Findings citing 21 CFR 211.34

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. Your firm also failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.113(b) and 21 CFR 211.58). Airflow Visualization (AFV) Smoke Study Deficiencies Our inspection noted deficient smoke studies. Our investigators determined you did not perform AFV smoke studies after modifying your (b)(4) Restricted Access Barrier Systems ( (b)(4) RABS) unit by removing the (b)(4) and remounting the nonviable particulate probe in suite (b)(4) of the (b)(4) filling line. Your validation department determined smoke studies were not necessary after the modification, despite your engineers proposing smoke studies be conducted. As another example, two interventions, including product spillage cleaning at the filling station and (b)(4) adjustment lacked adequate smoke to visualize unidirectional airflow. It is not clear whether airflow is adequate to protect the aseptic processing line. In your response, you state you will re-execute AFV studies, develop a standardized AFV protocol template, and revise the change control procedure. Your response is inadequate because you do not explain how you will ensure satisfactory conduct of smoke studies in the future. Thorough smoke studies are essential to evaluate the effects of such interventions on unidirectional airflow and suitability of design modifications. We also note that your Grade A suites (b)(4) are described as (b)(4) RABS. Although your firm characterizes these processing lines as (b)(4) RABS, their design and operation involve an excessive number of interventions and do not meet the minimum standards of a restricted access barrier system. The Grade A area is critical because sterile products are exposed during aseptic production and therefore are vulnerable to contamination if operations are not well designed and diligently controlled. Your aseptic processes should be designed, and operations executed, to prevent contamination hazards to your sterile product. Flaws in the design of cleanrooms and aseptic processing lines, or improper execution of operations, can promote influx of contamination into the critical processing area in which sterile drugs are exposed. Inadequate Environmental Monitoring We observed inadequate EM technique and insufficient EM locations. Our investigators observed the surface swabbing of the (b)(4) did not include the (b)(4) . Additionally, the analyst did not swab the maximum accessible area of the (b)(4) of each (b)(4) . In your response, you state the procedures will be updated and a retrospective EM review will be performed. You also performed a historical review of your EM data since 2024 which you indicate has no adverse trends. Your response is inadequate because the quality of the data was compromised by insufficient technique and locations. Environmental monitoring is only as meaningful as the quality of its sampling technique and locations. The purpose of environmental monitoring in an aseptic processing facility is to apply a risk-based approach to reliably detect routes of contamination. Facility Maintenance Deficiencies Your firm did not properly maintain classified areas used in the manufacture of drug products. Our inspection noted peeling paint on the walls and plastic debris on the floors within your Grade C hallway and product transfer room (b)(4) in Suite (b)(4) . In your response, you commit to implement post-cleaning visual inspection, require cleaning verification in the cleaning logs, and repair the facility. Your response is inadequate because your product impact evaluation states “…types of debris observed (e.g., paint, plastic) are non-viable particulates...” However, you do not explain the basis for the assertion that paint debris could not harbor microorganisms. In addition, your response does not adequately evaluate the cause of the paint bubbling and peeling from the walls and whether this has contributed to mold identified throughout all your classified areas. Deteriorating surfaces such as peeling paint are potential sources of particulate and microbial contamination. It is critical that the building is maintained to prevent exposure of sterile articles to potential contamination hazards in the manufacturing operation. In response to this letter, provide: Your systematic plan to assure adherence to appropriate aseptic practices, cleanroom behavior, and written procedures, including but not limited to an independent assessment of the following with accompanying CAPA: o suitability of actual practices based on extensive retrospective review and prospective observation of aseptic processing operations o deficiencies in production management oversight, and identification of specific improvements to ensure effective and routine supervisory oversight for all batches o frequency and depth of quality unit oversight (e.g., audit, ad hoc, daily interactions) of aseptic processing and its support operations o adequacy of written procedures o evaluate how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs A thorough, independent evaluation of airflow unidirectionality in your aseptic process. 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., neutrally buoyant media) to appropriately visualize airflow. Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment.…

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’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). Your firm failed to establish an adequate QU with the responsibilities and authority to oversee the manufacturing of drug products. For example, the QU failed to ensure: Establishment of appropriate written procedures for production and process controls, including appropriate qualification of the (b)(4) system (21 CFR 211.100(a)). Establishment of an appropriate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)). Establishment of adequate written procedures defining QU responsibilities and controls (21 CFR 211.22(d)). An adequate number of qualified personnel to perform and supervise the manufacturing, processing, packing, or holding of each drug product (21 CFR 211.25(c)). Your firm’s quality systems are inadequate. For help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211, see FDA’s guidance documents Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download, Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download, and ICH Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download. 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: 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. CGMP Consultant Recommended Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA. 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. Drug Listing Violations Section 510(j) of the FD&C Act and 21 CFR Part 207 set forth the requirements for the listing of drugs. In addition to listing a drug that you manufacture under your own labeler code, under 21 CFR 207.41(c)(1), you are required to list each drug you manufacture for commercial distribution under the trade name or label of a PLD using an NDC that includes such PLD’s labeler code. Evidence from the most recent inspection of your site and a search of eDRLS confirms that you are manufacturing KleenLine Alcohol-Free Sanitizing Wipes for a PLD, Brady Industries, Inc., but you did not list this drug under the PLD’s trade name and labeler code as required. Therefore, you failed to fulfill your drug listing obligations in accordance with section 510 of the FD&C Act. Failure to provide listing information for a drug in accordance with 510(j) of the FD&C Act is prohibited under section 301(p) of the FD&C Act. Under section 502(o), a drug is misbranded if it is not included in a list required by section 510(j). Under section 301(a), the introduction or delivery for introduction, or the causing thereof, into interstate commerce of any drug that is misbranded is prohibited. Complete, accurate, and up-to-date establishment registration and drug listing information is essential to promote and protect patient safety. FDA relies on establishment registration and drug listing information for several key programs, including drug establishment inspections, supply chain security, and post-market surveillance. Establishment registration and drug listing information is also widely used outside FDA for purposes such as electronic prescribing and electronic health records, insurance reimbursement, and patient education. We note that the labeling provided in your drug listing for Hand Sanitizing Alcohol-Free Wipes, NDC 84111-000, bears the trade name of what appears to be another PLD. Please update your labeling accordingly. It is your responsibility to ensure that all drugs manufactured at your establishment comply with all establishment registration and drug listing requirements under section 510 of the FD&C Act, 21 U.S.C. 360, 21 CFR Part 207, and all other applicable FDA regulations. Registration and listing information and instructions on how to properly register an establishment or submit drug listings can be found at Electronic Drug Registration and Listing Instructions .

Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). Your quality unit (QU) failed to perform adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following: Establishment of adequate written responsibilities and procedures applicable to the…

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)). You failed to ensure components and drug products are adequately monitored for microbiological…

Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63). Your (b)(4) system was inadequately designed, monitored, and maintained. You use (b)(4) for cleaning drug manufacturing equipment, and the same system feeds your (b)(4) system. During the inspection, we…