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Warning Letter 320-24-63

September 25, 2024

Dear Mr. Moon:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Outin Futures Corp., FEI 3011572099, at 150 Gieopdosil-Ro, Daesowon-Myeon Chungju, Chungcheongbuk, Korea (the Republic of) from March 25 to 29, 2024.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See 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 product is 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, “NEOGEN DERMALOGY AIRY SUNSCREEN Broad Spectrum SPF 50” drug product is misbranded under section 502(c), (f)(2), and (x) of the FD&C Act, 21 U.S.C. 352(c), (f)(2), and (x). Introduction or delivery for introduction of such product into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.

We reviewed your April 23, 2024 responses to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your laboratory records did not include complete data to support the analysis performed. For example, Neogen Dermalogy Day-Light Protection Airy Sunscreen product batch NJ09 were tested several times (i.e., re-test) for assay during batch release and stability study from September 2022 to March 2023. The out of specification (OOS) results obtained were not recorded in the batch release documents and not investigated by the quality control laboratory at the time.

In your response, you acknowledge the deficiencies and state that several retests were performed to condition the column and to confirm the reproducibility of the results. You also claim that such retest was a process to gain a higher level of trust by confirming whether the experiment was performed accurately.

Your response is inadequate. Your firm failed to evaluate the risk of the already distributed drug product batches that had failed to meet the assay specification. You also failed to evaluate the scope of retest and confirmation test deficiency in your laboratory.

Reliability of data is compromised when there is a failure to maintain complete records of the conditions and data associated with all tests. Furthermore, the lack of complete data compromises the quality unit’s (QU) ability to exercise its function of ensuring compliance to applicable standards.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download.

In response to this letter, provide:

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

2. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Your laboratory equipment used to generate analytical data for finished drug product release lacked restricted access and sufficient controls. There is no assurance that your systems have the appropriate controls to prevent data deletion and record modifications. Specifically, electronic raw data used for release testing of batches (e.g., (b)(4)) currently in the U.S. market was deleted and not accessible. Your firm did not adequately maintain backups of data generated by your laboratory equipment. In addition, your analysts had administrative rights for the chromatography data system capable of changing and deleting files and disabled audit trails for some of your chromatographic systems.

In your response, you state that you removed administrative rights for your analysts, enabled audit trails feature on for your chromatographic system, implemented a data backup schedule, and retested drug product batches that had missing electronic data.

Your response is inadequate. You failed to include a comprehensive review of all laboratory instruments.

In response to this letter, provide:

• A comprehensive, independent assessment of computer system performance and security. Provide a report that identifies vulnerabilities in the design and controls, and a thorough CAPA plan for each of your laboratory computer systems, which addresses the following elements.

o A list of all hardware (both standalone and networked) and software used by your laboratory.
o Identify and evaluate vulnerabilities in performance and security of all of these computer systems, including but not limited to, their configurations, administrative rights, password controls, audit trails capabilities and state of implementation for each system, qualification/validation status, deviation history, backup capabilities, network requirements, completeness of data records, suitability of current hardware/software for its intended use(s), change management, and management oversight.
o Detail the associated user privileges for each system.
  - Specify user roles and associated user privileges for all staff levels who have access to the laboratory computer system, and provide organizational affiliations, responsibilities, and titles. Clearly specify all staff who have administrator privileges.
  - Fully describe how you will ensure segregation of firm personnel involved with laboratory testing from those with administrator rights. For all staff roles that are permitted to have administrative rights, specify the scope and type of privileges.
o Assess each system to determine if unique usernames and passwords are used.
o Evaluate policies and procedures regarding computers and data governance, with special emphasis on audit trails, prohibiting data deletion, and appropriate modifications of results. Specify how your firm prevents data deletion and undocumented/inappropriate modifications of data. Also describe how you ensure original data and information is always preserved. Provide your procedures for audit trail review.
o Provide requirements for data retention and backup for all laboratory systems.
o Describe how you ensure that all quality control tests are performed by an analyst and receive second-tier review from a separate qualified individual (e.g., lab manager). Provide related procedure(s).
o Summarize your interim controls to assure reliable performance and security while your CAPA plan is being implemented.

3. Your firm failed to establish a quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, including drug products manufactured, processed, packed or held under contract by another company. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit. (21 CFR 211.22(a) and (d)).

Your QU did not adequately exercise its authority and responsibilities, including but not limited to, establishing effective procedures and oversight.

For example,

• There is lack of adequate procedure for out-of-specification (OOS) investigation of the over the counter (OTC) drug product Neogen Dermalogy Day-Light Protection Airy Sunscreen.
• Your QU released OTC drug product batch using retest result without conducting an investigation when the original assay test failed to meet the release specification.
• You did not qualify your active pharmaceutical ingredients (API) supplier, and your contract testing laboratory used for API testing.
• Changes to the OTC drug manufacturing operations were not implemented through change control program.
• There is no annual product review of the OTC drug product.

In your response, you state that you initiated the review of prior changes and provided a procedure to perform an annual review of the OTC drug product.

Your firm’s response is inadequate. You failed to provide evidence that your QU is capable of identifying deficiencies and implementing CAPA.

Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. 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, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

4. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Your firm’s process validation and equipment qualification programs are inadequate. For example:

• The OTC drug product manufacturing process validation failed to evaluate the homogeneity of the API in the bulk product.
• You lack adequate equipment cleaning validation.

In your response, you provide validation protocol for assessing the API homogeneity based on samples collected from (b)(4) of the tank. You also provide protocol for the equipment cleaning process validation.

Your response is inadequate. You have not conducted risk assessment on the distributed drug product batches that were manufactured using an inadequately validated process. In addition, the cleaning acceptance criteria for the residual APIs is not adequately justified. Further, you did not provide cleaning method validation to demonstrate API recovery.

In response to this letter, provide:

• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, and will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:

o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

Misbranding Violations

“NEOGEN DERMALOGY AIRY SUNSCREEN Broad Spectrum SPF 50,” 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.

Examples from the product’s labeling that provide evidence of the intended uses (as defined by 21 CFR 201.128) of this product as a drug include, but are not limited to, the following:

“NEOGEN DERMALOGY AIRY SUNSCREEN Broad Spectrum SPF 50”

• “Drug Facts…Uses ■ Protects the skin from sunburn” [from drug product label]

• “INTENSIVE DEFENSE AGAINST UVA/UVB RAYS” [from drug product label]

Based on the above labeling, “NEOGEN DERMALOGY AIRY SUNSCREEN Broad Spectrum SPF 50” is intended for use as a sunscreen drug product. The labeling for such a drug, like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in Title 21 of the Code of Federal Regulations (21 CFR).

However, your “NEOGEN DERMALOGY AIRY SUNSCREEN Broad Spectrum SPF 50” sunscreen drug product is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c) because the label fails to bear additional information required under Over-the-Counter Monograph M020: Sunscreen Drug Products for Over-the-Counter Human Use¹ (hereafter M020). Specifically, your product is missing the statement, “Other information: [bullet] protect the product in this container from excessive heat and direct sun” as required under M020.50(f).

Additionally, your sunscreen drug product is misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2) because the label fails to bear adequate warnings as required under M020. Specifically, your product is missing the warning "Do not use [bullet] on damaged or broken skin" as required under M020.50(d)(1)(i).

Lastly, your product is also misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x) because the label fails to include a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. 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).

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your CAPAs before you pursue resolution of your firm’s compliance status with FDA.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

C. A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

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. FDA placed your firm on Import Alert 66-40 on August 29, 2024.

Correct any violations promptly. 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 any violations.

Failure to address any violation may also result in the FDA continuing to refuse admission of articles manufactured at Outin Futures Corp, 150 Gieopdosil-Ro, Daesowon-Myeon Chungju, Chungcheongbuk, Korea (the Republic of) into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated or misbranded may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B) and are misbranded under section 502 of the FD&C Act, respectively.

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 day. 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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3011572099 and ATTN: Liming Zhang.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

_______________________

1 Section 505G(a)(1) of the FD&C Act specifies criteria under which certain nonprescription drugs without approved applications are deemed GRASE and not "new drugs," notably, conformance with conditions detailed in applicable OTC monograph documents issued by FDA under 21 CFR part 330, prior to enactment of the CARES Act. In the case of OTC sunscreen drug products, relevant documents were deemed under section 505G to be a final administrative order, Over-the-Counter Monograph M020: Sunscreen Drug Products for Over-the-Counter Human Use. (See Order ID OTC000006, available at FDA’s website OTC https://dps.fda.gov/omuf).