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  1. Warning Letters

WARNING LETTER

Brands International Corporation MARCS-CMS 689983 —

Delivery Method:
Via Email
Reference #:
320-25-25
Product:
Drugs
Recipient:
Recipient Name
Mr. David Kahan
Recipient Title
Managing Partner
Brands International Corporation

101 Chase Avenue Suite 204
Lakewood, NJ 08701
United States

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-25-25

December 17, 2024

Dear Mr. Kahan:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Brands International Corporation, FEI 3007389902, at 594 Newpark Blvd, Newmarket, Ontario L3X 2S2, Canada, from June 17 to 21, 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).

Our investigators documented your firm limited and/or delayed an FDA inspection. Under section 501(j) of the FD&C Act, 21 U.S.C. 351(j), your drugs are adulterated in that they have been manufactured, processed, packed, or held in an establishment where the owner or operator has limited inspection and/or delayed inspection.

Additionally, 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 July 15, 2024 response to our Form FDA 483 in detail.

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

Delaying, Denying, and Limiting the Inspection

Your firm limited and delayed the FDA inspection as follows:

• At the start of the second day of the inspection, June 18, 2024, investigators were admitted into the building and left in a conference room. Investigators went to your laboratory to continue discussions with your Quality Control (QC) Supervisor from the day before. Later, your Quality Manager entered the laboratory and exhibited hostility by shoving and shouting at our investigators for conducting the inspection without their presence. Additionally, laboratory staff refused to open a drug stability chamber based on his hostile behavior. Your management staff’s behavior impeded our investigators during the inspection.

• While attempting to ask questions to additional quality staff, our investigators were intercepted multiple times by your Quality Manager. For example, investigators requested drug product testing specifications from your QC Supervisor. However, your Quality Manager interrupted and stated that only he can explain and answer the requests. He also interfered when the investigators asked your supervisor questions about temperature monitoring and would not allow investigators to fully review temperature records used to support drug retention samples.

• Investigators requested complaint records on June 17, 2024. You then provided a list of complaints on June 18, 2024. FDA later found positive mold samples for Kissable Oatmeal Daily Moisturizing Body Lotion batches in the QC laboratory office linked to a customer complaint. This complaint, and its associated investigations, were not disclosed in the list of complaints provided to FDA.

• While interviewing an employee regarding the undisclosed positive mold results for your Kissable Oatmeal Daily Moisturizing Body Lotion, your Quality Manager entered the room and began berating the employee, who then left the room, impeding FDA’s review of your contamination investigation required under CGMP.

• Investigators requested a list of batches distributed to the U.S. market multiple times during the inspection. Your Quality Assurance Supervisor initially claimed that you had no system to track batches of drugs shipped to the United States. This was later refuted by another employee and eventually you provided the requested list after a significant delay.

Delaying, Denying, Limiting, or Refusing a Drug Inspection

When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document:
Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection (June 2024) at https://www.fda.gov/media/86328/download.

CGMP Violations

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 failed to adequately investigate customer complaints. For example, your customer reported mold contamination in a batch of Kissable Oatmeal Daily Moisturizing Body Lotion. You determined the root cause was related to the container closure delivery system, specifically the pumps, used in the packaging of this product. However, your investigation did not clearly identify the scope of the contamination, and you failed to extend your investigation to other products packaged with the same pumps. Though you recalled two batches of Kissable Oatmeal Daily Moisturizing Body Lotion due to mold contamination, you lacked adequate evidence to support the contamination was limited to only two batches of finished product. You later committed to expanding the recall to other products packaged with these pumps.

In your response, you state a procedure for investigations and root cause analysis will be developed. Furthermore, you explain there is no need for further investigation of the mold contamination issue because manufacturing and sales of this product have stopped.

Your response is inadequate. You lack evidence that you have properly evaluated the root cause and scope of the mold contamination. You also fail to provide a comprehensive assessment of your complaint handling system to ensure all complaints have been adequately investigated.

In response to this letter, provide:

• 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, corrective action and preventive action (CAPA) effectiveness, quality unit (QU) oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

• Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including customer notifications and recalls.

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 (21 CFR 211.165(a)).

You failed to adequately test drug products you manufactured, including the identity and strength of each active ingredient prior to release and distribution into the U.S. market. For example, your QU released multiple batches of drug products without performing active ingredient assay. Additionally, we noted your test methods are not validated.

Without adequate testing, you do not have scientific evidence that your drug product batches conform to appropriate specifications prior to release.

In your response, you state you will implement a procedure for finished product testing, and a protocol for validating your analytical procedures.

Your response is inadequate. You do not provide sufficient evidence that distributed drug products conform to all appropriate finished product specifications. You also fail to address the product quality impact and risk of releasing drug products based on test results from analytical methods that have not been validated.

In response to this letter, provide:

• 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 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.

3. 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)).

Your firm failed to adequately test incoming components, including active pharmaceutical ingredients (APIs), for identity before using them in the manufacture of your drug products. Additionally, your firm released APIs for use based on your supplier’s certificates of analysis (COAs) without establishing the reliability of your suppliers’ test analyses at appropriate intervals. Furthermore, you did not demonstrate that you adequately performed identity testing on incoming glycerin, which is at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination.

In your response, you state a procedure will be developed to ensure incoming active ingredients will be tested by an external or internal laboratory. You also commit to developing a plan to test glycerin for DEG and EG content.

Your response is inadequate. You lack evidence that your current raw material inventory conforms with identity requirements and all other appropriate specifications. You also lack sufficient detail describing how you will qualify your suppliers and validate their COAs. Furthermore, you did not provide a retroactive risk assessment of distributed products containing components at high-risk for DEG or EG contamination.

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 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 quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.

• 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 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.

• 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 COAs 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.

• 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 drug products you manufacture.

4. Your firm failed to have buildings used in the manufacture, processing, packing, or holding of drug products with adequate space for the orderly placement of equipment and materials to prevent mixups and contamination (21 CFR 211.42(b)).

Your drug manufacturing facility lacked adequate controls. For example:

A. Material storage
Investigators observed approximately (b)(4) truck trailers on your property used for the storage of components, finished products, and other items. These trailers were not climate controlled, and you were unable to accurately describe the contents of the trailers due to your inadequate inventory management system. Furthermore, (b)(4), an API in your drug products, was stored outdoors and exposed to the elements.

B. Pest control
Pest traps inside your raw material storage area were covered with filth and insects, and reports from your pest control service provider showed an ongoing pest issue.

In your response, you state a procedure will be developed for managing inventories, including the dispositioning of nonconforming material in your warehouse and shipping trucks. You also state your pest control procedure will be improved and followed effectively.

Your response is inadequate. You fail to demonstrate adequate controls over your inventory, including materials stored in trailers outside your facility. You also fail to comprehensively evaluate the scope and product quality risk of your pest control issue.

In response to this letter, provide:

• Your 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.

• Your plans to provide sufficient space for the orderly storage of materials and adequate protection from environmental elements.

5. 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).

You lacked a QU with appropriate oversight for the manufacture of your drug products. For example, we observed the following deficiencies:

A. You failed to establish and implement adequate procedures to validate your processes and qualify the equipment used to manufacture your drug products. (21 CFR 211.100(a))

B. You failed to perform cleaning validation studies for non-dedicated equipment used to manufacture your drug products (21 CFR 211.67(b)).

C. You failed to establish and maintain an ongoing testing program to support the labeled expiry on your distributed drug products. Therefore, there is no assurance your drug products will remain acceptable throughout their labeled expiry period (21 CFR 211.137).

In your response, you state you will update procedures to clarify responsibilities and authorities of the QU and other departments. You also state you will develop, improve, and implement process and cleaning validation procedures. Furthermore, you state you will develop a stability testing program.

Your response is inadequate. You do not provide a comprehensive review of your QU’s authority and ability to carry out its responsibility to ensure compliance with CGMP. You also lack sufficient details of your plans to fully execute process and cleaning validation studies. Furthermore, you do not provide results of reserve sample testing or any additional scientific evidence to support your expiration dates.

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 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 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 risk assessment for the distributed drug product(s) produced without performing any process validation studies.

• 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

• 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.

• 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.

Quality Unit Authority

Significant findings in this letter indicate that your QU is not able to fully exercise its authority and/or responsibilities. 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 CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/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 audit1 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.

Drug Recall

On June 10, 2024, you initiated a voluntary recall of Kissable Oatmeal Daily Moisturizing Body Lotion due to the presence of mold contamination. The company announcement was posted to the FDA website: https://www.accessdata.fda.gov/scripts/ires/index.cfm#tabNav_advancedSearch.

On November 13, 2024, you initiated a voluntary recall of additional products due to CGMP violations and potential mold contamination. However, as of the date of this letter, you have not answered our requests for additional information regarding the expanded recall.

Cosmetics Manufactured for Distribution in the United States

We also note that some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. A cosmetic is deemed adulterated under section 601(c) of the FD&C Act [21 U.S.C. 361(c)] if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health. Some conditions that cause the drug products you manufacture to be adulterated may also cause any cosmetics you manufacture to be adulterated. 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. Further, your facility may be subject to requirements of the Modernization of Cosmetic Regulations Act of 2022 (MoCRA). Information on MoCRA requirements may be found at https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra.

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 products offered for import into the United States from your firm on Import Alert 66-40 on October 28, 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 violations may also result in the FDA continuing to refuse admission of articles manufactured at Brands International Corporation, located at 594 Newpark Blvd, Newmarket, Ontario L3X 2S2, Canada, 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 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).

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 3007389902 and ATTN: Matthew Jensen.

Sincerely,
/S/

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

cc:
David Price
Chief Revenue Officer
594 Newpark Blvd.
Newmarket, ON L3X 2S2
Canada

_______________________

1 i.e. Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.

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