Delivery Method: VIA EMAIL WITH READ RECEIPT Reference #: 320-25-76 Product: Drugs Recipient:
Recipient Name
Ms. Manon Pilon
Recipient Title
President
Laboratoire Druide Inc.
154 Oneida Ave.
Pointe-Claire QC H9R 1A8
Canada
Issuing Office: Center for Drug Evaluation and Research (CDER)
United States
Warning Letter 320-25-76
May 29, 2025
Dear Ms. Pilon:
The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Laboratoires Druide Inc., FEI 3008226137, at 154 Oneida Avenue, Pointe-Claire, Quebec, Canada, from February 10 to 14, 2025.
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 March 6, 2025 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 conduct at least one test to verify the identity of each component 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(d)(1) and 211.84(d)(2)).
Your firm manufactures over-the-counter (OTC) drug products, such as (b)(4), sunscreens, skin protectants, (b)(4), and hand sanitizer. You failed to conduct adequate identity testing on incoming components, such as inactive ingredients, used in the manufacture of your OTC drug products. Furthermore, you relied on your suppliers’ certificates of analysis (COAs) without establishing the reliability of each of your component suppliers’ analyses at appropriate intervals.
You failed to adequately test each shipment of each lot of glycerin at high risk of diethylene glycol (DEG) and ethylene glycol (EG) contamination. Identity testing for glycerin and certain other high-risk drug components 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.
In your response, you state that you source your excipients from producers holding GMP or (b)(4) certification and that the glycerin manufacturer conducts the DEG/EG testing.
Your response is inadequate. You do not commit to performing at least one identity test for each lot of incoming raw materials nor do you provide sufficient details on how you will establish the reliability of your component suppliers’ COAs at appropriate intervals. Furthermore, you do not address how you will assess the quality of your components used in previously distributed drug products that are within expiry.
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 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 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 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 shipment 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 your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
2. Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess (21 CFR 211.100(a)).
Inadequate (b)(4) Validation
You failed to adequately qualify your (b)(4) to ensure it produces (b)(4) that meets appropriate chemical and microbial attributes for use in your OTC drug product manufacturing and equipment cleaning. You failed to test for total organic carbon (TOC), and your conductivity limit is inappropriate as it exceeds the (b)(4) USP monograph specifications. Furthermore, you did not monitor your (b)(4) for absence of biofilm forming microbes, such as Burkholderia cepacia complex (BCC). Additionally, you lacked documentation showing that you investigated out-of-specification microbiological test results obtained during validation of your (b)(4) that indicated your (b)(4) may not be in a state of control.
In your response, you state that you have established a procedure for sampling the (b)(4) prior to use in production and added TOC testing. You also state that you revised the procedure for (b)(4) and added alert and action limits.
Your response is inadequate because you do not provide supporting documentation and do not include a risk assessment of the drug products manufactured and released using the unsuitable (b)(4).
Lack of Process Validation
You lacked process validation data for your OTC drug products, such as (b)(4), sunscreens, skin protectants, (b)(4), and hand sanitizer. During the inspection, you were unable to provide the bulk hold time study for your (b)(4), which may be held in (b)(4). You had no data to demonstrate that your hold time did not adversely affect the quality of your drugs, including bioburden of the bulk formulation.
In your response, you state that you test all finished products prior to release to ensure they meet the quality attributes.
Your response is inadequate as you do not provide a timeframe for completion of process validation activities for each of your drug products, and your interim plan for any drugs distributed before validation activities are completed to ensure you produce drug products of acceptable quality.
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 and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.
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 response to this letter, provide:
- A comprehensive, independent assessment of your (b)(4) design, control, and maintenance.
- A thorough remediation plan to install and operate a suitable (b)(4). Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces (b)(4) adhering to (b)(4), USP monograph specifications, and appropriate microbial limits.
- Regarding the latter, ensure that your total microbial count limit and specified objectionable microorganisms for (b)(4) 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 (b)(4) 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.
- A process validation protocol which evaluates the impact of process variability (i.e., excipient and API quality, hold times, (b)(4), etc.) and determines appropriate control limits to ensure the quality of your finished drug products.
- An equipment qualification protocol as well as a calibration and maintenance program, as applicable, for each piece of major production equipment (i.e., (b)(4) and motors, filling equipment, etc.) to ensure physical and mechanical capabilities meet the needs of established operating parameters and that each is of appropriate design and construction for its intended use.
- A timeline for performing appropriate process performance qualification (PPQ) studies 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.
3. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
You have not demonstrated that your cleaning practices are adequate to remove contaminants from the shared equipment used to manufacture your OTC drug products. During the inspection, you stated that cleaning validation studies have not been conducted to demonstrate that residues are reduced to an acceptable level, nor could you provide any cleaning logs.
In your response, you state that you have developed a cleaning validation procedure and will initiate the study, and that you implemented a cleaning record that is now included in your batch records.
Your response is inadequate because you do not provide evidence that your cleaning methods are appropriate and effective, nor do you assess the impact of your unvalidated cleaning processes on drug product that is currently on the market and within expiry.
In response to this letter, provide the following:
- 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
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
- A summary of updated standard operating procedures that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
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/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.
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 CAPAs before you pursue resolution of your firm’s compliance status with FDA.
Cosmetics Manufactured for Distribution in the United States
In addition, some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. 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.
We also note that the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) provides new requirements with which facilities that manufacture cosmetic products must comply. You may find the FD&C Act, MoCRA, and FDA’s regulations through links on FDA’s website at www.fda.gov.
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 Laboratoires Druide Inc., 154 Oneida Avenue, Pointe-Claire, Quebec, 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 3008226137 and ATTN: Christopher Leach.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
