Cosco International, Inc. - 701209 - 04/14/2025

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Warning Letter 320-25-65

April 14, 2025

Dear Mr. Hoffman:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cosco International Inc, FEI 3000220439, at 1633 Sands Pl SE. Marietta, from October 15th to 25th 2024.

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, the drug products “(b)(4),” “Carpe ANTIPERSPIRANT FOOT LOTION,” and “Carpe ANTIPERSPIRANT HAND LOTION” are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a) and 331(d). Additionally, these products are 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 sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.

We have not received a response from your firm stating the actions you are taking to address the deficiencies identified during the inspection and cited on our Form FDA 483.

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. 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)).

Lack of Process Validation

You manufacture over-the-counter (OTC) drug products including topical drugs intended for wound treatment in children. You failed to adequately validate your manufacturing processes to demonstrate that your processes are reproducible and controlled to consistently yield drug products of uniform character and quality. For example, your OTC drug products, Berberex Wound Gel, Asystem Pain Roll On, Forticept Antimicrobial Gel, and Forticept Antiseptic Ear Flush, were manufactured without adequate process qualification studies.

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. 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.

Lack of Cleaning Validation

You failed to perform appropriate cleaning validation studies for non-dedicated equipment used to manufacture your OTC drug products. For example, you manufacture products on shared equipment using active ingredients such as Menthol, Benzalkonium Chloride, Lidocaine, or Ketoconazole, in addition to cosmetic products. You failed to demonstrate that your cleaning procedures can prevent potential cross-contamination between the various drug and cosmetic products mixed and filled on the same shared equipment.

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 your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing PPQ for each of the marketed drug products you produce.
• Process performance protocols and written procedures for qualification of equipment and facilities.
• 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 for qualification of your equipment and facility.
• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
• Timelines for completed PPQ for marketed drug products for which a state of control has not been adequately/fully established.
• 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 limited to, identification and evaluation of all worst-case:
  o Drugs with higher toxicities
  o Drugs with higher drug potencies
  o Drugs of 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
• In 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 standard operating procedures that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

2. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products (211.166(a)).

Your firm did not have adequate stability data to demonstrate that the chemical and microbiological properties of your drug products met established specifications and remain acceptable throughout their labeled shelf-life. For example, you distributed drug products intended for wound treatment in children without conducting accelerated or long-term stability studies.

Without appropriate stability studies, you lack adequate scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their labeled expiry.

In your 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.

3. 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 (211.160(b)).

You lacked appropriate sampling and testing to ensure the (b)(4) water used as a component in your drug products is suitable for the intended use, including in drug products intended for wound treatment in children. Specifically, you did not perform adequate testing for bacteria, fungi, and objectionable microorganisms on your (b)(4) water (e.g., Burkholderia cepacia complex (BCC), Pseudomonas species, etc.). In addition, neither of your test methods have been validated to demonstrate that they are equal to or superior to the compendial methodology. For example, you used (b)(4), a (b)(4) based microbiological test method, but you did not demonstrate that it was equivalent to or better than USP <62>. Your sampling plan was also not representative of daily use in manufacturing; it relied on a (b)(4) sampling point, despite your having (b)(4) points of use, vessels, and stages of treatment.

(b)(4) water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. Routine and representative monitoring of microbial counts and identification of contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in manufacturing operations.

Inadequate design, control, and/or maintenance of (b)(4) water systems have led to contamination with BCC and other water-borne opportunistic pathogens. See FDA's guidance for industry, Microbiological Quality Considerations in Non-Sterile Drug Manufacturing https://www.fda.gov/media/152527/download.

In response to this letter, provide:

• A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
• The current action/alert limits for total counts and objectionable organisms used for your (b)(4) water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm.
• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets (b)(4) Water, (b)(4) monograph specifications and appropriate microbial limits.
• A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
• A comprehensive, independent assessment of your water system design, control, and maintenance.
• A (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

4. 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) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:

• Establishment of an adequate stability program (21 CFR 211.137).
• Establishment of adequate procedures for rejection or recertification of expired raw materials (21 CFR 211.87).
• Establishment of appropriate controls of computerized records and access permissions for authorized personnel (21 CFR 211.68(b)).

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/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.

In your 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 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 An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
• 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.

Unapproved New Drug Violations and Misbranding Drug Violations

“(b)(4),” “Carpe ANTIPERSPIRANT FOOT LOTION,” and “Carpe ANTIPERSPIRANT HAND LOTION” 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.

Examples from the “(b)(4),” “Carpe ANTIPERSPIRANT FOOT LOTION,” and “Carpe ANTIPERSPIRANT HAND LOTION” product labeling that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the products as drugs include, but may not be limited to, the following:

(b)(4):
“(b)(4)” [from the product label]

Carpe ANTIPERSPIRANT FOOT LOTION:
“Carpe . . . ANTIPERSPIRANT FOOT LOTION . . . CLINICALLY PROVEN TO REDUCE FOOT SWEAT . . . Directions . . . Wash and dry soles thoroughly before application . . . Apply a small, dime-sized amount of Carpe to soles . . . Rub Carpe into soles vigorously…” [from the product label]

Carpe ANTIPERSPIRANT HAND LOTION:
“Carpe . . . ANTIPERSPIRANT HAND LOTION . . . CLINICALLY PROVEN TO REDUCE HAND SWEAT . . . Directions . . . Wash and dry hands thoroughly before application . . . Apply a small, pea-sized amount of Carpe to palms . . . Rub palms together vigorously…” [from the product label]

Based on the above labeling evidence, “(b)(4)” is intended for use as a skin protectant drug product and “Carpe ANTIPERSPIRANT FOOT LOTION” and “Carpe ANTIPERSPIRANT HAND LOTION” are intended for use as antiperspirant drug products. 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).

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. With certain exceptions not applicable here, a new drug 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 these drug products identified above.

Skin Protectant Drug Product

Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application —commonly referred to as "OTC monograph drugs"—may be legally marketed if they meet applicable requirements. With respect to nonprescription skin protectant such as “(b)(4),” in order to be GRASE and not classified as new drugs, the products must, among other things, conform to the conditions in the applicable OTC monograph, in this case, Over-the-Counter Monograph M016: Skin Protectant Drug Products for Over-the-Counter Human Use (hereafter referred to as “M016”).¹ However, “(b)(4)” does not conform to the conditions specified in M016 for the reasons described below.

Specifically, the combination of active ingredients identified in the product label for “(b)(4)” does not conform to the conditions of use set forth in M016. For example, the product includes a combination of (b)(4) and (b)(4) as active ingredients in the same drug product. While each active ingredient is permitted by M016 individually at the listed concentration, the monograph does not permit this combination of active ingredients in a single drug product [see M016.20(a)].

Thus, the “(b)(4)” product does not comply with the applicable conditions specified in M016 and has not otherwise been found GRASE.² Accordingly, this product is a new drug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), and there is no basis under section 505G of the FD&C Act under which this product would be legally marketed without an approved application. Because there is no application in effect for this product, this product is an unapproved new drug.

The introduction or delivery for introduction of this unapproved new drug product into interstate commerce violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).

Antiperspirant Drug Products

With respect to nonprescription antiperspirant drug products such as “Carpe ANTIPERSPIRANT FOOT LOTION” and “Carpe ANTIPERSPIRANT HAND LOTION,” in order to be GRASE and not new drugs, the products must, among other things, conform to the conditions in the applicable OTC monograph Over-the-Counter Monograph M019: Antiperspirant Drug Products for Over-the-Counter Human Use (henceforth “M019”).1 However, “Carpe ANTIPERSPIRANT FOOT LOTION” and “Carpe ANTIPERSPIRANT HAND LOTION” do not conform to the conditions specified in M019 for the reasons described below.

As labeled, “Carpe ANTIPERSPIRANT FOOT LOTION” and “Carpe ANTIPERSPIRANT HAND LOTION” have intended uses that are not permitted for antiperspirant drug products. For example, claims on these products for use as an antiperspirant on feet and hands, respectively, are not permitted by M019 or any other final administrative order in accordance with section 505G. M019 requires that the directions for use for antiperspirant products state “apply to underarms only” [see M019.50(d)].

Thus, the “Carpe ANTIPERSPIRANT FOOT LOTION” and “Carpe ANTIPERSPIRANT HAND LOTION” products do not comply with the applicable conditions specified in M019 and have not otherwise been found GRASE.3 Accordingly, these products are new drugs within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), and there is no basis under section 505G of the FD&C Act under which these products would be legally marketed without an approved application. Because there are no applications in effect for these products, these products are unapproved new drugs.

The introduction or delivery for introduction of these unapproved new drug products into interstate commerce violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).

Misbranded Drug Violations

Additionally, “(b)(4),” “Carpe ANTIPERSPIRANT FOOT LOTION,” and “Carpe ANTIPERSPIRANT HAND LOTION” 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.

The introduction or delivery for introduction of a misbranded drug into interstate commerce violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

In addition, some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. We note that under section 301(a) of the FD&C Act [21 U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.

We also note that the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) provides new requirements with which facilities that manufacture cosmetic products must comply. You may find the FD&C Act, MoCRA, and FDA’s regulations through links on FDA’s website at www.fda.gov.

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 evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system 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.

Conclusion

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.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.

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 3000220439 and ATTN: Zachary Bogorad.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

/S/

Tina Smith
Captain, U.S. Public Health Service
Director
Office of Unapproved Drugs & Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

____________________

1 M016 and M019 reflect the conditions set forth in the relevant final orders established and in effect under section 505G; see Order IDs OTC000005 and OTC000015, respectively, available at FDA’s website OTC Monographs @ FDA, https://dps.fda.gov/omuf.

2 FDA is not aware of any adequate and well-controlled clinical trials in the published literature that support a determination that the “(b)(4)” product is GRASE for use under the conditions prescribed, recommended, or suggested in its labeling, nor has FDA determined this drug product to be GRASE pursuant to an order issued under section 505G(b).

3 FDA is not aware of any adequate and well-controlled clinical trials in the published literature that support a determination that the “Carpe ANTIPERSPIRANT FOOT LOTION” and “Carpe ANTIPERSPIRANT HAND LOTION” products are GRASE for use under the conditions prescribed, recommended, or suggested in their labeling, nor has FDA determined these drug products to be GRASE pursuant to an order issued under section 505G(b).