Stream2Sea, LLC — FDA Warning Letter Findings

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.

Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)). 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 toxicities o drugs with higher drug potencies o drugs of lower solubility in their cleaning solvents o drugs with characteristics that make them difficult to clean o swabbing locations for areas that are most difficult to clean o 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. CGMP Consultant Recommended 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.

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.