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FDA Warning The FDA has warned the Changzhou SPL Company, Ltd of Changzhou China that its manufacturing processes for Heparin have violated the U.S. Current Good Manufacturing Practice (CGMP). Referencing the manufacture of active pharmaceutical ingredients (API), the raw material from which Heparin is made, the FDA stated in its warning letter: “These CGMP deviations cause your API to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 351(a)(2)(B)].” It cited four reasons for this warning:
1. There is no assurance that processing steps used to manufacture heparin sodium, USP are capable of effectively removing impurities. Our inspection disclosed that your firm lacked an adequate evaluation of the effectiveness of critical processing steps designed to remove impurities, and critical process parameters were not well defined or controlled (observation #1 of the FDA- 483). The inspection also found that an impurity profile has not been established for the heparin sodium API (observation #2 of the FDA-483). In your March 17,2008, response to observation #1, you state that the firm has conducted two successful process validation studies, one in 2002 and one in 2004. However, the validation studies failed to determine whether the process was capable of adequately removing identified and unidentified impurities. Your response does not include data to demonstrate that your process will consistently remove impurities, and your firm continues to lack established impurity limits for the API. It is essential that your firm establish that controls are in place for assuring the consistent performance of the processing steps to remove impurities in order to ensure the identity, quality and purity of the drugs your firm produces. In your response, your firm acknowledges certain deficiencies in providing evaluations of critical processing steps. Please provide data from validation studies that assess whether the process is capable of consistently removing impurities, and your evaluation of the reliability of the controls used to establish and monitor performance of the processing steps. In your March 17,2008, response to observation #2, you state that the current testing regimen for heparin sodium is consistent with industry practice reflected in the ICH Q7A Guidance (Laboratory Controls, Testing of Intermediates and APIs) which states that "Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin." Although a full impurity profile may not be necessary as part of the batch-to- batch testing of certain APIs, it is necessary that specifications for impurities be established for the production of all API and that each API batch be tested for conformance to these specifications. The ICH Q7A guidance (Laboratory Controls, General Controls) states that appropriate specifications should be established for APIs, including for control of impurities. Your firm failed to establish appropriate specifications for identified and unidentified impurities for the heparin sodium API. Your firm also failed to perform adequate tests to detect impurities in this API. In your March 17,2008, response to observation #2 your firm also states that the complexity of the investigation into the recent heparin product recalls demonstrates the difficulty of isolating and identifying impurities in heparin due to the nature of _____ the mixture _____. However, the mere fact that it is difficult to isolate and identify impurities is insufficient rationale for not establishing appropriate specifications for, and routinely monitoring, impurities during production. In fact, we note that you committed in your response to include an "impurity profile update" in each DMF annual report. Please note that it is essential for your firm to establish appropriate specifications and adequate testing to ensure the consistent removal of undesirable impurities, including those that are potentially harmful to human health. It is your responsibility to ensure that your API meets the identity, quality and purity characteristics that it is represented to possess.
2. You fail to have adequate systems for evaluating the suppliers of heparin crude materials, and the crude materials themselves, to ensure that these materials are acceptable for use. Our inspection found (Observation #6 of the FDA-483) that you received lots of material from an unacceptable workshop vendor that were used in your API. In your March 17,2008, response to observation #6, your firm acknowledges inadequacies in the firm's supplier qualification efforts. For example, you state that the firm received and used heparin crude materials from a workshop that had been designated by your firm in a "pre-audit" as "unacceptable" and that was ultimately not approved by your firm. Your firm used this crude material in the production of API lots that were shipped to the United States. All raw materials that are received and used in producing heparin sodium API should be qualified using a system to ensure that raw materials are of acceptable identity, quality and purity before use. It is important to establish appropriate specifications for these materials and to assure your suppliers provide materials meeting these specifications. These specifications should be approved by the quality unit. Your firm has failed to establish appropriate specifications for your incoming crude materials. Your vendor qualification program should provide adequate evidence that the manufacturer can consistently provide reliable and safe materials. Suppliers should be monitored and regularly scrutinized to assure ongoing reliability. It is your responsibility to 'ensure that raw materials received are suitable and approved by the quality unit prior to use.' There is nothing in the FDA warning letter that an internal audit should not have demanded far more. Did no one at SPL and Baxter care, or was this strictly: "I hear nothing, I see nothing?"
3. The test methods performed for heparin sodium USP have not been verified Our inspection found (Observation #4 of the FDA-483) that you have not ensured that certain USP compendial test methods were verified under actual conditions of use. Specifically, you have failed to conduct adequate verification of USP compendial test methods as applied to the production of your firm's API. The data you provided in your March 17,2008, response did not include information about the suitability, accuracy, and detection limits of certain test methods for API, such as the protein test method, used by your firm. There was no indication from these data that your firm's test methods could reliably detect and quantify the presence of proteins in the finished API. In addition, your firm had not conducted suitability testing of the method to determine In your March 17, 2008, response to the FDA-483, you state that the firm has conducted suitability tests. In addition, you state that the test method was not verified because it was a basic compendial test. You assert that USP <1226>, Verification of Compendial Procedures, states that verification is not required for basic compendial test procedures that are routinely performed unless there is an indication that the compendial procedure is not appropriate for the article under test. In your response, you also state that the laboratory performed basic suitability testing on the heparin sodium API analytical We disagree with your assertions that verification is not required for those USP test methods used by your firm. In accordance with cGMP, analytical methods should be validated unless the methods used are included in a relevant pharmacopoeia or other recognized standard reference. If the method is a compendial method, verification of the methods should be conducted to determine that the method is suitable for its intended use under actual conditions. We acknowledge that the USP informational chapter <1226> suggests that there is a lesser need for verification for the simplest tests such as loss on drying, residue on ignition, and pH measurements. However, these do not include the test methods at issue, including the protein test method. Further, the ICH Q7A guidance (Good Manufacturing Practices for Active
4. Equipment used to manufacture heparin sodium USP is unsuitable for its Our inspection team observed (Observation #7 of the FDA-483) that equipment tanks There should be written procedures for cleaning of equipment. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. Acceptance criteria should be established and cleaning procedures should be defined and evaluated. In your response to observation #7, you stated that the ___________tanks Please provide data that show how the ______ tanks are qualified and the cleaning procedures are validated. Your corrective action to replace ______tanks with ___ tanks is Once you have installed and qualified the _______ please provide
Next: Contaminated Heparin Can Do More than Kill For information on the recall, click here: To contact us, call 800-992-9447. Gordon Johnson is the Owner of the Johnson Law Office. ©Gordon S. Johnson, Jr. 2008 |
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