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  5. Kobayashi Healthcare International, Inc. - 637313 - 01/27/2023
  1. Warning Letters


Kobayashi Healthcare International, Inc. MARCS-CMS 637313 —

Delivery Method:
VIA Electronic Mail

Recipient Name
Mr. Norikazu Toyoda
Recipient Title
President and CEO
Kobayashi Healthcare International, Inc.

245 Kraft Dr.
Dalton, GA 30721-1502
United States

Issuing Office:
Office of Pharmaceutical Quality

United States

January 27, 2023

Case #637313


Dear Mr. Toyoda:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Kobayashi America Manufacturing, LLC, FEI 3003079019, at 245 Kraft Drive, Dalton, Georgia, from May 23 to 27, 2022.

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, “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is an unapproved new drug 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), and is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352 (ee). Introduction or delivery for introduction of such a product 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 reviewed your June 21, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(b)).

Your firm released over-the-counter (OTC) drug products, Zim’s Max Freeze Gel, Zim’s Max Freeze Roll-on, and Zim’s Max Freeze Liquid, without testing batches for microbiological quality. For example, Zim’s Max Freeze Roll-on, lot B87695, was released by your quality unit (QU) on January 20, 2022, without undergoing microbiological testing. Your Quality Assurance Director informed our investigators, during the inspection, that microbiological testing is not a part of finished product release testing.

Microbiological testing is essential to ensure each batch of your finished drug products conform to appropriate microbiological specifications. Testing prior to release and throughout the drug product’s life cycle is imperative to accomplish this standard.

In your response, you claimed there was no danger of objectionable microorganisms in the finished drug product as the percentages of alcohol in the products do not support microbial growth or survival. You also indicated that the finished drug products currently on the market are safe.

Your response is inadequate. You did not provide an appropriate scientific basis to support that your finished drug products are free from microbial growth or survival. It is well established that certain microorganisms are known to survive and thrive in alcohol. Additionally, you did not provide any retrospective testing to support the safety of your drug products currently on the market.

In response to this letter, provide:

  • A list of microbiological specifications (i.e., total counts, objectionable microorganisms), including test methods, used to analyze each lot of your drug products before a lot disposition decision.

    o An action plan and timelines for conducting full microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
    o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

  • An independent assessment of the microbiological test methods you plan to use to ensure that they are adequately validated and/or verified to be suitable for their intended purposes.
  • Appropriate scientific studies to evaluate antimicrobial effectiveness testing (AET) for your aqueous multi-dose drug products. AET by USP <51> testing should be performed at a range of preservative concentrations and should be inclusive of concentrations at or below that listed in the formulation for each drug product. In addition to initial USP <51> studies on your formulations, one of the primary batches of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the end of the proposed shelf life. The drug product specification should include a test for preservative content, and this attribute should be tested in all stability studies.

2. 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 lacked an adequate QU. Your QU failed to establish and follow procedures
describing its roles, responsibilities, and authorities. Furthermore, your QU’s oversight
of drug manufacturing operations was inadequate. For example:

  • Production and control records from your OTC drug product contract manufacturer were not reviewed or approved prior to release and distribution.
  • Zim’s Max Freeze S, lot B77086 was intended for the (b)(4), but you relabeled the lot for the (b)(4) without review and approval of manufacturing, packaging, and testing records to assure it met (b)(4) standards.
  • There was a failure to establish adequate procedures for maintaining and investigating customer complaints.

In your response, you stated that your batch record review and complaint investigation deficiencies were due to the lack of QU documentation and sufficient detail.

Your response is inadequate. Your response failed to provide an adequate retrospective review of production records to ensure all batches currently on the market were manufactured to your established specifications.

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 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.
  • A retrospective review of each batch currently on the market and its related information to determine if all established specifications were met before the QU disposition decision.

Quality Systems

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.

Use of Contract Manufacturers

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.

You are responsible for the quality of your drugs, regardless of agreements in place with your CMOs. 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/downloads/drugs/guidances/ucm353925.pdf.

Consultant Recommended

We strongly recommend engaging a consultant 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 resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Unapproved New Drug and Misbranding Violations

“ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is 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 it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as an external analgesic.

Examples of claims from the product’s labeling, including the website listed on product label, that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

  “BACK, Hip, Neck, Shoulder, Knee . . . Drug Facts . . . Uses . . . For the temporary relief of pain” [from your product’s outer carton]

  “Zim’s Max Freeze Hydro Cooling Pain Relief Patches provide immediate cooling relief . . . ready to use anywhere and anytime you need deep penetrating pain relief. Gently adheres to back, hips, neck, shoulders, and knees. . . . targeted pain relief that penetrates to the source of your discomfort.” [amazon.com/Zims-Max-Lidocaine-Cooling-P251220/dp/BOB33B3ZKM?ref_=ast+sto_dp] [from the website of one of your retailers, Amazon.com; your website “WHERE TO BUY” provides a direct link to this and other retailers].

“ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is a topical external analgesic drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G(a)(1) of the of the FD&C Act, 21 U.S.C. 355h(a)(1), category I drugs that were subject to the tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 are deemed to be GRASE and not “new drugs,” as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM and comply with all other applicable requirements. We note that OTC topical external analgesic products were addressed in the TFM for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983) and subsequent rulemakings. Under section 505G(b)(8) of the FD&C Act, the 1983 external analgesic TFM, in combination with subsequent rulemakings, was deemed to be a final administrative order.

This final administrative order addresses counterirritants, analgesic/anesthetics, and antipruritics, and it identifies active ingredients, dosage strengths, and indications for use corresponding to each of these categories of external analgesic drug products. Your “ZIM’S HYDRO COOLING PAIN RELIEF PATCH,” product does not conform to the conditions of use specified in the final administrative order, as described below.

Your “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is labeled for use as a counterirritant external analgesic drug product because it includes claims related to the relief of pain in muscles and joints. For example, your product is labeled with the indication “For the temporary relief of pain,” and it identifies the back, hip, neck, shoulder, and knee. The labeling thus conveys that the product is intended for use in the temporary relief of pain in muscles and joints, including the back, hip, neck, shoulder, and knee. Further, the outer carton describes “deep penetrating” and “cooling” relief, and the product’s name includes the term “cooling.” The final administrative order requires the statement of indication for counterirritant external analgesic drug products include the phrase, “For the temporary relief of minor aches and pains of muscles and joints,” and it allows certain other statements including “penetrating pain relief” and “cooling pain relief.” Other categories of products addressed in the final administrative order, including analgesic and anesthetic drug products, are not permitted to include such an indication or statements in their labeling.

However, your “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is not formulated as a counterirritant external analgesic drug product consistent with the final administrative order. The product is labeled to contain the active ingredients lidocaine at a dosage strength of 4% and menthol at a dosage strength of 1%. Lidocaine is not included as an active ingredient in the final administrative order for an external analgesic counterirritant drug product. Further, the final administrative order includes menthol in a dosage range of 1.25 – 16% for counterirritant external analgesic drug products. Therefore, even if menthol was the sole active ingredient, at a dosage of 1%, it falls below the allowable dosage strength range of 1.25 – 16% for menthol used in counterirritant external analgesic drug products.

We note that, pursuant to the final administrative order, analgesic and anesthetic drug products may contain lidocaine at a dosage strength of 0.5% to 4% and menthol at a dosage strength of 0.1% to 1%. However, as noted above, your “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is not labeled with statements that the final administrative order permits for analgesic or anesthetic drug products (not counterirritants).

FDA is not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” drug product is 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 this product would be legally marketed without an approved application. Accordingly, “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is an unapproved new drug 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 a product into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because “ZIM’S HYDRO COOLING PAIN RELIEF PATCH” is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is 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 is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).


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.

Your written notification should refer to the Warning Letter Number above (Case #637313). Please electronically submit your signed reply on your firm’s letterhead to Ronda R. Loyd-Jones, Director, Compliance Branch, at email to: Ronda.Loyd-Jones@fda.hhs.gov and orapharm2_responses@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Mr. Thao Ta, Compliance Officer, via phone at 214-253-5217 or e-mail at thao.ta@fda.hhs.gov.


Monica R. Maxwell
Division Director
Office of Pharmaceutical Quality Operation
Division II

cc: Via Electronic Mail
Mr. Hajime Furuie
Quality Assurance/Regulatory Affairs Director
Kobayashi Healthcare International, Inc.
245 Kraft Drive
Dalton, GA 30721

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