WARNING LETTER

Cetylite Industries, Inc. MARCS-CMS 622823 — April 14, 2022

Delivery Method:: VIA Electronic Mail
Product:: Drugs

Recipient:: Recipient Name

Mr. Gary L. Wachman; Recipient Title

President; Cetylite Industries, Inc.; 9051 River Road
Pennsauken, NJ 08110
United States

Issuing Office:: Division of Pharmaceutical Quality Operations I; United States

WARNING LETTER
WL# 622823

April 14, 2022

Dear Mr. Wachman:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cetylite Industries Inc., FEI 2242327, at 9051 River Road, from September 20 to September 24, 2021.

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 October 14, 2021, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent response. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

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

1. 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)).

You manufacture Cetacaine Mint Gel Topical Anesthetic, a United States Pharmacopeia (USP) article. You utilized a compendial method for the aerosol form instead of using the compendial method for Benzocaine, Butamben, and Tetracaine Hydrochloride Gel to analyze your drug product. You had not appropriately validated that the aerosol method was suitable for testing the gel form of this product. Your firm deviated from the (USP) for testing the potency of your finished aerosol, liquid, and gel topical anesthetic drug products from March 2019 onwards. Additionally, you failed to complete method validation studies for the “(b)(4)” method (b)(4) you used for the release testing of your finished drug products. Therefore, you did not adequately demonstrate that your method is equivalent or better than the current USP compendial method.

In your response, you stated that you will use your (b)(4) method to perform the release testing going forward. However, you did not include the validation package in your response demonstrating your method was equal to or better than the USP method. Additionally, data provided in your response demonstrated differing results from your custom test methods ((b)(4), (b)(4)) for assay versus the USP compendial method for your gel product. We note that your label does not specify that your product does not meet USP specifications therefore the USP monograph for Benzocaine, Butamben, and Tetracaine Hydrochloride Gel is the regulatory test method for your gel drug product.

Your response is inadequate, since you have not provided data to demonstrate the methods your firm uses for the determination are equivalent to or better than USP. Additionally, you did not provide a plan for addressing any product quality or patient safety risks should you determine that a batch failed its specification and was previously approved and released.

In response to this letter provide:

• Your commitment to using current USP compendial methods until alternative methods have been demonstrated to be equivalent or better than the USP methods.
• A comprehensive study that determines whether your test methods for your drug products are equivalent to, or better than, the USP method, if you are not using current USP compendial methods. Include all findings and deviations encountered in assessing whether your alternative method is equivalent or superior to the USP compendial method. For FDA’s current thinking regarding analytical test method validation, see Analytical Procedures and Methods Validation for Drugs and Biologics at https://www.fda.gov/media/87801/download.
• Updated test results using a validated test method (e.g., USP method) of all reserve samples for all drugs released to the market within expiry to ensure that your drug products conform to appropriate standards of identity, strength, quality, and purity.
• Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications, recalls, or market withdrawals.

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Your firm failed to adequately investigate an out of specification (OOS) test result when you analyzed your gel product utilizing the unvalidated method. Your analysis revealed an OOS for tetracaine HCl for potency of 114.7% and 115.2% ((b)(4)). During your investigation you retested using the USP compendial method for Benzocaine, Butamben, and Tetracaine Hydrochloride Gel which also resulted in an OOS of 118.9% and 118.3% ((b)(4)). Drugs that fail compendial test methods are considered adulterated under 501(b) of the Act.

Without adequate scientific justification you again retested the sample using two additional methods (b)(4) and (b)(4) and obtained passing results. You then released the product without adequate justification to invalidate the OOS test results including an OOS test result using a compendial test method.

In your response you stated that you believe that your OOS investigation was a thorough investigation that supported the quality unit’s decision to release the lot. Your response is inadequate, you repeatedly tested the sample until you achieved a passing result without establishing a scientifically sound justification for the repeated tests including an OOS when you used the compendial method. Well established procedures or protocols for retesting are a part of OOS investigations, however, the procedures must be based on scientifically sound principles and appropriately validated and verified methods.

In response to this letter, provide:

• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for US 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 invalidated 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.

• 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 investigations
o Identification of adverse laboratory control trends
o Resolution of causes of laboratory variation
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o Adequate scoping of each investigation and its CAPA
o Revised OOS investigation procedures with these and other remediations

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility in connection with your product(s). 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. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

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 orapharm1_responses@fda.hhs.gov. Please identify your response with FEI 2242327 and refer to WL# 622823. If you have questions regarding the content of this letter, please contact us through ORAPHARM1_RESPONSES@fda.hhs.gov, and cc Compliance Officer Nancy Scheraga, at (Nancy.Scheraga@fda.hhs.gov).

Sincerely,
/S/

Craig Swanson
Acting Program Division Director/District Director
Office of Pharmaceutical Quality Operations
Division I/New Jersey District