Zhejiang Huahai Pharmaceutical Co., Ltd.

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Huahai Pharmaceutical Co., Ltd., FEI 3003999190, at Xunqiao, Linhai, Zhejiang Province, from January 16 to 24, 2025.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your February 14, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

You manufacture prescription drug products used to treat various conditions such as (b)(4). Your cleaning procedures for your non-dedicated manufacturing equipment are inadequate. Our investigators observed residue on surfaces of several non-dedicated (b)(4), including (b)(4) ducts and associated valves, which had been documented in the cleaning records as having undergone product changeover cleaning. Your firm was also cited for unknown residue in the (b)(4) duct of a (b)(4) during a previous FDA inspection. Air flow over dirty surfaces can facilitate contamination of the drug being processed in an (b)(4). Additionally, your analytical testing during the inspection confirmed these residues contained multiple active ingredients. Furthermore, residues were observed on both product contact and non-contact surfaces of the (b)(4) equipment, which were previously indicated as clean.

In your response, you state that there is minimal risk for cross-contamination. Your rationale includes the test results of reserve drug product samples, as well as cross-contamination simulation experiments. You also indicate that you have revised your cleaning procedures, and you explain that (b)(4) and (b)(4) equipment are now appropriately inspected to verify cleanliness, which is recorded in your cleaning records.

Your response is inadequate. Your risk assessment, which included testing of reserve product samples and cross-contamination simulation experiments failed to scientifically demonstrate your products are free of contaminants from your visibly dirty equipment. Additionally, your investigation did not include an assessment for microbial contamination as a potential risk factor.

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. The lowest or highest results obtained from testing a small sample size is unlikely to reveal the true range of minimum and maximum contamination levels that exist in a batch exposed to the contamination hazards identified at your firm. Consequently, the range of variability of contamination levels in batches produced by your firm remain characterized by substantial residual uncertainty.

In response to this letter, provide:

• 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.

• A corrective action and preventive action (CAPA) plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

• An action plan and timelines for conducting microbiological testing of retain samples of all batches of drug product manufactured on (b)(4) and (b)(4) equipment distributed to the United States that are within expiry as of the date of this letter.

2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).

You also manufacture (b)(4) drug products used to treat various conditions including (b)(4). Our investigator observed a 2 cm x 126 cm piece of a non-sterile tape between (b)(4) below the HEPA filters and above the (b)(4) in an ISO 5 (Grade A) area. The (b)(4) were not securely fastened. One (b)(4) was hanging lower than the other (b)(4) and appeared to be missing a screw. Your firm stated that the tape was used to facilitate cleaning between the (b)(4) since April 2024. Your quality unit (QU) was not informed of the use of non-sterile tape in an aseptic area, and the tape remained in the classified area unnoticed until FDA investigators observed it during this inspection.

In your response, you state that there is no impact to the product following an assessment of your airflow patterns, cleaning practices, environmental monitoring results (non-viable and viable particulates), and retrospective review of batches and media fills.

Your response is inadequate. Your response lacks a comprehensive evaluation of your QU’s role in assuring the suitability of the facility and equipment when modifications are made during filling operations. It is unclear in your response if modifications to classified areas are permitted without QU approval or if the QU regularly performs visual inspections of classified areas according to established procedure and timeframes. While your response states that the tape was used to facilitate cleaning by filling a gap between the (b)(4), your response did not address the FDA investigators’ observation that the (b)(4) were not properly and securely fastened.

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:

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:o All human interactions within the Grade A (ISO 5) area. o Equipment placement and ergonomics. o Air quality in the Grade A (ISO 5) area and surrounding room. o Facility layout. o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations).

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review. Your plan should also ensure that appropriate actions are taken throughout the company network.

3. 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)).

Tablet compression rejections are established by setting the upper and lower limits of the main compression force. While your firm established reject limits and rates based on “prior manufacturing experience,” your firm lacks validation data for your U.S. marketed drug products to ensure the rates are suitable for producing drug products which consistently meet specifications. Of note, on at least one occasion, your firm received a complaint for a batch of product that failed specification for dissolution testing which you attributed to high main force compression value.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/media/71021/download.

In your response, you committed to updating batch records to include main compression force limits which are supported by reject-limit studies.

Your response is inadequate. Your response included your reject-limit study protocol in which main compression force is compared to tablet weight. This study is limited in scope, and there is no rationale provided for why other parameters, including hardness, were not measured or considered.

In response to this letter, provide:

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• A timeline for performing appropriate PPQ for each of your marketed drug products.

• Process performance protocol(s), and written procedures for qualification of equipment and facilities.

• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

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.

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.

During the inspection, our investigator observed a laboratory employee who appeared to be approving environmental monitoring records non-contemporaneously (or “backdating”). Upon initial inquiry, the employee acknowledged and confirmed the observed behavior which raises significant concerns regarding the reliability and authenticity of your data. The employee later recanted his statement, stating that he was not backdating records.

Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA).

See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Zhejiang Huahai Pharmaceutical Co., Ltd., located at Xunqiao, Linhai, Zhejiang Province, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days1 . Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3003999190 and ATTN: Rory Geyer.