Apotex - contamination   www.apotexterror.homestead.com         www.pharmaholocaust.com
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Apotex -FDA
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 
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 
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 
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 § 
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 § 
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
Richard L. Friedman,
Division of Manufacturing and Product
Office of Compliance
Center for Drug Evaluation and Research