NINGBO SMART PHARMACEUTICALÂ RELEASE WITH INCOMPLETE C of As
Comment
The Ningbo Smart Pharmaceutical Co. Ltd, Ningbo China, received an Active Pharmaceutical Ingredient (API) audit between October 25-29, 2010. During this audit, the investigator identified significant deviations from CGMP for the manufacture of APIs. They included:
Specific deviations observed during the inspection include, but are not limited, to the following:
1. Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.
For example, your Quality Control Unit (QCU) approved the release of four (b)(4) USP batches (#(b)(4)) without data to support that the test for organic volatile impurities (OVI) met release specifications.
While your Certificates of Analysis state that OVI levels conformed to specifications, the inspection found that no testing (BAF’s italics) was done.
It is essential that your firm only report results to customers when you have actually performed the analysis.
This serious CGMP deviation raises concerns regarding the reliability and integrity of other data generated by your firm. While we acknowledge the commitment in your November 19, 2010 response to improve the QCU, we remain concerned that your investigation is not comprehensive enough to determine the extent and impact of the problem. A review of the (b)(4) OVI records of batches that were not previously tested is not sufficient. In your response, provide a complete corrective action plan that includes a retrospective review of the analytical data and batch records for all products manufactured at your facility that remain within expiration. In addition, provide the actions taken to prevent recurrence of the problem. Your investigation should be expanded to all other products manufactured at this site and include the establishment of a comprehensive training program for analysts and QC personnel.
Comment
Certificates of Analysis that include conformance to specifications assume that testing was performed. The use of skip lot testing for selected assays is unacceptable (see ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical ingredients, 11.4 Certificates of Analysis). Section 11.42 states “the Certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained… Falsification of data is viewed very negatively by the FDA.
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2. Failure of your QCUÂ to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.
For example, the inspection revealed that your QCU released API lots to the U.S. without assuring that all required tests are performed. It is a basic responsibility of your QCU to ensure that all API lots produced meet specifications for quality and purity prior to being released. Your QCU also failed to detect that your COAs stated that OVI results conformed to specifications, although the test was not performed.
In addition to your failure to test (b)(4), USP, your QCU approved the release of (b)(4), USP batch # (b)(4) with no testing for OVI. This test is required under DMF (b)(4), submitted by your firm in 2005.
In your response, you stated that your former Head of Quality Control thought it was sufficient to test the organic volatile impurity in three (3) (b)(4) batches and then discontinue testing of future batches. We acknowledge that your firm has begun testing for organic volatile impurities.
Comment
Testing appearing on COAs must, in fact, be performed, and, discontinuing such testing (OVI) is unacceptable (see above, ICH Q7).
Within fifteen (15) days of receipt of this letter please send us a list of all APIs (include lot numbers and dates) that were not tested. Also provide a copy of a complete investigation and retrospective review of all test results generated by your laboratory, and corrective actions to prevent recurrence.
Your response also indicates that you revised the procedure for releasing batches and trained the Quality Control and Quality Assurance personnel. Your response is inadequate in that it does not address the failure of your QCU to detect inaccurate reporting of laboratory results. It also lacks a description of any training program provided to prevent recurrence of the problem.
Please provide a comprehensive corrective action plan that describes your commitment, procedures, actions, and controls to ensure data integrity. This plan should include training to all managers, supervisors, and quality unit personnel in detecting data manipulation and questionable practices.
3. Failure to perform at least one identity test of each batch of incoming material.
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For example, the starting material (b)(4) lot (b)(4), used for the production of (b)(4) USP, API lots (b)(4), was not tested for identity.
Please include a copy of your incoming raw material testing procedure and explain how your firm will assure all raw materials are tested prior to release for production in the future.
Comment
Starting materials used for the production of APIs require at least one test to assure the identity. Identity testing begins with CDER products as early as Phase 1 (see FDA Guidance for Industry, CGMP for Phase 1 Investigational New Drugs. July 2008 and also following paragraph).
“We recommend that you examine the certificate of analysis (COA) and/or other documentation on each lot of material to ensure that it meets established acceptance criteria for specified attributes. For some (e.g., human and animal derived material), documentation should include information on sourcing and/or test results for adventitious agents, as appropriate. If documentation for a material is incomplete for a specified attribute, we recommend that you test for the incomplete specified attribute of the material. For each batch of the API (or drug substance), you should perform confirmatory identity testing.”
 Raw materials cannot be released without the assurance of this testing (see 21 CFR §211.84 (6)(d)(1) and following).
“At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.”
You are responsible for the accuracy and integrity of the data generated by your firm. A firm must maintain all raw data generated during each test, including graphs, charts, and spectra from laboratory instrumentation. These records should be properly identified to demonstrate that each released batch was tested and met release specifications. Appropriate record retention policies should also be in place. Our inspection reported that your firm has destroyed some old, but foundational records for your products. We recommend that your firm reconsider your record retention policy for application-related records. Should product quality or safety concerns arise in the future, the original records pertaining to batches listed in an application may be integral in providing reasonable assurances to the Agency regarding a product and integrity of data submitted to support it.
When destruction of documents is appropriate, you should follow a document destruction procedure that ensures documents are destroyed in a controlled manner. This would include, at a minimum, identification of the appropriate documents and retention timelines, documentation of what was destroyed, and the names and signatures of those who witnessed the destruction.
We recommend that you conduct a complete and extensive evaluation of your overall quality and manufacturing controls to ensure that all APIs manufactured at your facility meet the quality and purity characteristics they purport to possess. We highly recommend that you hire a third party auditor, with experience in detecting data integrity problems, who may assist you in evaluating your overall compliance with CGMP.
