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Warning Letter 320-19-41

August 29, 2019

Dear Mr. Wang:


The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Hangzhou Badi Daily Use Chemical Company (FEI 3008481002) at No. 56 Shuguang Road, Yuyue Town, Huzhou City, Zhejiang Province from March 19 to 21, 2019.

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).

Your firm manufactures the OTC drug products "(b)(4)" and "(b)(4)." "(b)(4)" is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Furthermore, "(b)(4)" is misbranded under sections 502(c) and (x) of the FD&C Act, 21 U.S.C. 352(c) and (x). Introduction or delivery for introduction of "(b)(4)" and "(b)(4)" into interstate commerce is prohibited under section 301 (d) and (a) of the FD&C Act, 21 U.S.C. 331 (d) and (a), respectively. These violations are described in more detail below.

Furthermore, your (b)(4) brand (b)(4), and (b)(4) are adulterated within the meaning of section 601(c) of the FD&C Act, 21 U.S.C. 361(c), in that they have been prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth.

We reviewed your April 6, 2019, response to our Form FDA 483 in detail. Your response is inadequate because it did not provide sufficient detail or evidence of corrective action to bring your firm into compliance with CGMP.

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)).

Your firm released finished over-the-counter (OTC) drug product, (b)(4), to the U.S. market without adequate testing for the identity and strength of the active ingredient, (b)(4). Specifically, your firm could not provide data to show that identity and potency testing for the active ingredient in your OTC drug product was performed.

Complete testing of each batch before release is essential to determine if the drug products you manufacture meet appropriate specifications.

Moreover, your firm stated to our investigator that your (b)(4) formula does not contain the labeled active ingredient. Therefore, your drug product is also adulterated under section 501(c) of the FD&C Act, 21 U.S.C. 351(c), in that its strength·differs from, or its purity or quality falls below, that which it purports or is represented to possess.

In your response to this letter:
• Provide a list of all analytical test methods and specifications used to analyze each batch of your drug products before making the batch disposition decision. Include associated written procedures.

• Perform a comprehensive, independent review of your laboratory practices, procedures, methods, equipment, and analyst competencies. Based on this review, provide a detailed corrective action and preventive action (CAPA) plan to fully remediate your laboratory system. Your plan should also include the process you will use to evaluate the effectiveness of the implemented CAPA.

• Provide a summary of formulations and test results obtained from testing reserve samples of all drug products within expiry that have been distributed in the U.S. market. The formulation review and reserve sample test results should include identity and strength of active ingredients and all other appropriate quality attributes. If formulation review or testing reveals that you released drug products that did not meet specifications for identity or strength of active ingredients, indicate what corrective actions you have taken or will take, such as notifying customers or recalling products.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).

Your firm failed to test your incoming active pharmaceutical ingredient, (b)(4), and other components, for identity, purity, strength, and other quality attributes. Your firm stated you do not test your components used in the (b)(4) OTC drug products nor could you provide any record showing receipt of the labeled active ingredient.

In addition, you manufacture drug products containing glycerin, such as (b)(4). Failure to analyze each lot of glycerin to determine whether diethylene glycol (DEG) or ethylene glycol (EG) is present puts patient at risk. DEG contamination in pharmaceuticals has resulted in various lethal poisoning incidents in humans worldwide. 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/media/71029/download.

We note that the (b)(4) brand of (b)(4) was implicated in historical DEG contamination. See Import Alert 66-74, Detention Without Physical Examination of Dentifrice Products Containing Diethylene Glycol (DEG), at https://www.accessdata.fda.gov/cms_ia/importalert_207.html.

ln your response to this letter:
• Perform a comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, assigned appropriate expiration or retest dates, and incoming material controls are adequate to prevent use of unsuitable containers, closures, and components.

• Describe 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 testing results on your supplier's Certificate of Analysis (COA) in lieu of testing each component lot for purity, strength, and quality, specify how you will first establish the reliability and consistency of your supplier's test results for these attributes through initial validation (followed by periodic re-validation). In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• Provide the chemical and microbiological quality control specifications you will use to approve release of each incoming lot of components for use in manufacturing.

• Summarize test results obtained from full testing of all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.

• For your glycerin-containing products, test reserve samples of all glycerin lots for DEG and EG promptly. Indicate whether DEG or EG is present in any glycerin lot used to manufacture drug products.

• Provide a detailed risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. Take appropriate corrective actions based on the risk assessment.

3. 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)).

Your firm failed to validate the processes used to manufacture the (b)(4) OTC drug products you distributed to the U.S. market. For example, you did not conduct process performance qualification (PPQ) studies, nor did you have a rigorous ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.

Your firm has not demonstrated that you can consistently deliver quality drug products. See FDA's guidance document, Process Validation: General Principles and Practices, for general principles and approaches that FDA considers appropriate elements of process validation at http://www.fda.gov/media/71021/download.

In response to this letter, provide:
• A data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate parameters and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.

• Timelines for conducting PPQ studies for your drug products.

4. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

Your firm's (b)(4) OTC drug products lack the data to support an expiration date, nor have you established a written stability program. In addition, you stated that you lack the capability to perform a stability study to assess the stability characteristics of your OTC drug products.

In response to this letter, provide:
• A comprehensive, independent assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include but not be limited to a remediated SOP describing your stability program; stability-indicating methods; stability studies to support each drug product in its container-closure system before distribution is permitted; 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; and specific attributes to be tested at each station.

• Stability data to demonstrate that the chemical, physical, and microbiological properties of your OTC drug products remain acceptable throughout a scientifically established labeled expiry period.

Repeat Violations at Facility

In a previous inspection, dated March 28 to April 1, 2016, FDA cited similar COMP violations. You proposed specific remediation for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Drug Production Ceased

We acknowledge your commitment to cease production of drugs for U.S. distribution.

In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility in the future. If you plan to resume manufacturing drugs for U.S. distribution, notify this office prior to resuming your operations.

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 if your firm intends to resume manufacturing drugs for the U.S. market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for COMP compliance and that the consultant evaluates 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.

Unapproved New Drug Charges

"(b)(4) ROLL-ON"

"(b)(4) ROLL-ON" 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 the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or as defined 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 as an antiperspirant.

An example of a claim observed on the product label for "(b)(4) ROLL-ON" that establish the intended use, as defined in 21 CFR 201.128, of the product include, but may not be limited to, the following:

"ANTI-PERSPIRANT"

OTC drug products intended as antiperspirants, such as "(b)(4) ROLL-ON," are subject to the Final Rule for Antiperspirant Drug Products for Over-the-Counter Human Use (antiperspirant final rule) (21 CFR 350). However, this product is not labeled or formulated in accordance with this final rule for the reasons explained below.

The label for "(b)(4) ROLL-ON" does not distinguish active ingredients from inactive ingredients. Therefore, all of the product's labeled ingredients, "WATER, ALUMINUM CHLORHYDRATE, GLYCERYL STEARATE, PEG 100 STEARATE, MAGNESIUM ALUMINUM SILICATE, FRAGRANCE" are deemed to be represented as active ingredients as defined in 21 CFR 201.66(b)(2). However, none of these ingredients are permitted antiperspirant active ingredients described in the antiperspirant final rule (21 CFR 350.10).

Thus, as formulated and labeled, "(b)(4) ROLL-ON" does not comply with the final rule described above. Furthermore, we are not aware of sufficient evidence to show "(b)(4) ROLL-ON" as formulated and labeled, is generally recognized as safe and effective. Therefore, this product is a new drug within the meaning of section 201 (p) of the FD&C Act, 21 U.S.C. 321(p). As a new drug, "(b)(4) ROLL-ON" may not be legally marketed in the United States absent approval of an application filed in accordance with section 505(a) of the FD&C Act, 21 U.S.C. 355(a). "(b)(4) ROLL-ON" is not the subject of an FDA-approved application, and therefore, the current marketing of this product violates section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such product into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

Misbranding Charges

"(b)(4) Stick"

"(b)(4) Stick" 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 the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or as defined 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 as an antiperspirant.

Examples of claims observed on the product label for "(b)(4) Stick" that establish the intended uses, as defined in 21 CFR 201.128, of the product include, but may not be limited to, the following:

"Antiperspirant ... Reduces underarm wetness"

The labeling for such drugs, like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in Title 21 of the Code of Federal Regulations (21 CFR). However, "(b)(4) Stick" does not meet these requirements for the reasons described below.

"(b)(4) Stick" is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the label fails to bear a complete statement of identity as required under 21 CFR 201.61, 21 CFR 330.1(c)(1) and 21 CFR 350.S0(a). In the case of a drug that has an established name, the statement of identity must contain the established name and the general pharmacological action(s) or principal intended action(s) of the drug in the principal display panel (PDP). The label for this product fails to include the established name of the drug as part of the statement of identity. Specifically, the Drug Facts on the "(b)(4) Stick" label indicates that Aluminum Zirconium Tetrachlorohydrex Gly is the active ingredient, but this active ingredient is not included on the product's PDP.

"(b)(4) Stick" is also misbranded under section 502(x) of the FD&C Act 21 U.S.C. 352(x) because the product's label fails to disclose a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. For your information, section 201(k) of the FD&C Act defines the term "label" as " ... a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under the authority of this Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such ... also appears on the outside container .... " Therefore, the domestic address or domestic telephone number must appear on "(b)(4) Stick's" immediate container label and must also appear on the product's outside container label, if one exists.

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. 33 l(a).

Cosmetic Violations

Products, such as (b)(4), are drug-cosmetic products and subject to FDA dual jurisdiction and regulation as both. Products such as (b)(4) are typically defined as cosmetics under Section 201 (i) of the FD&C Act, 21 U.S.C. 321(i), because they are "articles intended to be rubbed, poured, sprinkled, or sprayed on ... the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance." Thus, the (b)(4) you make under contract are also subject to those sections of the FD&C Act regulating cosmetics and were evaluated for compliance with the FD&C Act. Your (b)(4) are adulterated within the meaning of section 601(c) of the FD&C Act, 21 U.S.C. 361(c), in that they have been prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth.

Violation of the FD&C Act regarding your manufacture of cosmetics is noted below.

1. You do not adequately clean and sanitize equipment surfaces to protect against the contamination of cosmetic products. Our investigator observed:
• (b)(4), product areas, and filling are covered in layers of filth, grime, and dirt.
• An encrusted buildup of white and (b)(4) colored debris at the base of (b)(4) or residue from a different day's production.
• The metal bin used for storage of (b)(4) products prior to filling is encrusted with (b)(4) and white residual material. The container and (b)(4) had previously been washed by the firm and were considered ready for use.

2. You do not keep buildings, fixtures, and other physical facilities in a sanitary condition and in repair to prevent cosmetics from becoming adulterated within the meaning of section 601 (c) of the FD&C Act. Our investigator observed:
• Cracks in the flooring under the (b)(4) in the production area.
• The floor had what appeared to be residues of product buildup after the production cleaning was completed.

3. The equipment and·utensils used for cosmetic manufacture are not designed and are not of such material and workmanship as to be effectively cleanable and are not maintained to protect against contamination of cosmetic products. Specifically, our investigator observed:
• (b)(4) with signs of filth in the interior are used to hold the in-process (b)(4) prior to filling the cosmetic (b)(4) formulation into product containers. A (b)(4) with rough welds and dents on the outside of the body and neck and signs of corrosion make it a surface that is not easily cleanable and that can harbor microbial contaminants.
• A layer of sediment and encrusted material was observed on the exterior and tops of production (b)(4) in use.
• (b)(4) tables used for filling the (b)(4) cosmetic products were in a significant state of disrepair, worn, and not easily cleanable.
• An accumulation of black debris, grime, dirty rags, and filth on the table used to fill the product located between the rooms and the (b)(4) refrigerator.
• Cigarette butts were found on the floor of the (b)(4)-floor production and packaging area, as well as several individual beverage cups including one directly on a packaging line during active packaging of a cosmetic product.

Conclusion

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.

FDA placed your firm on Import Alert 66-40 on July 30, 2019.

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 continuing to refuse admission of articles manufactured at Hangzhou Badi Daily Use Chemical Company, No. 56 Shuguang Rd, Yuyue Town, Huzhou City, Zhejiang Province 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 [email protected] or mail your reply to:

Bill Fowler
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA

Please identify your response with FEI 3008481002.

Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

 

CC:
(b)(4)