Longood Medicine (Beijing) Co Ltd MARCS-CMS 545459 —
Recipient NameMr. Shenglin Gao
- Longood Medicine (Beijing) Co Ltd
No. 13, Yunteng Road, Miyun Economic Development Area
- Issuing Office:
- Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993
Via UPS Warning Letter 320-18-72
Return Receipt Requested
August 27, 2018
Mr. Shenglin Gao
Longood Medicine (Beijing) Co., Ltd.
No. 13, Yunteng Road, Miyun Economic Development Area
Dear Mr. Gao:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Longood Medicine (Beijing) Co., Ltd. at No. 13, Yunteng Road, Beijing, from September 25 to 29, 2017.
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 also manufactures unapproved new drug products in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a).
We reviewed your October 13, 2017, response in detail and acknowledge receipt of subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, including drug products manufactured, processed, packed or held under contract by another company. Your firm failed to establish a quality unit with the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).
You failed to ensure that your third-party contractor uses a validated terminal sterilization process, consistent with the requirements of 21 CFR 211.113(b), to sterilize your drug product, Chlora-Cleanze Proprep applicators, purported as sterile and labeled for “use prior to surgery.”
You released Chlora-Cleanze Proprep applicators without assurance of their sterility. For example, you were unable to provide adequate records demonstrating that your contractor terminally sterilized Chlora-Cleanze Proprep applicators lot 20170601, distributed to the United States. You also failed to provide evidence that your quality unit reviewed all appropriate records prior to releasing the lot.
In your response, you acknowledged that your terminal sterilization contractor provided incomplete records for Chlora-Cleanze Proprep applicators (lot 20170601). Your response is inadequate. You failed to describe how your firm determined the lot was acceptable for release without complete documentation from your contractor. In addition, you failed to provide evidence from your contractor demonstrating this lot was terminally sterilized.
Your response also provided terminal sterilization validation documentation for a different (b)(4) product ((b)(4)) to support the sterilization of Chlora-Cleanze Proprep applicators. Your response is inadequate in that it lacks sufficient validation data to support sterilization efficacy. You did not provide scientific rationale demonstrating validation studies for the (b)(4) sterilization process are representative of the sterilization process for Chlora-Cleanze Proprep applicators. (b)(4) drug product has a different formulation, including a different active ingredient. You failed to address whether you will validate the terminal sterilization process for the Chlora-Cleanze Proprep applicators.
In your response to this letter, provide:
- Your qualification procedures for assessing the suitability and competence of potential contractors before outsourcing, and for ongoing monitoring and review of the performance of the contract facility to identifying and implement any needed improvements;
- A detailed plan for ensuring that the process your contractor uses to terminally sterilize all products, including Chlora-Cleanze Proprep applicators, is adequately validated;
- Complete sterilization records from your contractor for Chlora-Cleanze Proprep applicators, lot 20170601. If you do not have sufficient evidence that the lot in question or any lot intended for the U.S. market was adequately sterilized, indicate the corrective actions you will take, such as customer notifications and product recalls.
- A corrective action and preventive action (CAPA) plan to fully remediate your review and release procedures for finished drug products. Your procedures should require that third-party contractors provide sufficient production and control records to demonstrate compliance with established, approved written procedures and specifications before a lot is released or distributed by your quality unit.
Our investigators found numerous uncontrolled and unofficial production and laboratory records associated with Chlora-Cleanze Proprep applicators (lot 20170601) during the inspection. These include duplicate records which contain incomplete fields and strike-throughs.
In your response, you state that you will examine your document control procedures and provide training to management. Your response is inadequate. Training should include all employees involved in the manufacturing process. Additionally, you failed to indicate whether the uncontrolled and unofficial production and laboratory records for lot 20170601 were reviewed prior to release of the lot. Further, you did not perform a full retrospective review to determine the extent of the production and laboratory record deficiencies, and commit to a CAPA plan to comprehensively identify and address root causes.
In your response to this letter, provide:
- A comprehensive, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are deficient. Include a detailed CAPA plan that systemically remediates deficient documentation practices, and ensures you retain complete and accurate records.
- A comprehensive CAPA for your training program to ensure all staff at your facility are fully trained in CGMP. Provide a fully remediated training program for your entire operation. Place special emphasis on assuring that all staff involved in any CGMP function are trained and competent in acceptable recordkeeping practices, such as retaining all records, completing records contemporaneously, documenting any error in records, and ensuring that all procedures are approved by quality unit.
2. 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 does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality for your Chlora-Cleanze Proprep applicators. You told our investigator that you had validated your process for manufacturing another drug product, and that the process was similar to your Chlora-Cleanze Proprep manufacturing process. You did not provide validation of the Chlora-Cleanze Proprep manufacturing process.
Your response states that you conduct in-process testing of batches (b)(4) to filling operations. You also state that you will conduct stability testing on Chlora-Cleanze Proprep applicators. Your response is inadequate. In the absence of process validation, testing alone is insufficient to determine whether your processes are of sound design and operating in a state of control throughout a product’s lifecycle.
In response to this letter, detail your validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for your Chlora-Cleanze Proprep applicator manufacturing process, and describe your program for vigilantly monitoring batch-to-batch variation to ensure an ongoing state of control for all of your products. Also include your PPQ protocol.
When significant variability is observed in one or more stages of pharmaceutical production, it is essential that executive management support and implement effective actions to address the source(s) of the variation and provide for a continued state of control. See FDA’s guidance document, Process Validation: General Principles and Practices, for approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070336.pdf.
CGMP Consultant Recommended
Based upon the nature of the CGMP 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 effectiveness of any corrective actions and preventive actions you have implemented. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
Unapproved New Drug Violations
As formulated and labeled, Biotronix Healthcare Chlora-Cleanze Proprep-I Applicators (Chlora-Cleanze Proprep) are unapproved new drugs. Examples of claims observed on your product label for Chlora-Cleanze Proprep that establish the intended uses of the product include, but may not be limited to, the following:
- “Chlorhexidine gluconate 2% w/v…Antiseptic”
- “Isopropyl Alcohol 70% w/v…Antiseptic”
- “Antiseptic Solution”
- “Use prior to surgery to prepare patient’s skin. Helps in the reduction of potentially harmful bacteria”
Based on the above claims, Chlora-Cleanze Proprep 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 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 a patient pre-operative skin preparation.
Drug products, such as Chlora-Cleanze Proprep intended for OTC use as preoperative skin preparations, are being evaluated as part of the OTC Drug Review. See the Tentative Final Monographs for First Aid Antiseptics, Healthcare and Consumer Antiseptics for Over-the-Counter Use, 43 FR 1210 (January 6, 1978) and amended at 56 FR 33644 (July 22, 1991), 59 FR 31402 (June 17, 1994), 78 FR 76446 (December 17, 2013), 80 FR 25166 (May 5, 2015) and 81 FR 42911 (June 29, 2016). Pending a final rule, the agency does not intend to pursue regulatory action against products marketed in conformance with the conditions proposed in the tentative final monographs and each general condition in 21 CFR 330.1. Such marketing, however, is subject to the risk that a final rule may require reformulation and/or relabeling or FDA approval through the “new drug” procedures of the FD&C Act (section 505).
However, the formulation for Chlora-Cleanze Proprep is not consistent with the applicable tentative final monographs for pre-operative skin preparations. The active ingredient, chlorohexidine gluconate (CHG), is not covered under the OTC Drug Review for topical antimicrobial use in humans. See 59 FR 31402 at 31412-31413. Therefore, any topical antimicrobial product that contains CHG as an active ingredient requires an FDA-approved application for marketing. Based on our review, Chlora-Cleanze Proprep does not have such an approval.
Thus, as formulated and labeled, Chlora-Cleanze Proprep does not conform with the tentative final monographs described above. 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, Chlora-Cleanze Proprep may not be legally marketed in the United States absent approval of an application filed in accordance with section 505 of the FD&C Act, 21 U.S.C. 355(a). Chlora-Cleanze Proprep 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 of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
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 the recurrence, and for preventing other violations.
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 refusing admission of articles manufactured at Longood Medicine (Beijing) Co., Ltd., No. 13, Yunteng Road, Beijing, 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 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-OMQ-Communications@fda.hhs.gov or mail your reply to:
Mr. Rory Geyer
U. S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3011090864.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research