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Thursday, June 25, 2009

Laboratoire Atlas Inc. 6/25/09












  

hhsbluebirdDepartment of Health and Human Services


Public Health Service

Food and Drug Administration
 Silver Spring, MD 20993

 

 

Warning Letter



Via Fed Ex



WL: 320-09-07

June 25, 2009



Mr. Mario Ostiguy

President

Laboratoire Atlas, Inc.

9600 Boul Des Sciences, Ville d'Anjou, Quebec

Canada, H1J3B6



Dear Mr. Ostiguy:



This is regarding a September 2-5, 2008, FDA inspection of your pharmaceutical manufacturer facility in Ville d'Anjou, Canada by Investigator Carla Lundi and Chemist Katherine Szestypalow. The inspection revealed significant deviations from U.S. current good manufacturing practice (CGMP) regulations [Title 21 Code of Federal Regulations (CFR), Parts 210 and 211] in the manufacture of human drug finished products. These deviations were listed on an Inspectional Observations (FDA 483) form issued to you at the conclusion of the inspection.

These CGMP deviations cause your drug products to be adulterated within the meaning of section 501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. 351 (a)(2)(B)]. Section 501(a)(2)(B) of the Act requires that all drugs, as defined in the Act, be manufactured, processed, packed, and held according to CGMP. Failure to comply with CGMP constitutes a failure to comply with the requirements of the Act. Also, your firm has imported into the United States the (b)(4) product, labeled under the trade name" (b)(4) an (b)(4) that is not sterile and is therefore in violation of 21 CFR 200.50.

We have reviewed your October 24, 2008 response to the FDA-483 observations and note 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 include, but are not limited to:



Misbranded Drug

During the inspection, you stated that your firm does not intend to market any products in the United States. However, our records indicate that your firm shipped (b)(4) liters of (b)(4) (lot# (b)(4) Expiration Date 05/2011) into the US in January 2008.



In addition to not complying with 21 CFR 200.50, as set forth below, the 1% (b)(4) product is labeled in a manner that suggests that the (b)(4) properties (b)(4) may have this effect directly on the (b)(4) of the person using the (b)(4). This raises "new drug" issues that would require the product to be approved in a new drug application (NDA) to be legally marketed in the United States. Therefore, if these are not the intended uses, the product should be labeled to clearly indicate that the (b)(4) properties only relate to the (b)(4) effect on the (b)(4) itself and does not have this effect on the (b)(4).

In addition, the product does not contain the required labeling information in a drug facts panel in accordance with 21 CFR 201.66. Therefore, this product is misbranded under section 502(c) of the FD&C Act because the information that is required to appear on the labeling is not prominently placed thereon with such conspicuousness and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use.

Please provide in your written response the appropriate and immediate corrective actions taken to address this issue.

Current Good Manufacturing Practice

1. Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of any sterilization process. [21 CFR 211.113(b)]



The (b)(4) product is an (b)(4) that must be sterile in accordance with 21 CFR 200.50. However, the review disclosed that the product is not subjected to a validated sterilization process; in fact, our investigators observed that your firm manufactures only non-sterile products.

 

It also appears from the labeling that the sterility test described in the United States Pharmacopeia (USP) 30 <(b)(4)> is not performed for this product; the product is only labeled as complying with the USP 30 <(b)(4)> (b)(4) effectiveness test. The failure to perform sterility testing for an (b)(4) product purporting to be sterile (see 21 CFR 200.50) is a violation of21 CFR 211.67(a).

 

This is of significance since the unsterilized product may pose a potential risk of contamination to the public. Please provide in your written response the appropriate and immediate corrective actions taken to address this issue, including the specific type of sterilization process that will be used for this product. Please also note that, in accordance with 21 CFR 310.502, if the product is sterilized by irradiation it requires NDA approval.



According to your manufacturing coding system for finished product lot, lot# (b)(4) represents the (b)(4) batch manufactured in November 2008. Our review found that this same lot of (b)(4) was shipped on December 17, 2007, one year earlier from being produced, and received by your US consignee on January 11, 2008. Please provide clarification regarding this discrepancy, along with the supportive

documentation.

 

2. Unexplained discrepancies and failure of a batch or any of its components to meet specifications are not adequately investigated by the quality control unit. [21 CFR 211.192]

 

a. Your firm failed to identify microbial contaminates isolated from the (b)(4) system, failed to investigate the source and cause of microbial contamination and failed to take appropriate corrective and preventive actions. The (b)(4) is used to manufacture the (b)(4) and for cleaning of manufacturing equipment.



The inspection revealed that between August 2007 and 2008, (b)(4) samples of USP (b)(4), tested by the contract laboratory, were outside the limits for total aerobic microbial counts of (b)(4). These (b)(4) samples of USP (b)(4) were obtained from distribution line (b)(4) used for the final rinse of all manufacturing equipment, including (b)(4) tanks and (b)(4) hoses used for the production of (b)(4)



The inspection also found that seven (7) additional samples of USP (b)(4) collected between February 2008 and August 2008, from distribution lines (b)(4) were above the alert limit of (b)(4), as reported by your contract laboratory. Although results above your alert limits may be an indication of an ongoing uncorrected problem, no investigation was conducted to identify a potential root cause of the problem. Additionally, three (3) out of these seven (7) USP (b)(4) samples were used as a pharmaceutical component for production batches. The microbial count results for these three (b)(4) samples (b)(4) were (b)(4) (tested on 06/26/2008), (b)(4) (tested on 02/21/2008), and (b)(4) (tested on 03/06/2009), respectively.

 

According to your limits for (b)(4) issued on May 01, 2008, in cases where microbial test results are above the alert or action limits, "You must notify the Director of Quality Control (QC) to take corrective action to restore the situation". The SOP also states, "You must also register the warning on the form LAB-2056 and need to monitor the situation by comparing the results." Please provide documentation showing what corrective actions were taken by your Firm to address the exceeded alert or action limits and to ensure that the pharmaceutical products made using (b)(4) were not impacted.

 

In your written response to the FDA-483, you submitted a copy of a retrospective investigation No. DL-08-07 conducted after the conclusion of the recent inspection. This investigation failed to address an evaluation of the distribution line involved in the contamination of all five (5) microbial test failures. Please explain your assessment of all the sampling points and production lines, along with information regarding any requalification of your water system. You should include supportive documentation.



b. Your firm invalidated failing microbial test results of (b)(4) obtained from your contract testing laboratory and retested four of the five samples without conducting an investigation or providing scientific justification.



The following five (5) out-of-limit (OOL) microbial test results ((b)(4)) of USP (b)(4) reported by your contract laboratory were discarded without conducting any investigation or justification. Specifically, (1) sample (b)(4), tested on 08/23/2007 obtained (b)(4) (2) sample (b)(4), tested on 01/17/2008 obtained (b)(4), while a retest of 01/21/2008 obtained (b)(4); (3) sample# (b)(4) tested on 01/31/2008 obtained (b)(4); (4) sample # (b)(4), tested on 05/22/2008 obtained (b)(4); and (5) sample # (b)(4), tested on 07/24/2008 obtained (b)(4).



Your firm's retests were used to inappropriately replace four of five failing samples with the following results: (b)(4). Further, no investigation was conducted for the last (b)(4) sample, (b)(4), when the retest reached the alert limit. Your Firm accepted the passing results obtained by your firm's laboratory without conducting any investigation or providing any scientific justification for invalidating the initial failing results.



Please include in your written response to this letter your sampling and retest SOP for (b)(4) tested for microbial counts, along with your scientific rational to identify (b)(4) results tested by different laboratories as retest samples.



c. In your response you indicated that after the FDA inspection your firm tested twenty three (23) retain samples of (b)(4) finished products manufactured during the same dates in which the OOL test results in (b)(4) were obtained. These samples were found within limits for total microbial counts. Based on your results your firm concluded that the five OOL results obtained in your (b)(4) had no impact on the microbial quality of the finished product.

 

Your response fails to demonstrate that the batches of finished products tested are representative of all the products manufactured during the date and time of the OOL occurrences. In addition, relying on finished product test results to conclude that the product is free of microbial contamination without conducting a thorough investigation to identify the root cause(s) of the problem and implement corrective and preventive actions is unacceptable.



Your firm also lacked a trend analysis of your (b)(4) sample results and failed to monitor the (b)(4) level prior to or after the (b)(4). These issues were discussed during the inspection but not addressed in your response to the 483 observation.



Please include in your response to this letter the corrective actions implemented to address these deficiencies and provide a copy of your standard operation procedure (SOP) for cleaning, sanitizing and monitoring of your (b)(4) system. The corrective actions should include your (b)(4) sampling methods, frequency and sites of sampling, the frequency and methods of sanitization, your program for monitoring the chemical and microbial quality of the (b)(4), trending analysis of your (b)(4) samples, and periodic review of the (b)(4) system's performance and requalification.



The (b)(4) produced by your firm must comply with the USP standards and related regulatory requirements whether the (b)(4) is used as a raw material during the manufacturing of your pharmaceutical products or to rinse the equipment, or both. Furthermore, all OOL results obtained from the in house laboratory or a contract laboratory must be fully investigated and documented, and appropriate corrective and preventive action should be taken to maintain adequate control of the system.



3. Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that components conform to appropriate standards of identity, strength, quality and purity. [21 CFR 211.160(b)]



There is no procedure that delineates the timeliness of microbial enumeration testing of (b)(4) samples after collection. (b)(4) sample # (b)(4) was tested on 01/17/2008 by the contract laboratory with an initial microbial OOL result of (b)(4) This same sample was retested by the same contract laboratory on 01/21/2008 with a result of (b)(4). No investigation was conducted either by your firm or the contract laboratory to determine why the microbial test results were significantly different. Additionally, there is no data available to assure that the recovered microbial levels obtained after the delayed retesting would have been the same had the testing been performed shortly after sample collection. The number of recoverable bacteria in the sample can decrease or increase over time after sample collection due to various factors (i.e., either poor nutrient for certain microorganism to grow or unclean sample container). It is generally appropriate for microbial testing of (b)(4) samples by contract laboratories to be completed within 48 hours after sample collection, provided the samples are held at (b)(4).



Please clarify this issue in your response to this Warning Letter. Provide a copy of your current (b)(4) sampling procedure with further details on how (b)(4) samples are collected, conditions of sample transport and storage, and the time interval between sampling and testing.



In addition, according to your manufacturing coding system for raw materials and bulks, the above (b)(4) sample (b)(4) appears to have been collected in November 2007. Our review found that this same (b)(4) sample was tested on 01/17/2008, two months after sample collection. The similar discrepancy was also found in the (b)(4) samples (b)(4) (collected in Nov 2007 and microbial test results dated 01/31/2008) and (b)(4) (collected in Feb 2008 and microbial test results date 05/22/2008).



Please clarify these discrepancies and provide supportive documentation.



4. Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use. [21 CFR 211.63]



In July 2007 your firm upgraded your (b)(4) system by installing a new (b)(4) system (b)(4) to increase its total output capacity from (b)(4) to (b)(4) However, the (b)(4) system has not been adequately qualified to ensure that it is capable of producing USP (b)(4) since increasing the capacity of the system.



In your response to the FDA 483 you indicated that the Installation Qualification and Operation Qualification have been completed and that the Performance Qualification of your (b)(4) system is expected to be completed by the end of 2009. You stated that a preliminary study and periodic monitoring of the system has to be done. However, no details of protocol, short term or long term action plan with supportive documentation were included in your response. Most of your products are anti-infective, oral and topical products where is used in large quantities either as a component or for rinsing equipment. Please provide documentation that demonstrates that your (b)(4) system is operating and maintained under controlled conditions and capable of producing USP (b)(4) when operated over extended time periods.



In addition, there is no assurance that the (b)(4) used in the preparation of your (b)(4) (for (b)(4)) meets the USP requirements for (b)(4) because your facility has not completed the requalification of the (b)(4) system.



5. The responsibilities and procedures applicable to the quality control unit are not fully followed. [21CFR 211.22(d)]

 

During upgrading your (b)(4) system in July 2007, your distribution loop and (b)(4) pump were accordingly modified for purportedly eliminating dead legs and allowing continuous recirculation for both distribution line (b)(4) and (b)(4). However, your Quality Control Unit failed to follow your change control procedure (SOP-3141, dated on December 15, 1998) to document and also assess the impact of these changes on the new (b)(4) system prior to commissioning of this new equipment.



Your firm's response indicated that your firm modified the distribution loop after updating the system in July 2007 and again after inspection. Please provide details, including a scientific rationale, of the two modifications implemented, especially for the post-inspection modifications.



Meanwhile, your response provided only one training record to showing that one person from the production department has received training. Your response did not demonstrate that other people who have been involved with the change control procedure have been trained, as well. Please clarify and provide any supportive documentation if applicable.



6. Adequate written procedures for the storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected have not been established and followed. [21 CFR 211.142(b)]

 

Your firm's warehouse used for the storage of raw materials and finished products is not controlled and adequately monitored. SOP #3229 requires the warehouse to be monitored for temperature and humidity, on a bi-monthly basis, in six different locations. Our inspection disclosed that only 16 log recordings were made between January, 2006 and July, 2008. Thirteen out of sixteen readings were taken prior to noon and no readings were taken after 4:00pm.



We acknowledge your revision of the SOP and your commitment to improve your temperature monitoring system by conducting temperature mapping studies and installing appropriate recorders (data loggers). However, your response does not provide information on the corrective and preventive actions taken to ensure that the warehouse temperature can be maintained and controlled within the acceptable USP storage requirement for (b)(4), (e.g., preserved in tight containers, protected from light, at controlled room temperature). Please revise your SOP and address this issue with supportive documents.



7. Adequate laboratory facilities for testing and approval or rejection of components are not available to the quality control unit. [21 CFR 211.22(b)]



Your firm did not qualify the contract laboratories used for the testing of (b)(4).



We acknowledge your commitment included in the October 2008 response to create an SOP related to the audit of contract-testing laboratories by the end of February 2009 for the (b)(4). Please include in your response to this letter a copy of the revised or new SOP implemented, along with the related training records.



Meanwhile, it is FDA's expectation that your firm have a quality agreement with the contract laboratories in place. We recommend that this agreement be signed by all parties involved and that it include, as a minimum, specific details delineating the roles and responsibilities of each party. A description of the materials, services, communication, and all testing expected to be performed by each party should also be included. Your firm should ensure that the contract laboratory facility is compelled to produce accurate analytical results for the tested material, conduct adequate laboratory investigations of out-of-specification results, and report to the client such investigations or any changes.



8. Written procedures are not established for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. [21 CFR 211.180(e)(2)]



Your firm lacks established written procedures for the review of drug products on an annual basis, to include provisions of reviewing complaints, recalls, returned or salvaged drug products. We acknowledge that your firm and the applicant will be jointly responsible for the annual report and planned to issue an SOP related to all aspects of annual product review by the end of February 2009. Please provide a copy of that SOP and of your 2008 annual product review quality standard evaluation for each current pharmaceutical product marketed in US.



9. Individuals responsible for supervising the manufacture, processing, packing, holding of a drug product lack the education, training, experience to perform their assigned functions in such a manner as to assure the drug product has the safety, identity, strength, quality and purity that it purports or is represented to possess. [21 CFR 211.25(b)]



During the inspection, your Director of Quality Control, acknowledged not being familiar with the US CGMP regulations. Our review of your firm's training program disclosed that there was no requirement for on-going CGMP training of employees. The firm only had an initial CGMP training and did not provide regular CGMP training to all employees involved in the manufacture of drug products. There is no reference to CGMP training of supervisors or directors.



Please provide in your written response the appropriate and immediate corrective actions taken to address this issue.



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



Until FDA has confirmed correction of the deficiencies and compliance with CGMP, this office may recommend withholding approval of any new applications or supplements listing your Ville d'Anjou facility as a manufacturer of finished drug products. In addition, shipments of articles manufactured by your firm are subject to refusal of admission pursuant to Section 801(a)(3) of the FD&C 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 FD&C Act [21 U.S.C. 351(a)(2)(B)].



Additionally, your firm is neither registered nor has it listed with FDA every product in the commercial distribution in US, as required by 21 CFR 207.40. The FDA investigators had discussed this issue with you during the inspection. Your response did not address this issue. Information on how to register is available on-line at the following internet website: http://www.fda.gov/cder/drls/registrationlisting.htm.This should be completed and evidence of its completion included with your response to this letter.



Please respond to this letter within thirty days of receipt and identify your response with FEI #3007083710. We also recommend that you contact Giuseppe Randazzo at Giuseppe.Randazzo@fda.hhs.gov or at (301) 796-3277 within five days of receipt of this letter to schedule a meeting. For any questions or concerns regarding this letter, contact Yanyan (Jenny) Qin, Compliance Officer, at the address and telephone number shown below.



U.S. Food & Drug Administration

Center for Drug Evaluation and Research

Division of Manufacturing and Product Quality

International Compliance Team

White Oak Building 51

10903 New Hampshire Avenue

Silver Spring, Maryland 20993

Tel: (301) 796-3207

Fax: (301) 847-8742



Sincerely,

/S/

Richard L. Friedman

Director

Division of Manufacturing and Product Quality

Office of Compliance

Center for Drug Evaluation and Research

-

Apotex Inc.

  

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 Federal Express
WL: 320-09-06


June 25, 2009


Mr. Lance Lovelock
Vice President Quality
Apotex Inc. (Corporate Office)
150 Signet Drive
Toronto, Ontario, Canada M9L 1T9


Dear Mr. Lovelock:


This is regarding a December 10 -19, 2008 inspection of your drug product manufacturing facility in Etobicoke, Ontario, Canada by Investigators Debra M. Emerson and Rochelle L. Campbell. 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 non-sterile oral solid dosage drug products. The CGMP deviations were listed on an Inspectional Observations (FDA-483) form issued to Ms. Carol M. Austin, Associate Director of Compliance, at the close of the inspection.


These CGMP deviations cause your drug products 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.


In addition, our inspection revealed that you failed to submit NDA Field Alert reports (FARs) to FDA in compliance with 21 CFR § 314.81 (b)(1)(ii), as required by section 505(k) of the Act (the Act) [21 U.S.C. § 355(k)]. 21 CFR § 314.81 (b)(1)(ii) requires an applicant to submit information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of drug product to meet the specifications established for it in the application.


We have reviewed your January 30, 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 fails to adequately address multiple, serious deficiencies. Specific violations include, but are not limited to:


1. Failure to thoroughly investigate the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. [21 CFR §§ 211.192]


A. During the inspection, our investigators were provided with a list of drug products and in-process materials rejected during December 2006 to December 2008. This list reports that your firm has rejected a total of 554 batches during this period. However, your firm did not provide records of investigations for these batch failures. Additionally, it appears that two of the rejected batches (Acyclovir Batches (b)(4) and (b)(4)), also included in the list of finished product batches manufactured, may have been shipped to the U.S. since December 2006. Please clarify if these batches were partial rejects and if portions of these batches with passing testing results were shipped into the US. Please also provide copies of your investigation reports for the two Acyclovir batches, including any out-of-specification (OOS) investigation addressing the reason for the non-conformances, if the initial test results were invalidated, and your justification if these lots were released.


The list of rejected products includes multiple batches of therapeutically significant drug products such as Cyclosporine, Gabapentin, Topiramate, Divalproex and Carbidopa-Levodopa. This unusual high number of rejected batches demonstrates a lack of adequate process controls and raises significant concerns regarding the capability and reliability of your processes to consistently manufacture drug products meeting predetermined specifications.


B) Our inspection also disclosed that your firm has manufactured (b)(4) scale-up batches of Hydrochlorothiazide 12.5 mg capsules during January-June 2008. (b)(4) out of (b)(4) batches ((b)(4)) failed assay after encapsulation. The initial assay failure occurred in March 2008 and your investigations of these initial OOS test results had not been completed at the time of the inspection, nor had your QC unit identified a root cause for the assay failures. When asked by our investigators why the firm had not yet identified the reasons for the assay failures, Mr. (b)(6), Associate Director of Technical Operations, responded the firm is "working on it." Please provide a copy of the completed OOS investigations for these (b)(4) Hydrochlorothiazide batches and a letter confirming that the (b)(4) batches have been destroyed after completion of your investigation.


C. On January25, 2007, your firm submitted an NDA Field Alert for OOS test results initially obtained on October 15, 2005 for an unknown peak detected during the three month stability interval testing of Ketoconazole, Lot (b)(4). The peak was later determined to be (b)(4). Your investigation determined that the tablets contained (b)(4) of (b)(4) and that this cross-contamination occurred in the (b)(4) of (b)(4) Ketoconazole batches made. Your investigation did not mention the root cause of the cross-contamination, whether other batches or products manufactured in the same area and equipment were affected, or what corrective actions were taken to prevent other incidents of cross-contamination in your plant. Please provide a copy of the completed OOS investigation for this lot, documentation regarding other incidents of cross-contamination, and a summary of what corrective actions you have taken to prevent cross-contamination of drug products in your manufacturing facility.


These examples illustrate problems in the quality control unit's ability to conduct thorough investigations, as required by 21 CFR 211.192, to determine the cause of OOS results. The source of OOS results should be identified either as an aberration of the measurement process or an aberration of the manufacturing process. Even if a batch is rejected based on an OOS result, an investigation is necessary to determine if the result is associated with other batches of the same drug product or other products. Batch rejection does not negate the need to perform the investigation.


Your OOS investigation procedure should emphasize the importance of conducting and documenting thorough investigations of all OOS test results. To be meaningful, each investigation should be thorough, timely, unbiased, well documented, and scientifically sound.


It remains your responsibility to ensure that all OOS investigations are thorough, objective, and completed in a timely manner with corrective and preventive actions. For additional information, please 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.


Please provide a copy of your current procedure for conducting OOS investigations and documentation of corrective actions you have taken to address the 554 rejected batches manufactured since December 2006.


2. Failure to submit NDA/ANDA field alert reports (FARs) in the required timeframe, within 3 working days of becoming aware of information concerning any significant chemical, physical, or other change or deterioration in the distributed drug product. [21 CFR § 314.81(b)(1)]


Your firm's work instruction entitled: NDA Field Alerts, WI-QA-651-013-X, requires that field alert reports (FARs) be submitted to FDA "within 3 working days of confirming there might be a concern with the product". Our inspection uncovered several instances where FARs were not submitted to FDA within the timeframe as required by 314.81(b)(1).


A. Ketoconazole Tablets (ANDA 75-912), Lot (b)(4)


As mentioned in Section 1(C) above, this lot was OOS due to an unknown peak detected during stability testing. Laboratory records show that the unknown peak was first detected on October 15, 2005, during the three month stability-testing interval, and the OOS was confirmed on January 5, 2006. The FAR was not filed with FDA until January 25, 2007, more than fifteen months after the initial OOS report. Furthermore, the FAR states that Apotex became aware of the OOS result on January 22, 2007, but laboratory records document that your firm became aware of the OOS test result fifteen months earlier.


In your response, please explain why this FAR was submitted to FDA fifteen months late and what corrective actions you are taking to assure that field alerts are submitted to FDA within the required timeframe, and do not contain inaccurate statements and information.


B. Glipizide Tablets (ANDA 75-795), Lot (b)(4)


This batch was found OOS on February 23, 2007, when an unknown peak was detected at the eighteen months stability test interval. The initial FAR was filed with FDA on April 5, 2007, and the final FAR confirming the peak was filed on August 8, 2007. The peak was later identified and a (b)(4) to the product's specifications.


C. Omeprazole Tablets (ANDA-76-048), Lots (b)(4) and (b)(4)


These batches were found OOS in May 2008, when an unknown related compound that exceeded the established limit (b)(4) of was detected at the eighteen months stability test interval. The initial field alert was submitted on June 11, 2008, and the final field alert was provided on September 10, 2008. The compound was later identified and the investigation determined that the Omeprazole is sensitive to (b)(4) in (b)(4). Also, the investigation determined that packaging of the product in large package size ((b)(4) count bottles) reduced stability. Our inspection disclosed that your firm is not labeling the product with an eighteen month expiration date.


D. Lovastatin Tablets (ANDA77-748), Lot (b)(4)


Apotex became aware of a complaint on May 21, 2008, concerning two or three tablets of Lovastatin in three bottles that were thicker than the rest of the tablets in the bottles. Your investigation revealed that compliant bottle #1 had four tablets above the target weight limit, and complaint bottle #3 had five tablets above the target weight limit. The initial field alert was not submitted to FDA until November 13, 2008.


The NDA/ANDA Field Alert reporting requirements in 21 CFR 314.81(b)(1)(i) and (ii), effective since May 23, 1985, require holders of NDAs and ANDAs to submit certain information about distributed drug products to the jurisdictional FDA district office within three working days of receipt by the applicant. The intent of the 21 CFR § 314.81(b)(1) regulation is to establish an early warning system so that significant problems are brought to the Agency's attention by applicant holders in order to prevent potential safety hazards from drug products already in distribution. Field alert reports are required to be submitted for confirmed and unconfirmed problems meeting the definition of the regulation within three working days of becoming aware of the problem.


In your response, you report that the delays in submitting FARs within the required three business days was due to significant delays in reporting between the "discovery of the concern by Apotex personnel and it being reported to senior management to facilitate an investigation of the incident." You attribute these delays to the fact that training on this procedure was limited to its users. To correct this communication problem and ensure that all staff is trained and aware of these reporting requirements, you've committed to revise the SOPs covering the commercial stability complaint process, the product compliant process, and the procedure covering the final review of QC laboratory results. We acknowledge your firm's commitment to update these written procedures to ensure that requirements for reporting of initial OOS test results and submission of FARs are known to all staff. Please provide a copy of the revised and approved SOPs for our review.


3. Failure to include a specimen or copy of each approved label and all other labeling in the master production and control record. [21 CFR § 211.186(b)(8)]


Your firm's response states that your firm achieves the intent of the regulations in Section § 211.186 without including copies of the approved labels and labeling in the master record, by utilizing a variety of electronic controls for your systems and processes. Please explain how the various involved departments approve labels and labeling and revisions of labels and labeling and whether the physical copies of approved labels and labeling are cross-referenced in the master production record. Also, explain how your SAP system integrates with your current paper-based document system to ensure compliance with this regulation.


The CGMP deviations identified above, or on the FDA-483 issued to your firm, are not an all-inclusive list of the deficiencies at your facility. FDA inspections are audits, which are not intended to address all deviations from CGMP and all violations that may exist at a firm. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to assure 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 deficiencies and your firm's compliance with CGMPs, this office may recommend withholding approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA denying entry of articles manufactured at Apotex, Inc. Etobicoke, Canada into the U.S. The articles could be 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).


Please respond to this letter within thirty days of receipt and identify your response with FEI #3002808376. We also recommend that you contact Giuseppe Randazzo at Giuseppe.Randazzo@fda.hhs.gov or at (301) 796-3277 within five days of receipt of this letter to schedule a meeting. For any additional questions or concerns regarding this letter, contact Hidee Molina, 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 Team
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3671
Fax: (301) 847-8741

 

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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