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Warning Letter 320-25-09

November 5, 2024

Dear Mr. Wallace:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Tom's of Maine, Inc., FEI 1218077, at 27 Community Dr., Sanford, ME, from May 7 to 22, 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 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 June 13, 2024, 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 follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).

Microbiological Results in Water Samples and Finished Product

Your firm produced (b)(4) water and used it as a component in your OTC drug products and as a final rinse after equipment cleaning.

A. You recovered Pseudomonas aeruginosa in multiple (b)(4) water samples, from June 2021 to October 2022. This water was used to manufacture Tom’s Simply White Clean Mint Paste, batch (b)(4), and for the final rinse of numerous equipment cleaning processes. None of these incidents were investigated to assess product impact and water system performance.

B. You also reported multiple incidents where too numerous to count (TNTC) Ralstonia insidiosa was recovered from water points of use. Your investigations included testing of new samples collected at least 4 days after the initial sampling. Batches manufactured after these incidents were released based on the microbial testing of the finished OTC product despite the quality of the water used as a component or to clean the equipment.

C. You recovered gram-negative cocco-bacilli Paracoccus yeei in your OTC finished product, Wicked Cool! Anticavity Toothpaste, batch 3025UST11B. Your investigation concluded, without sufficient justification, that the growth was due to sample contamination. The batch was released based on retest results.

In your response, you state you are performing a retrospective review of your microbial incidents in water and in OTC products. You also acknowledge that you do not have adequate specifications for the water used for the final rinse of equipment. You also state in your response that the root cause for P. yeei was related to a laboratory error even though the initial investigation stated no laboratory errors were identified.

Your response is inadequate. It does not include additional supporting evidence or testing results for the finished products. In addition, you are resampling the water points of use, 4 days after initial sampling, without further evaluation of manufacturing activities or water use during those 4 days that may impact other products.

In response to this letter provide:

• A comprehensive assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
• A detailed risk assessment addressing the hazards posed by distributing OTC drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
• Complete investigations into all batches with potential objectionable microbial contamination or an OOS microbiological result (whether or not later invalidated). The investigations should detail your findings regarding the root causes of the contamination.
• Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.
• All chemical and microbial test methods used to analyze each of your drug products.
• A summary of results from testing reserve samples of all drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.

Inadequate Water System

You failed to adequately qualify your (b)(4) water system that produced water used for equipment cleaning and in formulating your product. The installation qualification and operational qualification (IQ/OQ) was performed on October 23, 2019, and data collection was completed in September 2022. You did not evaluate this data at the time and presented the performance qualification (PQ) to Quality Assurance for review and approval after our inspection. This qualification was performed using a validation criterion of (b)(4) for total aerobic count but lacked the analysis for total organic carbon (TOC) and conductivity. Also, the absence of gram-negative microorganisms, which is required in your OTC product specifications, was not addressed.

In your response, you provide the PQ report approved in June 2024. You also acknowledge that the validation criteria are insufficient for formulating OTC drug products and for rinsing final equipment when the OTC finished product specification requires the absence of gram-negative microorganisms. You commit to start a new validation in the (b)(4) and plan to (b)(4) the water system by the (b)(4).

Your response is inadequate. It lacks an evaluation of the quality of OTC products already distributed that may be impacted by the use of water with possible microbial issues.

Water is a major ingredient in many of your OTC drug products. It is essential that you employ a water system that is robustly designed, and that you effectively control, maintain, and monitor the system to ensure it consistently produces water suitable for pharmaceutical use.

In response to this letter, provide:

• A comprehensive remediation plan for the design, control, and maintenance of the water system.
• (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.
• Your total microbial count limits to monitor whether this system is producing water suitable for the intended uses for each of your OTC products.
• 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 or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

2. Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58).

Our investigator observed a black mold-like substance at the base of the hose reel and behind the water storage tank in the (b)(4) clean out of place (b)(4) room. The black substance was within one foot of stainless-steel pails and other product-contact equipment used for OTC drug production. The base of the wall behind the water tank in the (b)(4) room was also observed to have an uneven surface that contained a similar-appearing black mold-like substance.

Our investigator also observed powder residues at a stainless-steel tray adjacent to the (b)(4) used to compound Tom’s Silly Strawberry Anticavity, batch (b)(4). These residues were observed prior to the addition of any solid raw materials.

It is essential that your facility is in a good state of repair and sanitary conditions are maintained to protect drug products from potential routes of contamination.

In your response, you state the (b)(4) room was thoroughly cleaned to remove the black substance which was located at a non-smooth surface transition susceptible to moisture accumulation and in a hard-to-clean area that missed some cleaning activities. You also state the powder observed in the (b)(4) was immediately cleaned prior to adding any solids. You identify that a final check of the area where the powder residues were observed was not part of the (b)(4) required to be completed prior to starting a batch, and the (b)(4) was modified.

Your response is inadequate because it only addresses the equipment and manufacturing areas cited during the inspection and does not include a comprehensive evaluation of the clean and sanitary condition of your facility and equipment used to manufacture OTC drug products.

In response to this letter provide:

• A corrective and preventive action (CAPA) plan and status to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product.

3. Your firm failed to establish and follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product, including provisions for review by the quality control unit of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 21 CFR 211.192 (21 CFR 211.198(a)).

Your complaint procedure is inadequate because not all quality related issues are investigated. You only investigate complaints related to adverse event, foreign matter, and incorrect product. For example, approximately 400 complaints related to odor, color, and taste in your toothpaste products, including those for children, were not investigated. These complaints are not investigated because your procedure requires an investigation only if a trend is identified.

Although you state complaint investigations were not required because there was no trend identified, you did not provide a documented evaluation determining the lack of trend for the quality issue specific to each complaint. Instead, you included a general statement from the procedure in each of the complaint’s documentation.

In your response, you state that due to the high number of complaints received, you use a risk-based approach and that an individual complaint by itself is not sufficient to implicate a failure of a drug product to meet any of its specifications. You also state you trend your complaints by (b)(4) global quality managers to determine the need for an investigation.

Your response is inadequate. You provide results for an organoleptic flavor evaluation of reserve samples for non-expired batches; however, this evaluation did not include color, odor, or microbial results. Your proposed modification of the complaint procedure does not ensure all complaints will be investigated.

In response to this letter, provide:

A comprehensive assessment of your overall system for investigating complaints. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all complaint investigations are appropriately conducted.

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 assist your firm in meeting CGMP requirements. 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.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.

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 1218077 and ATTN Vilmary Negron Rodriguez.

Sincerely,
/S/

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