The U.S. Food and Drug Administration (FDA) inspected Daito Kasei Kogyo Co., LTD. from July 18 to 21, 2017. They subsequently were placed on an Import Alert 66-40 on October 25, 2017 and received a Warning Letter on January 19, 2018.
During the inspection, the investigator observed specific deviations including, but not limited to, the following.
- Failure to ensure that, for each batch of API, appropriate laboratory tests are conducted to determine conformance to specifications.
You released numerous drugs without completing all required testing. You claimed that the drugs were tested for identity and assay, and met required specifications for these attributes. However, these tests were never conducted, so you had no assurance that the drugs conformed to specification. Your actions may have put consumers at risk in at least two ways: first, through use of potentially ineffective (b)(4), and second, through possible exposure to toxic impurities such as (b)(4) and (b)(4).
In your response, you said that the former quality control manager decided that identification tests would not be required if “…identification tests of raw materials were confirmed with COA provided by the raw material manufacturers” and that “The QC manager at the time approved the product without testing…” Your revised SOP for issuing COA requires confirmation of raw data.
Your response was inadequate because you have not shown how you intend to confirm such data, who is responsible for conducting tests, and how you intend to ensure the integrity of this data. You also failed to conduct a risk assessment on the effects of the lack of release testing on the quality of drugs you distributed.
In response to this letter, provide:
- A detailed description of how you plan to test each component for conformity with all appropriate written specifications for identity, purity, strength and quality.
- A detailed description of how you plan to test bulk API to determine conformance to specifications.
- A detailed explanation of who will conduct raw material and finished API testing and how you plan to assure the suitability of test methods and the reliability of test results.
- A risk assessment for any API within the re-test date and distributed within the United States that were released with inaccurate COA.
Comments:
The Company failed to follow 21 CFR 211.160 General Requirements. Within Section (a) it states that “the establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanism required by this subpart, including any change in such specifications, standards, sampling plans test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit.”
Section (b) states the “laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials…conform to appropriate standards of identity, strength quality, and purity.”
Laboratory controls shall include:
- “Determine of conformity to applicable written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified.
- Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified.
- Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products.”
- Failure to completely report test results on certificates of analysis.
During the inspection, we reviewed certificates of analysis (COA) for batches of (b)(4) API that you manufactured and released between June 2011 and February 2016. Your quality control unit signed these COA, which indicated that all required tests had been conducted on these batches. However, you told our investigator during the inspection that you signed these COA without having conducted all the tests for which you reported results on these COA. For example, your COA reported the results of identity and impurities tests that you never conducted.
You falsified the COA you issued to your customers. Regulators and customers rely on COA for accurate information about the quality and sourcing of drugs and their components. Falsifying information about the quality of your drugs on COA compromises supply chain accountability and traceability, and may put consumers at risk.
We acknowledge that, due to our inspection, your firm conducted a voluntary recall of all lots of (b)(4) API that you produced between June 2011 and February 2016.
In your response to the inspection, you said you had no standard operating procedure (SOP) that required you to check the raw data before issuing COA, and that the quality control manager decided identity tests could be assessed by COA of raw materials. In addition, you said the quality control manager deleted columns for the results of these tests from your Product Analysis Data Sheet, and that although “…subsequent personnel involved in quality control had recognized this deviation, it continued without being corrected.”
Your response was inadequate. You did not identify the extent of falsification at your facility, or provide details of your plans to correct the conditions that led to falsification of your COA.
Comments:
The Company failed to follow 21 CFR 211.165 Testing and Release for Distribution. Within Section (a), it states: “For each batch of drug product, there shall be 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…”
(b) “There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.”
(c) “Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed.”
(d) “Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels.”
(e) “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented….”
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