YAZ pill subject of August 2009 FDA Warning Letter to Bayer AG

Our lawyers are currently speaking with women who suffered serious health problems after use of Yaz oral contraceptive pills.

Some of the health risks to taking Yaz pills include blood clots, deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and heart attack. Below is an FDA warning letter sent to Bayer regarding problems found in an inspection of a facility that makes the product:

This letter is regarding a March 2-10, 2009 inspection of your active pharmaceutical ingredient (API) facility in Bergkamen, Germany, by U.S. Food and Drug Administration (FDA) Investigator Jose Cruz and Chemist Miguel Martinez. The inspection revealed significant deviations from U.S. current good manufacturing practices (CGMP) in the manufacture of non-sterile APls. These deviations were listed on an Inspectional Observations FDA Form (FDA-483) issued to you at the close of the inspection.

These CGMP deviations cause your APls to be adulterated within the meaning of Section 501(a)(2)(B) [21 USC 351(a)(2)(B)] of the Federal Food, Drug, and Cosmetic Act (the Act). Section 501(a)(2)(B) states that drugs are adulterated when they are not manufactured, processed, packed, and held according to current good manufacturing practices. Failure to comply with CGMP constitutes a failure to comply with the requirements of the Act.

We have reviewed your April 7, 2009 written response to the FDA-483 observations. We acknowledge that some corrections appear to have been completed or will soon be implemented. However, your response does not adequately address some of the deficiencies. Specific violations found in the inspection include, but are not limited to:

Laboratory Controls
Laboratory controls are deficient in that your firm has established procedures that allow for the averaging of out-of-specification (OOS) and within-specification analytical test results from separate samples. The use of these approved procedures resulted in API batches being released to the U.S. market based on passing averaged assay results.

The investigators were informed during the inspection that the analyst is the first person to review the individual results. If the individual results do not vary more than (b)(4), the average of the results is permitted according to procedure #QCB.PKA00132, Determination of Values and Rounding of Results. This procedure allows the analyst to make the decision to re-inject the samples or to accept the assay result and continue documenting the values obtained as final results without conducting an investigation.

Quality Management
Your quality management system fails to ensure that APIs manufactured and released by your firm meet established specifications.

Specifically, the API batches shown below were released based on reportable assay results obtained from the average of two independent sample results. One of the sample results was out-of-specification (ODS) while a second result was within specification. The averaged passing reportable assay result was compared against the established specifications, and the batches were released to the marketplace.

In your April 7, 2009 response you reported that you had conducted a retrospective investigation that extended to all "U.S. relevant" (i.e., sent to facilities that further processed them into finished drug products intended for the U.S. market) API batches produced between 2007 and 2009. You identified nine additional incidents where OOS results were averaged with passing results. In all cases, your firm concluded that no analytical errors had been identified and that the values were true DOS results. Your firm concluded that these OOS results were within the accepted variation of the analytical method and that the quality of these batches was not affected. We disagree with your rationale and conclusion. An assay test is used to determine potency, not method variability. The validation of your analytical method should address robustness or variability, while system suitability is designed to address instrument variation performance, which was met in each of these instances. We believe that these results were true ODS values and that these batches should not have been released for distribution.

In your written response, you indicate that your current procedure allows the average of two individual sample preparation results, if the difference of the single values does not exceed (b)(4) absolute. Your revised DRAFT SOP QCB.PKA00132, "Determination of Values and Rounding of Test Values" appears adequate, in that going forward you will treat each individual test result independently and will only average values that are within-specification. Please submit a translated version of the revised SOP once it is approved, along with appropriate training documentation.

We remain concerned with your released and distributed API batches used in the manufacture of finished products intended for the U.S. market, in which the reportable results were based on the average of out-of-specification and within-specification analytical test results. Include in your response to this letter a complete list of all API batches shipped to the U.S. (also include lot numbers, date of shipment, customer name and address), using reportable passing average results consisting of out-of-specification and passing results. Please inform this office of any additional corrective action you plan to take to correct this violation.

We are concerned that GMP Directive #CMSD08-50-01-1, Handling of Out of Specification Results, is a corporate directive that may be in place in other manufacturing and testing facilities. Provide in your response to this letter the corrective and preventive actions implemented throughout your corporation to address this deficiency, and ensure that adulterated APIs have not been shipped into the U.S.

The inspection reported that your analysts had been trained to average passing and OOS results, and to report the average passing results. Please submit the translated training records for all analysts demonstrating that they have been trained in your new revised procedures.

Quality Unit Problems
The Quality Unit failed to maintain responsibility and authority to review and conduct investigations. Your firm failed to conduct adequate investigations that included scientific justification to support conclusions. In addition, the investigations did not include proper corrective actions.

For example:, out-of-specification (OOS) results were disregarded, and no OOS investigations were conducted after obtaining individual OOS assay results during release and stability testing of your APIs.

Your April 7, 2009, written response reports that you are revising your OOS standard operating procedure (SOP) to emphasize the importance of conducting and documenting a thorough investigation of all OOS test results, including determining root cause analysis and evaluation of corrective and preventative actions. Your response indicates that the SOP became effective and training was completed by May 2009. Provide copies of the translated revised procedure and training records.

Written Procedures for Cleaning and Maintenance of Equipment
Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment.

The inspection revealed that production equipment, specifically the surface of the (b)(4) on production vessel (b)(4), used in the manufacturing process of Ethinylestradiol API, was not maintained in a clean condition even though the equipment was labeled cleaned, and had been inspected and verified as cleaned by the Production Department Shift Supervisor. This (b)(4) is in direct contact with the product when inside the vessel. Your response lacks an explanation and documentation to support your conclusion that the operator may not have detected the brown residue, because the equipment was wet when examined.

The CGMP deviations identified above, or on the FDA-483 issued to your firm, are not to be considered an all-inclusive list of the deficiencies that may exist at your facility. FDA inspections are audits, which are not intended to determine all CGMP deviations or violations that exist at a firm. If you wish to continue to ship your APIs to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm's compliance with CGMP, this office may recommend withholding approval of any new applications or supplements listing your firm as an API manufacturer.

In addition, failure to correct these deficiencies may result in FDA denying entry of articles manufactured by your firm into the United States.

Read the FDA Warning Letter.

How Weitz & Luxenberg Can Help You
If you have experienced serious help problems after taking YAZ, you may be entitled to file a Yaz lawsuit against the manufacturer.

A lawyer with experience in birth control litigation can help evaluate your claim.

Many women around the country have suffered from life-threatening Yasmin pulmonary embolism side effects but are unaware they have a right to seek monetary compensation by filing a claim against Bayer.

For a free no-obligation case review of your possible YAZ lawsuit, please complete the form below. A representative of our firm will be in touch shortly.

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see also:

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Warnings YAZ Birth Control FDA Warning Letter | Weitz & Luxenberg Lawyers
Free lawsuit review if injured from the use of Yaz birth control pills