Pharma FDA Warning Letter -October 2, 2023
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Seoul Cosmetics Co., Ltd., FEI 3007253462, at 12, Namdongdong-ro 63beon-Gil, Namdong-gu, from January 30 to February 3, 2023.
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).
In addition, (b)(4), and (b)(4) products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d). Further, (b)(4), and (b)(4) are also misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.
We reviewed your February 21, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with drug CGMP requirements.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. 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 quality unit (QU) with the responsibilities and authority to oversee the manufacture of your over-the-counter (OTC) drug products intended for the U.S. market. For example, you failed to ensure:
- Test methods were appropriately validated (e.g., accuracy, sensitivity, specificity, and reproducibility) (21 CFR 211.165(e)).
- Adequate stability data supported your drug expiration dates (21 CFR 211.166(b)).
- Specific identity tests were conducted for glycerin, used in a drug product, (b)(4), manufactured at your facility (21 CFR 211.84(d)(1)).
An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. Your firm’s quality systems are inadequate.
The use of ingredients contaminated with Diethylene Glycol (DEG) or Ethylene Glycol (EG) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at risk for DEG or EG contamination, at https://www.fda.gov/media/167974/download.
In response to this letter, provide the following:
- 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.
- A comprehensive assessment of your laboratory practices, procedures, and methods. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
- A comprehensive assessment and corrective action and preventive action (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 this CAPA plan to ensure the adequacy of your stability program and other elements of your remediated stability program.
- A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all potentially affected finished drug product batches for the presence of DEG and EG.
- A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including but not limited to glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective actions and preventive actions that secure supply chains in the future, including but not limited to ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
- A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s certificate of analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the United States Pharmacopeia (USP) monograph.
- The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
2. 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)).
You failed to adequately validate your manufacturing processes for your OTC drug products, which would provide assurance that you are capable of consistently delivering a quality product.
Further, you did not adequately qualify the equipment used in the manufacturing of your drug products to assure that the equipment is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. Qualification of equipment demonstrates suitability for use and is an integral part of your process validation program.
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 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.
Without adequate process validation, incorporating all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. See FDA’s guidance for industry, 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 response to this letter, provide the following:
- 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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
- A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
- Include your process performance protocol(s).
- Provide 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 and written procedures for qualification of your equipment and facility.
Unapproved New Drug and Misbranding Violations
(b)(4) and (b)(4) are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, (b)(4), and (b)(4) are intended as over-the-counter (b)(4) drugs. (b)(4) and (b)(4) are intended as (b)(4) drugs.
Examples of the claims from the products’ labeling, including your product labels and website (https://m.en.dashukorea.com), where products are available for purchase, that provide evidence of the intended uses (as defined by 21 CFR 201.128) of these products as drugs include, but may not be limited to, the following:
(b)(4) [from the (b)(4) label]
(b)(4) [from the (b)(4) label]
(b)(4) [from the (b)(4) label]
(b)(4) [from your website at (b)(4)
(b)(4) [from the (b)(4) label]
(b)(4) [from the (b)(4) label]
Unapproved New Drug Violations
Based on the above labeling claims, (b)(4) and (b)(4) are intended as OTC (b)(4) drugs. (b)(4) and (b)(4) are intended as OTC (b)(4) drugs. As described below, these drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).
In general, a drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling; and in general, new drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for the six products identified above.
(b)(4) and (b)(4) Drug Products
Based on the above labeling claims, (b)(4) and (b)(4) are (b)(4) drug products subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Specifically, your (b)(4) products fall under section 505G(a)(5) of the FD&C Act because the Agency has determined any OTC drug products offered for external use as a (b)(4) or for (b)(4) are not generally recognized as safe and effective under a final determination issued under 21 CFR part 330.
Therefore, (b)(4) and (b)(4) are new drugs within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). No FDA-approved applications pursuant to section 505 of the FD&C Act are in effect for these drug products. Accordingly, (b)(4) and (b)(4) are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a).
Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
(b)(4) Drug Products
Your (b)(4) and (b)(4) are intended for use for the (b)(4) based on the labeling claims identified above. (b)(4) drugs are subject to section 505G of the FD&C Act, 21 U.S.C. 355h, may be legally marketed if they meet applicable requirements2. Drug products intended for OTC use to (b)(4) are deemed to be GRASE and not new drugs if, among other things, they conform to the conditions of use set forth in the (b)(4).3 Your (b)(4) and (b)(4) do not conform to the conditions of use specified in the (b)(4) for the reasons described below.
These products are not formulated and labeled consistent with (b)(4). Specifically, your (b)(4)4 and (b)(4)5 products are labeled to contain active ingredients not identified in the final administrative order. Thus, as formulated and labeled, (b)(4) and (b)(4) do not comply with the applicable (b)(4).
In addition, we are not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that (b)(4), and (b)(4) are GRASE for use under the conditions prescribed, recommended, or suggested in its labeling. Moreover, there is no evident basis under the FD&C Act under which these products would be legally marketed without an approved application. No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for your products. Accordingly, your products are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a).
Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Misbranded Drug Violations
Additionally, (b)(4) and (b)(4) are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because these products are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but do not comply with the requirements for marketing under that section and are not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.
Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
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.
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 assist your firm in meeting drug CGMP requirements. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluate 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 any violations and for preventing their recurrence or the occurrence of other violations.
FDA placed your firm on Import Alert 66-40 on June 8, 2023.
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 continuing to refuse admission of articles manufactured at Seoul Cosmetics Co., Ltd., 12 Namdongdong-ro 63beon-Gil, 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 or misbranded 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) and are misbranded under section 502 of the FD&C Act, respectively.
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 days. 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.