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Warning Letter 320-25-108

September 11, 2025

Dear Ms. Rendel:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Columbia Cosmetics Manufacturing Inc, FEI 2919184, at 1661 Timothy Dr., San Leandro, CA, from April 7 to 14, 2025.

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 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).

We reviewed your May 2, 2025, response 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 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).

You manufacture over-the-counter (OTC) sunscreen drug products. Your firm failed to conduct adequate investigations into out-of-specification (OOS) results. For example, an OOS result for bulk batch (b)(4) indicated subpotency for one of the active pharmaceutical ingredients (APIs). The corrective action was to reprocess the drug product by adding additional API. The subsequent finished drug product retesting showed that this batch remained subpotent.

Furthermore, this reprocessing was performed without the review and approval of your Quality Unit (QU). Your QU released failing drug product without an investigation regarding the finding of subpotent finished product.

You did not thoroughly investigate these unexplained discrepancies or identify failures in a drug product to meet any of its specifications. An investigation into the failure of bulk product was initiated only after drug product was released. This investigation was inadequate in that its conclusion, API “evaporation,” was not scientifically supported. Additionally, this investigation failed to address the improper release of subpotent finished product, implement appropriate corrective action and preventive action (CAPA), and expand the investigation to evaluate the impact on other batches of drug products.

In your response, you revise your standard operating procedure (SOP) to require investigation of OOS results by your QU. Your response also attempts to invalidate the OOS of finished drug product. Your response is inadequate. Without adequate scientific justification, you claim the test method associated with the OOS is not suitable. Additionally, you fail to extend your investigation to other batches impacted by this method. Therefore, your investigation fails to identify a sufficiently supported root cause or implement appropriate corrective actions. Moreover, your response does not propose to perform any retrospective impact assessment of previously distributed drug products or to re-evaluate the adequacy of any previously invalidated OOS results. As a manufacturer, you have a responsibility to fully investigate unexplained discrepancies and failures to assess impact to drug product quality.

For more information about handling failing, OOS, out-of-trend (OOT), 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 retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS:
  o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
  o For investigations that conclusively establish laboratory root cause, provide rationale, and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
  o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
• A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include, but not be limited to, addressing the following:
  o QU oversight of laboratory investigations.
  o Identification of adverse laboratory control trends.
  o Resolution of causes of laboratory variation.
  o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified.
  o Adequately scoping of each investigation and its CAPA.
  o Revised OOS investigation procedures with these and other remediations.
• 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.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final QU decisions, and is fully supported by executive management.

2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. 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 211.84(d)(2)).

You did not perform adequate identity testing on each shipment of each lot of incoming components (e.g., glycerin) used in the manufacture of your OTC drug products. Additionally, you relied on your suppliers’ certificates of analysis (COAs) without establishing the reliability of each of your suppliers’ analyses at appropriate intervals (e.g., avobenzone).

For example, you failed to adequately test your incoming components at high risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination for identity before using them to manufacture your drug products. This includes, but is not limited to, testing of glycerin to determine its appropriate identity.

Identity testing for glycerin and certain other high-risk drug components include a limit test in the USP to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the manufacture of your drug products.

In your response, you commit to performing testing for DEG and EG in glycerin and provide test results performed on retained component samples. Your response is inadequate in that it fails to consider other high-risk components used in your drug products, including but not limited to, propylene glycol. In addition, your response does not provide sufficient details on how you will establish the reliability of your component suppliers’ COAs at appropriate intervals.

The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.

In response to this letter, provide:

• A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of DEG and EG.
• A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate CAPAs that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your suppliers’ COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers’ results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
• The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
• A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.

3. 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)).

You failed to adequately validate your manufacturing processes to demonstrate that your processes are reproducible and controlled to consistently yield drug products of uniform character and quality. For example, your OTC drug products, Rejuva Mineral Daily Wear Face Protection Moisture SPF16 and (b)(4), were manufactured without adequate validation of your manufacturing processes, including performance of process qualification studies.

In your response, you state that you will perform a retrospective validation of the drug products that you manufactured using an unvalidated process. You also state that you will develop a procedure for prospective validation of reprocessed drug products.

Your response is inadequate because you do not commit to ensuring prospective validation studies are completed prior to continued distribution of these drug products, nor do you include a risk assessment for marketed drug products manufactured by unvalidated processes. Moreover, it is unclear from your response how your proposed prospective validation of reprocessing will cover every potential reprocessing situation for all drug products manufactured at your facility.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. See FDA’s guidance for industry, Process Validation: General Principles and Practices, for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In response to this letter, provide:

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing appropriate PPQ for each of your marketed drug products. Also include an explanation how you will ensure proper satisfactory PPQ studies are performed prior to future distribution of any drug products.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

Ineffective Quality Systems

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production operations, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

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 CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

Responsibilities as a Contractor

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate 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.

Cosmetics Manufactured for Distribution in the United States

In addition, some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. We note that under section 301(a) of the FD&C Act [21 U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.

We also note that the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) provides new requirements with which facilities that manufacture cosmetic products must comply. You may find the FD&C Act, MoCRA, and FDA’s regulations through links on FDA’s website at www.fda.gov.

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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 2919184 and ATTN: Andrew Haack.

Sincerely,
/S/

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