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WARNING LETTER

September 26, 2022

Dear Ms. Hunter:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Advanced Cosmetic Research Laboratories Inc., FEI 3003059934, at 20550 Prairie Street, Chatsworth, from April 21 to 27, 2022.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

In addition, (b)(4) 5% LIDOCAINE CREAM is an unapproved new drug introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a), and is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.

We have not received a detailed response from your firm for corrective actions to the observations identified during the inspection in our Form FDA 483. The correspondence received included a commitment to respond on or before October 1, 2022, with more information.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state repair (21 CFR 211.58).

You failed to adequately design your facility, which is used to manufacture over-the-counter (OTC) topical drug products such as (b)(4) Antibacterial Acne Soap, and maintain it in a good state of repair.

For example:

• Pipes with apparent rust, dirt and/or debris were located directly above partially open mixing tanks. Our investigators observed foreign particles floating in a mixing tank used to manufacture human drug products that was located directly underneath one of these pipes.
• Numerous aluminum sheet panels located on the ceiling above partially open mixing tanks and filling/packaging lines were falling, torn or had gaps which exposed the environment below to apparent dirt and debris from plywood sheeting supporting the roof.
• Multiple bug zappers were observed in close proximity to filling/packaging lines. Insects killed by the zappers could fall into open equipment and finished product packaging.

It is essential that your facility is in a good state of repair and sanitary conditions are maintained.

In response to this letter, provide:

• Your corrective action and preventative action (CAPA) plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
• Photographic evidence of any repairs made to your facilities and equipment.

2. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22(a) and (d)).

Your quality unit (QU) failed to have adequate procedures, documentation and practices to properly exercise its functions.

For example, regarding your batch record for (b)(4) Sunscreen SPF-30 lot (b)(4):

• Finished drug “Product Analysis Report” used for batch release, was signed as reviewed and approved on March 23, 2022, even though the batch was still being filled on March 28, 2022.
• Out-of-specification (OOS) results for viscosity and specific gravity in bulk and finished drug product were not investigated.
• “LINE SET-UP” form did not have an approval signature, yet the line was used to manufacture drug product.

The procedure for handling complaints was not followed as both your firm’s CEO and Project Manager confirmed that product quality complaints are not recorded, evaluated, or investigated.

Furthermore, OOS results were not being appropriately investigated per your procedure for handling OOS results and non-conforming drug product. During the inspection, our investigators were informed that your firm did not maintain a list of OOS test results and that investigations were not conducted. FDA inspected your firm’s contract testing laboratory from (b)(4), where numerous analytical OOS results involving your firm’s drug products were observed. An investigation is required whenever an OOS test result is obtained and a written record of the investigation must include conclusions and follow-up.

Without adequate quality procedures and oversight, you cannot ensure the consistency of your manufacturing processes and the purported identity, strength, quality, and purity of drug products released to the market. See FDA's guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of the CGMP regulations (21 CFR, parts 210 and 211) at https://www.fda.gov/media/71023/download.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
    o A determination of whether procedures used by your firm are robust and appropriate
    o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
    o A complete and final review of each batch and its related information before the QU disposition decision
    o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging
manufacturing/quality issues and to assure a continuing state of control.

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
• An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.

Unapproved New Drug and Misbranding Violations

(b)(4) 5% LIDOCAINE CREAM is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as a topical external analgesic.

Examples of labeling claims observed on the (b)(4) 5% LIDOCAINE CREAM product label that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the products include, but may not be limited to, the following:

“(b)(4) 5% LIDOCAINE CREAM
“Lidocaine 5% . . . Uses: for the temporary relief of pain and itching associated with minor burns, sunburn, minor cuts and scrapes . . . 30g | 5% Lidocaine Cream . . .” [from your product label]

(b)(4) 5% LIDOCAINE CREAM is a topical external analgesic drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G(a)(1) of the FD&C Act, 21 U.S.C. 355h(a)(1), category I drugs that were subject to a tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 are deemed to be generally recognized as safe and effective (GRASE) and not “new drugs,” as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM and comply with all other applicable requirements. We note that over-the-counter (OTC) topical external analgesic products were addressed in the TFM for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983) and subsequent rulemakings. Under 505G(b)(8) of the FD&C Act, the 1983 external analgesic TFM, in combination with subsequent rulemakings, was deemed to be a final administrative order.

However, (b)(4) 5% LIDOCAINE CREAM does not conform to the conditions of use specified in the final administrative order. Specifically, the labeled active ingredient in the product, Lidocaine 5%, is above the allowable dosage concentration for use as an over-the-counter external analgesic product (0.5 – 4%).

In addition, FDA is not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that (b)(4) 5% LIDOCAINE CREAM is GRASE for use under the conditions prescribed, recommended, or suggested in its labeling. Moreover, there is no evident basis under the FD&C Act under which this product would be legally marketed without an approved application. Accordingly, this product is an unapproved new drug marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under section and 301(d) of the FD&C Act, 21 U.S.C. 331(d).

Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because (b)(4) 5% LIDOCAINE CREAM is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.

The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist 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.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Your response should refer to unique identifier CMS 631902 and be sent electronically to ORAPHARM4_Responses@fda.hhs.gov or mailed to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food and Drug Administration
19701 Fairchild Road
Irvine, CA 92612

If you have any questions regarding this letter, please contact Jamie Dion, compliance officer, at 303-236-3133 or by email at Jamie.Dion@fda.hhs.gov.

Sincerely,
/S/

CDR Steven E. Porter
Director, Division of Pharmaceutical Quality Operations IV
 

CC: Ms. Celeste Guillen, CEO (via email (b)(6))
Advanced Cosmetic Research Laboratories Inc.
20550 Prairie Street
Chatsworth, CA 91311-6006