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Wednesday, May 13, 2009

911 Water












  

hhsbluebirdDepartment of Health and Human Services


Public Health Service

Food and Drug Administration
  

From:   FDAFLUTASKFORCE-CDRH@fda.hhs.gov

Date:    May 13, 2009

To:       http://www.drinking-water-filter-system.com

Subject: Urgent Message from the Food and Drug Administration Regarding H1N1 Flu Virus-Related Products Marketed by Your Firm

UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

ROCKVILLE, MD 20855

 

TO:                   http://www.drinking-water-filter-system.com and info@inmarketsolutions.com

FROM:              Food and Drug Administration

RE:                   Unapproved/Uncleared/Unauthorized Products Related to the H1N1 Flu Virus

DATE:              May 13, 2009

 

WARNING LETTER

 

This is to advise you that the United States Food and Drug Administration (FDA) reviewed your website at the Internet address http://www.drinking-water-filter-system.com on May 7, 2009.  The FDA has determined that your website offers products for sale that are intended to diagnose, mitigate, prevent, treat or cure the H1N1 Flu Virus in people.  This product has not been approved, cleared, or otherwise authorized by FDA for use in the diagnosis, mitigation, prevention, treatment, or cure of the H1N1 Flu Virus.  This product is the “Pandemic Swine Flu Kit for Child or Small Adult.”  The marketing of these products violates the Federal Food, Drug, and Cosmetic Act (FFDC Act).  21 U.S.C. §§ Â§Â§ 331, 351, 352.  We request that you immediately cease marketing unapproved, uncleared, or unauthorized products for the diagnosis, mitigation, prevention, treatment, or cure of the H1N1 Flu Virus. 

 

Some examples of the claims on your website include: 

 

“Pandemic Swine Flu Kit for Child or Small Adult.”

 

The Secretary of Health and Human Services, under section 319 of the Public Health Service Act,   42 U.S.C. § 247d, has determined that a public health emergency exists nationwide involving the H1N1 Flu Virus that affects or has the significant potential to affect national security.  Following this determination and in response to requests from the U.S. Centers for Disease Control and Prevention, FDA issued letters authorizing the emergency use of certain unapproved and uncleared products or unapproved or uncleared uses of approved or cleared products, provided certain criteria are met, under 21 U.S.C. § 360bbb-3.  The marketing and sale of unapproved or uncleared  H1N1 Flu Virus -related products that are not authorized by and used in accordance with the conditions of an Emergency Use Authorization, is a potentially significant threat to the public health.  Therefore, FDA is taking urgent measures to protect consumers from products that, without approval or authorization by FDA, claim to diagnose, mitigate, prevent, treat or cure H1N1 Flu Virus in people.

 

You should take immediate action to ensure that your firm is not marketing, and does not market in the future, products intended to diagnose, mitigate, prevent, treat or cure the H1N1 Flu Virus  that have not been approved, cleared, or authorized by the FDA.  The above is not meant to be an all-inclusive list of violations.  It is your responsibility to ensure that the products you market are in compliance with the FFDC Act and FDA's implementing regulations. We advise you to review your websites, product labels, and other labeling and promotional materials to ensure that the claims you make for your products do not adulterate or misbrand the products in violation of the FFDC Act.  21 U.S.C. §§ 331, 351, 352.  Within 48 hours, please send an email to FDAFLUTASKFORCE-CDRH@fda.hhs.gov describing the actions that you have taken or plan to take to address your firm's violations.  If your firm fails to take corrective action immediately, FDA may take enforcement action, such as seizure or injunction for violations of the FFDC Act without further notice.  Firms that fail to take corrective action may also be referred to FDA's Office of Criminal Investigations for possible criminal prosecution for violations of the FFDC Act and other federal laws. 

 

FDA is advising consumers not to purchase or use H1N1 Flu Virus-related products offered for sale that have not been approved, cleared, or authorized by FDA.  Your firm will be added to a published list on FDA's website of firms and websites that have received warning letters from FDA concerning marketing unapproved/uncleared, and unauthorized H1N1 Flu Virus-related products in violation of the FFDC Act.  This list can be found at http://accessdata-test.fda.gov/scripts/h1n1flu/.  Once the violative claims and/or products have been removed from your website, and these corrective actions have been confirmed by the FDA, the published list will be updated to indicate that your firm has taken appropriate corrective action.

 

If you are not located in the United States, please note that unapproved, uncleared, or unauthorized products intended to diagnose, mitigate, prevent, treat, or cure the H1N1 Flu Virus  offered for importation into the United States are subject to detention and refusal of admission.  We will advise the appropriate regulatory or law enforcement officials in the country from which you operate that FDA considers your product(s) listed above to be unapproved, uncleared, or unauthorized products that cannot be legally sold to consumers in the United States. 

 

Please direct any inquiries to FDA at FDAFLUTASKFORCE-CDRH@fda.hhs.gov.

-

Thursday, May 7, 2009

Lupin Limited 5/7/09












  

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


Public Health Service

Food and Drug Administration
 

CENTER FOR DRUG EVALUATION AND RESEARCH

Office of Compliance

International Compliance Team

10903 New Hampshire Avenue,

WO Bldg 51

Silver Spring, MD 20993


Warning Letter

Via FedEx

WL: 320-09-05

May 7, 2009

Dr. Desh Bandhu Gupta

Chairman

Lupin Limited

Plot No. C-25, Laxmi Towers

"G" Block, "C" Wing, 4th Floor, Bandra Kurla Complex

Bandra (East) Mumbai, India 400 051

Dear Dr. Gupta,

This is regarding an inspection of your sterile and non-sterile pharmaceutical manufacturing and sterile active pharmaceutical manufacturing facility (Mandideep), in Bhopal, India by Investigator Michael R. Goga and Microbiologist Parul M. Patel during the period of October 31 - November 12, 2008. The inspection revealed significant deviations from U.S. current good manufacturing practice (CGMP) regulations (Title 21, Code of Federal Regulations, Parts 210 and 211) in the manufacture of finished drug products.

These deviations were listed on an Inspectional Observations (Form FDA 483) issued to Vilas S. Satpute, Senior Vice President, API Manufacturing and Site Head at the close of the inspection. These CGMP deviations cause the drug products and APIs 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)]. Section 501(a)(2)(B) of the Act 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 received your December 9, 2008, January 13, 2009, February 12, 2009, and March 10, 2009 written responses to the FDA-483 observations. We acknowledge that some corrections appear to have been completed or will soon be implemented. However, your responses do not adequately address some of the deficiencies. Specific violations include, but are not limited to:

1. Failure to maintain production, control, or distribution records associated with a batch of drug product for at least 1 year after the expiration date of the batch. [21 CFR 211.180(a)]

A. Numerous boxes were observed containing production, control, or distribution records in the destruction area of a separate building (Plant [(b)(4)]). For example, one of these boxes contained a Batch Packing Record (BPR) for Ceftriaxone for Injection USP lOg, Batch Number [(b)(4)], dated August 25, 2008 and August 26, 2008 was awaiting destruction as observed by Investigator Goga. Refer to FDA Form 483, Observation #2.

Your Quality Corporate Management explained during the inspection that Plant [(b)(4)] had no involvement with the Mandideep drug production facility in any way. Yet when our inspection team visited Plant [(b)(4)], they observed 20 boxes containing documents and files from the Mandideep Plant [(b)(4)] facility. Please explain the discrepancy in the information given by your Quality Management to our investigators.

You state in your December response that the documents seen by our investigators during the inspection, and referred in Form FDA 483, Observation #2, were either expired or outside the specified retention time period specified in your document retention policy. In addition, you explained to our inspection team that the 20 boxes of documents stored in Plant [(b)(4)] were being held waiting for destruction. Your December response referencing Batch Packing Records (BPRs) from 2006, does not explain why the partial BPR for Ceftriaxone for Injection USP l0g was awaiting destruction. This record falls within the storage period specified in your document retention policy. Your response should provide an explanation regarding your decision to destroy these records.

2. Failure to follow appropriate written procedures designed to prevent microbiological contamination of drug products to be sterile. [21 CFR 211.113(b)]

A. All personnel who enter the aseptic filling area are not monitored. Refer to FDA Form 483, Observation #7.



Our inspection team reviewed documents of individuals entering and exiting the aseptic fill area. Personnel such as maintenance, cleaning, supervisors, and operators (i.e.: filling machine operators, [(b)(4)] operators) were not required to follow written procedures that they be microbiologically monitored. Your December response (Attachment 15) is incomplete in that it did not specify the roles of personnel who completed training for the "Environmental Monitoring Procedure - Vial Filling facility" your firm provided. Please provide more detailed information showing the roles of employees such as maintenance, cleaning, and supervisors who completed this training.

3. The controls to prevent contamination in defined (critical) areas are deficient regarding operations related to aseptic processing of products. [21 CFR 211.42(c)(10)]

A. Smoke studies of Class [(b)(4)] in critical areas were inadequate in that they were not performed under dynamic conditions and the results were not recorded for subsequent review. Refer to FDA Form 483, Observation #5.

You included a CD ROM of the smoke study summary report with your December response. However, this CD ROM was unable to be opened for review, thus we could not read the attached documents. Re-submit the supporting documentation including the video showing the smoke study your firm conducted on November 19, 2008.

4. Failure to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, or electronic equipment, including computers, used in the manufacture, processing, packing and holding of a drug product. [21 CFR 211.68]



A. The Enterprise Resource Planning System known as the firm's Systems Applications and Products (SAP) computer database allows rejected batches of drug product to be in Unrestricted Status (to be released for distribution). Refer to Form FDA 483, Observation #3.



Please provide additional information to support that your current Enterprise Resource Planning SAP system provides limited access to only "approved QA personnel" versus warehouse or production personnel. Your December response states any correction or change in Usage Decision (UD) will require next-level QA authorization in SAP. Explain how you are able to ensure that only QA authorized personnel are changing the status of the lots in the SAP system, and how it is documented and/or tracked.

In addition, your December response in Attachment #4, "Performance Qualification Report for SAP R/3 Enhancement", shows lots that can be "Partially Approved" without selecting a Usage Decision. Provide an explanation as to what "Partially Approved" is defined as, who has the authority to make this decision, how it is documented, and why this status is "not applicable" in the Usage Decision status.

B. Failure to retain original calibration data for [(b)(4)] used in the re-qualification of the [(b)(4)]. Refer to Form FDA 483, Observation #4b.

During the inspection, you provided our FDA investigators a spreadsheet that you stated contained data for calibration of [(b)(4)], however, you were not able to provide the raw calibration data. In addition, the calibration data for the [(b)(4)] that you provided in your December response in Attachment #9 do not correspond to the [(b)(4)] observed by our FDA investigators. The [(b)(4)] observed during our inspection had a different manufacturer, tag number, and temperature range than the [(b)(4)] for which you provided data in your response. Please explain this discrepancy.

C. Written records of calibration were not adequately verified. Refer to Form FDA 483, Observation #9.

The inspection team was shown internal calibration certificates for [(b)(4)] that were performed at readings of [(b)(4)], yet the raw data does not document these readings. This data was verified and signed by a second individual and calibration certificates were generated. In addition, the calibration of a [(b)(4)] shows incorrect entries on the Instrument Calibration record. Yet this record was also verified and signed by a second individual. Your response do not show that investigations were conducted. Please provide the investigation reports.

Your December response states all data is now concurrently verified by immediate supervisors, however this is not stated in your attached, revised procedure, "[(b)(4)], Calibration of Instruments." In addition, you stated in your response that calibration records will be routinely reviewed by QA. Provide the relevant written procedure(s) to reflect this review is conducted.

5. Failure to follow written procedures describing the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures. [21 CFR 211.80(d)]

A. Approximately [(b)(4)] bulk empty glass vials were not labeled with any identification such as an item code, material code, SAP code, lot number or acceptance status. These vials were located in a separate building - Plant [(b)(4)] Refer to Form 483, Observation #1.

Your December response stated that these vials were segregated due to minor cosmetic defects and were labeled with an item code. Yet the inspection team reported that they did not observe any type of identification on the vials or the containers. Please explain how you determined which vials were destined for the Indian market without an item code. Include an explanation of the [(b)(4)] vials [(b)(4)] Type ([(b)(4)]) that were "approved" that were stored in Plant [(b)(4)]. Please provide supporting documentation showing that the defective vials were dest1byed as stated in your written response. Your December response states that the [(b)(4)] vials had been stored in Plant [(b)(4)] due to storage space constraints in the main warehouse. Your responses do not address whether you will continue to use Plant [(b)(4)] to store drug components, including drug containers and closures.

6. Documentation of each significant step in the manufacture, processing, packing or holding of the batch was not performed by the persons performing each significant step in the operation. [21 CFR 211.188(b)(11)]

A. The batch production records for the system simulation (Batch#: [(b)(4)]), do not document the results by the individual who performed the actual visual inspection of the media fill vials in Phase [(b)(4)]. Refer to FDA Form 483, Observation #6.

Your written responses state Quality Assurance (QA) is now responsible for recording the observations of the media fills. Please provide further details on the microbiological qualifications and GMP training of the QA personnel who will be recording the media fill results.

7. Failure to maintain buildings in a clean and sanitary condition used in the manufacture, processing, packing, or holding of a drug product. [21 CFR 211.56(a)]

A. The inspection team observed a collection of water with black residue in the surrounding area underneath and in the area adjacent to the [(b)(4)]. Refer to FDA Form 483, Observation #12

Your responses did not address the investigation conducted or the identification of the black residue. Provide in your response the investigation report with your findings including the cleaning methods you performed. Please provide the location of this sampling port and the equipment surrounding it. Also, explain if any drug processing, holding, or repackaging is conducted in this area.

In addition, the inspection team observed an accumulation of water on the floor in the [(b)(4)] treatment plant which can become a source of [(b)(4)] contamination. A greenish film was observed in the bottom of the water drain channel in the [(b)(4)] plant. Refer to Form FDA 483, Observation #8.



Your responses did not address if an investigation was conducted or confirmation that the green color on the bottom of the drain was identified as paint or if it was biofilm. Provide the investigation report and supporting documentation.

8. Failure to investigate the failure of a batch or any of its components to meet any of its specifications. A written record of the investigation shall be made and shall include the conclusions and follow-up. [21 CFR 211.192]

A. The QA monthly report dated 01 JAN 08 included one finished product sample that failed, however there is no record that an Out-of Specification investigation was performed. Refer to Form FDA 483 Observation #13.

You explained in your December response that the OOS reported in the January 2008 Monthly Quality Report was a typographical error. Please provide the documentation for the investigation you performed to make this conclusion.

Please provide further explanation regarding your position that QA monthly reports are not subject to GMP requirements, given that the reports include information such as testing summary, Out of Specification results, audits, complaints, and changes implemented. At the end of the inspection. you explained to our inspection team that the QA monthly reports were considered [(b)(4)] reports and not GMP documents. We have reviewed the information collected and agree with our inspection team that the QA monthly reports are subject to GMP requirements. Your December response to Form FDA 483, Observation #13 states the monthly report "is used as a management tool only." In addition, your response states this document is prepared and issued to your Corporate Management to apprise them of potential adverse quality trends.

GENERAL COMMENTS:

Regarding your written responses to FDA Observation #4:

In your December response, Attachment #7 describes the Performance Qualification (PQ) Validation Plan for the [(b)(4)] Mapping Plan of the [(b)(4)]. The validation plan of the [(b)(4)] describes [(b)(4)] studies, however does not include any [(b)(4)] Test (single run for l0ml vial). Since the [(b)(4)] is used for [(b)(4)] provide the justification as to why an [(b)(4)] test was not performed as part of your PQ. In addition, for other size vials shipped to the U.S. market, explain the justification to perform your PQ using a single run for the l0ml vial.

In addition, your firm stated in your responses that you compared the [(b)(4)] logger data obtained using your new data logger with the data from the earlier qualification reports and found the new and old data to be comparable (Attachment #8). Provide an explanation with supporting documentation as to the actual raw data generated from the older data loggers used in the earlier qualification reports and how you compared the older data with the data from the new data logger.

Regarding other documents observed in Plant [(b)(4)]:

The [(b)(4)] logbooks 2006-2007 and Operational Log for Air Handling Unit 2007 are documents that pertain to equipment usage. Your December response states that these documents were not required to be retained by the previous record retention policy. These logbooks maintain information relating to system functioning, prior, during, and after the manufacture of drug products, and need to be retained. Please provide further explanation as to the reason for their planned destruction and which other production-related documents are destroyed under this policy.

There were additional files observed in different locations of Plant [(b)(4)], referred as "corridor boxes", but not mentioned in the FDA Form 483 such as Daily Observation and Complaint file, Raw Data Cleaning Validation, Environmental Monitoring Record for the year 2006, [(b)(4)] Analysis Reports, Manufacturing Differential Pressure Monitoring Record, to name a few. When this observation was discussed at the end of the inspection, your management did not provide our investigators information as to the final disposition of these records, or why they were being held at Plant [(b)(4)] for destruction and not Plant [(b)(4)].

Please explain.

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 finished drug products and APIs to the United States, it is the responsibility of your firm to assure compliance with all U.S. standards for current good manufacturing practices.

Until all corrections have been completed and FDA can confirm your firm's compliance with CGMP, this office will recommend disapproval of any new applications or supplements listing your firm as a manufacturing location of finished dosage forms and APIs. In addition, shipments of articles manufactured by your firm are 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 Practice 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# 3002807511. Please contact Yumi Hiramine, Compliance Officer, at the 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

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.

Sincerely,

/s/

Richard L. Friedman

Director

Division of Manufacturing and Product Quality

Office of Compliance

Center for Drug Evaluation and Research

-

Wednesday, May 6, 2009

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.

Sincerely,

/s/

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

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