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April 1, 2020

WARNING LETTER

Case # 594743

Dear Mr. Delk:

From August 20, 2018, to October 24, 2018, U.S. Food and Drug Administration (FDA) investigators inspected your facility, Tailor Made Compounding, LLC, located at 200 Moore Drive, Nicholasville, KY 40356. 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 investigators noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.

FDA issued a Form FDA 483 to your firm on October 24, 2018. FDA acknowledges receipt of your facility’s response, dated November 16, 2018. We also acknowledge your voluntary recall of tesamorelin products produced between July 6, 2018, and September 11, 2018, due to an incorrect beyond use date (BUD) on the vial labels. 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 practices (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.

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 that your firm compounded drug products using Follistatin, GHRP-2, GHRP-6, Endurobal, AOD 9604, BPC 157, Bremelanotide (PT-141), Cerebrolysin, DSIP, Epitalon, GHK-Cu, IGF1-LR3, Ipamorelin, LL-37, Melanotan II, PEG-MGF, Selank, Semax, CJC 1295, SARMS, LGD-4033, and MK 677. Drug products compounded using these bulk drug substances are not eligible for the exemptions provided by section 503A(a) because they are not the subject of an applicable USP or NF monograph, are not a component of an FDA-approved human drug, and do not appear on the 503A bulks list.²

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 your firm has not established a hold time for sterilized stoppers, vials and seals used in sterile drug production.
• Your firm uses non-sterile disinfectant for cleaning inside your ISO 5 areas.
• Your firm’s media fills were not performed under the most challenging or stressful conditions.
• Your firm has not performed smoke studies under dynamic 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. 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 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 cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
3. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).
4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
5. Your firm failed to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, electronic equipment, or other types of equipment, including computers, used in the manufacture, processing, packing, and holding of a drug product (21 CFR 211.68(a)).
6. 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).

Our investigators noted that your firm released and distributed several drug products in which the strength exceeded the label claim. For example, your firm released and distributed injectable glutathione (200mg), which was determined to have 88% the amount of glutathione listed on the label. Under section 501(c) of the FDCA [21 U.S.C. § 351(c)], a drug is adulterated if it is unrecognized in an official compendium and its strength differs from, or its quality or purity falls below, that which it purports or is represented to possess. The strength of your injectable glutathione differed from and exceeded the labeled amount of glutathione the product was purported to possess, causing it to be adulterated under section 501(c) of the FDCA.

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.

Unapproved New Drug Products

You do not have any FDA-approved applications on file for the ineligible drug products that you compounded.³ 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 fails to bear adequate directions for their intended uses.⁴ Accordingly, these ineligible drug products are misbranded under section 502(f)(1) of the FDCA. 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 response to the Form FDA 483.

Regarding the insanitary condition observations in the Form FDA 483, 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. Your firm stated that a lot number tracking system has been implemented to document each batch of stoppers, vials, etc. being sterilized in the (b)(4) and (b)(4). In your response, your firm states that the items can be used for up to (b)(4) from the date of sterilization. However, your firm did not include sufficient information or supporting documentation (e.g. storage conditions, study showing sterility can be maintained under these storage conditions, etc.).

2. Your firm has agreed to begin cleaning the inside of the ISO 5 hood with sterile agents; however, your firm did not include sufficient information or support documentation (e.g., sterile agent labeling, updated cleaning procedure (s), cleaning logs, etc.).

3. Your firm stated that you had your clean rooms retested in November 2018, but you did not provide copies of the certification or video documentation of the smoke studies under dynamic and static conditions.

4. Your firm stated that you are updating the media fill process and procedures to ensure simulations are performed under the most stressful conditions; however, your firm did not include sufficient information or supporting documentation (e.g., updated procedure(s) addressing large batch sizes, training records, results of latest media fills, incorporation of lyophilizer, etc.).

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.

In addition, regarding issues related to the conditions of section 503A of the FDCA, we acknowledge your letter, dated September 23, 2018, which states that your firm has “formally removed [GHRP-2 and GHRP-6] from [your] formulary and will no longer compound these products.” We also acknowledge your letter, dated October 8, 2018, which states that you “have decided to cease selling Follistatin and have removed it from [your] formulary.” However, you have not addressed the other ineligible bulk drug substances listed above.

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.⁵

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.

Please address your reply via email to: [email protected]

Attention: Tina M. Pawlowski, Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations Division III

Your written notification should refer to the Warning Letter Number above (Case #594743). If you have questions regarding the contents of this letter, please contact Tina M. Pawlowski, at (313) 393-8217.

Sincerely,
/S/

Art O. Czabaniuk
Program Division Director
Division of Pharmaceutical Quality Operations Division III

__________________________

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 On June 9, 2016, FDA issued a 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 nominated for inclusion on the 503A bulks list; however, they were not nominated with adequate support for FDA to evaluate the substance. Follistatin, Endurobal, AOD 9604, BPC 157, Bremelanotide (PT-141), Cerebrolysin, DSIP, Epitalon, GHK-Cu, IGF1-LR3, Ipamorelin, LL-37, Melanotan II, PEG-MGF, Selank, Semax, CJC 1295, SARMS, LGD-4033, and MK 677 have not been 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.

3 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.

4 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). 

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