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WARNING LETTER

Betone S.A. de C.V. MARCS-CMS 674299 —


Delivery Method:
VIA UPS
Reference #:
320-24-26
Product:
Drugs

Recipient:
Recipient Name
Dr. Edith Parra de la Torre
Recipient Title
CEO
Betone S.A. de C.V.

Periferico Poniente #7100
Col. Ciudad Granja
45010 Zapopan, Jal.
Mexico

Issuing Office:
Center for Drug Evaluation and Research | CDER

United States


Warning Letter 320-24-26

March 21, 2024

Dear Dr. Parra de la Torre:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Betone S.A. de C.V, FEI 3016998650, at Periferico Poniente #7100, Col. Ciudad Granja, Zapopan, Jalisco 45010, from November 6 to 10, 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 December 1, 2023 response to our Form FDA 483 in detail.

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

1. 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)).

Your firm manufactures over-the-counter (OTC) (b)(4) wipe drug products. Your firm failed to adequately test your (b)(4) wipe drug products for the identity and strength of the active ingredient (b)(4) prior to release and distribution.

In your response, you state that you implemented a standard operating procedure to conduct testing for the active ingredient (b)(4) in each lot of drug product. Your response is inadequate because you failed to assess drug products released without adequate testing.

Full release testing, including strength and identity testing of the active ingredient, must be performed before drug product release and distribution. Without adequate testing, you do not have adequate scientific evidence to assure that your drug products conform to appropriate specifications before release.

In response to this letter, provide:

  • A comprehensive 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.
  • A list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot disposition decision, and the associated written procedures.

2. Your firm failed to formulate batches of your drug product with the intent to provide not less than 100% of the labeled or established amount of active ingredient (21 CFR 211.101(a)).

Your firm failed to ensure that your (b)(4) wipe drug products were formulated to contain the (b)(4) active ingredient at the labeled strength of (b)(4)%. Drug products must be formulated to contain the amount of active ingredient they are represented to possess.

In your response, you confirmed that your formulation was subpotent vs the label claim, (containing (b)(4)% (b)(4)) and that this concentration aligns with the permissible range stipulated by the FDA’s temporary guidance for (b)(4) drug products. Your response is inadequate as FDA’s temporary guidances were not applicable to your (b)(4) using (b)(4) as the active ingredient.1 In addition, you propose changing the label and marketing the product as a (b)(4) drug product, but no draft labeling or timeframe for making these changes was provided.

In response to this letter, provide a remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all your drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing (including both production and packaging) 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.

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)).

You failed to adequately test your incoming components (e.g., active ingredient (b)(4), and glycerin) before using the components to manufacture your (b)(4) wipe drug products. You also relied on your suppliers’ certificates of analysis (COA) without establishing the reliability of your suppliers’ test analyses at appropriate intervals.

Products Containing Glycerin

Glycerin, along with other high-risk components, requires identification testing per the United States Pharmacopeia (USP) to ensure that it meets safety limits for diethylene glycol (DEG) or ethylene glycol (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 glycerin used in the 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.

In your response, you state that you will send samples of components to an external laboratory for testing of DEG and EG. Your response is inadequate. You did not address testing of all other components, including identity testing, used in the manufacture of your drug products. Without appropriate testing of components, you cannot ensure the quality and safety of your drug products.

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 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.
  • 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 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.

4. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

You failed to establish and maintain an ongoing stability testing program to support the labeled expiry on your distributed drug products. There is no assurance that your drug products will remain acceptable throughout their labeled expiry period without an ongoing stability program.

In your response, you state that drug product samples are sent to an external laboratory for analysis. Your response is inadequate. Your stability studies are only (b)(4) in duration and do not include full shelf-life studies, including testing for the active ingredient (b)(4). In addition, the temperature and humidity parameters are not specifically defined for each of your proposed storage conditions.

In response to this letter, provide:

  • A comprehensive 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.

Additional Considerations

Additionally, we note that your “DODY’S Antiseptic Hand Sanitizer Wipes” drug product is marketed as “antiseptic wipes.” Antiseptic wipes generally refer to consumer antiseptic rub drug products that are not intended to be rinsed-off after use. However, the label for your “DODY’S Antiseptic Hand Sanitizer Wipes” also suggests that it can be used as a consumer antiseptic wash. For instance, the label states, “For hand washing to decrease bacteria on the skin.” An antiseptic wipe drug product marketed under section 505G of the FD&C Act cannot also be a consumer antiseptic wash as the directions for use conflict with each other and a wipe is not an acceptable dosage form for an antiseptic wash.2

Lastly, we note in your response that you are considering changing the marketing of your “DODY’S Antiseptic Hand Sanitizer Wipes” from the monograph conditions under the 1994 TFM titled “Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products,” as further amended by the 2016 Consumer Antiseptic Rubs Proposed Rule, to the monograph conditions referenced under the final Monograph “Over-the-Counter (OTC) Monograph M003: First Aid Antiseptic Drug Products for Over-the-Counter Human Use.” To help ensure that any corresponding revised labeling and product change meets the monograph conditions outlined in Section 505G of the FD&C Act, it is incumbent upon your firm to retain the services of a reputable food and drug law consultant or attorney for assistance. Please note that FDA does not object to the lawful marketing of OTC products under section 505G if the product is marketed in accordance with the OTC monograph conditions AND complies with all other relevant regulations including CGMPs and general OTC drug labeling requirements. In addition, we also remind you to take a comprehensive review of your OTC drug product inventory to ensure that your OTC drug products comply with all requirements of federal laws and applicable regulations.

Quality Systems

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.

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 CAPA 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 March 11, 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 Betone S.A. de C.V., Periferico Poniente #7100, Col. Ciudad Granja, Zapopan, into the United States that appear to be adulterated 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 continuing to refuse admission of articles manufactured at Betone S.A. de C.V., Periferico Poniente #7100, Col. Ciudad Granja, Zapopan, 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 3016998650 and ATTN: Joel Hustedt.

Sincerely,
/S/

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

CC: Registered US Agent
Mr. Carlos Jimenez
EPort USA LLC
4490 Via Aciando
Camarillo, CA 93012 - 4044

__________________

1 (b)(4)

2 Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under section 505G(a)(3) of the FD&C Act, drugs that were classified as Category III for safety or effectiveness in a TFM that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 – and that were not classified as Category II for safety or effectiveness – are not required to have an approved application under section 505 in order to be marketed, as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM, including dosage form, and comply with all other applicable requirements. The permitted dosage forms for consumer antiseptic washes are set forth here: “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016).

 
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