K.C. Pharmaceuticals, Inc. — FDA Warning Letter Findings

Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)). Complaint Handling Your QU did not adequately ensure procedures were established and followed. For example, your procedure for customer complaints and inquiries is inadequate. Your approach to determining severity and adverse events resulted in delayed and incomplete investigations. Additionally, investigations were based on the client and not the severity of the complaint. Also, adequate complaint investigations were not completed in a timely manner. In your response, you commit to revising your procedure and reviewing past complaints to ensure serious events are properly investigated. Your response is inadequate. You did not provide the status of open complaint investigations or whether additional complaints have been received since the close of the inspection. Stability Program Your QU failed to ensure stability testing was conducted according to your program procedures. Your firm missed stability time points, missed stability tests, or performed incorrect tests on batches placed into your stability program. In your response, you acknowledge the lack of proper QU oversight of the stability program. You commit to performing an impact assessment with the assistance of external consultants and revising your stability program procedure. Your response is inadequate. You did not provide details on how the impact of incomplete stability testing will be assessed for product batches that have been distributed to the US. market. In response to this letter, provide: A comprehensive, independent review of your overall complaint system, including a retrospective review of all complaints for the last three years from the initial date of the inspection, with an assessment that includes but is not limited to: o Nature of complaint, and potential associated risk. o Date of first notification and subsequent contacts with complainant. o Timing and sufficiency of followups with complainant to obtain photographs and the complaint sample, as well as to obtain any additional contextual information. Determine relevant complaint samples were available and extent of efforts to obtain the complaint sample. If insufficient attempts were made, identify the root cause(s) for not adequately pursuing their return. o Review of long-term history for similar or same defects. o Identification of potential causes of the defect that led to the complaint, including evaluation whether the scientific justification and evidence relating to the identified root cause(s) were adequately documented. In the event a complaint was attributed to factors outside of the firm’s control (e.g., user error), assess the strength of this determination and whether it was based on conclusive or inconclusive information. o CAPA steps taken, including but not limited to manufacturing/quality improvements (e.g., manufacturing operation, raw materials, supplier, quality control), as well as recalls or heightened quality surveillance (additional testing/examinations, adding batch to stability program). o For all complaint investigations found by the retrospective review to be deficient due to insufficient root cause or CAPA, perform a thorough analysis of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, out-of-specification history, batch failure history). o Based upon this independent review, provide a comprehensive assessment of the complaint system that identifies all deficiencies and needed improvements. o The status of your review of open complaint investigations and whether additional complaints have been received since the procedure has been revised. 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: o Stability indicating methods. o Stability studies for each drug product in its marketed container-closure system before distribution is permitted. o 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. o 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. o All procedures that describe these and other elements of your remediated stability program. Your firm’s quality systems are inadequate. See FDA’s guidance document, Quality Systems Approach to Pharmaceutical CGMP Regulations , for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download. Quality Unit Authority Your inspectional history indicates that your QU is not able to fully exercise its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. Drug Production Suspended We acknowledge your commitment to suspend production of all OTC (b)(4) drug products at this facility. If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.…

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.…

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 did not adequately perform system suitability testing for laboratory equipment before testing your (b)(4) and other critical samples. For example, your firm routinely performed total organic carbon (TOC) and conductivity measurements without prior system suitability of the analyzer. In your response, you acknowledge inadequate procedural requirements and insufficient analyst and supervisor training for performing day-of-use system suitability. You commit to revising procedures and to holistically investigate other test methods. Your response is inadequate. You did not provide details of your review of historical system suitability results that concluded there were no adverse trends for drug products on the market within expiry. Additionally, you did not address the lack of system suitability performance for the other examples cited on the Form FDA 483 and did not expand the review to other laboratory systems beyond the TOC and conductivity systems or retrospectively review results generated with the other systems for accuracy. 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. Your retrospective review of system suitability results from laboratory equipment used to generate data in support of drug product manufacturing and release for distribution, including risk assessments and remediation plans.

Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)). Your firm has not established stability indicating methods for the OTC (b)(4) drug products you distribute to the U.S. market. For example, the validation protocol for the assay of Naphazoline HCl (NPZ) in the (b)(4) formulation detailed a stress study; however, the report stated that the stress study would be performed later and reported separately. Assay for NPZ is a test conducted for stability studies of the (b)(4) formulation. Without forced degradations studies to establish specificity, the accuracy of the test assay results cannot be assured throughout the shelf-life of the product during stability. In your response, you acknowledge that initial forced degradation studies for the current OTC (b)(4) formulations could not be located, and you commit to repeating these studies and creating an action plan based on the results. In addition, you commit to conducting a three-year retrospective review for the active pharmaceutical ingredient (API) testing during stability for each product code and to conducting a review of prior annual product reviews to evaluate any stability trends observed for the API and preservative systems for each product code. Proper document control and data management is foundational to CGMP to ensure the availability and integrity of data. Data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA) to ensure complete and accurate records. Your response is inadequate. Your review of retrospective data using methods that have not been validated as stability indicating provides insufficient confidence in your marketed drug products. Upon development of your stability indicating methods, you should add additional batches to your stability program, including retains of older batches (e.g., (b)(4) ). You did not assess the impact of inadequate stability testing and the potential for degradation products in OTC (b)(4) drug products within expiry distributed to the U.S. market. 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 comprehensive independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to: o Stability indicating methods. o Stability studies for each drug product in its marketed container-closure system before distribution is permitted. o 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 o 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. o All procedures that describe these and other elements of your remediated stability program. A commitment to notify FDA within 3 days of any stability failures.

Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). Media Fills Your firm continued to manufacture and release sterile drug products manufactured by aseptic processing following media fill failures on June 21, 2024, September 4, 2024, and November 4, 2024 as well as inconclusive media fill results and other significant quality events. Your firm lacked timely and adequate media fill investigations. For instance, your root causes were unsupported and lacked effective corrective actions. Following the inspection, you committed to recalling (b)(4) batches of drug products made from (b)(4) which reflects the timeframe between the failing media fills. In addition, you commit to improving your quality unit (QU) escalation procedures to ensure proper awareness and to engaging an outside consultant to provide oversight of your QU for six months. Your response is inadequate. You did not provide a retrospective review of all media fills to ensure additional deviations, atypical events, and unexpected results during commercial manufacturing were adequately represented in your media fill programs. Poor Practices in the Aseptic Processing Areas We observed poor practices and behaviors in ISO 5 areas during commercial operations and media fills. These poor practices, included but are not limited to: Operators inserting their upper torso into the (b)(4) restricted access barrier system ( (b)(4) RABS) during interventions, breaching the ISO 5 barrier. An operator performing a (b)(4) RABS intervention directly with the (b)(4) RABS (b)(4) instead of using forceps. Shorter operators opening the (b)(4) RABS (b)(4) and bypassing the (b)(4) during difficult-to-reach interventions, while taller operators used the (b)(4) RABS (b)(4) . In your response, you commit to retraining the operators on appropriate aseptic behaviors. Also, you commit to revising procedures and engaging outside consultants to review practices. Your response is inadequate. You do not address how you plan to ensure operators follow appropriate procedures in the future, including supervisory and quality assurance oversight. Additionally, these poor aseptic practices were not investigated to determine the impact to sterile drug products manufactured under these conditions and distributed to the U.S. market. Your response also fails to reevaluate your aseptic processing design. Specifically, you do not identify and evaluate hazards posed by various manual activities (e.g., planned interventions, unplanned interventions, (b)(4) ) or address the risks that insufficient design poses. Airflow Visualization Studies (AVS) and Process Design Our inspection identified aseptic processing design deficiencies which pose significant hazards to drug product sterility, as well as multiple inadequacies in your airflow visualization studies (i.e., smoke studies). For example, unidirectional airflow could not be evaluated in certain AVS. There were interventions performed in which the camera is placed behind the operator and the impact of the intervention on the airflow cannot be visualized. Our inspection also noted other AVS deficiencies. For example, the smoke source was not always positioned at the HEPA filter face to confirm unidirectional airflow and uniform velocity. We previously discussed inadequate smoke studies in our August 3, 2023, Warning Letter issued to your firm. In addition, the worst-case locations for environmental monitoring of the ISO 5 filling room and (b)(4) RABS have not been defined through adequate risk assessment. In your response, you commit to suspending filling operations until remediation activities, including improvements to AVS, are completed. You also acknowledge appropriate smoke studies are required to demonstrate unidirectional airflow patterns and proper aseptic techniques and behaviors are critical elements of sterility assurance. You commit to improve your smoke study protocol with the assistance of external consultants and to re-execute smoke studies in ISO 5, 7, and 8 areas prior to resuming operations. Your response is inadequate. You did not address how drug products made with inadequate aseptic processing design and distributed to the U.S. market will be evaluated to ensure their sterility assurance. Your response also fails to consider line design changes that would minimize the need for frequent operator interaction with the aseptic processing line. See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download. In response to this letter: Provide your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications and recalls. Review prior “passing” aseptic process simulations (media fills) for previously missed deviations, unusual activities, and unexpected results. Explain actions taken to evaluate and address the acceptability of (b)(4) drugs produced using your aseptic filling process that were distributed to the U.S. market. Perform a critical evaluation of airflow unidirectionality in your aseptic process, with the assistance of a qualified consultant. Ensure smoke studies are conducted under dynamic conditions, with thorough and complete evaluations of aseptic processing line airflow unidirectionality, including the impact of dynamic interactions and aseptic interventions. These thorough smoke studies should be performed after you remediate your aseptic operation and be conducted using proper practices (e.g., (b)(4) ) to appropriately visualize airflow.…