Guangzhou Four E’s Scientific Co., Ltd.

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our March 4, 2024 request, and subsequent correspondence, for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Guangzhou Four E’s Scientific Co. Ltd., FEI 3009155756, at 5th Floor, Building C, No. 2 Ruitai Road, Huangpu District, Guangzhou, Guangdong 510700, China.

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

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding of drugs described in your response to our 704(a)(4) request 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)).

Following review of records and other information provided pursuant to section 704(a)(4) of the FD&C Act, significant violations were observed including, but not limited to, the following:

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 quality unit (QU) failed to have adequate oversight and procedures for your contract manufacturing organization (CMO) to ensure that they operate in compliance with CGMPs.

Your firm utilized a CMO, (b)(4), to perform manufacturing, processing, and packaging activities on your behalf. You received drug products from this CMO and declared your firm as the manufacturer on import records.

The records and information you provided demonstrate that your firm did not effectively exercise its CGMP responsibilities. Specifically, your firm’s QU failed to ensure that all drug products produced for your firm possessed appropriate quality attributes. For example, your quality agreement indicates that you establish your quality requirements and your CMO must satisfy the quality requirements. Your product is labeled as sterile. However, in your response dated March 18, 2024, you submitted specifications from your CMO for your (b)(4) product labeled as sterile, showing microbiological testing with specifications of “≤(b)(4)” for aerobic plate count.1 Sterile products introduced to the U.S. market must meet United States Pharmacopeia (USP) <71>, Sterility Tests, to be free from viable microorganisms.

Further, drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

A 704(a)(4) records review of your CMO, (b)(4), found significant violations of CGMP including, but not limited to, inadequate testing of raw materials, incomplete process validation and inadequate testing of finished products. These CGMP violations render the products manufactured by (b)(4) adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act. FDA placed products offered for import to the United States from (b)(4) on Import Alert (b)(4), on (b)(4), and issued Warning Letter (b)(4) on (b)(4).

You, including your QU, are responsible for the quality of your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov>media>download.

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.

In response to this letter, provide:

• 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, including an evaluation of your contract manufacturer qualification program, 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. o A complete evaluation of drug product specifications for the (b)(4) to determine whether the specifications are appropriate.

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 products offered for import into the United States from your firm on Import Alert 66-40 on October 17, 2024.

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 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 for Guangzhou Four E’s Scientific Co., Ltd., at No. 2 Ruitai Road, Huangpu District, Guangzhou, Guangdong, 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 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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3009155756 and ATTN: Maria Pavco.