Vegewax Candleworx Ltd.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Vegewax Candleworx Ltd., FEI 3005787511, at 300 North Rivermede Rd., Concord, from October 16 to 19, 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 November 2, 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.

You failed to perform adequate identity testing for each component lot used in the production of your over-the-counter (OTC) drug products, including (b)(4), your active pharmaceutical ingredient (API). Additionally, you did not test (b)(4) content and (b)(4) for the presence of (b)(4). You relied on the certificates of analysis (COAs) from your suppliers and failed to establish the reliability of each of your suppliers’ COA for component specifications and characteristics.

Component testing is fundamental to quality. Without adequate testing, you do not have scientific evidence that your incoming components conform to appropriate specifications before use in the manufacture of drug products.

Products Contain (b)(4)

You manufacture multiple drugs that contain (b)(4). The use of (b)(4) contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide.

See FDA’s guidance document (b)(4).

(b)(4)

The use of ingredients contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for (b)(4) contamination at (b)(4)

Your response is inadequate. You fail to address the full scope and impact of the CGMP deficiencies as well as the associated risks to drug product quality, including addressing batches already in distribution. With respect to your (b)(4) containing products, you have not addressed if your evaluation will include all lots of (b)(4) for each drug product batch you manufactured and that remains within shelf-life in the U.S. market. Without appropriate testing of components and ingredients, you cannot ensure the quality and safety of your drug products.

In response to this letter, provide:

A commitment to provide (b)(4) 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 (b)(4).

A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4)). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4), 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 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 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.

A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

2. Your firm’s quality control unit failed to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192).

Out-of-specification (OOS) assay results

In November 2020, your quality unit released for distribution a (b)(4) batch that failed potency testing. Instead of conducting a thorough investigation, you (b)(4) the batch by adding more (b)(4) and released it under a new batch number in (b)(4). You failed to determine the root cause of the out-of-specification (OOS) and implement the appropriate CAPA.

Microbiological results

You failed to adequately investigate multiple microbiological excursions in samples collected from your (b)(4) system in (b)(4). You also failed to isolate and speciate microorganisms, and to determine the root cause for out-of-limit (OOL) test results. In response to these excursions, you proposed CAPAs. However, your CAPAs were inadequate to prevent recurrence.

In addition, you failed to identify batches potentially contaminated with (b)(4), produced at your facility between the referenced sampling periods.

In your response, you state that your (b)(4) batch is expired. However, your response is inadequate because your investigations are limited in scope and lack comprehensive review for potentially affected products and root cause determination. Additionally, you failed to provide any supporting documentation, including details of your corrective actions, with your initial 483 response.

In response to this letter, provide:

A retrospective, independent review of all OOS (including in-process and release/stability testing) results for U.S. products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS:o Determine whether the scientific justification and evidence relating to the OOS result conclusively or inconclusively demonstrates causative laboratory error.o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:o Quality unit oversight of laboratory investigationso Identification of adverse laboratory control trendso Resolution of causes of laboratory variationo Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identifiedo Adequately scoping of each investigation and its CAPAo Revised OOS investigation procedures with these and other remediations

A summary of the steps you have taken to ensure timely root cause evaluations and effective CAPA for all drug products.

A report of periodic assessments of the implementation and effectiveness of CAPAs.

A commitment to increase the frequency of your microbial testing to an appropriate time frame (e.g., at least daily).

A detailed risk assessment addressing potential effects of water system deficiencies on the quality of all aqueous-based drug product lots currently on the market within expiry.

We acknowledge your commitment to use purchased purified water for production of drug products and cleaning your production equipment. Provide your plan for qualification of your purified water supplier, an analysis on the water prior to release of the water for use, and control of the water during the production and cleaning process.

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.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download

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 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 audit 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.

The violations cited in this letter are not intended to be an all-inclusive list of violation 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 Vegewax Candleworx, Ltd., 300 North Rivermede Rd., Concord, Ontario, L4K 3N6, 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 3005787511 and ATTN: Yasamin Ameri.