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WARNING LETTER

Huaian Zongheng Bio-Tech Co., Ltd MARCS-CMS 590789 —


Delivery Method:
VIA UPS
Product:
Drugs

Recipient:
Recipient Name
Mr. Lin Li
Recipient Title
General Manager
Huaian Zongheng Bio-Tech Co., Ltd

No. 615 North Xiangyu Road
Huai'an Shi
Jiangsu Sheng, 223300
China

Issuing Office:
Center for Drug Evaluation and Research | CDER

10903 New Hampshire Avenue
Silver Spring, MD 20993
United States



Warning Letter 320-20-16

January 9, 2020

Dear Mr. Li:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Huaian Zongheng Bio-Tech Co., Ltd., FEI 3007628845, at No. 615 North Xiangyu Road, Huaian, from July 1 to 5, 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).

We reviewed your July 25, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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 contract manufactures over-the-counter (OTC) (b)(4) drug products, including versions specifically marketed for children. You released your drug products without adequate testing, including identity and strength testing for each active ingredient. For example, you did not test drug products (b)(4) for their labeled active ingredient, (b)(4), prior to release.

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

In your response, you provided third-party testing results for assay of (b)(4) contained in (b)(4) drug product lot of (b)(4) and (b)(4) drug product lot of (b)(4). You also provided the revised finished product specifications for both drug products to add the requirements for (b)(4) assay testing prior to release in the future.

Your response is inadequate. Your testing was limited to assay, and you failed to specify and perform at least one test to verify the identity of (b)(4) in (b)(4) batch of drug product you manufacture containing the active ingredient. Further, you failed to test all of your retain samples of drug products containing (b)(4) within expiry to determine whether they meet established specifications for identity and assay. Your response is also inadequate because you did not include sufficient information about your testing procedures, methods, or a detailed description of the tests you will conduct (e.g., identity, strength, and purity).

In response to this letter, provide the following:

• A list of chemical and microbial specifications, 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 chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States 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

• A comprehensive, independent 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.

• Your procedure to ensure that any test methods performed by a contract testing laboratory on your behalf are properly validated before use.

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)).

You failed to test incoming components used to manufacture your drug products to determine their identity. For example, your firm did not ensure that at least one specific identity test was conducted for each lot of active ingredients (b)(4).

In your response, you stated that you revised the specifications for incoming active ingredients (e.g., (b)(4)) to include an identification test. You also provided an example of the revised specification sheet for (b)(4), in addition to an example of a third-party laboratory test report for the (b)(4) content in (b)(4) lot of (b)(4) raw material.

Your response is inadequate. You failed to specify and perform at least one test to verify the identity of all of the components you use to manufacture your drug products. Further, you failed to test your retain samples of active ingredients used in the manufacture of drug products to determine whether they meet established specifications for identity.

In response to this letter, provide the following:

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
    o An action plan and timelines for conducting full. chemical and microbiological testing of API retain samples to determine the quality of all batches of active ingredients used in the manufacture of drug products distributed to the United States within expiry.
    o A summary of all results obtained from testing API retain samples from each batch. If such testing reveals substandard quality drug substances, take rapid corrective actions, such as notifying customers and product recalls

• 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 Certificates 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• A summary of results obtained from testing 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.

• A summary of your program for qualifying and overseeing contract facilities that test the drugs you manufacture.

3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Your firm did not have an adequate stability testing program to demonstrate that the chemical and (b)(4) properties of your drug products remain acceptable throughout their labeled expiry period. Your firm does not have adequate stability data to support the assigned expiration date of up to 36 months.

In your response, you committed to revising your stability procedures to include extending your accelerated stability studies from three months to six months with new drug samples, requiring 36 months of real-time stability for drug products, and conducting stability studies at the appropriate humidity and temperatures with respective monitoring. You also purchased an (b)(4).

Your response is inadequate. While you state in your response you have real time stability data for one identical drug product formula for another market, you did not provide the supporting data for this assertion. Additionally, for other drug product formulas you failed to provide data to demonstrate that the chemical and (b)(4) properties of your drug products will remain acceptable throughout their labeled expiry period of up to 36 months.

In response to this letter, provide the following:

• A comprehensive, independent 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 these and other elements of your remediated stability program.

4. 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 adequately validate the manufacturing processes for your drug products. You performed process validation for only one of your drug products; however, you manufacture numerous drug products with different formulations and with multiple active pharmaceutical ingredients. During the inspection you provided your rationale for this practice, stating that each active ingredient was similar in its chemical propet;ties and that during actual manufacturing you tested the formulation and the drug products had met specification. However, one of the active ingredients in your formulations is (b)(4), which you failed to test in finished product batches as detailed above.

In your response, you committed to reperforming process validation for one drug product. Your response is inadequate. You did not provide sufficient process performance qualification (PPQ) protocols or studies for each formulation of your drug products.

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 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 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 PPQ for each of your marketed drug products.

• Your process performance protocol(s) and written procedures for qualification of equipment and facilities.

5. Your firm failed to use equipment in the manufacture, processing, packing or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended used and for its cleaning and maintenance (21 CFR 211.63).

You have not established that your (b)(4) is adequately designed, controlled, maintained, and monitored to ensure it consistently produces (b)(4) that is suitable for use in your drug products. For example, neither your (b)(4) qualification nor your routine monitoring of the (b)(4) includes testing the (b)(4) for (b)(4).

In your response, you stated that you revised the monitoring and testing frequency of your (b)(4) for (b)(4) to twice a month, and you provided the test report from a third-party laboratory who performs these tests on your behalf.

Your response is inadequate. You failed to provide data to demonstrate that your (b)(4) system is capable of producing (b)(4) in a reproducible manner that consistently meets the (b)(4) USP monograph and appropriate microbial specifications. Further, you failed to conduct a risk assessment to determine the potential impacts of substandard (b)(4) on the drug products that you manufacture.

In response to this letter, provide the following:

• A comprehensive, independent assessment of your (b)(4) design, control, and maintenance.

• Then, a comprehensive remediation plan for the design, control, and maintenance of the (b)(4).

o Followed by a (b)(4) validation report to evaluate whether the remediated system design consistently produces (b)(4) adhering to (b)(4), USP monograph specifications and appropriate microbial limits. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces (b)(4) that meets (b)(4), USP monograph specifications and appropriate microbial limits.

• A tabular summary of the chemical and microbial monitoring results that you have collected from testing your (b)(4) for the past two years. Also include within the table the following:

    o specifications for the tested attribute
    o date of sampling
    o point of use (POU) from which the sample was collected

In addition, provide a description of the location of each POU and how it is used in drug manufacturing, along with a description of the (b)(4) during (b)(4) testing.

• A detailed risk assessment addressing the potential effects of the observed (b)(4) failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

Concerns Regarding Glycerin

The drug products you manufacture contain glycerin as an ingredient. The use of glycerin contaminated with diethylene glycol (DEG) 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 CGMP requirements when distributing glycerin for use in drug products, including testing for DEG and recommendations for supply chain integrity, at https://www.fda.gov/media/71029/download.

Responsibilities as a Contractor

You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA's guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

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. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP 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.

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 these violations and for preventing their recurrence or the occurrence of other violations.

FDA placed your firm on Import Alert 66-40 on November 8, 2019.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Huaian Zongheng Bio-Tech Co., Ltd., at No. 615 North Xiangyu Road, Huaian 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 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 CDER-OC-OMO-Communications@fda.hhs.gov or mail your reply to:

Philip Kreiter
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire A venue
Silver Spring, MD 20993
USA

Please identify your response with FEI 3007628845.

Sincerely,
/S/

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

 
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