Dasan E&T Co., Ltd. MARCS-CMS 525897 —
Recipient NameMs. Jeong Soo Ahn
- Dasan E&T Co., Ltd.
- Issuing Office:
- Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993
Via UPS Warning Letter: 320-17-52
Return Receipt Requested
September 22, 2017
Ms. Jeong Soo Ahn
Chief Executive Officer
Dasan E&T Co., Ltd.
98, Samdo-Ro, Yangchon-Eup, Gimpo-Si, Gyeonggi-Do
Gimpo, Kyonggi-do 421808
Republic of Korea
Dear Ms. Jeong Soo Ahn:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Dasan E&T Co., Ltd., Inc. at 98, Samdo-Ro, Yangchon-Eup, Gimpo-Si, Gyeonggi-Do Gimpo, Kyonggi-do, from January 23–26, 2017.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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 16, 2017, response in detail.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
You released your (b)(4) drug products, including (b)(4) Cream (lot (b)(4)), without testing each active ingredient for identity and strength. You also released your drug products, including (b)(4), without testing for conformance with the established levels of (b)(4).
Your response stated that you “will test the . . . labeling ingredients and (b)(4) content in the final product test.” You also provided your firm’s procedure.
Your response is inadequate because the procedure you provided lacks specific details, such as a complete list of testing attributes and methods used by your firm to test each batch.
In response to this letter, provide the following:
- The quality control test methods and specifications used to analyze each drug product batch prior to a batch release decision. Include both chemical and microbial quality attributes.
- A list of all quality control tests and specifications (both chemical and microbiological) you currently use as part of your stability program.
- An action plan and timelines for conducting tests of retain samples to determine the identity and strength of active ingredients and (b)(4) content in all drug products distributed to the U.S. that are within expiry. If such testing reveals substandard quality drug products, provide your proposed corrective actions, such as notifying customers and product recalls.
2. 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 demonstrate that the microbial limits test method is suitable to detect microorganisms in the presence of your drug product, (b)(4). Method suitability testing demonstrates that drug products will not inhibit the growth and detection of microorganisms.
Your response stated that you will conduct suitability testing. Your response is inadequate because you did not provide sufficient detail or evidence of corrective actions.
In response to this letter, provide the following:
- The protocol and timeline for completing suitability testing for each of your products. If such testing reveals a deficient method, provide your CAPA plan.
- A comprehensive review of the adequacy of laboratory controls, including procedures, practices, testing, and staff competencies.
3. 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)).
Poor control of manufacturing processes
You have not validated the processes used to manufacture your (b)(4) drug products. You did not perform process performance qualification studies, and also lack an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.
Inadequate control of (b)(4) system
You also have not performed validation studies on your (b)(4) system to evaluate whether you can effectively maintain, sanitize, monitor, and control the system to ensure it consistently produces (b)(4) that meets the (b)(4) USP monograph specifications and appropriate microbial limits. You use (b)(4) from this unvalidated system as a component in your drug products (b)(4).
In addition, you lacked sufficient testing of the (b)(4) produced by this system. Pharmaceutical (b)(4) must be suitable for its intended use, and adequately tested with sufficient frequency to ensure ongoing conformance with appropriate chemical and microbiological attributes.
Your response stated that you will validate your (b)(4) system. Your response is inadequate because you did not provide sufficient detail or evidence of corrective actions.
In response to this letter, provide an action plan with detailed timelines.
- Timelines for process performance qualification for your (b)(4) drug products, and a detailed summary of your approach for routinely monitoring intra-batch and inter-batch variation.
- Detailed procedures for validating, maintaining, controlling, and monitoring your (b)(4) system.
- A thorough assessment to determine insufficiencies in microbiological analytical methods established for testing (b)(4) produced by your system. Include a full remediation plan with appropriate analytical methods to be used for testing.
4. Your firm failed to conduct adequate testing of each lot of component (21 CFR 211.84(d)(1)) for conformance with appropriate specifications, including at least one identity test.
Your firm failed to analyze glycerin raw material from your supplier prior to the quality unit releasing the glycerin for use in drug product manufacturing. Glycerin is an ingredient in multiple drug products you manufacture. Your firm did not test each lot to determine if diethylene glycol (DEG) or ethylene glycol (EG) was present. DEG contamination in pharmaceuticals has resulted in various lethal poisoning incidents in humans worldwide.
Your response stated that you will conduct DEG and EG limit testing according to the USP standards for glycerin.
Your response was insufficient. You did not address whether your firm tested all lots of drug product that you distributed to the United States for DEG and EG.
In response to this letter, provide an update regarding implementation of DEG and EG testing for all lots of glycerin. Also provide a detailed risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. In addition, test retain samples of all lots for DEG and EG.
See FDA’s guidance document, Testing of Glycerin for Diethylene Glycol, to help you meet the CGMP requirements when manufacturing drugs containing glycerin at https://www.fda.gov/downloads/Drugs/.../Guidances/ucm070347.pdf
Additional response inadequacies
You submitted a number of inadequate procedures with your response. None of these procedures had sufficient documentation control and oversight. For example, procedures lacked dates, version control numbers, and evidence of quality control unit review and approval. Your firm should comprehensively evaluate your document control system and adequacy of written procedures.
In response to this letter, summarize your evaluation, and describe your management’s steps to ensure that your systems and procedures will assure CGMP compliance.
CGMP consultant recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant, qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations in your facility.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in FDA refusing admission of articles manufactured at Dasan E&T Co., Ltd. in Gimpo, Kyonggi-do, Republic of Korea into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles 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-OMQ-Communications@fda.hhs.gov or mail your reply to:
W. DeVore Irick
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3010829786.
Thomas J. Cosgrove
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research