FDA 就韩国 Hanlim Pharm 工厂无菌生产违规发出警告信 320-27-03

Delivery Method:

VIA ELECTRONIC MAIL READ/DELIVERY RECEIPT REQUESTED

Reference #:

320-27-03

Product:

Drugs

Recipient:

Recipient Name

Mr. Jungjin Kim

Recipient Title

Chairman

Hanlim Pharm Co., Ltd.

Seocho-Daero, 52-Gil 42
Seongdong-gu
Seoul
South Korea

(b)(4)

Issuing Office:

Center for Drug Evaluation and Research (CDER)

United States

October 2, 2026

WARNING LETTER
Reference number: 320-27-03

To Mr. Jungjin Kim:

This warning letter advises you of significant violations observed during a U.S. Food and Drug Administration (FDA) inspection of your facility. Promptly address the violations described herein without delay, including ensuring that appropriate resources are allocated to fully address the violations and prevent their recurrence. This is not intended to be an all-inclusive list of the violations that exist at your facility. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations. Failure to adequately address violations may result in regulatory or legal action without further notice including, without limitation, seizure and injunction.

FDA Inspection

Violations were observed and documented during an inspection of your drug manufacturing facility, Hanlim Pharm Co., Ltd., FDA Establishment Identifier (FEI) 3004886113, at 2-27 Yeongmun-ro, Yonginsi Ceoin-gu, Gyeonggi-do, from April 16 to April 24, 2026. This inspection was conducted under FDA’s statutory authority and public health responsibilities to protect the public from unsafe, ineffective, and poor quality drugs.

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 May 15, 2026, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

Violations of the Federal Food, Drug, and Cosmetic Act

The following are violations identified during our inspection and review. As a reminder, this is not an all-inclusive list of violations at your facility.

1. 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)).

Poor Aseptic Practices and Cleanroom Behavior

You manufacture sterile, (b)(4) drug products (including (b)(4)). We observed poor aseptic practices during set-up and filling operations including, but not limited to:

• Operators repeatedly broke first air by reaching their arms, torsos, and heads over open sterile tubes, (b)(4), and open (b)(4) during (b)(4) interventions.
• Operators used (b)(4) directly over open bottles, (b)(4), and caps.
• An operator was observed working in the Grade A area of the (b)(4) line wearing a visibly stained gown.

Inadequate Smoke Studies

Dynamic airflow visualization (smoke) studies demonstrated that airflow patterns failed to adequately protect the aseptic processing line, including exposed sterile product and product contact equipment, from significant contamination hazards.

For example, your dynamic smoke studies did not demonstrate unidirectional airflow protection of the production line when barrier (b)(4) were open. The studies showed air moving at a sharp angle upward toward return vents, leaving critical areas of your aseptic processing lines unprotected throughout the period in which the (b)(4) are opened. This fundamental design flaw enables the entrainment of lower-quality air from the surrounding lower-classified (Class 10,000/ISO 7) cleanroom into the Class 100 (ISO 5) aseptic processing line, posing a severe risk to product sterility.

We also observed other design flaws in your production equipment that led to poor ergonomics and deficient aseptic practices that compromised unidirectional airflow.

In addition, smoke studies were incomplete, as they failed to sufficiently evaluate airflow directionality during critical aseptic processing activities.

In your response, you state you will assess and redesign your (b)(4) filling line (b)(4) to address deficiencies noted by FDA, and you will perform smoke studies on the newly redesigned line. Additionally, you state you will conduct extensive classroom and hands-on training, along with qualification to improve aseptic operator behavior.

We acknowledge your commitment to redesigning the (b)(4) solution line, and your decision to decommission your (b)(4) solution lines.

Your response is inadequate. It lacks a comprehensive program to effectively monitor personnel practices during commercial production, which is especially concerning given our past inspectional findings of poor aseptic behavior.

Further, your response failed to provide sufficient plans to improve your airflow visualization program. Notably, your response lacked adequate provisions to improve quality assurance oversight, and ensure thorough and objective evaluation of future airflow unidirectionality studies by qualified subject matter experts.

Your aseptic manufacturing 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 aseptic operations can promote influx of contamination into the critical processing area.

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 corrective action and preventive action (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 (QU) oversight (e.g., audit, ad hoc, daily interactions) of aseptic processing and its support operations.
  o Adequacy of written procedures and operational ergonomics.
  o The assessment should also evaluate how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
• An independent, comprehensive evaluation of airflow unidirectionality in your aseptic processing operations. Ensure smoke studies are conducted under dynamic conditions with thorough and complete evaluations of aseptic processing line airflow unidirectionality, including the impact of aseptic interventions and dynamic interactions with the surrounding cleanroom. Conduct these smoke studies after you remediate your aseptic operation and using proper practices (e.g., neutrally buoyant media) to appropriately visualize airflow.

2. Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)), and your firm failed to establish and follow adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (21 CFR 211.110(a)).

Inadequate Equipment Cleaning and Sterilization

Your aseptic processing operation is inadequately designed to prevent contamination of your sterile (b)(4) drug products.

For example, you did not appropriately sterilize critical container-closure contact surfaces, such as the (b)(4), bowl, track and (b)(4) equipment, as well as the (b)(4), bowl, track, and (b)(4) equipment. Instead, you wipe these surfaces with sporicidal disinfectants.

To ensure sterility, it is imperative that only sterilized equipment comes into direct contact with the sterile formulation, containers, and closures.

Inadequate Environmental Monitoring

You also failed to ensure adequate environmental monitoring (EM) of classified areas used for aseptic production of sterile (b)(4) drug products.

The EM program used to monitor critical areas was deficient. You failed to demonstrate that the locations and frequencies established for viable air sampling, surface monitoring, and non-viable particulate sampling were adequately justified and sufficient to promptly detect contamination risks. For example, sampling was not adequate to evaluate the environment in proximity to containers and closures, nor on the surfaces of barriers facing your ISO 5 (Grade A) spaces.

Because you had not established a sufficient EM program, you lacked evidence of daily environmental control that is foundational to assuring sterility of aseptically processed products.

A vigilant, ongoing personnel and environmental monitoring program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.

Inadequate Visual Inspection Program

Your visual inspection program for sterile (b)(4) drug products was deficient. Your firm failed to routinely categorize defects as part of your visual inspection program. In addition, you did not establish appropriate acceptance criteria. Notably, your process has experienced significant defect rates.

It is important that visible particulate contamination is appropriately evaluated. When categorizing visible particles, extrinsic or foreign matter should receive special attention, as it may indicate possible insanitary or microbial contamination. Sterile manufacturing operations should be designed to prevent foreign contaminants, and such contamination should trigger a thorough investigation and appropriate CAPA.

In your response, you state you will assess your (b)(4) filling line and improve its design. You state you will also revise cleaning and disinfection procedures, and conduct an EM risk assessment and subsequent EM performance qualification. Additionally, your response commits to improvements in visual inspection equipment, with better categorization of rejects and established acceptance criteria.

Your response is inadequate. It fails to systematically address the need for robust aseptic processing operations and collection of more meaningful data to support aseptic operational control. It also lacks details describing how you will ensure use of sterilizable equipment in the future and conduct EM with sufficient frequency at locations where significant activity or exposure occurs during aseptic production. Additionally, you failed to provide the details of your improved visual inspection program, including how you will ensure thorough investigations, when appropriate.

In response to this letter, provide:

• A comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including but not limited to:
  o All human interactions within the ISO 5 area (e.g., risk reduction or elimination of (b)(4) interventions wherever possible)
  o Equipment suitability (e.g., reliability, capability, ergonomics, placement) and sufficient cleanroom space
  o Air quality in the ISO 5 area and surrounding room including, but not limited to, air volume and flow
  o Facility layout
  o Personnel Flow and Material Flow (movement throughout all rooms used to conduct and support sterile operations, and all material transfers)
  o Disinfection practices and procedures
  o Specific CAPA recommendations that will comprehensively address the design and control hazards identified in the risk assessment
• 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 at your facility and explain how this CAPA plan will robustly remediate your deficient sterile manufacturing operations. Include comprehensive changes to the design of (b)(4) your aseptic processing lines and cleanrooms. Also, describe your plans for qualification and validation of your extensively remediated operations.
• A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Include the following as part of the assessment and CAPA plan:
  o A detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning, disinfection, and sterilization
  o A list of improvements, with an explanation how each will enhance cleaning and disinfection effectiveness
  o Improved ongoing verification of proper cleaning and disinfection execution
  o And, any other needed remediations
• A comprehensive, independent assessment and remediation plan for your drug product visual inspection program to ensure compliance with CGMP. The assessment and remediation should include, but not be limited to, the following:
  o Implement enhancements to your 100% visible particulate inspection practices, including defining critical, major, and minor defects and establish associated individual defect limits.
  o Ensure adequate methods, equipment, and personnel qualifications to reproducibly detect visible particulates, include particulates which historically have been found in your operation.
  o Conduct rigorous qualification studies to ensure your (b)(4) visible particulate inspection systems consistently and reproducibly detect the variety of visible particulates encountered in your drug products.
  o For drug products that are difficult to inspect (e.g., (b)(4) containers), implement destructive testing and other advanced technologies (e.g., (b)(4)) as appropriate, with statistically significant sample sizes to test for defects.
  o Incorporate product-specific knowledge, process experience, deviation investigation analysis, complaint data, recall data, and quality risk management to improve the visual inspection program.
  o Associated remediations to your visual inspection program, including newly established written procedures, equipment, and methods. Include a summary of the review and recommendations made by your independent consultant.

3. Your firm’s quality 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 manufacture of drug products. For example, you failed to ensure:

• Adherence to a stability program that supports the drug products’ expiration dating (21 CFR 211.166(a)).
• Contemporaneous documentation of EM and personnel monitoring sampling data in laboratory records (21 CFR 211.194(a)).

In response to this letter, provide:

• A comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous (ALCOA) records throughout your operation.
• A comprehensive assessment and remediation plan to ensure your QU is given the authority, independence, and resources to effectively function that includes, but is not limited to:
  o A determination of whether procedures used by your firm are robust and appropriate
  o Provisions for independent QU oversight throughout your operations to ensure satisfactory procedures and 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
  o Also, describe how executive management will support robust quality assurance at your firm, including but not limited to timely provision of resources that enable proactive detection and resolution of emerging manufacturing/quality issues to assure a continuing state of control

Ineffective Quality System

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production and laboratory 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.

Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA guidances: Q8(R2) Pharmaceutical Development at https://www.fda.gov/media/71535/download, Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download.

Drug Production Ceased and Suspended

We acknowledge your commitment to suspend production of (b)(4) Drugs at this facility for the U.S. market and to cease production of all other (b)(4) solutions.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. If you resume CGMP activities, you are responsible for resolving all deficiencies and systemic
flaws to ensure your firm is capable of ongoing CGMP compliance. In addition, 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 assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit¹ of your entire operation for CGMP compliance and evaluate the completion and efficacy of all 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.

In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.

Repeats Violation at Facility

In a previous warning letter (WL 320-19-01), FDA cited similar CGMP violations. You proposed specific remediations for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Additional Guidance on Aseptic Processing

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.

Conclusion

You are responsible for investigating and determining the root causes of any violations and implementing corrective and preventative measures to ensure future and sustained compliance so that these violations and any others do not occur.

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 Hanlim Pharm Co., Ltd. at 2-27 Yeongmun-ro, Yonginsi Ceoin-gu, Gyeonggi-do 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).

Send your written response to [email protected] within fifteen (15) business days of receipt of this letter². Identify your written response with FEI 3004886113 and ATTN: Compliance officer Philip Kreiter in the letter.

If you have information that you believe demonstrates that your products are not in violation of the FD&C Act and FDA regulations, include that information for our consideration.

FDA posts warning letters to www.FDA.gov.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

cc: Registered U.S. Agent
Toscano Consulting Group, Inc
(b)(4)

_____________________

1 i.e. Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.

2 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.