- Delivery Method:
- VIA UPS
- Reference #:
Recipient NameMr. Beom Zoo Lee
Recipient TitlePresident and CEO
- Chemland Co., Ltd.
77 Gaejeongsaneopdanji-ro, Miyang-myeon
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
10903 New Hampshire Avenue
Silver Spring, MD 20993
Warning Letter 320-20-22
Dear Mr. Lee:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Chemland Co., Ltd, FEI 3010165627, at 77 Gaejeongsaneopdanji-ro, Miyang-myeon, Anseong-si, Gyeonggi-do, from August 19 to 22, 2019.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. Sec 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 September 11, 2019, response to our Form FDA 483 in detail. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
During our inspection. our investigator observed specific violations including, but not limited to the following.
1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
Your quality unit (QU) lacked adequate responsibilities and authorities to assure reliable operations. For example:
A. You failed to ensure the audit trail feature was enabled on your Inductively Coupled Plasma - Optical Emission Spectrometry (lCP-OES) instrument to track creation, modification, or deletion of data. This instrument was used to obtain assay results for your drug products.
B. You stored your master batch records as unlocked Excel files which were open to alteration, duplication, and deletion by unauthorized personnel.
C. Your analysts used open Excel files for documenting sample preparation information and final calculations. These records were not retained. For example, your personnel admitted during the inspection that records and data, such as volume of test solution, sample weight, and final calculations, are not retained.
Manufacturing data must be retained to support CGMP activities including but not limited to your batch disposition decisions, stability studies, and investigations.
In your response, you stated your plan to purchase compliant software for your ICP-OES and to begin using Ecount, your Enterprise Resource Planning program, to issue batch records. You also indicated that you will revise your test record form to capture test information and calculations. Your response is inadequate because it did not include interim control measures to prevent alteration and deletion of data. You also did not assess the impact of releasing products without complete CGMP data.
In response to this letter, provide:
• Your interim controls to prevent deletion and modification of data for all computerized systems used in COMP-related operations at your facility.
• Timelines for the implementation and qualification of your updated software for the ICP-OES. Include procedural updates and associated training for user role assignments, review of audit trail data, and other appropriate controls.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm's documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.
• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed CAPA plan to remediate the effectiveness of your laboratory system.
• A comprehensive, independent 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.
• 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
Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
2. Your firm failed to establish 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 firm failed to validate the manufacturing processes for your (b)(4) over-the-counter (OTC) drug products. In addition, the inspection found that (b)(4) of a batch of (b)(4) was (b)(4) of a different batch of (b)(4). This operation was not included in your master batch record and there is no assurance that the quality of the product was not adversely affected.
You also lacked qualification for your (b)(4) and your ICP-OES instrument. This equipment was used to manufacture your products and for release testing.
Furthermore, you lacked appropriate written cleaning procedures and cleaning validation for the (b)(4). Your personnel stated that this equipment was not disassembled after use and instead was cleaned as a single unit. During the inspection, a cleaning procedure was verbally described to the investigator. This equipment was used in the manufacture of (b)(4) OTC drug products and was non-dedicated until June 2019.
In your response, you stated that you will retain a CGMP consulting firm to qualify your equipment used to manufacture these drugs and that you will also conduct process validation studies. You also committed to revise your cleaning procedures for the (b)(4). Your response is inadequate because you did not provide a detailed validation plan for your products or equipment. You also failed to provide interim controls until your CAPA are fully implemented.
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 determine whether an initial state of control has been established.
Successful process quaIification 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 for industry, Process Validation: General Principles and Practices, at: https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf
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 how your program ensures appropriate design, process performance qualification, and vigilant monitoring of both intra-batch and inter-batch variation to ensure an ongoing state of control. Also include your program for qualification of your equipment and facility.
• A timeline for performing process performance qualification (PPQ) for each of your marketed drug products.
• Your process performance protocol(s), and written procedures for qualification or equipment and facilities.
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be Iimited to identification and evaluation of all worst-case:
o drugs with higher toxicities
o drugs with higher drug potencies
o drugs or lower solubility in their cleaning solvents
o drugs with characteristics that make them difficult to clean
o swabbing locations for areas that are most difficult to clean
o maximum hold times before cleaning
ln addition. describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
3. Your firm failed to establish and follow an adequate 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)).
You lacked an adequate stability program for your OTC drug products. You initially established a (b)(4) shelf life based on insufficient accelerated and long-term stability data. Only one batch of each OTC product was included in these studies. The accelerated stability studies consisted of only (b)(4) at (b)(4) with no relative humidity controls. Your long-term stability studies were conducted at "(b)(4)" in your quality control laboratory, which was not controlled or monitored for temperature or humidity.
In addition, your stability timepoints did not include assay tests to demonstrate the active ingredients, (b)(4), remain within specification. Furthermore, your stability and retain samples were packaged in (b)(4) containers while the finished drug product was packaged in (b)(4) containers. Stability samples should be stored in containers that simulate the market container.
In your response, you committed to verify the (b)(4) shelf life of your OTC products, purchase stability chambers, and start using (b)(4) containers for retain and stability samples. Your response is inadequate because you failed to provide stability protocols, including all relevant quality attributes and acceptance criteria, and to provide assurance that your test methods (e.g., assay) will be adequate to assess drug stability. Further, your response did not provide interim plans to assure that the shelf-lives of your products in distribution are supported by adequate stability studies.
ln response to this letter. provide:
• 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 if the shelf-life claim remains valid
o Detailed definition of the specific attributes to be tested at each station (timepoint)
• All procedures that describe these and other elements of your remediated stability program
Data Integrity Remediation
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. 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/media/119267/download.
We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements.
In response to this letter, provide the following:
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
C. A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, if your firm intends to resume manufacturing drugs for the U.S. market, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions 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.
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 these violations and for preventing their recurrence or the occurrence of other violations.
FDA placed your firm on Import Alert 66-40 on December 17, 2019.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Chemland Co., Ltd, 77 Gaejeongsaneopdanji-ro, Miyang-myeon, Anseong-si, 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 may be subject to refusal of 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).
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. 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-OMO-Commun ications(@,fda.hhs.gov or mail your reply to:
Carlos M. Gonzalez
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3010165627.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research