- Delivery Method:
- VIA UPS
- Reference #:
- Cao Medical Equipment Co., Ltd.
Number 19 Baihe Road
Langfang Industrial Zone
Hebei Sheng, 065001
- Issuing Office:
- Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993
Dear Mr. Cao:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cao Medical Equipment Co., Ltd. at Number 19 Baihe Road, Langfang Industrial Zone, Langfang, Hebei, from July 16 to 20, 2018.
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 August 3, 2018, response in detail and acknowledge subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to perform, 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, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and (b)).
You manufacture (b)(4) drugs intended for use during (b)(4) procedures and applied to (b)(4). Drugs applied to (b)(4) must be free of objectionable microorganisms. However, you failed to test your finished drug products for total aerobic microbial count and objectionable microorganisms prior to release and distribution. In addition, you also failed to test each batch of drug products for identity and strength of active ingredients prior to release and distribution. Without this testing, you do not have scientific evidence that all drug product batches you manufactured meet their established specifications prior to release.
2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. 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)).
Your firm failed to test incoming active pharmaceutical ingredients and other components used to manufacture your drug products to determine their identity, purity, strength, and other appropriate quality attributes. Instead, your firm relied solely on certificates of analysis (COA) without verification of your suppliers COA, or in other instances, you used components to manufacture drugs without having received a COA.
Your firm also uses glycerin as an ingredient in (b)(4) drug products. Your firm failed to analyze lots of glycerin raw material from your supplier for the presence of diethylene glycol (DEG) and ethylene glycol (EG) prior to releasing it for use in drug product manufacturing. DEG contamination in glycerin has resulted in various lethal poisoning incidents in humans worldwide.
3. 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 use and for its cleaning and maintenance (21 CFR 211.63).
You failed to adequately design, qualify, and control your (b)(4) system used to manufacture drug products. You do not test your source (b)(4) or your production (b)(4) before use in manufacturing. A (b)(4) at your facility is (b)(4) and open to the outdoor environment where it is exposed to vermin, animal waste, and various contaminants.
You lack adequate installation, operational, and performance qualifications to ensure your (b)(4) system is capable of sustainably producing (b)(4) of adequate quality for its intended use in drug products. In addition, you do not protect your (b)(4) from the ingress and proliferation of objectionable microorganisms.
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 have not validated the processes used to manufacture your drug products, you did not define or identify critical process parameters, and you lack an ongoing program for monitoring process controls to ensure stable manufacturing operations and consistent drug quality.
Inadequate Response and Recall Initiated
Your August 3, 2018, response to FDA’s inspectional observations was inadequate. You failed to evaluate the impact of your lack of controls on the quality and safety of drugs distributed to the United States within expiry. Furthermore, FDA review of import records demonstrated you continued to ship drugs to the United States despite stating in your response that you would immediately stop manufacturing and distributing drugs to the United States.
We acknowledge that you agreed to recall all drug products in the United States market, within expiry, on November 9, 2018, after FDA discussed with you the CGMP violations at your facility.
CGMP Consultant Recommended
If your firm intends to resume manufacturing drugs for the United States market, 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 before you pursue resolution of your firm’s compliance status with FDA.
If you intend to resume manufacturing and shipping drugs to the U.S., you should provide comprehensive corrective actions which include systemic remediation of the finished product, raw material, laboratory testing, process validation, and (b)(4) violations listed above as well as global assessment and remediation of all (b)(4) systems of your manufacturing operations.
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.
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 their recurrence, and for preventing other violations.
FDA placed your firm on Import Alert 66-40 on November 26, 2018.
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 continuing to refuse admission of articles manufactured at Number 19 Baihe Road, Langfang Industrial Zone, Langfang, Hebei,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 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.
LT Matthew Schnupp, PharmD.
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 No. 3004475754.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research