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Warning Letter 320-25-27

December 18, 2024

Dear Mr. Cortazar:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sombra Cosmetics, Inc., FEI 1629960, at 5951 Office Blvd NE, Albuquerque, New Mexico, from July 15 to 26, 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 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 August 16, 2024 response to our Form FDA 483 in detail. Your response is inadequate because you failed to provide supportive documentation for evaluation or adequate evidence of corrective actions taken to bring your operations into compliance with CGMP.

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

1. 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)).

Inadequate Water System

You manufacture over-the-counter (OTC) drug products such as topical analgesic creams and hand sanitizers. Your firm used water as a component in your OTC drug product manufacturing and equipment cleaning, without adequately demonstrating that your water was suitable for its intended use. For example, you failed to conduct adequate TOC and conductivity testing to ensure that your water met (b)(4) Water United States Pharmacopeia (USP) monograph specifications.

Additionally, we noted that multiple microbiological water samples resulted in colonies that were “TNTC” (too numerous to count) with “GNR” (gram negative rods). These microorganisms were not further isolated to determine the identification of the bacteria or fungi species.

Your response is inadequate. You indicated that validation of your water systems will need to be “re-done” after upgrades are performed. You did not provide a detailed remediation plan listing the upgrades to be performed and the projected timelines for the implementation of qualification, validation, and adequate monitoring activities required for each water system. In addition, your proposed (b)(4) and (b)(4) water quality monitoring is insufficient given your manufacturing operations and the finished drug products that you produce. Furthermore, you also did not consider retrospective testing of retained finished drug products that used water from either system.

(b)(4) water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. Routine monitoring of microbial counts and identity of contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in manufacturing operations.

Inadequate Process Validation

You failed to provide sufficient data to demonstrate you have adequately validated your manufacturing processes used to manufacture your OTC drug products. Furthermore, you failed to provide sufficient data to demonstrate qualification of your manufacturing equipment (e.g., steam jacketed kettles, mixers, filling machines, labelers, etc.).

Your response is inadequate because there was no assurance of completed process validation for each product that you currently market. While you provided a sample process validation, it did not include acceptance criteria or the applicable product specifications. Further, you did not provide a timeline for the validation of your processes and did not consider a retrospective review of previously distributed drug products.

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 evaluates 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 comprehensive independent remediation plan for the design, control, and maintenance of the water system.
  o A (b)(4) water system validation report specific for each water system in each building. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance for each water system.

• A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

• A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.

• The current action/alert limits for total counts and objectionable organisms used for your (b)(4) water system.

• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.

• 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.

• Include your process performance protocols, and written procedures for qualification of equipment and facilities.

• 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.

• 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 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 standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

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 failed to perform adequate identity testing for each component lot used in the production of your OTC drug products, including your active pharmaceutical ingredients (APIs). You relied on the certificates of analysis (COAs) from your suppliers and failed to establish the reliability of each of your suppliers’ COA for component specifications and characteristics.

Products Contain Ethanol (Methanol Risk)

You manufacture multiple drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol at: https://www.fda.gov/media/173005/download.

Products Contain Ingredients at Risk for Diethylene Glycol or Ethylene Glycol (DEG or EG) Contamination

You manufacture multiple drugs that contain glycerin. 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.

Your response is inadequate. You did not discuss how you intend to independently validate the results and product characteristics reflected in each supplier COA. Furthermore, there was no plan to routinely or periodically verify the information in the supplier COA.

Without adequate testing and confirmation of reliability of supplier and external laboratory testing results, you lack scientific evidence that the components or drug products conform to appropriate specifications.

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 corrective action and preventive action (CAPA) 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 supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s 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 United States Pharmacopeia (USP) monograph.

• The chemical and microbiological 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.

• A summary of your program for qualifying and overseeing contract facilities that test the components and drug products you manufacture.

3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your firm failed to demonstrate that your microbiological test methods were appropriate to assure that your product conforms to appropriate standards of identity, strength, quality, and purity. Specifically, you could not provide evidence of method suitability for microbiological testing performed at your facility.

In your response, you state that you are in the process of implementing testing for “USP methodologies”. Your response is inadequate. While you provided updated procedures, your method for growth promotion does not test for the presence of fungal microorganisms (yeast and mold). Further, you did not provide a timeline for the validation of your methods and did not consider a retrospective review of previously distributed drug products.

The ability of microbial testing methods to detect objectionable microorganisms in the presence of each drug product must be established.

In response to this letter, provide:

• A list of chemical and microbiological test methods and specifications used to analyze each batch of your drug products before making a batch disposition decision, and the associated written procedures.
  o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
  o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

• 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.

4. Your firm failed to establish an adequate 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 and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure:

• Adequate investigations into customer complaints (21 CFR 211.192) such that the investigation process has sufficient rigor and scope to determine root causes and to implement CAPA.

• Establishment of a written testing program designed to assess the stability characteristics of drug products and determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

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.

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.

• A comprehensive independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification 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.

• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability-indicating methods.
  o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
  o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
  o Detailed definition of the specific attributes to be tested at each station (timepoint).
  o All procedures that describe these and other elements of your remediated stability program.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm and because you failed to correct repeat violations, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. 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.

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 1629960 and ATTN: Frank Wackes.

Sincerely,
/S/

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