Complaint and recall handling Findings

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.

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). Your quality unit (QU) failed to thoroughly investigate multiple microbial count results that exceeded (b)(4) colony forming units/milliliters from your (b)(4) system. You use (b)(4) from this system as a component to manufacture your drug products. Instead, you continued to use (b)(4) from this system with out-of-limit (OOL) test results to manufacture drug products that were ultimately released, distributing potentially contaminated drug products to market. Your response is inadequate. You provided your (b)(4) System Monitoring Program procedure and CAPA-2026-005 which references enhanced (b)(4) monitoring and investigation procedures. However, neither document addresses specific microbiological alert or action limits, sampling frequencies, or acceptance criteria for (b)(4) used in drug product manufacturing. Furthermore, your response does not demonstrate that your firm has implemented adequate investigation procedures or completed retrospective reviews of the OOL events. Inadequate investigations can lead to unidentified root causes, ineffective CAPAs, and recurring problems that compromise your ability to manufacture safe and effective drug products. In response to this letter, provide: A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOL 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, QU oversight, and written procedures. Address how your firm will ensure that all phases of investigations are appropriately conducted. A detailed risk assessment addressing the potential effects of the observed (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

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)). Your post-fill visual inspection of aseptically filled over-the-counter (OTC) (b)(4) drug products was insufficient to identify particulate matter and defects which may be present in each unit. Your drug product containers are (b)(4) , and only very slightly (b)(4) , and particulates can be seen through them readily, which does not meet the criteria for “difficult to inspect.” For example, your firm only conducted subvisible particulate testing on a sample of units based on your assertion that the bottles were (b)(4) and not suitable for visual inspection. Further, your Acceptable Quality Limit (AQL) testing was designed to examine for filling, labeling, and packaging defects only, and did not include defect categories for particulates or foreign matter. Your firm’s inadequate visual inspection program provides insufficient assurance to prevent release of (b)(4) drug products with particulate matter or foreign material defects. In your response, you acknowledge that 100% visual inspection is not performed and that you lack the proper procedures and/or equipment. You commit to modifying your visual inspection program to include the reliable detection of particulate contamination and other visible defects prior to resuming production operations. Your response is inadequate. Although you commit to evaluating the visual inspection program and replacing the (b)(4) , you did not consider a combination of (b)(4) inspection methods to ensure detection of the wide array of potential visible product defects. Also, you did not consider the impact of particulates or foreign matter in (b)(4) drug products that were distributed to the U.S. market. We encourage the use of suitable (b)(4) visual inspection for particulates to augment the 100% (b)(4) visual inspection program. (b)(4) methods should be rigorously studied, and qualified, to assess their capability and robustness under various conditions, machine settings, container-closure sizes, defect types, product characteristic, and other variables. In addition, any use of (b)(4) particulate inspection as an adjunct method does not supplant the need for 100% (b)(4) visual inspection, for various other attributes (e.g., cracks, deformities, closure issues, volume, insufficient crimping, leaks, (b)(4) , discoloration, turbidity, other appearance defects). In addition, your firm failed to provide adequate data to demonstrate manufacturing systems were adequately maintained, operated, and monitored. For example, you lacked a formalized process and procedure for responding to your (b)(4) alarms. Alarms occurred at multiple timepoints from 2024 to 2026 without documented evidence of a systematic or appropriate response. OTC (b)(4) drug products manufactured at your firm use (b)(4) as the main component for each formulation. Further, your firm has not completed commitments made during the Regulatory Meeting held January 10, 2025. In your response, you commit to creating new procedures for the (b)(4) maintenance and operation, including responding to alarms and performing a comprehensive review of alarm histories to determine if notable alarms require further investigation. Your response is inadequate. You did not provide documentation or details on the review of alarms for potential impact to drug products made with (b)(4) from your (b)(4) . We acknowledge that you are using an independent third-party consultant to evaluate your visual inspection program. You should consider performing a comprehensive assessment and remediation plan for your visual inspection program to ensure compliance with CGMP. The remediation plan should incorporate U.S. Pharmacopeia (USP) <790> Visible Particulates in Injections and USP <771> (b)(4) Products-Quality Tests, including container-specific testing protocols (e.g., (b)(4) ) for each container type. Your strategy should include: Implementing 100% visible inspection using enhanced lighting with background contrast methods, as appropriate, for difficult-to-inspect products (DIP) (e.g., (b)(4) containers) that allow visual inspection. For drug products that preclude visual inspection (e.g., products packaged in (b)(4) containers), using destructive testing (e.g., subvisible particulate matter) with appropriate, statistically significant sample sizes to test for critical defects. Where traditional visual inspection methods cannot be used, establishing periodic in-process visible particulate matter testing for both bulk solution and fill/finish operations to ensure process control, and implementing enhanced manufacturing controls, including strengthened (b)(4) and environmental controls. Developing a product-specific, risk-based visual inspection approach incorporating product knowledge, process experience, deviation investigation analysis, and recall/complaint data to ensure ongoing compliance with USP <790>, USP <771>, and CGMP requirements. Additionally, in response to this letter, provide: An evaluation of customer and clients’ complaints received for potential particulates that were overlooked due to use of inadequate defect criteria during visual inspection. A comprehensive remediation plan for the design, control, and maintenance of the (b)(4) , including: o A (b)(4) system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance. Your total microbial count limits to monitor whether this system is producing (b)(4) suitable for the intended uses for each of your drug products. A detailed risk assessment addressing the potential effects of the observed (b)(4) failures on the quality of all drug product lots currently in U.S. distribution or within expiry.…

Routine GMP inspection was performed on 29 January and 26 February 2026 . Two critical, four major and three other deficiencies were defined. The two critical deficiencies were regarding the following: 1. The quality of the certified veterinary medicines cannot be assured concerning the results of the ongoing stability studies. A high number of out of specifications on ongoing stability were reported of which at least four exceed the internal specifications of Belgica de Weerd, the rationale to not recall these batches and inform the authorities was insufficient. The rationale for accepting the out-of-specification results on the ongoing stability batches does not account for the spectrum of action of the antibiotic, the safety, therapeutic window, the synergistic effect of the different active ingredients and the development of antimicrobial resistance. This poses a risk to animal safety and public health. Also, Belgica de Weerd uses specifications for the amount of active ingredient during on-going stability of 90%-110% of the label claim. In the rationale for these limits the spectrum of action of the antibiotic, the safety, therapeutic window, the synergistic effect and the development of antimicrobial resistance of these limits are not accounted for. These limits are set for all products without a rationale to account for the different product composition of these products. In the risk assessment for an OOS on ongoing stability it is stated that it does not apply to the batches on the market, while a stability batch is representative for batches on the market. This poses a risk to animal safety and public health in the market. 2. Belgica de Weerd does not comply to GMP annex 16 and can not sufficiently assure the quality of the certified products on the market. The QP could not make clear against which specifications in the registration dossier the batches were certified since the QP had no access to the registration dossiers. This poses a critical compliance risk. The batch documentation does not comply to the release specifications in the registration dossier for several products and a variation for the change in contract manufacturing organization was not submitted to the competent authorities, while the batches produced by the new CMO were released to the market. After withdrawal of the GMP certificate of the contract manufacturer the QP continued to release the produced batches. Action taken/proposed by the NCA: Withdrawal, of current valid GMP certificate No. NL/V 23/0006 The competent authority is not granting a new GMP certificate because of GMP NC which was determined by the Dutch Inspectorate during the inspection in February 2026. This decision has been sent to the company by means of an official decision on the 29th of July 2026. Following this decision, a NCS will be issued by the Dutch NCA in EudraGMDP, whereby the current GMP certificate,will be withdrawn from EudraGMDP. Recall of batches already released The concerned products are only National registrated in The Netherlands (NL) and Romania (RO). If the concerned medicinal products are potentially critical, the marketing authorization holder (MAH) must report this to the competent authorities. The competent authority may determine whether a particular VMP is critical for the market and, based on a risk assessment, can be released to the market if shortages occur. This information is not yet available for the Dutch market. If the concerned VMP’s are assessed as critical, a recall will not be initiated.