RNA Bio/Pharma, Incorporated

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, RNA Bio/Pharma, Incorporated, FEI 3023116, at 19470 Navarre Coulee Road, Chelan, Washington, from April 9 to April 11, 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 have not received a response from your firm stating the actions you are taking to address the deficiencies identified during the inspection and cited on our Form FDA 483. As of the date of this letter, you have not responded to the Form FDA 483, Inspectional Observations, despite two inquiries from the Agency regarding your intent to do so.

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

1. Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality. 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 manufacture oral liquid homeopathic drug products, including drug products intended for children. You failed to perform adequate testing for purity, strength, quality, and identity for the components used in the manufacture of your oral drug products. In addition, you relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Ingredients at Risk for Diethylene Glycol (DEG) or Ethylene Glycol (EG) Contamination

You failed to adequately test your incoming components at high risk of DEG and EG contamination for identity before using them to manufacture your drug products. This includes but is not limited to testing of glycerin to determine its appropriate identity. The identity testing of glycerin includes a limit test, according to the United States Pharmacopeia (USP), to ensure that the component meets the relevant safety limits for the levels of DEG or EG.

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 risk for DEG or EG contamination, at https://www.fda.gov/media/167974/download.

Products Containing Ethyl Alcohol

You relied on your suppliers’ COA without establishing the reliability of your component suppliers’ test analyses at appropriate intervals. For example, you failed to adequately test your incoming (b)(4) ethanol, used as an inactive ingredient in your formulations, for impurities, such as benzene. You also failed to adequately perform identity testing of your ethanol for methanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol at https://www.fda.gov/media/173005/download to help you meet the CGMP requirements when manufacturing drugs containing ethanol.

Alcohol used as a component in homeopathic drugs must meet the specifications in the USP monograph for alcohol (ethanol or ethyl alcohol). These specifications establish acceptance criteria for impurities for methanol, acetaldehyde and acetal, benzene, and the sum of all other impurities, and the identity test for alcohol specifies a limit test for methanol to prevent methanol contamination. Alcohol that does not meet the USP monograph is adulterated under section 501(b) of the FD&C Act. We note that your finished drug product formulations indicate that they contain (b)(4)% alcohol in the formulation.

Products containing Potentially Toxic or Harmful Ingredients

You failed to adequately test your incoming components to confirm their identification, purity, strength (e.g., dilution), and quality before using them to manufacture your drug products. For example, (b)(4) testing, primarily for (b)(4), was not performed on (b)(4) (more commonly known as (b)(4)). You also failed to perform testing of (b)(4) to detect the levels of (b)(4) (a highly toxic, well-studied poison that is used as a rodenticide). We note that (b)(4) is an ingredient used in your “(b)(4)” drug product, and (b)(4) is an ingredient used in your “(b)(4)” drug product.

Furthermore, you utilize homeopathic active pharmaceutical ingredients (mother tinctures) in your finished drug product production. During the inspection, you stated that testing was not performed on the mother tinctures.

Without appropriate testing of components and ingredients, you cannot ensure the quality and safety of your drug products. Drug products that do not meet quality standards can pose a safety risk to the public. Potentially toxic or harmful substances (including substances derived from animal venom and from botanical flowers and plants) are routinely used in your formulations and at your facility, and caution should be taken when they are used for children, with vulnerable populations, or with frequent dosing or extended use of the drug product.

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 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) to secure supply chains in the future, including but not limited to ensuring that all incoming raw material lots are from fully qualified manufacturers and are free from unsafe impurities. Detail these actions in your response to this letter.

A risk assessment for biologic substances (including (b)(4)) that will ensure and address whether these substances have been rendered sterile or have not been adulterated by pathogens or other deleterious substances.

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 suppliers’ COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers’ 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 USP monograph.

A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.

A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures are individually qualified and whether the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent the use of unsuitable components, containers, and closures.

2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Water is the major component of your drug products. However, you did not demonstrate that your water system was designed, validated, or maintained adequately for its intended use in drug manufacturing. For example, your water system consists of a (b)(4) located underneath a sink. It was not continuously circulating, which could foster the development of biofilms. Additionally, you dispensed the water from your system into separate (b)(4) storage containers for future use and assigned them lot numbers. However, you failed to monitor the quality of the water at the point of use or from the individual containers for appropriate chemical and microbiological limits over time, including but not limited to microbial enumeration and the presence of objectionable microorganisms.

You did not adequately demonstrate that your water, at a minimum, meets the (b)(4) Water USP monograph and appropriate chemical and microbiological limits.

A well-designed water (b)(4) system with procedures for monitoring, cleaning, and maintenance is an important part of ensuring that water used as a component is of appropriate quality. Water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. Monitoring of water quality is critical to ensuring that microbial counts are below established limits and that the water is free of objectionable microorganisms. Identification of contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in pharmaceutical manufacturing operations.

In response to this letter, provide:

A comprehensive remediation plan for the design, control, and maintenance of the water system.o Include a (b)(4) water system validation report.o Include a summary of any improvements made to the system design and to the program for ongoing control and maintenance.

A comprehensive remediation plan for the design, control, and maintenance of the water system.

A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.

The current action/alert limits for total counts and objectionable organisms used for your water system. Ensure that the total count limits for your water are appropriate for the intended use of the products produced by your firm.

A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets the (b)(4) Water USP monograph specifications and appropriate microbial limits.

Scientific justification to demonstrate that the water you use is suitable for use in drug manufacturing operations. If you determine that the water 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.

FDA documented during the inspection that you utilized ingredients with potentially dangerous effects that are marketed for use in children. For instance, one of your products contains minute levels of ethylene glycol (also known as “(b)(4)”) and is labeled to assist with detoxification. Given the nature of your ingredients, dilution control is paramount to ensure safety of your homeopathic drug products. In response to this letter, provide scientific data that your manufacturing processes ensure that the dilutions of your ingredients are reproducible and supported by scientific evidence.

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 CAPA before you pursue resolution of your firm’s compliance status with FDA. See FDA’s guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download.

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 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 with 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 3023116 and ATTN: Frank Wackes.