record, including results on environmental monitoring and personnel monitoring.
c. The bag media fill master batch record and an executed batch record.
3. In response to Observation 6 of the Form FDA 483, you stated you had installed adhesive hangers for holding cleaning supply bottles in the cleanroom. From the photo provided, it appears there is a “gap” between the hanger and the hood which creates a hard-to-clean place that might harbor bacteria. You have not provided evidence, including but not limited to, the room certification and hood cleaning validation to show these hangers are appropriate for use within a cleanroom.
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).]
You did not address certain issues related to the conditions of section 503B of the FDCA, for example:
1. Some of your facility’s drug products did not include the following information on the label: “a list of active and inactive ingredients, identified by established name and the quantity or proportion of each ingredient.”
2. 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.4 For example:
1) Your SOP makes no references to the required adverse event submission process utilizing the Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG);
2) Your SOP does not outline the four data elements (Identifiable Patient, Identifiable Reporter, Suspect Drug Product, Serious Adverse Event) that should be collected;
3) 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);
4) Your SOP does not include timelines for reporting adverse events;
5) 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 to FDA; and
6) 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 inadequate instructions for reporting. Furthermore, your procedures for adverse event reporting must also comply with the requirements as specified in 21 CFR 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.
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.
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 592187). Please submit your reply via email to ORAPHARM3_RESPONSES@FDA.HHS.GOV.
If you have questions regarding the content of this letter, please contact Compliance Officer Brett R. Havranek at 913-495-5189.
Art O. Czabaniuk
Program Division Director
Division of Pharmaceutical Quality Operations III
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.