Nubratori, Inc. dba Nubratori Rx - 700513 - 01/22/2025

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WARNING LETTER
WL #700513

1/22/2025

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 February 24, 2017, and most recently on October 22, 2024. From July 16, 2024, to July 26, 2024, an FDA investigator inspected your facility, Nubratori, Inc. dba Nubratori Rx located at 381 Van Ness Avenue, Suite 1507 Torrance, CA 90501. During the inspection, the investigator noted serious deficiencies in your practices for producing drug products, which put patients at risk.

FDA issued a Form FDA 483 to your facility on July 26, 2024. FDA acknowledges receipt of your facility’s responses, dated August 16, 2024, and October 22, 2024. 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.

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.

C. Violations of the FDCA

Adulterated Drug Products

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, the investigator observed:

1. Lack of adequate personnel sampling. Specifically, glove fingertip sampling was conducted after gloves had been sanitized. Therefore, glove fingertip sampling results are not representative of the aseptic process and may not provide accurate results.

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 establish acceptance criteria for the sampling and testing conducted by the quality control unit that are adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. (21 CFR 211.165(d))

2. Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile. (21 CFR 211.113(b))

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas. (21 CFR 211.42(c)(10)(iv))

4. Your firm failed to follow written procedures for cleaning and maintenance of equipment. (21 CFR 211.67(b))

5. Your firm failed to conduct microbiological testing before use of each lot of a component with potential for objectionable microbiological contamination in light of its intended use. (21 CFR 211.84(d)(6))

6. Your firm failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals. (21 CFR 211.84(d)(2))

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.

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.

D. Corrective Actions

We have reviewed your facility’s response to the Form FDA 483. Some of your corrective actions appear adequate; however, we are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:

1. We acknowledge your response to observation #2 and your statement that there was an unplanned deviation from your normal processes. Based on your response, due to this deviation, compounder (b)(4) was unable to return and assist with the batch, as a result, compounder (b)(4) could only take glove fingertip sampling at that moment. However, glove fingertip sampling should take place prior to sanitizing, as it can prevent recovery of microorganisms that were present during aseptic manipulation. While your firm provided training document detailing the information and training session provided to employees, not enough information was provided explaining what future deviations and ISO 5 manipulations would be taken into account before personnel monitoring is performed.

2. In your response to observation #4, you provided updated standard operating procedures (SOP) 3.84 Visual Inspection of Sterile Products and Visual Inspection Personnel Qualification, to describe how you will document the complete results of the Quality Control check, however, you did not provide batch records showing how these forms would be implemented and utilized. In addition, no training documentation was provided to show visual inspectors were trained on updated procedures. The updated SOPs provided instructions for a selection of appropriate (b)(4) for inspection of amber vials and established a minimum time for the inspection of each vial against (b)(4). In your response, you state a minimum of (b)(4) would be used, however, your SOP 3.84 states that amber containers “shall use a light of at least (b)(4).” Your response lacked supporting documentation, such as batch records to ensure appropriate (b)(4) will be used during visual inspection. Additionally, no training records were provided to show visual inspectors are trained on updated procedures, nor was it explained how your firm would implement and verify proper length of visual inspection time against (b)(4).

In your response, you state, “Defect kit will be updated prior to release of the next production batch for each product. Visual inspectors will be fully trained on each product prior to release of next sterile production batch.” However, you have not provided additional information regarding your updated defect kits and documentation of training performed by your visual inspectors prior to the release of your next sterile production batch. Additionally, your SOP makes note of your Acceptance Quality Limit (AQL), with action and alert limits noted for critical, major, and minor defects. It is unclear how you will utilize this practice going forward, as you did not provide supporting documentation of your firm’s use of AQL, as well as training records.

Lastly, updated SOP 3.85 does not provide details on how new defects will be added to your defect kit. SOP 3.85 states “5.1.6. If defects are identified for a distribution batch that is not representative of the current Inspection Qualification Test Kit then the new defected will be added to the library of visual defect form and in the kit.” You did not provide an example of the library of visual defect form. It is unclear if you have a separate and distinct “Inspection Qualification Test Kit” and “Library of Visual Defects.” There was also no training documentation provided to show visual inspectors were trained on updated procedures.

3. Your response to observation #1A included updated SOP 3.83 Placing and Releasing (b)(4) from Quarantine and any current lots of (b)(4) were quarantined and sent out for growth promotion testing. However, you did not provide results of your growth promotion testing. Growth promotion testing should be performed on all lots of prepared media.

4. Your response to observation #3 included training documentation showing operators had been trained on updated SOP 4.11 Cleaning Procedure for Cleanroom Before and After Compounding. However, the updated SOP was not provided for evaluation.

5. Your response to observation #5 states you sent out current Active Pharmaceutical Ingredient (API) for microbial and endotoxin testing. You also provided an updated procedure, SOP 3.58 Placing and Releasing API from Quarantine for review. However, you did not provide supporting documentation indicating your new limits for endotoxin and microbial counts in the updated SOP, nor did you provide rational as to how these limits were established. Additionally, you did not provide training information and documentation supporting your employees have been properly trained on your new process of evaluating incoming material.

Some of your corrective actions appear deficient:

1. In your response to observation #6, you provided updated SOP 3.57 Vendor Setup and Qualification for API and state (b)(4) additional lots have been sent out for full COA testing. Your updated SOP states API re-qualification will be completed (b)(4). However, your response did not include any additional information on when API re-qualification will occur and what specific testing will be performed. Components that are not approved finished drug products (both APIs and inactive ingredients) must be tested to verify identity and evaluate for conformity with appropriate specifications and, if necessary and depending on the intended use. Your updated SOP did not provide sufficient details explaining how this new process will be implemented. Also, your response failed to mention the other (b)(4) identified APIs and the plans to send those lots out for testing. Additionally, you did not provide training information and documentation supporting your employees have been properly trained on your new process of evaluating incoming material.

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 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 any violations. Failure to adequately address any 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 address any violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. This letter notifies you of our concerns and provides you an opportunity to address them. If you believe your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot completely address this matter within fifteen (15) working days, state the reason for the delay and the time within which you will do so.

Your response and any questions regarding the contents of this letter should be sent to compoundinginspections@fda.hhs.gov. In your response, refer to the Warning Letter Number above (#700513) and include a subject line that clearly identifies the submission as a Response to Warning Letter.

Sincerely,
/S/

F. Gail Bormel, JD, RPh
Director
Office of Compounding Quality and Compliance
Office of Compliance
Center for Drug Evaluation and Research

cc: Gulshakar Khwaja, RPH, MS, PharmD, Chief Operating Officer

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