- Delivery Method:
- Certified Mail
Recipient NameMr. Shenxiang Zhai
Recipient TitleGeneral Manager
- Beijing Xinggu Lvsan Technology Co., Ltd. Formerly known as Beijing Lvsan Technology Co., Ltd.
No. 48 Pingwang Street
Xinggu Development Zone
Beijing Shi, 101200
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-23-01
October 5, 2022
Dear Mr. Zhai:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Beijing Xinggu Lvsan Technology Co., Ltd.(formerly known as Beijing Lvsan Technology Co., Ltd.), FEI 3017227582, at No. 48 Pingwang Street, Xinggu Development Zone Pinggu District, Beijing, China, from April 11 to 15, 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 product is 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, SierraSoft Alcohol Hand Sanitizer and SierraSoft Non-Alcohol Foam Hand Sanitizer are unapproved new drugs 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 are misbranded under section 502(c) and (ee) of the FD&C Act, 21 U.S.C. 352(c) and (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 reviewed your May 10, 2022, 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 conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).
Your firm manufactures over-the-counter (OTC) hand sanitizer drug products, including 75% alcohol hand sanitizer and (b)(4).1 You failed to adequately test your incoming components for identity before using the components to manufacture your drug products. Additionally, you relied on certificates of analysis (COA) for specifications of the components from unqualified suppliers. By not adequately analyzing your components for identity, purity, strength, and quality, you failed to ensure your incoming components meet appropriate specifications.
In your response, you provided the test methods for the two APIs used in manufacturing your hand sanitizers, (b)(4), and ethanol. You also provided the test results of two alcohol hand sanitizer reserve samples, which indicated non-detectable levels of methanol.
Your response is inadequate because you have not provided details for the associated test methods for your active ingredients and components demonstrating that your test methods are equivalent to or better than United States Pharmacopeia (USP) methods. In addition, you have not addressed how you plan to establish the reliability of, and periodically validate, the test results on your suppliers’ COA.
In response to this letter, provide:
- A retrospective risk assessment on impact of the lack of adequate tests for incoming components on the identity, purity, strength, quality, and safety of the drug products currently in the U.S. market within expiry.
- The chemical and microbiological quality control specifications you use to test and release each incoming lot of components 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 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 drug products you manufacture.
- 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.
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
You manufacture drug products using the same equipment that you use to manufacture non-drug industrial products such as (b)(4) and (b)(4). Inadequate removal of residues from manufacturing equipment during cleaning can lead to contamination of drug products subsequently manufactured on the non-dedicated equipment.
In your response, you provided a document outlining your procedures for cleaning and disinfecting manufacturing equipment. It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture industrial products due to the risk of cross-contamination.
In response to this letter, provide:
- A risk assessment for all drugs you have previously produced on equipment shared with industrial products. For each product, assess the risk of potential contamination due to the shared equipment, and provide your plans for addressing the product quality and patient safety risks for any product still in distribution, including potential recalls or market withdrawals.
- Your plans regarding the manufacture of both pharmaceutical and non-pharmaceutical products at your facility. If you intend to continue to manufacture both pharmaceutical and non-pharmaceutical products at your facility, provide your plan to separate the areas in which you will maintain dedicated manufacturing equipment for your pharmaceutical manufacturing and industrial product manufacturing operations.
- A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
3. 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 batch records indicate that you did not perform microbial testing on your finished hand sanitizer drug products. Without testing each batch prior to release, you did not have scientific evidence that all drug product batches conformed to the appropriate microbial quality specifications.
In response to this letter, provide:
- 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 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 within expiry. If such testing reveals substandard quality drug products, take rapid corrective actions you will take, such as notifying customers and product recalls.
4. Your firm failed to establish 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)).
You failed to validate the manufacturing processes for your OTC hand sanitizer drug products. For example, you have not sufficiently identified critical manufacturing variables including, but not limited to, (b)(4) and time. You did not demonstrate that your manufacturing processes were controlled to consistently yield a drug product of uniform character and quality.
In your response, you provided procedures for the production processes of your OTC hand sanitizer drug products to be implemented after April 18, 2022.
Your response is inadequate. You have not addressed whether you would validate the processes used to manufacture your drug products.
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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
- A timeline for performing appropriate process performance qualification for each of your marketed drug products, including how you will ensure proper validation prior to distribution of drugs.
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 https://www.fda.gov/media/71021/download.
5. 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 OTC drug products. For example:
- Your batch records lacked information on the drug product release date and were not signed by your QU.
- Your QU could not locate the laboratory test results in your electronic system (the New Century System) and there was inadequate backup of the electronic data.
- Test results recorded in the laboratory notebook for the (b)(4) were not legible and the record was not attributable.
- When our investigator requested a COA for (b)(4), you gave our investigator a COA for food-grade alcohol.
An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality.
In your response, you provided several documents describing the responsibilities of the QU, a record control procedure, a batch production record form, a (b)(4) record form, and a production batch management system.
Your response is inadequate because you failed to address the fundamental deficiencies in your QU that led to these failures. Your response lacked documentation and sufficient detail to demonstrate that you are establishing appropriate operational programs, systems, data governance, and related procedures to ensure product quality.
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
- A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
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.
Data Integrity Remediation
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you test. See FDA's guidance document Data Integrity and Compliance with Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
In response to this letter, provide:
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and analyses of the risks posed by ongoing operations.
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm, including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
Unapproved New Drug and Misbranding Violations
SierraSoft Alcohol Hand Sanitizer 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 a consumer topical antiseptic.
Examples of labeling claims observed on the SierraSoft Alcohol Hand Sanitizer and SierraSoft Non-Alcohol Foam Hand Sanitizer product labels and labeling that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the products include, but may not be limited to, the following:
SierraSoft Alcohol Hand Sanitizer:
“SierraSoft Alcohol Hand Sanitizer . . . Protect yourself from viruses, bacteria and germs.”
“Alcohol Hand Sanitizer . . . Active Ingredient . . . Ethyl Alcohol 75%v/v . . . Purpose . . . Antibacterial . . . Function: 75%Alcohol [sic] hand sanitizers kill most bacteria, and fungi, and stop some viruses. . . . Directions . . . Apply amount of sanitizer in your palm to thoroughly cover your hands, rub hands together briskly until dry, no rinsing required.”
SierraSoft Non-Alcohol Foam Hand Sanitizer:
“Drug Facts . . . Active Ingredient . . . Benzalkonium Chloride0.1% [sic] . . . Purpose . . . Antimicrobial . . . Uses . . . For handwashing to decrease bacteria on the skin. Recommended for repeat use. . . . Directions . . . Apply foam sanitizer to hands. Rub over surfaces of both hands for 15 seconds. No rinsing required.”2
These topical antiseptic products are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are lawfully marketed under section 505G of the FD&C Act (which is not the case for these products, as further described below) or under exceptions not applicable here. 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, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your SierraSoft Alcohol Hand Sanitizer and SierraSoft Non-Alcohol Foam Hand Sanitizer drug products are GRASE for use under the conditions suggested, recommended, or prescribed in their labeling. Accordingly, these 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).
We note that over-the-counter (OTC) topical antiseptic products had been the subject of rulemaking under the Agency’s OTC Drug Review. In particular, such products were addressed in a tentative final monograph (TFM) entitled “Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products,” Proposed Rule, 59 FR 31402 (June 17, 1994) (1994 TFM), as further amended by “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 81 FR 42912 (June 30, 2016) (Consumer Antiseptic Rubs Proposed Rule). Over the course of these rulemakings, three active ingredients (benzalkonium chloride, ethyl alcohol (ethanol), and isopropyl alcohol) were classified as Category III for use in consumer antiseptic rub products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use as a consumer antiseptic rub. Additionally, OTC consumer antiseptic washes were addressed in “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) (Consumer Antiseptic Washes Proposed Rule) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016).
Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under section 505G(a)(3) of the FD&C Act, drugs that were classified as Category III for safety or effectiveness in a TFM that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 – and that were not classified as Category II for safety or effectiveness – are not required to have an approved application under section 505 in order to be marketed, as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM, including the active ingredient, and comply with all other applicable requirements.
However, SierraSoft Alcohol Hand Sanitizer and SierraSoft Non-Alcohol Foam Hand Sanitizer do not conform to the 1994 TFM, nor any other TFM, proposed rule, or final rule, and do not meet the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505.
According to the product label, SierraSoft Alcohol Hand Sanitizer indicates that it protects against viruses and kills fungi and stops some viruses. These labeled intended uses go beyond merely describing the general intended use of topical antiseptics as set forth in the 1994 TFM, as amended by the 2016 proposed rule.3
In addition, as previously noted, statements on the SierraSoft Non-Alcohol Foam Hand Sanitizer label provide evidence that the product is intended for use as a handwash, with claims such as “for hand washing to decrease bacteria on the skin,” and as a consumer antiseptic rub, with claims such as “Apply foam sanitizer to hands. Rub over surfaces of both hands for 15 seconds. No rinsing required.” However, such a combination that suggests the product can be simultaneously used both as a wash (to be rinsed off), and as a rub (to be left-on) is not in conformity with the most current applicable TFMs or proposed rules for these monograph products. Accordingly, this product does not meet the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505.
Furthermore, SierraSoft Alcohol Hand Sanitizer is not labeled in accordance with the Drug Facts labeling requirements described in 21 CFR 201.66. Specifically, the product label fails to follow 21 CFR 201.66 format specifications, such as including the content requirements per 21 CFR 201.66(c). Therefore, this product is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the information that is required to appear on the labeling is not prominently placed thereon with such conspicuousness and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use.
Lastly, these products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because SierraSoft Alcohol Hand Sanitizer and SierraSoft Non-Alcohol Foam Hand Sanitizer 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 subjects of applications 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).
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 and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also 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.
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.
FDA placed your firm on Import Alert 66-40 on August 1, 2022.
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.
Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Beijing Xinggu Lvsan Technology Co., Ltd., No. 48, Pingwang Street, Xinggu Development Zone, Pinggu District, Beijing 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 that appear to be adulterated and misbranded may be detained or refused 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) and are misbranded under section 502 of the FD&C Act, respectively].
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 3017227582, and ATTN: Emily Wu.
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. The guidance was withdrawn effective December 31, 2021 (86 Fed Reg at 56960). This guidance communicated the Agency’s temporary policy that we did not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepared 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 included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. A review of the formulations of the drug products indicates that such products were not prepared consistent with FDA’s temporary policy set forth in the guidance. Because Beijing Lvsan Technology hand sanitizer drug products were not consistent with the formulations described in these guidances, they did not fall within any temporary Agency policy not to take action against firms manufacturing hand sanitizer drug products for violations of section 505 of the FD&C Act.
2 We note that your SierraSoft Non-Alcohol Foam Hand Sanitizer labeling contains conflicting information regarding whether it should be used as a consumer antiseptic wash or a consumer antiseptic rub. The term “hand sanitizer” generally refers to consumer antiseptic rubs, and the Drug Facts Label of your product both indicates that the product is to be used for handwashing (presumably with water) and suggests that it should be used without water (i.e., “Rub over surfaces of both hands for 15 seconds. No rinsing required.”). The SierraSoft Non-Alcohol Foam Hand Sanitizer product, however, does not conform to the requirements for either a consumer antiseptic rub or a consumer antiseptic wash, as further described below.
3 The 1994 TFM covers health care antiseptics that are indicated for use to help reduce bacteria that potentially can cause disease and health care and consumer antiseptics that are indicated for use to decrease bacteria on the skin. 59 FR at 31443.