Apotex Inc.

Department 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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