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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Synkem 5/6/09


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD 20993

Warning Letter

Via FedEx

WL: 320-09-04

May 6, 2009

Mr. Henri Mandrillon
President and CEO
Synkem SAS
47 Rue de Longvic
B.P. 50
21301 Chenove Cedex, France

Dear Mr. Mandrillon:

This is regarding a September 15 - 19, 2008 inspection of your active pharmaceutical ingredient (API) facility in Chenove Cedex, France, by U.S. Food and Drug Administration (FDA) Investigator Kevin Gonzalez and Chemist Javier Vega. The inspection revealed significant deviations from U.S. current good manufacturing practices (cGMP) in the manufacture of non-sterile APIs. These deviations were listed on an Inspectional Observations (FDA Form 483) issued to you at the close of the inspection.

These cGMP deviations cause your APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), (21 USC, Section 351(a)(2)(B)). Section 501(a)(2)(B) requires that all drugs, as defined in the Act, be manufactured, processed, packed, and held according to current good manufacturing practices.

We have reviewed your October 16, 2008 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:

1. Out of Specification (OOS) results are disregarded or negated without a documented investigation that clearly demonstrates the cause as laboratory error. In addition, initial OOS test results are not adequately investigated to determine the root cause and source of the OOS results. 
For example:

A. Although your firm submitted information to the Agency in 2004 to indicate that your manufacturing process for Cilclopirox was validated, your firm continues to obtain failing residual moisture results during release testing of Ciclopirox batches. Your firm claims that the failures obtained are related to the sampling method used during the [(b)(4)] operation. However your firm did not provide sufficient scientific data/documentation to support your conclusion. Your response also mentions that you have drafted a sampling procedure and that this is still pending approval by the Quality Unit (QU). Refer to FDA 483, Observation 1F. Please provide a copy of the approved sampling procedure for our review.

B. Investigation of Ciclopirox batches [(b)(4)], related to an impurity peak from an unknown source that was detected in the [(b)(4)] for the residual solvent test, failed to determine the source of the OOS results. The batches were released by your QU while the OOS investigations were still on-going. Refer to FDA 483, Observation #1A.

C. Since 2006, approximately ten OOS investigations of Fenofibrate API have been initiated and closed without determining the root cause and source of the initial OOS tests results and without implementing appropriate corrective and preventive actions. Refer to FDA 483, Observation 1B.

D. Initial test results for [(b)(4)] (known as [(b)(4)]), used as the starting material for the manufacture of Ciclopirox API, showed [(b)(4)] results over [(b)(4)] for Lots [(b)(4)]. These lots were re-analyzed without invalidating the original laboratory test results. In addition, Lots [(b)(4)] were subsequently released to production. Refer to FDA 453, Observation 1C.

Your October 16, 2008 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 and that this SOP procedure would be completed by October 31, 2008. Please provide the revised procedure and assure that it provides for a complete analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions.

Your written response should also include the corrective actions under consideration or implemented to address the OOS test result examples (A-G) cited on the FDA 483 under Observation #1. Provide a description of the corrective actions for each example cited along with the expected dates of completion, as well as a more comprehensive review to ensure the revised OOS SOP's overall adequacy.

Similar deficiencies related to OOS investigations and the lack of corrective actions were found during our May 2000 FDA inspection. It remains your responsibility to ensure that all OOS investigations are thorough, objective, and completed in a timely manner with corrective and preventive actions. Your firm should conduct a thorough review of your OOS investigation procedure as well as the investigations for all U.S. approved APIs. Refer to the October 2006 Guidance for Industry - Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, available at http://www.fda.gov/cder/guidance/3634fnl.pdf.

2. Failure of the quality unit(s) to review and approve appropriate quality related documents.

Our inspection team observed the use of copies of the batch production record for Ciclopirox that were unauthorized in that there were no signatures showing who in the Quality Unit reviewed and approved the release of these documents. Specifically, production personnel used unauthorized copies to complete the recording (time and [(b)(4)]) during the [(b)(4)] of Ciclopirox lots [(b)(4)]. Refer to FDA 383, Observation #8a.

In addition, our inspection disclosed that the production assistant made 10 unauthorized, duplicate copies of the batch cleaning record for [(b)(4)] (a [(b)(4)] used in the discharge room of Ciclopirox). These copies were not identified with a batch number and did not identify the person who issued the documents. In addition, there is no reconciliation of the forms to ensure proper control by the quality unit. Refer to FDA 483, Observation #8b.

Batch production records prepared for each intermediate and API should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible, accurate reproduction of the appropriate master production instruction. These records should be numbered with a unique batch or identification number, dated and signed when issued.

Your response does not address the procedures and controls that will be instituted to assure that batch production and control records are properly duplicated, reviewed and authorized by the Quality Unit. Provide a copy of the procedures used to indicate the control of records by the quality unit(s).

3. Failure to adequately investigate, document and explain the process deviation that occurred during the manufacture of API Ciclopirox (Validation Batch [(b)(4)]).

Your investigation [(b)(4)], dated June 12, 2008, related to a [(b)(4)] of material observed in the [(b)(4)] evaluated out of a set of [(b)(4)] and [(b)(4)] during the [(b)(4)] of Ciclopirox, Lot# [(b)(4)], was found to be inadequate. This lot was released to manufacture Ciclopirox API without identifying and determining the origin of the [(b)(4)] material in the API. In addition, there was no explanation provided to justify the failure to evaluate [(b)(4)]. Refer to FDA 483, Observation 1E.

Your investigation did not evaluate other production processes for potential contamination (i.e., [(b)(4)]) and only addressed the [(b)(4)] operation. In addition, your investigation did not expand into other lots manufactured during the same campaign and/or period.

4. Failure to adequately qualify your supplier of the raw material [(b)(4)] (known as [(b)(4)]) and demonstrate that the supplier can consistently provide material that meets established specifications. 
This is demonstrated by the following:

A. Our inspection team found that [(b)(4)] of [(b)(4)] lots of [(b)(4)] had been investigated since 2006 for initial OOS test results for appearance, stability, assay and [(b)(4)]. Refer to FDA 483, Observation #5. For example, on May 29, 2007, one of [(b)(4)] of [(b)(4)] Batch [(b)(4)] initially failed the [(b)(4)] test. Your investigation did not determine whether the OOS test results were due to laboratory error and the remaining [(b)(4)] were released with a new batch number [(b)(4)].

B. Prior to use in API manufacturing on September 7, 2007, your firm retested [(b)(4)] Batch [(b)(4)] and found that the batch failed the HPLC assay test. You concluded that the [(b)(4)] supplier was not responsible for this anomaly. However, you did not provide any justification or documentation to support this conclusion. In addition, your written response reports that [(b)(4)] Batches [(b)(4)] showed degradation during the stability study. Again, your firm concluded that the supplier was not responsible for this anomaly. Your response lacks any explanation or documentation to support your conclusions.

C. Your response to FDA 483, Observation #5 states the following: "In conclusion, [(b)(4)] of [(b)(4)] batches showed non-compliance linked with the quality of [(b)(4)] upon receipt." Your response is inadequate in that it does not include documentation to support your statement.

D. Your firm tested [(b)(4)] Batch [(b)(4)] that originally failed the [(b)(4)] analysis. Your response does not explain the rationale and include documentation to support your conclusion that the supplier was not responsible for this anomaly. Please provide the supporting documentation.

E. [(b)(4)], Batch [(b)(4)] was rejected due to an OOS test result for assay and Batch [(b)(4)] was rejected due to OOS test result for [(b)(4)].

Your response states that both non-conforming test results were due to a problem linked with the quality of [(b)(4)]. Provide a detailed explanation with documentation to support your statement.

5. Your firm did not conduct product quality reviews for Ciclopirox from 2003-2007 and for [(b)(4)] in 2006.

Your response did not explain why these product quality reviews were not conducted nor did your firm provide a copy of the updated written procedure for conducting product quality reviews of your APIs. Refer to FDA 483, Observation #6.

Quality reviews of APIs should be conducted and documented annually with the objective of verifying the consistency of the process. Such reviews should include at least:

• A review of critical in-process control and critical API test results
• A review of all batches that failed to meet established specification(s)
• A review of all critical deviations or non-conformances and related investigations
• A review of any changes carried out through the processes or analytical methods
• A review of results of the stability monitoring program
• A review of all quality-related returns, complaints and recalls
• A review of the adequacy of corrective actions

The results of this review should be evaluated to determine whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented and the necessary corrective actions should be completed in a timely and effective manner.

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 at your facility. FDA inspections are audits, which are not intended to determine all deviations from CGMPs 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 assure that all APIs manufactured by your firm are in compliance with all U.S. standards for current good manufacturing practices.

Failure to correct these deficiencies may result in FDA denying entry of articles manufactured by your firm into the United States. The articles could be subject to refusal of admission pursuant to Section 801(a)(3) of the Act in that the methods and controls used in their manufacture do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B) of the Act.

Please respond to this letter with requested documents translated in English within 30 days of receipt and identify your response with FEI# 3002808295. Please contact Yumi Hiramine, Compliance Officer, at the address and telephone number shown below, if you have any questions or concerns regarding this letter.

U.S. Food & Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Avenue
Silver Spring, Maryland 20993
Tel: (301) 796-4166

To schedule a re-inspection of your facility, after corrections have been completed and your firm is in compliance with cGMP requirements, send your request to: Director, Division of Field Investigations HFC- 130, 5600 Fisher's Lane, Rockville, MD 20857. You can also contact that office by telephone at (301) 827-5655 or by fax at (301) 443-6919.



Richard L. Friedman
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research