WARNING LETTER
Multaler et Cie SAS
MARCS-CMS 685009 —
November 05, 2024
Delivery Method:
VIA UPS
Reference #:
320-25-10
Product:
Drugs
Recipient:
Recipient Name
Mr. Alexis Wolkowinski
Recipient Title
President
Multaler et Cie SAS
1 Rue Ambroise Croizat
Argenteuil
95100
Val d’Oise
France
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
Warning Letter
320-25-10
November 5, 2024
Dear Mr. Wolkowinski:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Multaler et Cie SAS, FEI 3010165406, at 1 Rue Ambroise Croizat, Argenteuil, Val d’Oise, from April 15 to 17, 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 product is 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, YONKA PARIS YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN is an unapproved new drug introduced or delivered for introduction into interstate commerce in violation of section 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act,) 21 U.S.C. 355(a), 331(d). Additionally, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act, 21 U.S.C. 331(a) and (d). These violations are described in more detail below.
We reviewed your April 30, 2024 response to our Form FDA 483 in detail.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. 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 manufacture a topical over-the-counter (OTC) drug product for the U.S. market. You failed to adequately test your incoming components, including propylene glycol, glycerin, and active ingredients such as octocrylene, for identity before using them in your drug product. Additionally, you relied on your suppliers’ certificates of analysis (COA) without establishing the reliability of each of your suppliers’ analyses at appropriate intervals.
Glycerin & Propylene Glycol
You failed to adequately test each shipment of each lot of glycerin and propylene glycol for identity, components at higher risk for diethylene glycol (DEG) and ethylene glycol (EG) contamination. Identity testing for glycerin, propylene glycol, and certain other high-risk drug components
1
includes 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 adequate 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 product.
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.
Without adequate testing, you do not have appropriate assurance that components conform to appropriate specifications prior to use in the drug products you manufacture.
In your response, you committed to establishing specific identity tests in accordance with USP. You also committed to periodically verify the analyses provided by your suppliers. Your response is inadequate. You did not provide a detailed plan for how components will be tested, including test methods and review of compendial requirements, or a timeline for implementing the corrective actions proposed. Your response also lacked sufficient detail on how you plan to establish the reliability of the test results on your suppliers’ COAs at appropriate intervals. Further, you did not consider a retrospective review of previously distributed 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 drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product lots 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 actions and preventive actions (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 USP monograph.
The chemical and microbiology quality control specifications you use to test each incoming lot of each incoming lot of components, including, 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 standard operating procedure that describes this COA validation program.
A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
2. 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 chemical and 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 documentation that the analytical methods used by your contract laboratory for chemical release assays were validated for your specific drug product.
You could not provide method suitability for microbiological testing performed at your facility, nor information demonstrating that the antibacterial agents used in your media do not inhibit yeast or mold growth.
Your microbiological testing was performed without positive or negative controls.
You only tested for the presence of three organisms whereas USP <62> describes six specified species.
You did not test for
Burkholderia cepacia
complex (BCC), a contamination risk in non-sterile water-based drug products.
For further information regarding the significance of BCC and other objectionable contamination of non-sterile, water-based drug products, see FDA’s advisory notice posted on July 7, 2021, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile.
In your response, you stated that you are in process procuring, through your contract laboratory validated chemical test methods for your drug product. You also stated that you will review microbiological methods to ensure that methods meet USP requirements.
Your response is inadequate. You failed to provide sufficient details about the review of and improvements for your microbiological test methods. You also did not provide details or a timeline for validation of your chemical methods. Further, you did not consider a retrospective review of previously distributed drug products tested with inadequate methods.
In response to this letter, provide:
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.
A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before lot disposition decision.
o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all lots 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 lot. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
3. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).
Your firm uses purified water as a component to manufacture your OTC drug product. The
(b)(4)
water system was not designed and maintained appropriately for its intended use. For example, your non-circulating
(b)(4)
water system included dead legs, which could foster the development of biofilms. When not in use, water from this system sat stagnant, including in a line that was used to dispense water for your drug product.
In your response, you state that you will carry out a feasibility study and “evaluate the cost” of modifying the water system, remove the dead leg and add a water loop. Your response is inadequate. You did not describe any immediate actions to modify or monitor your system to ensure the quality of
(b)(4)
water in your current manufacturing process. Lastly, you did not consider a risk assessment or retrospective review of your previously distributed drug products.
In response to this letter, provide:
A comprehensive, independent assessment of your water system design, control, and maintenance.
A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to
(b)(4)
Water, USP monograph specifications, and appropriate microbial limits.
Regarding the latter, ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
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. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
Unapproved New Drug Violations and Misbranding Drug Violations
YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN 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 a sunscreen drug product.
Examples from the YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN product labeling that provide evidence of the intended use (as defined in 21 CFR 201.128) of the product as a drug include, but may not be limited to, the following:
YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN
“Face sunscreen” ; “Helps prevent sunburn” [from product label]
Unapproved New Drug Violations
Based on the above labeling evidence, YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN is intended for use as a sunscreen drug product. As described below, this drug product is an unapproved new drug marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).
A drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. With certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for this drug product identified above.
Your drug product is marketed as a sunscreen drug product and is subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application —commonly referred to as "OTC monograph drugs"—may be legally marketed if they meet applicable requirements. With respect to nonprescription sunscreen drug products, such as your YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN, such products are deemed to be GRASE and not a new drug if, among other things, they conform to the conditions in the applicable OTC monograph(s), here M020 Sunscreen Drug Products for Over-the-Counter Human Use.
2
However, YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN does not conform to the conditions specified in M020 for the reasons described below.
Specifically, the product is labeled to contain the ingredients Octocrylene, Oxybenzone, Avobenzone, and Ensulizole. However, this combination of active ingredients is not permitted under M020.20.
Thus, your YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN product does not comply with the applicable conditions specified in M020 and has not otherwise been found to be GRASE.
3
Moreover, there is no evident basis under the FD&C Act under which this product would be legally marketed without an approved application. Accordingly, this product is a new drug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). Because there is no application in effect for this product, this product is an unapproved new drug marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a).
The introduction or delivery for introduction of this unapproved new drug product into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Misbranded Drug Violations
Additionally, YONKA PARIS SOLAR CARE SPF 50 UVA/UVB BROAD SPECTRUM FACE SUNSCREEN is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because this product is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.
The introduction or delivery for introduction of a misbranded drug into interstate commerce violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
Cosmetic Product Manufacture
Some of the products you manufacture appear to be cosmetics, as defined in section 201(i) of 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 [21U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated. Further, your facility may be subject to requirements under 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.
CGMP Consultant Recommended
We acknowledge your commitment to suspend exporting your drug product to the United States.
In response to this letter, clarify whether you intend to resume manufacturing drugs for the U.S. market at this facility in the future. If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. Should you resume manufacturing drugs for the U.S. market, 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 audit4 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.
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 Multaler Et Cie SAS, 1 Rue Ambroise Croizat, Argenteuil, Val d’Oise, 95100, France, 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 3010165406 and ATTN: Christina Capacci-Daniel.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
/S/
Tina Smith, M.S.
Captain, U.S. Public Health Service
Director
Office of Unapproved Drugs & Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research
____________________
1
Components with higher risk of DEG or EG contamination compared to other drug components.
2
M020 reflects the conditions set forth in the relevant final order(s) established and in effect under section 505G; see Order ID OTC000008, available at FDA’s website OTC Monographs@FDA [https://dps.fda.gov/omuf/ordersearch]
3
FDA is not aware of any adequate and well-controlled clinical trials in the published literature that support a determination that Solar Care SPF 50 UVA/UVB Broad Spectrum Face Sunscreen is GRASE for use under the conditions prescribed, recommended, or suggested in its labeling.
4
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 at https://www.fda.gov/media/71023/download.
Content current as of:
11/12/2024
Regulated Product(s)
Drugs