Rite-Kem Incorporated - 697272 - 01/28/2025

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Warning Letter 320-25-35

January 28, 2025

Dear Mr. Lovil:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Rite-Kem Incorporated, FEI 1000337046, at 703 Westmoreland Dr, Tupelo, Mississippi, from September 9 to 12, 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 acknowledge receipt of your response to our Form FDA 483.

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

1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

Your firm manufactures over-the-counter (OTC) drug products including hand sanitizers antimicrobial hand soap, and antimicrobial towels. Your firm failed to adequately test batches of your drug products for the identity and strength of your active ingredients (e.g., (b)(4), benzalkonium chloride, and chloroxylenol) before release and distribution. According to your batch records, your finished product testing only includes pH, viscosity, color, appearance, and odor. Additionally, it appears your firm is not performing microbiological testing for each batch of your drug products prior to release.

In your response, you state that you will develop a system to test your finished products, and that it will take approximately 9 months to implement. Your response is inadequate, as it only discusses the active ingredient ethanol, and does not provide sufficient information or documentation. Additionally, your response states that it will take approximately 9 months to create and fully implement adequate finished product testing without justification. Furthermore, you did not consider a risk assessment or retrospective review of products that have been released without appropriate testing and remain within expiry.

Testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use. Because you lacked adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished product specifications and are suitable for release to consumers.

In response to this letter, provide the following:

• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a 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 batches 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 batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

2. 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)).

You failed to perform adequate identity testing of each component lot used in the manufacture of your OTC drug products. You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Glycerin

You failed to adequately test each shipment of each lot of glycerin for identity, a component at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. Identity testing for glycerin and certain other high-risk drug components¹ includes a limit test in the United States Pharmacopeia (USP) to ensure the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform 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 this component for use in the manufacture of your drug products.

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/regulatory-information/search-fda-guidance-documents/testing-glycerin-propylene-glycol-maltitol-solution-hydrogenated-starch-hydrolysate-sorbitol.

(b)(4)

You failed to adequately test your incoming (b)(4), used as an active pharmaceutical ingredient, for methanol. The use of (b)(4) contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4).

In your response, you state that you will develop a system to test your components and qualify your suppliers, and that it will take approximately 9 months to implement. Your response is inadequate as it does not provide sufficient information or documentation. Additionally, your response states that it will take approximately 9 months to create and fully implement adequate component testing without justification. Furthermore, you did not consider retrospective identity testing of reserve samples, or assessment by other methods, of the components used in your OTC drug products that were manufactured, distributed, and remain within expiry.

Furthermore, we note that you are using (b)(4) as a component in the manufacture of your drug products. At a minimum, you must use (b)(4) (refer to USP General Chapter (b)(4)) to manufacture your topical, non-sterile drug products. (b)(4) must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.

Without adequate testing, you do not have scientific evidence that components conform to appropriate specifications prior to use in the manufacture of your drug products. As a manufacturer, you have a responsibility to sample, test, and examine drug components before use in production to assure adequate quality.

In response to this letter, provide the following:

• 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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• 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 (SOP) that describes this COA validation program.
• 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 batches 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.
• Provide scientific justification to demonstrate the (b)(4) you use is suitable for use in drug manufacturing operations. If you determine the (b)(4) you used to manufacture drugs was not suitable, provide a detailed risk assessment addressing the potential effects on the quality of all drug product lots currently in U.S. distribution and within expiry. Specify actions you will take in response to the risk assessment.

3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following:

• Adequate validation of your production and process controls used in the manufacture of your drug products, including to qualify the equipment used to manufacture your drug products (21 CFR 211.100(a)).
• The establishment of adequate QU procedures including, but not limited to, complaint handling, cleaning and maintenance of equipment, employee training, and labeling operations (21 CFR 211.22(d)).
• Adequate training for employees engaged in the manufacture, processing, packing, or holding of drug products (21 CFR 211.25(a)).
• Appropriate batch production and control records that include documentation of the accomplishment of each significant step in manufacturing of your drug products (21 CFR 211.188(b) & 211.22(c)).
• Establishment of an adequate, ongoing stability program (21 CFR 211.166(a)).
• Adequate equipment cleaning and cleaning procedures, as well as appropriate cleaning validation (21 CFR 211.67(a) and 67(b)).

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.

In response to this letter, provide the following:

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
  o A determination of whether procedures used by your firm are robust and appropriate.
  o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
  o A complete and final review of each batch and its related information before the QU disposition decision.
  o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability indicating methods.
  o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
  o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
  o Detailed definition of the specific attributes to be tested at each station (timepoint).
• All procedures that describe these and other elements of your remediated stability program.
• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing PPQ for each of your marketed drug products.
• Process performance protocol(s), and written procedures for qualification of equipment and facilities.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
• Your firm also manufactures non-pharmaceutical products, including industrial chemicals such as anti-freeze, concrete cleaner, urinal blocks, and asphalt release. It is unclear if your manufacturing equipment and surrounding areas are dedicated to drug manufacturing. Confirm:
  o Whether the equipment utilized in drug product manufacturing is dedicated. If not, provide a list of all other products manufactured on the equipment, including all their components.
  o Whether the area used for manufacturing drug products are utilized to manufacture, process, pack, or hold any non-drug products. If so, provide a list of all other products manufactured, processed, packed, or held in this area, including all their components.

Drug Production Suspended

We acknowledge your commitment to temporarily cease the production of drugs at this facility while you implement corrective actions.

When you resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPAs.

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.

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. 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 CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 1000337046 and ATTN: CDR Frank Verni.

Sincerely,
/S/

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

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1 Components with higher risk of DEG or EG contamination compared to other drug components.