Stream2Sea, LLC

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Stream2Sea, LLC, FEI 3015234524, located at 2498 Commerce Ct., Bowling Green, FL, from July 9 to 15, 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 reviewed your August 5, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators 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 failed to perform adequate analytical and microbiological release testing for each batch of your over the counter (OTC) drug products prior to distribution. For example, your “(b)(4)” batch (b)(4), was manufactured on October 3, 2024. Samples were collected for pH, microbiological and assay testing between October 3 and October 7, 2024. Two months later, on December 23, 2024, this bulk batch underwent additional manufacturing by (b)(4). No testing of the resulting final drug product, “(b)(4)” batch (b)(4), was conducted.In addition, you released the same finished drug product batch prior to obtaining documented product release approval by the quality unit.

Drug product batches must be tested for identity, strength, quality, and purity prior to release. Testing is an essential part of ensuring that the drug products you manufacture conform to all predetermined quality attributes and are appropriate for their intended use. Without adequate testing, you lack basic data to support that each drug product batch conforms to appropriate specifications before release.

In your response, you acknowledge lack of understanding of the regulations. You commit to implement a comprehensive finished drug product testing plan. You state that all active finished drug products in-house have been sent for microbial testing and active pharmaceutical ingredient (API) analytical testing. You also commit to perform retrospective testing for all active and recently distributed lots using third-party analytical and microbiological verification.

Your response is inadequate because your firm did not provide a procedure describing how you will ensure your finished drug products, not only the bulk products, meet the appropriate quality standards prior to release. You did not provide details on the acceptance criteria of the tests performed by the third party and did not provide an impact assessment for products on the market and within expiry.

In response to this letter, provide:

A comprehensive, independent 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 specifications, including test methods used to analyze each lot of your drug product before making a batch disposition decision and the associated written procedures.

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)).

Your firm failed to perform identification testing on raw materials and components including APIs prior to use in your OTC drug products. For example, your firm did not perform any testing on the raw material (b)(4), lot# (b)(4).

In addition, you relied on your suppliers’ certificates of analysis (COAs) in lieu of testing each component lot for purity, strength, identity, and quality. You also did not establish a supplier qualification program to assess (i.e., initially and periodically) the reliability of your suppliers’ test results for these attributes.

In your response, you acknowledge the failure to conduct identity testing on incoming raw materials. You commit to confirming that the bulk lot was fully tested for identity and quantification by a third party before further processing. You also commit to performing identity testing for all API lots currently in inventory and retain samples.

Your response is inadequate. Your response provides no assurance that all incoming materials will be tested for identity as required. In addition, you did not provide any procedures or testing methods for review. Your test report for incoming raw material is unclear on who performs the identification test or whether the results recorded are from the supplier’s COA. Also, you did not provide a plan for your supplier qualification program.

In response to this letter, provide:

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 components 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 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 SOP that describes this COA validation program.

You failed to adequately validate your cleaning procedures to ensure the removal of API residue and cleaning agents, as well as control of potential microbial contamination for your non-dedicated manufacturing equipment.

In addition, you failed to adequately document the type of cleaning performed or the specific cleaning agent used to clean your equipment that is shared to manufacture both your OTC drug products and cosmetics.

In your response, you acknowledge the weakness in your cleaning validation and cleaning documentation practices and commit to revalidating your cleaning process and updating your cleaning procedure.

Your response is inadequate. You fail to provide sufficient details on the proposed cleaning revalidation and product impact assessment.

In response to this letter, provide:

Appropriate improvements to your cleaning validation program with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:o drugs with higher toxicitieso drugs with higher drug potencieso drugs of lower solubility in their cleaning solventso drugs with characteristics that make them difficult to cleano swabbing locations for areas that are most difficult to cleano maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

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 including both API and finished products.

Based upon the nature of the violations we identified at your firm, we strongly recommend that your firm 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.

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 address this matter promptly and adequately 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 3015234524 and ATTN: Joan Johnson.