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Recipient NameMr. Qi Lei
Recipient TitleGeneral Manager
- Henan Kangdi Medical Devices Co. Ltd
SME Pioneer Park, No. 4, 2nd Area
Henan Sheng, 466700
- Issuing Office:
- Center for Drug Evaluation and Research
December 3, 2019
Warning Letter 320-20-09
Dear Mr. Qi Lei:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Henan Kangdi Medical Devices Co. Ltd., 3009271465, at SME Pioneer Park, No. 4, 2nd Area, Zhoukou, Henan, from March 4 to 7, 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 "Capsicum Plaster HOT" and " 1st Medx-Patch With 4% Lidocaine." These products are unapproved new drugs in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d). These violations are described in more detail below.
We reviewed your March 22, 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 manufactures and distributes various over-the-counter (OTC) transdermal patch drug products such as "Capsicum Plaster HOT" pain relieving and " (b)(4) for the United States market. Our inspection found that you did not test your finished drug products to determine whether each batch met identity and strength specifications before being released to the U.S. market. Complete testing of each batch before release is an essential part of determining if a drug product batch meets its specifications.
The quality unit must be empowered to make final quality decisions. It is essential that the quality unit be enabled to provide timely oversight of all laboratory and manufacturing data that could impact product quality, whether or not lots have already been distributed. When making batch disposition decisions, the quality unit must be provided with all batch production and control records, including all deviations and test data, to enable a fully informed and appropriate decision regarding suitability for distribution. The quality unit must assure that drug products are fully tested for all critical attributes prior to release.
In your response, you stated that you will search for a third-party testing laboratory with adequate capabilities. Additionally, you committed to test for the active ingredient in each batch of finished drug products sold within the U.S. market to ensure product specifications are met.
Your response is inadequate because you did not include information about your third-party testing laboratory including name and location, methods, or a detailed description of the tests they will conduct (e.g., identity, strength and purity). Furthermore, you did not provide how you will evaluate the capability of your third party to perform the intended tests. Additionally, you provided no testing documentation for finished drug product batches currently in the U.S. market.
In response to this letter, provide:
• A comprehensive and 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 procedures you will use to evaluate the effectiveness of the implemented CAP A plan.
• 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.
• A summary of test results obtained from retrospective testing of retain samples of all drug product batches currently in distribution in the U.S. Include test results for identity and strength of active ingredients, and all other appropriate chemical and microbial quality
attributes. If you released any batch that was out of specification, indicate the corrective actions you will take, such as customer notifications and product recalls. Provide a timeline for completing this testing expeditiously.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture. Your summary should include, but not be limited to, your procedure to ensure that any test methods performed by a contract testing laboratory on your behalf are properly validated prior to use for batch analysis. Additionally, include the procedure to evaluate the capability of your third party to accomplish the testing they are contracted to perform.
2. 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 (2)).
You failed to test incoming active pharmaceutical ingredients (API) and other raw materials (e.g., (b)(4)) used to manufacture your drug products to determine their identity, purity, strength, and other appropriate quality attributes. Instead, our investigator observed your firm released API and other materials for use in manufacturing based solely on a visual inspection of the contents of material containers and a review of component suppliers· analyses reports. You did not retain these suppliers' analysis reports, but discarded them after review. Additionally, you did not establish the reliability of your suppliers' analyses through appropriate validation. Your firm did not ensure that at least one specific identify test was conducted for each lot of your incoming materials. This violation was also observed during the December 2016 inspection, after which you committed to test incoming raw material.
In your response, you stated your intent is to find a qualified third-party testing laboratory, revise your procedure for incoming material, and send to the third-party laboratory each lot of active ingredient used in drug products for U.S. supply.
Your response is inadequate because you did not commit to cease manufacturing drugs until the required testing of drug components is in place, and you did not conduct a risk assessment for products already in distribution in the United States. Furthermore, your response did not include the testing of raw materials, other than active ingredients, used in your finished drug products. Additionally, you failed to address how you will establish the reliability of your suppliers' analyses, and provided no documentation to support your CAPA plan.
In response to this letter, provide:
• 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 have incoming material controls adequate to prevent use of unsuitable components, containers, and closures.
• The chemical and microbiological quality control specifications you will use to determine disposition of each incoming lot of components before 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 testing results on your suppliers' certificates 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 suppliers' test results for these attributes 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 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 that describes this COA validation program.
3. 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 has not established an adequate stability program to support the (b)(4) expiration date assigned to your drug products. You lack sufficient data to demonstrate that the chemical and microbiological properties of your drug products will remain acceptable throughout their labeled expiry period.
In your response, you committed to conduct stability testing on your drug products under accelerated conditions, and to ensure such testing are on samples held under appropriate temperature and humidity control.
Your response is inadequate because you failed to provide stability protocols, including all relevant quality attributes and acceptance criteria, and you did not provide assurance that your test methods will be adequate to assess drug stability. In addition, you did not clarify whether your stability testing will be conducted under real time conditions to support your OTC drug product expiry. Furthermore, you did not indicate any actions to ensure that all distributed drug product batches maintain their quality attributes through their labeled expiry.
Based upon the lack of material testing, finished testing, and stability testing, there is minimal assurance that your drug manufacturing operations are capable of operating in a state of control.
In response to this letter, provide:
• A comprehensive, independent assessment and CAP A 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.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
• A description how top management will support quality control, quality assurance, and reliable operations, including but not limited to timely provision of oversight and resources to proactively address deficiencies in laboratories and manufacturing in order to support robust operations.
Quality Unit Authority
Significant findings in this letter indicate that your quality unit is not fully exercising its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. 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.
Repeat Observations at Facility
In a previous inspection, dated December 12 to 14, 2016, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
Use of Contract Manufacturers
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
You are responsible for the quality of your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure 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 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 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.
Unapproved New Drug Charges
"Capsicum Plaster HOT" and "1st Medx-Patch With Lidocaine 4%"
"Capsicum Plaster HOT" and " 1st Medx-Patch With Lidocaine 4%" are drugs as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or as defined by section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, these products are intended for use as external analgesics.
Examples of claims observed on the product labeling that establish the intended uses (as defined in 21 CFR 201.128) of the products include, but may not be limited to, the following:
"Capsicum Plaster HOT" Label Claims
"For long lasting relief of Rheumatism, Lumbago, Notalgia, and Sciatica, Arthralgia, Stiff Shoulder and Muscle Pain."
"1st Medx-Patch With Lidocaine 4%" Labeling Claims
"For the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains, sprains, muscle soreness and stiffness."
OTC drug products such as "Capsicum Plaster HOT" and " 1st Medx-Patch With Lidocaine 4%" that are intended for external analgesic indications such as the relief of pain are being evaluated as part of the OTC Drug Review. They have been proposed to be classified as generally recognized as safe and effective and not misbranded under the Tentative Final Monograph (TFM) for External Analgesic Drug Products for Over-The-Counter Human Use (48 FR 5852, February 8, 1983). Pending the promulgation of a final rule, FDA generally does not intend to pursue regulatory action against products marketed in accordance with the conditions proposed in the TFM and each general condition in 21 CFR 330.1 unless a particular product poses a public health concern. 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, "Capsicum Plaster HOT" and " 1st Medx-Patch With Lidocaine 4%" do not meet these conditions for the reasons explained below.
The formulation for "Capsicum Plaster HOT" includes capsicum in a concentration that exceeds what has been proposed in the External Analgesic TFM (see 48 FR 5852 at 5868, February 8, 1983). "Capsicum Plaster HOT" is labeled to contain Capsicum Extract 2.89%, while the External Analgesic TFM allows Capsicum in a concentration of 0.025% to 0.25%. Additionally, the product label for "Capsicum Plaster HOT" includes indications such as "long lasting relief of rheumatism, lumbago, notalgia, and sciatica" that are not proposed under this rulemaking or any rulemaking being considered under the OTC Drug Review.
The formulation for "1st Medx-Patch With Lidocaine 4%" includes lidocaine but this product is considered a counterirritant under the External Analgesic TFM because it is labeled for the temporary relief of minor aches and pains of muscles and joints. Lidocaine is not proposed as a counterirritant active ingredient in the External Analgesic TFM nor does the TFM propose the combination of anesthetic ingredients, such as lidocaine, with counterirritant ingredients (48 FR 5852 at 5868, February 8, 1983).
Furthermore, we are not aware of any adequate and well controlled clinical trials in the published literature that support a determination that "Capsicum Plaster HOT" and " 1st Medx-Patch With Lidocaine 4%" are generally recognized as safe and effective for their labeled indications. Additionally, we are not aware of similar OTC products as formulated and labeled that were available in the United States market on or before the inception of the OTC Drug Review.
"Capsicum Plaster HOT" and "1st Medx-Patch With Lidocaine 4%," as labeled, are therefore new drugs within the meaning of section 201 (p) of the FD&C Act because they are not generally recognized among scientific experts as safe and effective for the drug uses described in its labeling. "New drugs" may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FD&C Act is in effect for the drug.
"Capsicum Plaster HOT" and " 1st Medx-Patch With Lidocaine 4%" are not the subject of approved new drug applications; therefore, marketing these products in the United States is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d) and violates section 505 of the FD&C Act.
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 October 25; 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 Henan Kangdi Medical Devices Co. Ltd., SME Pioneer Park, No. 4, 2nd Area, Zhoukou, Henan 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-OMQ-Communications@fda.hhs.gov or mail your reply to:
Joseph Lambert, Pharm.D.
U.S. Food and Drug Administration
White Oak Building 51 , Room 4235
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3009271465.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research