Heparin Deaths

• 1. That the processing steps were inadequate to assure removal of impurities:
  
• 2. Improper systems for evaluating the suppliers’ crude materials;
  
• 3. The test methods for testing the product were not sufficient and
  
• 4.The equipment being used was not adequate.
  

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.