- Delivery Method:
- VIA UPS
Recipient NameMr. Zhao Liqun
- Yuyao YiJia Daily Chemical Co., Ltd.
No.8 Tongji Road
lndustrial Park, Simen Town
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-21-16
January 22, 2021
Dear Mr. Liqun:
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 31, 2020 request 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, Yuyao YiJia Daily Chemical Co., Ltd., FEI 3015592903, at No.8 Tongji Road, lndustrial Park, Simen Town, Ningbo.
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)).
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 listed over-the-counter (OTC) drug products, including hand sanitizer1, (b)(4), (b)(4) products, and (b)(4), with FDA. Your response to our request for records and other information under section 704(a)(4) indicates that you did not conduct adequate finished drug product testing on drug products shipped to the United States. For example, in response to our 704(a)(4) request for all finished product specifications and test methods either performed in-house or by a third party, you submitted finished product test reports for your OTC (b)(4) but did not include adequate records demonstrating that you conducted appropriate testing for identity and strength of the active ingredient, (b)(4). Your response also lacked the test methods and only listed equipment. When we requested this missing information in our follow-up communication on May 8, 2020, you restated your original response and added that you used a third party testing laboratory for assay testing, but did not include test specifications or methods for identity and strength testing used by the third-party laboratory. The documents you provided in response to our 704(a)(4) request indicate that you do not perform assay testing for identity and strength of your active ingredients. Without adequate testing, there is not scientific evidence that your drug product batches conform to appropriate specifications prior to release.
Following our 704(a)(4) request, we note that you shipped several lots of hand sanitizer to the United States. Ensure that your response to the items below includes documentation that applies to hand sanitizer and any drug products intended for U.S. distribution.
In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:
• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
• 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 that are within expiry as of the date of this letter.
• A summary of all results obtained from testing reserve 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.
• Methanol test results for all batches of hand sanitizer shipped to the United States within expiry.
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)).
Based on the records and information you provided, you have not demonstrated that you are testing incoming raw materials used to manufacture your drug products to determine their identity.
For example, when we requested whether you perform raw material identity testing, you replied that the testing is done by your supplier. When we requested which identity test is performed in our follow-up communication on May 8, 2020, you provided the supplier certificate of analysis (COA) for the (b)(4), which does not include a specification or results for identity testing, and you did not provide documentation showing that you have qualified the supplier or that you have verified the information on the supplier’s COA. You also did not provide identity testing information related to other products shipped from your facility.
In response to this letter, provide the following for all components used in drug products imported to the United States prior to and after our 704(a)(4) request:
• A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• 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 COA instead of testing each component lot for strength, quality, and purity, specify how you will establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. We note that identity testing is required for every lot of components regardless of supplier test result validation.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract laboratory facilities that test the active ingredients used in the drug products 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)).
You did not provide adequate stability data to demonstrate that the chemical properties of your drug products remain acceptable throughout the labeled expiry period. For example, your stability data for (b)(4) does not include testing for the active ingredient. Therefore, the data does not demonstrate that the drug’s active ingredient is stable throughout its shelf life. Additionally, the data provided does not include microbiological stability data.
In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:
• A comprehensive, independent assessment and corrective and preventive action 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)
o All stability data from your ongoing stability program for all products manufactured from January 1, 2016 to present
• All procedures that describe these and other elements of your remediated stability program
4. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)).
The records and information you submitted demonstrate that you lack an adequate quality unit (QU). For example, your firm failed to provide adequate written procedures for QU responsibilities such as batch record review, supplier qualification, equipment qualification and calibration, process validation, cleaning validation, and annual product review.
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
Based on FDA’s review of records and information provided in response to our request, your firm’s quality systems are inadequate. Please see FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for helpful information regarding 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.
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 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.
The violations cited in this letter are not intended to be an all-inclusive list of violations associated with your drug products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
Note that FDA placed all drugs and drug products manufactured by your firm on Import Alert 66-40 on September 23, 2020, as the methods used in and controls used for the manufacture, processing, packing, or holding of these products do not appear to conform to current good manufacturing practice within the meaning of section 501(a)(2)(B) of the FD&C Act. Drugs and drug products that appear to be adulterated or misbranded may be detained or refused admission without physical examination pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).
All drugs and drug products manufactured by your firm may remain listed on this import alert until there is evidence establishing that the conditions that gave rise to the appearance of this violation have been resolved, and the Agency has confidence that future entries will be in compliance with the FD&C Act. This may include an inspection prior to the Agency considering the appearance of adulteration to be addressed.
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 re-inspect to verify that you have completed corrective actions to 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 deviations and 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 do so 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 3015592903 and ATTN: Marisa Heayn.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, FDA published the Guidance for Industry: Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) on March 19, 2020, and subsequently updated the guidance several times, most recently on August 7, 2020. This guidance communicates the Agency’s temporary policy that we do not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepare alcohol-based hand sanitizers for consumer use (or for use as a health care personnel hand rub) during the public health emergency, provided certain circumstances described in the guidance are present. These circumstances include preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. A review of your drug products’ labeling , including those submitted in response to our 704(a)(4) request indicates that these products are not prepared consistent with FDA’s temporary policy set forth in the guidance. Therefore, these products do not fall within the Agency’s temporary policy not to take action against firms manufacturing hand sanitizer products for violations of section 501(a)(2)(B) of the FD&C Act.