US FDA Complaint and recall handling findings

Aw@ -Field Alert Report was not submitted within three working days of receipt of information concerning a failure of one or more distributed batches of a drug to meet the specifications established in the application.

Your response fails to address the specific deficiencies in the cited investigations and non-conformances. For the particulate complaint (COMP-2025-0005), your firm did not determine root cause for the confirmed cellulose particles or translucent fibers found in the returned vials or the retain sample, reconcile the particulate finding in the retain sample with the multiple particulates observed in the returned vials, or implement corrective actions for the visual inspection failure that allowed particulates to reach distributed product. You classified cellulose as an “intrinsic” particle without scientific justification, despite potential sources (e.g., cleaning wipes) indicating extrinsic contamination. Your response does not clearly commit to identifying and characterizing all observed particulates (including fibers and residues) in future investigations, nor does it define when such identification is required. Additionally, although you revised POL-030 (Product Complaint Handling) and implemented a training checkpoint, you did not provide evidence that the training was completed and did not establish a defined effectiveness verification plan for these corrective actions. For the batches released despite exceeding critical defect limits, your responses rely on retrospective risk assessments, passing targeted/second 100% reinspection and (b)(4) AQL without thorough root-cause investigations or (b)(4) process corrections for recurring defects (e.g., dislodged caps, partially crimped seals, particulates). These risk assessments are outcome-based, focusing primarily on the absence of complaints or adverse events rather than evaluating the adequacy of your production and inspection controls. Furthermore, lot disposition for batches exceeding the (b)(4) critical reject rate was contingent on the outcome of a pending risk analysis (ISSUE-2025-0008) rather than on a completed investigation and upstream correction, indicating that risk assessment is being used as a substitute for corrective action rather than a complement to it. You also provided no scientific justification for limiting reinspections to preselected defect types rather than conducting a comprehensive 100% visual inspection across all potential defects, and you provided no evidence that CAPA-2025-0017 has been completed. This pattern of relying on reinspection and risk review to achieve passing results, without addressing underlying process failures, fails to demonstrate that the root causes of these defects have been identified, addressed, or controlled.

Failure to design a documented, ongoing stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates. Your firm’s stability program is inadequate. For example, you were unable to provide the laboratory control records used to support your labeled (b)(4) expiry dates for tadalafil and sildenafil citrate APIs, respectively. Additionally, your sample storage chambers were observed to be powered off, and out-of-specification for temperature and/or humidity when powered on. Further, you were unable to locate stability samples of tadalafil, which were scheduled for future time-point testing. In your response, you acknowledge the deficiencies of your stability program and propose corrective actions that include revising SOPs, investigating missing samples and affected time points, and performing an impact assessment for ongoing studies. Your response is inadequate because it does not address why the chambers were powered off, and it does not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP. Without an adequate stability program, you cannot ensure that your APIs meet established specifications and all predetermined quality criteria throughout the APIs’ assigned shelf-life. In response to this letter, provide 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: Stability-indicating methods Stability studies for each drug product in its marketed container-closure system before distribution is permitted An ongoing program in which representative batches of each product are added each year to the program to determine whether the shelf-life claim remains valid Detailed definition of the specific attributes to be tested at each station (timepoint), as part of a program that encompasses each quality attribute that may change over the product shelf-life All procedures that describe these and other elements of your remediated stability program 4. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP. Your quality unit (QU) failed to exercise its basic responsibilities for oversight of API production and testing operations. For example, your QU failed to: Evaluate the risk of process-related impurities on non-dedicated manufacturing equipment (i.e., microbial contamination, API cross-contamination, (b)(4) impurities) Establish written procedures for the cleaning and maintenance of facilities and equipment Qualify contract laboratories prior to use for CGMP testing Validate manufacturing operations prior to commercial distribution Calibrate and maintain equipment as appropriate for its intended use in API production operations Test materials for conformance with in-house or compendial specifications prior to use in manufacturing APIs Perform product reviews at least annually In your response, you acknowledge inadequate QU oversight and the absence of a validation lifecycle approach to manufacturing. You commit to establishing an independent QU with the authority to address the deficiencies found during FDA’s inspection. Your response is inadequate because you did not provide a detailed remediation plan or procedures to address the identified deficiencies, nor did you provide any evidence of implemented corrections. Additionally, you have not evaluated the impact of these deficiencies on previously released batches or committed to withhold further distribution until appropriate CAPAs have been implemented and verified. Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective management oversight of your production operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements. 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: A determination of whether procedures used by your firm are robust and appropriate Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices A complete and final review of each batch and its related information before the QU disposition decision Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products Drug Recall On July 27, 2026, FDA held a teleconference with you, recommending that you recall all your APIs currently in distribution within the U.S. market. On August 4, 2026, you initiated a voluntary recall of all your APIs currently distributed within the U.S. market. The recall was posted to the FDA’s Enforcement Report website at https://www.accessdata.fda.gov/scripts/ires/?Event=99547. Additional API CGMP Guidance FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.gov/media/71518/download. Cross Contamination Assessment Contamination is generally nonuniformly distributed. Data obtained from retrospectively testing a small proportion of a batch (e.g., retain samples) is limited in its ability to retrospectively assess the extent of contamination in other portions of a batch.…

Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). You failed to adequately investigate customer complaints for the large volume parenteral (LVP) bag drug products you manufacture. Your investigations were not thorough and did not appropriately evaluate the risk to product quality. You also failed to identify and implement adequate and timely corrective actions and preventive actions (CAPAs). Specifically, in August 2025 you initiated an investigation due to a complaint trend for leaking bags of Delflex Peritoneal Dialysis Solution. This investigation noted that you eventually received 35 complaints covering approximately 156 bags from multiple batches. Your investigation attributed the bag leaks “to holes caused by printing.” Despite your Risk Management Matrix indicating peritonitis as a potential harm and recommending the highest severity level, you instead assigned the lowest severity level with the potential harm being “damage of property.” Although you ultimately conducted a recall in April 2026 after our inspection, you chose not to conduct a recall following the results of your August 2025 investigation. Your justifications for these decisions included: the lack of attributable peritonitis cases, product labeling instructed users to inspect bags for leaks, the leaks should be readily detected before treatment, and leaking fluid should collect in the overwrap. Notably, following our inspection, you state that you reexamined part of one batch and “found presence of perforations in the primary container without substantial fluid present in the overwrap,” demonstrating your error in assuming that users can consistently detect leaks. Moreover, users should not be relied upon to detect leaking bags. In addition, once you knew of the trend of leaking bags in marketed product, there should have been a commensurate increase in urgency to contain the issue. Your decision not to recall these batches at that time exposed peritoneal dialysis (PD) patients to potentially non-sterile drug products. The use of non-sterile PD solution elevates the risk of developing peritonitis, the clinical consequences of which may include serious and potentially life-threatening complications. In addition, a significant component in this drug, dextrose, could serve as a nutritional source for contaminating microorganisms and promote their growth. In your response, you acknowledge that the risk assessment should have been based on peritonitis risk, and you should not have assumed that users would detect any leaking unit. Your firm reassessed the risk for this incident and decided to recall the impacted lots. You also revised your procedure to assure that known and potential harms are evaluated during risk assessments. Your response is inadequate. It does not include a sufficient CAPA, including improving detection of leaking units during manufacturing to prevent their release and distribution. This is especially concerning considering the numerous complaints, Field Alert Reports, and recalled batches in the last three years for leaking LVP bags manufactured at your facility. Notably, two Field Alert Reports you previously submitted involved leaking LVP bags with microbial contamination. In response to this letter, provide: A comprehensive, independent assessment of the root causes of leaking bags including, but not limited to: o A failure mode analysis for the potential causes of leaking bags that addresses the deficiencies in the printing technology used by your firm, as well as any other potential causes associated with handling of bags by equipment and personnel o An independent review of your printing controls and their capabilities, including potential for contributing to leaking bags o An analysis of alternative printing technologies that can minimize or eliminate the printing step as a cause of leaking bags o CAPA to address the identified root causes of leaking bags, such as the replacement of the current printing technology A comprehensive assessment and remediation plan to ensure your quality unit (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 assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted. An independent review of in-process criteria for major and critical defects, including but not limited to leakers. Perform a retrospective evaluation, including: o A list of the number and types of all defects o Detailed long-term summaries (i.e.…

Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates, as required by 21 CFR 211.166(a). For example, your firm assigns a 24-month expiration date to your products without supporting stability testing data. The CGMP violations applicable to your Bello and Regen facilities pertaining to your products include, but are not limited to, the following: 7 6. The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed, as required by 21 CFR 211.22(d). For example, at the time of the inspection, written procedures describing the responsibilities of the quality unit had not been established, including but not limited to, procedures for the approval or rejection of drug products (21 CFR 211.22(a)) and the handling of all written and oral complaints regarding a drug product (21 CFR 211.198(a)). Responses to the Form FDA-483 We have reviewed your responses to the Form FDA-483s issued to each of your Bello and Regen facilities dated January 08, 2026 and January 06, 2026, as well as your correspondence dated November 20, 2025, in detail. While you represented that you have implemented or plan to implement certain corrective actions, the described corrective actions are not adequate to remedy the violations noted above. For example, your responses do not address your continued distribution of your products or specific plans for disposition of the remaining inventory manufactured under the violative conditions outlined above. We note that certain corrective actions cannot be evaluated because they lack supporting documentation. Further, for your previously distributed products, you do not describe actions you have taken or plan to take that adequately address the impact of the above-noted deficiencies on your distributed products that are still within expiry and were manufactured under the above-described violative conditions. We acknowledge your commitment to temporarily suspend manufacturing operations until you have made corrections to the observations listed on the Form FDA-483 issued to each of your Bello and Regen facilities. However, this does not resolve the violations outlined in this letter because your responses do not adequately address your failure to have an Investigational New Drug (IND) in effect to study your products addressed in this letter or your lack of an approved BLA to lawfully market your products. FDA has previously provided notice to you, David Greene, in a letter dated May 28, 2019, that based on a review of your website for R3 Stem Cell, LLC (www.r3stemcell.com) at that time, your firm appeared to offer “regenerative stem cell therapies” while promoting these stem cell therapies for numerous diseases or conditions, such as amyotrophic lateral sclerosis (ALS), diabetes, kidney failure, Lyme disease, Parkinson’s disease, and stroke. Based on that review, R3 Stem Cell, LLC did not appear to qualify for any exception under 21 CFR 1271.15; the “regenerative stem cell therapies” were intended for nonhomologous uses and thus would be regulated as drugs as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. However, our review of your current websites and various social media accounts, which are also linked to your websites, indicates umbilical stem cell therapy and exosome therapy continue to be offered by R3 Stem Cell, LLC for treatment of various diseases and conditions, as described above. Additional Concerns In addition to the violations described above, we have the following concerns: FDA’s review of information and records collected during the inspections documented Bello also manufactures the following umbilical cord derived 8 products: BelloWJ, BelloXO, and BelloXOL. Your response dated January 08, 2026 asserts that Bello is a manufacturer of HCT/Ps and is subject only to current good tissue practice (CGTP) requirements of 21 CFR Part 1271 and is regulated solely under section 361 of the PHS Act); however, review of the evidence collected shows these products do not appear to meet the relevant criteria to be regulated solely under section 361 of the PHS Act, for the reasons discussed above. These products appear to be drugs and/or biological products, which are subject to premarket review and approval requirements. FDA review of Bello’s manufacturing records revealed that (b)(4) is a component of the (b)(4) used during Bello’s manufacturing process of products derived from umbilical cord tissue; however, there did not appear to be evidence that testing for (b)(4) had been performed prior to the release of these products, as required by (b)(4) . Bello determines donor eligibility upon review of relevant medical records per your contract agreement with (b)(4) . The “ Donor Eligibility Criteria ” documents (effective date 08/15/2023) submitted with your January 8, 2026, response and also collected during the inspection do not include “qualifiers/comments” for Transmissible Spongiform Encephalopathy (TSE). In accordance with 21 CFR 1271.75(a)(1)(iv), all donors of cells or tissues, except as provided under 1271.90, must be screened by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases, including human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease.…

Your firm failed to conduct appropriate laboratory testing, as necessary, for each batch of drug product required to be free of objectionable microorganisms (21 CFR 211.165(b)). You failed to ensure adequate microbiological testing for each batch of your drug product prior to release. Your non-compendial test method used to determine microbiological attributes (e.g., total count, objectionable microorganisms) for your finished OTC drug product was inadequate. Specifically, you lacked appropriate incubation times, lacked appropriate method suitability, and lacked positive and negative controls. In addition, you did not validate this non-compendial method. Your response is inadequate. You state that a contract laboratory will perform validation of United States Pharmacopeia (USP) <61> and <62> test methods for future release testing. While you submitted your Laboratory Controls and Test Method Management procedure and CAPA-2026-005, which references validation planning for microbiological methods, your response does not demonstrate adequate corrective actions to ensure that distributed product was appropriately tested prior to release, nor does it include a retrospective assessment of product quality. Testing is essential to ensure that the drug product you manufacture conform to all predetermined 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: A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision. 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. 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.