Recipient NamePramod K. Sharma
Recipient TitleVice President of Quality
- ImprimisRx CA, Inc., dba ImprimisRx
9257 Research Drive
Irvine, CA 92618
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
Irvine, CA 92612-2506
VIA SIGNATURE CONFIRMED DELIVERY
March 26, 2019
Pramod K. Sharma
Vice President of Quality
ImprimisRx CA, Inc.
9257 Research Drive
Irvine, CA 92618
Dear Dr. Sharma:
From March 27, 2017, to March 31, 2017, U.S. Food and Drug Administration (FDA) investigators inspected your facility, ImprimisRx CA, Inc., dba ImprimisRx, located at 9257 Research Drive, Irvine, CA 92618, following the Agency’s receipt of a MedWatch report describing an adverse event in which a patient reportedly experienced cardiac arrest and died after an infusion of intravenous (IV) curcumin containing PEG 40 castor oil compounded by your facility.1 During the inspection, the investigators 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. The inspection also revealed serious deficiencies in your practices for producing sterile drug products, other product quality issues, and issues related to the labeling of drug products, which put patients at risk.
FDA issued a Form FDA 483 to your firm on March 31, 2017. FDA acknowledges receipt of your facility’s responses, dated April 20, 2017, June 27, 2017, and December 15, 2017. Additionally, we acknowledge that on June 19, 2017, your firm conducted a recall of all product lots containing P2404 PEG 40 castor oil within expiry, including several lots of curcumin emulsion products for injection. We also acknowledge your email dated August 23, 2017, in which you stated that your firm has “(b)(4).” 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)].2 Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A.
In addition, for a compounded drug product to qualify for the exemptions under section 503A, bulk drug substances used to compound it must: (I) comply with the standards of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, if a monograph exists, and the USP chapter on pharmacy compounding; (II) if such a monograph does not exist, be components of drugs approved by the Secretary; or (III) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, appear on a list developed by the Secretary through regulation (“503A bulks list”) (section 503A(b)(1)(A)(i) of the FDCA).
B. Failure to Meet the Conditions of Section 503A
During the inspection, the FDA investigators noted that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigators noted:
Your firm compounded drug products using growth hormone-releasing peptide 2 (GHRP-2), growth hormone-releasing peptide 6 (GHRP-6), green tea extract, and artesunate. Drug products compounded using GHRP-2, GHRP-6, green tea extract, and artesunate are not eligible for the exemptions provided by section 503A(a), because these substances are not the subject of an applicable USP or NF monograph, are not components of an FDA-approved human drug, and do not appear on the 503A bulks list. Further, they are not eligible for FDA’s interim enforcement policy.3
Therefore, you compounded drug products that do not meet the conditions of section 503A and are not eligible for the exemptions in that section from 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 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, the investigators observed that the ISO-5 hood, used for all your sterile production, had visible yellow/brown and black stains across the HEPA filters. In addition, the investigators found that your firm failed to demonstrate through appropriate studies that your hood was able to provide adequate protection of the ISO-5 area in which sterile products were processed. Therefore, your products may be produced in an environment that poses a significant contamination risk.
Your drug products are also adulterated under section 501(c) of the FDCA [21 U.S.C. § 351(c)], because they are unrecognized in an official compendium and the strength differs from, or the quality or purity falls below, that which they purport or are represented to possess. FDA collected and analyzed samples of curcumin from an IV bag administered to a patient and the vial of the curcumin emulsion product used to prepare the IV bag. FDA found that the concentrations of curcuminoids (curcumin and related compounds) in the intravenous curcumin medication were substantially less than intended and labeled. FDA found that the IV bag administered to the patient contained approximately 1% of the concentration (0.00234 + 0.00014 mg/mL) intended to be administered. The label of your curcumin emulsion product indicated that the vial contained 10 mg/mL of curcumin. FDA found that the vial used to prepare the IV bag contained 2% of the concentration represented on the label (0.205 mg/mL in the product labeled 10 mg/mL). Another sample contained 48% of the declared concentration (4.8 ± 0.3 mg/mL in the product labeled 10 mg/mL). A third sample contained 49% of the declared concentration (4.9 ± 0.3 mg/mL in the product labeled 10 mg/mL).
Your drug products are further adulterated under section 501(d) of the FDCA [21 U.S.C. § 351(d)], because the drug and any substance had been mixed or packed therewith so as to reduce its quality or strength. Your curcumin emulsion product contained an ungraded inactive ingredient, polyethylene glycol (PEG) 40 castor oil.4 FDA analyzed the samples of your curcumin emulsion product and identified the presence of Diethylene Glycol (DEG), which is a known manufacturing impurity of castor oil. DEG contamination has resulted in various lethal poisoning incidents in humans worldwide.
In addition, 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 establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
2. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).
3. 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)).
Unapproved New Drug Products
You do not have any FDA-approved applications on file for the ineligible drug products that you compounded.5 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 failed to bear adequate directions for their intended uses.6 Accordingly, these ineligible drug products were misbranded under section 502(f)(1) of the FDCA.
Further, several drug products were misbranded in violation of section 502(a) of the FDCA in that their labeling is false or misleading because they did not include material facts regarding the potential for serious adverse reactions. Specifically, intravenous drug products, including FDA-approved drug products, containing castor oil have been associated with severe and sometimes fatal hypersensitivity reactions and include warnings about these reactions in their labels. The labeling of your facility’s curcumin emulsion product did not include warnings associated with PEG 40 castor oil. As a result, the labeling of these products was misleading because it failed to reveal consequences that may result from the use of the article under conditions of use prescribed in the labeling or under such conditions of use as are customary or usual.
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
We have reviewed your firm’s responses. We acknowledge that on June 19, 2017, your firm conducted a recall of all product lots containing PEG 40 Castor Oil (part Number P2404) within expiry. We also acknowledge your email dated August 23, 2017, in which you stated that your firm has “(b)(4).” However, you did not indicate whether you investigated the cause of the sub potency or took appropriate corrective actions to ensure that it will not occur for other products. In addition, you failed to provide detail regarding your firm’s current policy for drug component selection and the use of non-pharmaceutical-grade ingredients.
Regarding the HEPA filter deficiency, your response is inadequate. You stated that the microbiological air and surface samples, non-viable particulate results, and airflow measurements verified the recertification of the HEPA filters despite the yellow/brown and black stains across the outer filter matrix. Based on the two successful certifications, you determined that the stains on the Laminar Air Flow Workbench (LAFW) HEPA filters were aesthetic in nature, did not affect the operating parameters of the LAFWs, and did not affect the quality of products prepared in the LAFWs. However, as your firm does not monitor non-viable air particles daily, your conclusion does not consider long-term impact of the stain on continuing operating parameters and future product quality impact.
Further, should your facility 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.7
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), 200.10(b).
We also note that the products Timolol-Brimonidine-Dorzolamide-Latanoprost PF Solution, Timolol-Latanoprost PF Solution, and Latanoprost PF Solution contained PEG 40 castor oil, but the labeling for these products did not include PEG 40 castor oil on the lists of inactive ingredients together with the other inactive ingredients. This implies that the lists of inactive ingredients on the labeling were complete, when in fact PEG 40 castor oil had been omitted. We note under section 502(a) that a drug is misbranded if its labeling is false or misleading in any particular.
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 if you have taken any specific steps to correct the violations cited in this letter. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion. If you intend to resume production of curcumin emulsion with PEG 40 castor oil, please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation.
Your written response should refer to the Warning Letter number above (CMS 541375). Please address your reply to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
United States Food and Drug Administration
19701 Fairchild Road
Irvine, CA 92612
If you have any questions about the content of this letter, please contact Jessica Mu, Compliance Officer, at 949-608-4477 and reference unique identifier CMS 541375 on all correspondence.
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
1 The Agency is aware of another patient who was administered an infusion of curcumin and likewise, may have experienced immediate hypersensitivity reaction to the PEG 40 castor oil, a component in your facility’s curcumin emulsion product. A compounding safety alert, issued on August 4, 2017, describes in more detail FDA’s investigation into the adverse events associated with your facility’s curcumin emulsion product for injection and the Agency’s findings. Accessible at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm570192.htm.
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 503A of the FDCA.
3 In January 2017, FDA issued a revised final guidance titled, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act. This guidance describes FDA’s interim regulatory policy for State-licensed pharmacies, Federal facilities, and licensed physicians that compound human drug products using bulk drug substances that do not otherwise meet the conditions of section 503A(b)(1)(A)(i) while the 503A bulks list is being developed. Specifically, the guidance sets out the conditions under which FDA does not intend to take action against a State-licensed pharmacy, Federal facility, or licensed physician for compounding a drug product using a bulk drug substance that is not the subject of an applicable USP or NF monograph or a component of an FDA-approved drug, until the substance is identified in a final rule as included or not included on the 503A bulks list. These conditions include that the substance may be eligible for inclusion on the 503A bulks list, was nominated with adequate support for FDA to evaluate it, and has not been identified by FDA as a substance that appears to present significant safety risks pending further evaluation. GHRP-2 and GHRP-6 were not nominated with adequate support for FDA to evaluate the substances. Green tea extract and artesunate are not subject of an applicable USP or NF monograph or a component of an FDA-approved drug, and were not nominated for inclusion on the 503A bulks list. For additional information, see the guidance at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469120.pdf. For a list of bulk drug substances that have been nominated for use in compounding under section 503A, see https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM467373.pdf.
4 The label of the tested PEG 40 castor oil includes the warning “CAUTION: For manufacturing or laboratory use only.”
5 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.
6 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).
7 In this letter, we do not address whether your proposed corrective actions would resolve the CGMP violations noted above.