Aruba Aloe Balm N.V. - 674911 - 05/13/2024

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Warning Letter

May 13, 2024

Dear Mr. Veel:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Aruba Aloe Balm N.V., FEI 3004117460, at Pitastraat 115, Oranjestad, from November 13 to 16, 2023.

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).

In addition, ISLAND REMEDY ALL-DAY REVITALIZING MOISTURIZER is misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). This violation is described in more detail below.

We reviewed your December 7, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

CGMP Violations

1. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and 211.84(d)(2)).

You failed to ensure that incoming lots of active pharmaceutical ingredient (API) were suitable for use in manufacturing your over-the-counter (OTC) drug products intended for the U.S. market.

Your firm does not test incoming raw materials for identity, purity, strength, and quality. Your firm’s quality control (QC) manager reported you only test incoming raw materials for physiochemical attributes such as appearance, smell, and miscibility.

During the inspection, you provided certificates of analysis (COAs) for Ethyl Alcohol that contained the statement that the material was “not intended for use as an active ingredient in drug manufacturing.” However, you used this API to manufacture your OTC drug products.

Without adequate testing, you do not have scientific evidence that your raw materials conform to appropriate specifications before use in the manufacture of your drug products.

Drug Products Containing Ethanol

You manufacture 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.

Your firm used two lots of ethanol that contained approximately 4.75% methanol (per COAs). Although your firm was aware of the methanol content in two batches of ethanol and of FDA’s concern regarding contaminated ethanol, the material was used in the manufacture of drug products, including hand-sanitizers and the Alcoholada Gel product. Your firm indicated that these drug products were distributed to the United States.

Methanol is not an acceptable ingredient for hand sanitizers and should not be used due to its toxic effects. Skin exposure to methanol can cause dermatitis, as well as transdermal absorption with systemic toxicity. Substantial methanol exposure can result in nausea, vomiting, headache, blurred vision, permanent blindness, seizures, coma, permanent damage to the nervous system, or death. Although all persons using these products on their hands are at risk, young children who accidentally ingest these products, and adolescents and adults who drink these products, are most at risk for methanol poisoning.

On April 5, 2024, you agreed to recall multiple lots of Aruba Aloe Hand Sanitizer Gel 80% Alcohol and Alcoholada Gel for the potential presence of methanol, that were distributed in the United States at the following website: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/aruba-aloe-balm-nv-issues-voluntary-nationwide-recall-aruba-aloe-hand-sanitizer-gel-alcohol-80-and

On April 15, 2024, FDA notified the public of the methanol contamination of your drugs at the following website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use

Additionally, we acknowledge your decision to discontinue the manufacture and distribution of these products.

Drug Products Containing Glycerin

You manufacture drugs that contain glycerin and propylene glycol. Your firm failed to adequately test each shipment of each lot of incoming components at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. This includes, but is not limited to, testing of glycerin you use in manufacturing drug products to determine its appropriate identity. Identity testing for this and certain other high-risk drug components¹ include a limit test in the United States Pharmacopeia (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 manufacture of your drug products.

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.

(b)(4) Water System

Your firm produces (b)(4) water that is used as a component in the production of many of your OTC drug products. Your firm has not demonstrated that the water is suitable for use and meets the USP (b)(4) water monograph. Your firm failed to adequately monitor the microbiological quality of the water you use to manufacture your aqueous-based OTC drug products.

In your response you indicate you are actively seeking a contract laboratory to conduct testing on incoming raw materials, including for impurities such DEG/EG for incoming batches of glycerin and propylene glycol. Also, you committed to conduct sampling and testing of your water system prior to the production for any OTC drug product.

Your response is inadequate. You fail to provide sufficient details such as your testing procedures, a timeline for implementing corrective action and preventive action (CAPA), and a risk assessment of products released without appropriate assay or microbial testing.

In response to this letter, provide the following:

• A comprehensive 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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• 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 certificate of analysis (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 re-validation. 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.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• 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 your 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 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.
• 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 remediation plan for the design, control, and maintenance of the water system.

    o A (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.
Aruba Aloe Balm N.V., Oranjestad FEI 3004117460 page 5

• 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.
• Your total microbial count limits to monitor whether this system is producing water suitable for the intended uses for each of your drug products.

2. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and 211.165(b)).

Your firm failed to adequately test your OTC drug products for identity and strength of active ingredients prior to release and distribution into the U.S. market. Also, you lacked adequate microbiological testing for each batch of your OTC drug products prior to release. For example, you released your Alcoholada Gel drug product based on testing pH, viscosity, weight, and appearance.

In addition, you lacked an adequate stability testing program and supporting data to show that the chemical and microbial properties of your drug products remain acceptable throughout the labeled expiry period (see 21 CFR 211.166(a) and 211.166(b)). We note that your firm suspended stability testing in 2020 and 2021 due to financial constraints.

In your response, you state you will ensure all forthcoming batches undergo comprehensive analytical testing before release and throughout stability studies, and you will perform microbiological testing for each batch of released OTC drug product including for B. cepacia. You also indicate you will continue to use contract laboratories to conduct both analytical and microbiological testing of your drug products.

Your response is inadequate. You fail to provide sufficient details such as your testing procedures, specifications, a timeline for implementation, and a risk assessment of products released without appropriate assay or microbial testing. Additionally, your response lacks adequate information on how you will evaluate the suitability of your contract laboratories to perform testing of your drug products.

Full release testing, including for identity, strength, impurities, and microbiological assessment must be performed prior to drug release and distribution. Without adequate testing and stability studies, there is no scientific evidence to assure that your drug products conform to appropriate specifications before release and retain their quality attributes through their labeled expiry.

In response to this letter, provide the following:

• A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.

    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 (including contract laboratory) practices, procedures, methods, equipment, documentation, and analyst competencies. This assessment should include, but not be limited to, a review of method suitability criteria, and validation (or verification for USP compendial methods) to determine whether they are fit for their intended use. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• 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)

All procedures that describe these and other elements of your remediated stability 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)).

Your firm failed to adequately validate your production and process controls. As such, you do not have assurance that you are capable of consistently manufacturing OTC drug products with defined quality attributes.

In addition, in response to complaints regarding the viscosity of your (b)(4) formula, you changed the concentration of two ingredients without an adequate change control or justification for failing to validate this revised process.

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 to ensure the quality of raw material inputs, in-process materials, and finished drugs. Process validation studies determine whether an initial state of control has been established.
See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/media/71021/download.

In your response, you state you were instituting a structured approach to process validation.

Your response is inadequate. You fail to provide adequate validation procedures, protocols, a timeline for implementing CAPA, or a risk assessment of products released without appropriate validation or testing.

In response to this letter, provide the following:

• A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
• 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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed 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.

Misbranded Drug Violation

ISLAND REMEDY ALL-DAY REVITALIZING MOISTURIZER 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 sunscreen.

Examples of claims observed on the ISLAND REMEDY ALL-DAY REVITALIZING MOISTURIZER product label and labeling that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

“Drug Facts . . . Purpose . . . Sunscreen . . . Uses . . . Helps prevent sunburn” [from your product carton]

However, ISLAND REMEDY ALL-DAY REVITALIZING MOISTURIZER is misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2) because the product label does not include all of the applicable warnings as required under the Over-the-Counter Monograph M020: Sunscreen Drug Products for Over-the-Counter Human Use (hereinafter “M020”).

Specifically, the product label for your ISLAND REMEDY ALL-DAY REVITALIZING MOISTURIZER sunscreen fails to include the warning “Do not use [bullet] on damaged or broken skin” on the Drug Facts panel (see M020.50(d)(1)(i)).

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, 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 audit2 of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions 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.

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 April 15, 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 inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Aruba Aloe Balm N.V. located at Pitastreet 115, Oranjestad, Aruba, 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 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 3004117460 and ATTN: Maria Pavco.

Sincerely,
/S/

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

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1 Components with higher risk of DEG or EG contamination compared to other drug components.