BEO Pharma Inc. dba BEO Pharmaceuticals Inc. - 701364 - 04/09/2025

---

---

---

Warning Letter 320-25-64

April 9, 2025

Dear Ms. Ambrose,

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, BEO Pharma Inc. dba BEO Pharmaceuticals Inc., FEI 3027036172, at 16255 Aviation Loop Dr., Brooksville, FL 34606, from October 16 to November 4, 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 November 25, 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 test samples of each component for identity and 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 failed to perform adequate incoming testing of each component lot used in the manufacture of your over-the-counter (OTC) liquid drug products, such as (b)(4), and (b)(4). For example, you failed to adequately test each lot of active pharmaceutical ingredient (API) for identity prior to use in your OTC 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.

Products Containing High-Risk Drug Components

You also failed to adequately test for identity each shipment of each lot of (b)(4) and (b)(4), components at higher risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. Identity testing for (b)(4) and certain other high-risk drug components 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 these components 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/media/167974/download.

In your response, you provide the COA for (b)(4), in which (b)(4) was used as a component, and the COAs for (b)(4) finished drug products in which (b)(4) and (b)(4) were used as APIs. You state that your testing protocol has been revised to require that all raw materials received will be tested by your third-party laboratory for identity and assay analysis, at a minimum. Additionally, you state that you previously tested the (b)(4) lots of raw materials from each manufacturer against the COA received.

Your response is inadequate. You do not provide your revised testing protocol, nor do you provide the results of the (b)(4) lots for each API or other raw materials that were used to qualify your suppliers. Your initial response does not address testing your high-risk drug components for DEG or EG contamination.

We acknowledge that after the inspection and a discussion with FDA on January 24, 2025, you sent all lots of (b)(4), and (b)(4) used in finished drug products for analysis of DEG or EG contamination as well as finished drug products within expiry that contain these high-risk drug components for DEG or EG contamination. Based on the provided results, you concluded that there was no DEG or EG contamination in the samples of retains tested.

In response to this letter, provide:

• 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 full risk assessment for drug products that are within expiry. 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 actions and preventive actions (CAPAs) 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. Include a list of test specifications and test methods for each component. 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 (b)(4), and certain additional high-risk components, we note that this includes the performance of parts A, B, and C of the 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, 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.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• 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 that describes this COA validation program.

2. Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and 211.22(d)).

Release of Batch with Incomplete Finished Product Testing

Your firm failed to establish an adequate quality unit (QU) to oversee the manufacture of your drug products. For example, your QU approved drug products for release without complete finished product testing. Your firm shipped a batch of (b)(4) to your customer on January 8, 2024; however, microbial testing for that batch was not received until January 10, 2024. Your QU approved the release of this batch, which stipulated all required test results for this batch were complete on December 24, 2023.

In your response, although you do not specifically indicate that batch of (b)(4) was shipped under quarantine, you provide your Quality Agreements and Shipping Addendums with your customers, which state that if you ship product “Under Quarantine,” your customers agree to hold the product in their “Quarantine” area until the final COA is received from your contract laboratory. You also state that if you ship product “Under Quarantine,” each pallet is appropriately labeled as such and communicated with each customer.

Your response is inadequate. It is not permissible to ship finished drug products “Under Quarantine” status. Full release testing, including microbial testing, must be performed before drug product release and distribution (21 CFR 211.165(a)).

Lack of Raw Material Reserve Samples

Your firm failed to retain reserve samples of incoming raw materials, including APIs and high-risk components, in accordance with your written procedure.

In your response, you state that you tested the (b)(4) lots from each manufacturer against the manufacturer’s COA to ensure accuracy.

Your response is inadequate. You did not commit to retain reserve samples for all lots of API used or explain why you are not retaining reserve samples of raw materials as required by your procedure.

In response to this letter, provide:

• 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.

3. 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)).

You failed to adequately validate your manufacturing processes for all your OTC drug products and provide assurance that you are capable of consistently manufacturing a drug product with defined quality attributes. The process validation reports provided during the inspection lacked sufficient detail, such as a complete list of the equipment used, the establishment of appropriate critical process parameters, adequate sampling instructions, and acceptance criteria. You provided (b)(4) process validation reports; however, only (b)(4) of these reports included drug manufacturing data generated using your current facility. These (b)(4) reports were only signed as prepared and approved in October 2024, even though you shipped batches of these (b)(4) products as early as May 2023. The other (b)(4) process validation reports included data from manufacturing operations in 2011 to 2015, while under a previous business at a different address.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In addition, the inspection documented that you have not established that your (b)(4) water system is adequately designed, controlled, maintained, and monitored to ensure it is consistently producing water that meets the USP monograph for (b)(4) water and appropriate microbial limits. Water from your system is used as a component in your liquid drug products and used for cleaning your manufacturing equipment and utensils. Your current schedule for (b)(4) water system maintenance and (b)(4) microbiological testing is insufficient.

In your response, you state that you have completed process validation for the remaining (b)(4) OTC drug products you have manufactured since 2023 and provided the reports.

Your response is inadequate. You do not address why your manufacturing processes for drug products were not validated prior to commercial distribution. In addition, similar to the reports provided during the inspection, the reports provided as part of your response still lack sufficient detail.

In response to this letter, provide:

• A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing (including both production and packaging) operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
• 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 appropriate 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.
• 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 (b)(4) Water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each 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 (b)(4) Water, USP monograph specifications and appropriate microbial limits.

4. 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)).

Your firm failed to demonstrate that your microbiological test methods were appropriate to assure that your product conforms to appropriate standards of identity, strength, quality, and purity. Specifically, you could not provide evidence of method suitability for microbiological testing performed by your third-party laboratory. The ability of microbial testing methods to detect objectionable microorganisms in the presence of each drug product must be established.

In your response, you provide the documentation from your third-party laboratory showing that system suitability has been conducted on all liquid drug products to ensure the recovery of any objectionable organism in your finished product.

Your response is inadequate. The system suitability protocols for the methods specified in USP <60> and USP <62> lacked the final step to confirm the identity of the recovered microorganisms in the tests. As a result, the methods were not confirmed as suitable.

In response to this letter, provide:

• A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• A list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot disposition decision, and the associated written procedures.

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.

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 3027036172 and ATTN: Emily Stoklosa.

Sincerely,
/S/

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