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Warning Letter 320-24-18

January 31, 2024

Dear Mr. Toledano:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Les Importations Herbasanté Inc., FEI 3003175217, at 377 Sainte-Croix Ave., Saint-Laurent, from August 14 to 18, 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).

We reviewed your September 13, 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:

1. Your firm failed to appropriately sample, test, or examine the components, containers or closures released for use in the manufacture of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84).

As a contract manufacturing organization (CMO) of homeopathic drug products, you failed to perform adequate identity testing of each drug component lot used in the manufacture of your drug products (e.g., (b)(4) products intended for infants and children). You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ testing at appropriate intervals.

Glycerin

You failed to adequately test each shipment of each lot of glycerin for identity, a component at higher risk for diethylene glycol (DEG) and ethylene glycol (EG) contamination. We note that glycerin is an ingredient used in your pediatric drug products, (e.g., “(b)(4)”)¹. Identity testing for glycerin and certain other high-risk drug components2 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. These products are finished drug products consisting of various homeopathic active pharmaceutical ingredients and other components.

The use of glycerin 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 risk for DEG or EG contamination, https://www.fda.gov/media/167974/download.

(b)(4)
You failed to perform adequate identity testing of each lot of (b)(4) and establish the reliability of the analysis (e.g., purity, strength, quality) of your supplier COAs. This is significant because you manufacture various homeopathic drug products from ingredients that pose potentially toxic effects. For example, some of your pediatric drug products, such as “(b)(4) API” (Code (b)(4)), are labeled to be manufactured with (b)(4), which contains (b)(4), a highly toxic poison that is used as a (b)(4).

(b)(4)
You purchase (b)(4) for use in the manufacture of your drug products. You failed to demonstrate that the (b)(4) used to produce your pediatric drug products meet (b)(4) monograph and appropriate microbial limits. You rely on the supplier’s COA without establishing the reliability of your supplier’s testing.

In your response, you commit to updating the specifications and frequency of your component evaluation by December 2023 and updating your procedures for supplier qualification. Your response is inadequate because your interim plans, including your plans to perform retrospective and future component testing, are unclear and it lacks supportive documentation. In addition, your response did not consider a retrospective evaluation of potential impact to your products currently on the U.S. market.

Without appropriate testing of components and ingredients, you cannot ensure that the identity, purity, strength, quality, and safety of the components used to manufacture your homeopathic drug products meet specifications and are suitable for their intended uses.

In response to this letter, provide:

• 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 components for use in manufacturing.
• A summary of results obtained from testing all components to evaluate the reliability of COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.
• 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 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.
• If you intend to use a contract testing laboratory to test drug components, a summary of your program for qualifying and overseeing contract facilities that test the components should be included.
• 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 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.

2. 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 have not validated your manufacturing process used to produce homeopathic drug products, including those intended for infants and children. During the inspection, you indicated that you were not aware of the requirement.

In your response, you commit to performing process validation on (b)(4) drug product, discontinuing the use of your (b)(4) equipment, and opting to (b)(4) your drug products manually (i.e., by hand). Your response is inadequate because you must assure that your production process is capable of assuring all of your drugs are of acceptable quality, identity, strength, and purity. During process validation, the process design should be evaluated to determine if it is capable of reproducible commercial manufacturing. Manual (b)(4) is an inherently variable process. In addition, your response did not consider a retrospective assessment of potential impact to product quality.

Without adequate process validation, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. 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 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 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.
• 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.
• Your process performance protocol(s), and written procedures for qualification of equipment and facilities.
• Timelines for completed PPQ for marketed drug products.

3. 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).

Your quality unit (QU) did not adequately oversee your drug manufacturing operations. For example, your QU failed to ensure:

• Performance of periodic (i.e., at least annually) product reviews for all of your drug products (21 CFR 211.180(e)).
• Use of qualified contract testing laboratories (21 CFR 211.22(a)).
• Master production and control records include all required elements (21 CFR 211.186).
• Batch production and control records include documentation of the accomplishment of each significant step in the manufacture, and processing, of the batch, for each batch of drug product (21 CFR 211.188(b)).

Your firm’s quality systems are inadequate. 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 other QU duties to ensure identity, strength, quality, and purity of all products.

• A description of 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.

Repeat Violations at Facility

In previous inspections, FDA cited similar CGMP findings. You proposed specific remediation for these findings in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Responsibilities as a Contractor

Drugs must be manufactured in conformance with CGMP. The FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. The 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/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.

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 if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit³ 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 in connection with your products 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 January 26, 2024.

Until FDA is permitted to inspect your facility and confirms compliance with CGMP, we may withhold approval of any new applications or supplements listing your firm as a drug manufacturer. In addition, shipments of articles manufactured at Les Importations Herbasanté, Inc., at 377 Sainte-Croix Ave., Saint-Laurent into the United States that appear to be adulterated or misbranded are subject to being detained or refused admission pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).

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 refusing admission of articles manufactured at Les Importations Herbasanté, Inc., at 377 Sainte-Croix Ave., Saint-Laurent 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 3003175217 and ATTN: Reba Gates.

Sincerely,
/S/

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

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1 While you label your drug products “API" we note that these are finished dosage form drug product in bulk containers, further shipped to your customers for packaging.

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

3 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.