| Public Health Service Food and Drug Administration |
Silver Spring MD 20993 |
Department of Health and Human Services
Warning Letter
VIA UPS MAIL
WL: 320-11-011
April 14, 2011
Mr. Xavier Castellsague
Managing Director
Moehs Iberica, S.L.
Poligono Rubi Sur
Cesar Martinell I Brunet, 12A-08191, Rubi (Barcelona)
Dear Mr. Castellsague:
During our December 13-17, 2010 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Moehs Cantabra, S. L. located at Poligono Industrial Requejada, 39313 Polanco Cantabria, Spain, an investigator from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. These deviations cause your API(s) 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)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have reviewed your firm’s response of January 14, 2011 and note that it lacks sufficient corrective actions.
Specific deviations observed during the inspection include, but are not limited, to the following:
1. Failure to investigate and document out-of-specification results obtained for (b)(4), API.
For example, on January 12, 2009, (b)(4) lot #(b)(4) failed the assay test with an average out-of-specification (OOS) of (b)(4)% (specification is (b)(4)%). However, your firm released the batch using a passing retest result without conducting an investigation.
In your response you state that the OOS could not be related to the quality of the product because of the individual values obtained ((b)(4)% and (b)(4)%). Your response is inadequate in that you provided no scientific justification to support your conclusion. All out-of-specification results must be investigated and documented. We are concerned that you released this batch based on a passing retest result without conducting an investigation.
In response to this letter, inform this office of your action plan to correct this GMP deviation.
Please also provide a retrospective review of all API batch analyses that yielded OOS results. Include a complete list of all API batches shipped to the United States since Jan. 1, 2007, with lot numbers, date of shipment, customer name and address, the test value reported to the customer, and all other test results obtained for the lot (including the original OOS result). Also provide your evaluation and conclusions for each of the OOS investigations, and corrective actions to prevent recurrence.
2. Failure to ensure that approved test procedures for (b)(4) and (b)(4) HPLC are followed.
For example, the inspection found no scientific justification for the current sequence of chromatographic injections performed, which is different to the sequence included in the approved analytical method. Your analytical method requires that (b)(4) and then by the injection of the samples to be tested. The inspection found that a different sample and standard sequence was used for the assay analysis of (b)(4) lots (b)(4) through (b)(4). Although your response to the inspectional observations state that analysts have been retrained, we remain concerned about current laboratory practices, in that not all injection results are being reported. For example, the assay test for lots # failed to include all the injection results performed as part of the chromatographic run. Your response provides no explanation regarding why analytical results are selectively reported.
We are concerned with your firm's overall policy for handling OOS results. In response to this letter, please provide a copy of the investigation concerning the 18 lots of (b)(4), for which you did not follow the HPLC procedure. Please include all individual and average assay results obtained during the assay re-test or re-calculation.
3. Failure to have complete and reliable laboratory control records derived from all tests conducted to ensure compliance with established specifications and standards.
For example, the inspection revealed that your firm lacks raw data of the sample and standard weights used for the HPLC assay of (b)(4) and (b)(4). The only record available was an Excel spreadsheet with values entered to calculate the final assay results. In addition, some of the HPLC chromatographs of the lots tested were not included in the batch record.
In your response you acknowledged missing raw data, and stated that all raw data is now required to be maintained and included as part of the batch record. However, you made no commitment to evaluate the extent of the problem and review all previous batches where critical data may be missing.
4. Failure to have adequate product quality reviews.
For example, the 2008 annual product review (APR) for (b)(4) stated that impurities (b)(4) and (b)(4) were less than % for all batches produced. However, the data attached to the APR shows several lots with results higher than (b)(4)%, and some as high as (b)(4)%. No explanation was provided related to this discrepancy.
5. Failure of your quality unit to review and approve all appropriate quality related documents.
For example, the inspection revealed that the production batch records do not include weigh tickets or printouts of the raw materials, in-process materials, or finished APIs. The batch records also lack the dates, amounts, and identity of the person weighing the material. We are concerned that your quality unit is not exercising its responsibility during the review of the production batch records to ensure the required information is available, prior to releasing your API products.
In response to this letter, please detail what global improvements your firm is making to your production and quality systems to address these issues. Include a copy of the master batch records for (b)(4) and (b)(4) products.
The deviations detailed in this letter are not intended to be an all-inclusive statement of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. If you wish to continue to ship 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 deviations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct these deviations may result in FDA refusing admission of articles manufactured at Moehs Cantabra, S.L., Poligono Industrial Requejada, 39313 Polanco Cantabria, Spain into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)] in that the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute (b)(4), USP and (b)(4), and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI #3004096632.
If you have questions or concerns regarding this letter, contact Rafael Arroyo, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-4839
Fax: (301) 847-8741
Sincerely,
/Carmelo Rosa/
Carmelo Rosa on behalf of Richard L. Friedman
Rick L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
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