Department of Health and Human Services Public Health Service
Food and Drug Administration
Silver Spring, MD 20993
Via Federal Express
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
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
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
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
GAMING THE SYSTEM IS MANIPULATION OR EXPLOITATION OF THE RULES DESIGN TO GOVERN A GIVEN SYSTEM IN AN ATTEMPT TO GAIN AN ADVANTAGE OVER OTHER USERS.
THE UGLIEST OF ALL SUPPORTED BY MENTIONED IS USE AND ABUSE OF THE LAW AGAINST WHOLE SEGMENT OF SOCIETY / POPULATION IN ORDER TO BE ABLE TO SUBORDINATE THEM TO MAKE PEOPLE BLINDLY SUBJECT THEMSELVES TO SOMETHING WITHOUT ENOUGH OF A "KLINICAL SCRUTINY / CLINICAL TRIALS " TO BE ABLE TO INDEPENDENTLY SAY THAT " PRODUCT " IS ENOUGH GOOD FOR HUMAN COMPETITION, THAT WILL NOT CAUSE SHORT OR / AND LONG TERM PROBLEMS "SIDE EFFECTS OF SYSTEMS " THAT WILL NOT PROMPT UNFORSEEN / IRREVERSIBLE D.N.A. CHANGES etc.
I INSURED CANADIAN, WORKING FOR A LONG TIME FOR PREMIER CANADIAN EMPLOYER, WHEN I NEEDED DESPERATELY IMMEDIATE HELP DUE TO EMPLOYER's YEARS OF CONSCIOUS CRIMINAL NEGLIGENCE , HELP WAS NOT ANYWHERE TO BE FOUND. GOVERNMENT AGENCIES WHICH SUPPOSED TO BE OF HELP / ASSISTANCE, TURNED TO BE THE WORST PREDATORS, ENEMY " ENEMY WITHIN". I HORRIBLY SICK PERSON SUFFERING FROM INFLICTED TERRIBLE SIDE EFFECT (MOSTLY SYNTHETIC CHEMICALS / LETHAL , PRODUCED IN SECRECY BY EMPLOYER, WITHOUT ANY PERMITS, IN FACILITY NOT READY FOR / UNDER BIGEST IN ONTARIO CONSTRUCTION etc. I NEEDED ALL HELLP I CUD GET AND MORE UNTIL TODAY AND PENDING I WAS DEPRIVED ALL HELP / ASSISTANCE.
My ex- employer Torpharm / Apotex, Government Agencies involved with my Claim, Provincial / Federal Governments etc. defrauded me ( extremely impaired on toxic / lethal mostly synthetic products ) employee and processed only half of my entitlements for ALL my payments ( C.P.P., Unemployment etc. ) forcing me into years of extreme poverty. ( 19 + YEARS and pending ).
I HOLD ADDITIONALLY ALL DEALING WITH MY CLAIM / CASE PERSONALLY, CRIMINALLY AND SEVERLY RESPONSIBLE / LIABLE FOR ALL MY SUFFERS, TORTURES, DISABILITIES, IMPRIZONMENT AND ALL OF WHAT I ALLEAG (Bill - 107, Bill - 45, Bill - 168, Bill -133, C-27, etc. ......:) etc.!
ALL PEOPLE ACTING IN MY CASE ON BEHALF OF EX - EMPLOYER AND / OR GOVERNMENT AGENCIES MISREPRESENTED THEMSELVES, ACTED ON BEHALF OF EX - EMPLOYER AND / OR ILLEGALLY ON THEIR OWN ON BEHALF OF ANY OF GOVERNMENT AGENCIES AND DID SO ON THEIR OWN terms AGAINST LAW AND AGAINST THE EMPLOYER's INFORMATION CONTAINED IN SEPARATION LETTER ON FRONT PAGE ADMITTING TO CRIMES AND TO EX - EMPLOYER's GOOD WILL, CONDITIONS OF EMPLOYER's TO BE OBSERVED FULFILMENT OF MENTIONED INTO MY BENEFIT, BENEFIT OF A PERSON ILLEGALLY UNKNOWINGLY PRODUCING END VERY NEGATIVELY IMPACTED BY / AFFECTED BY URGENCY OF THE SITUATION. WITH UNKNOWN SIDE EFFECTS ALREADY HEAVILY EFFECTING IMPAIRED EMPLOYEE NEEDED INSTANT MEDICAL ATTENTION. PEOPLE / EMPLOYEES COMMITTED FRAUD FOR 19+ YEARS AND PENDING IGNORING THE URGENCY OF THE SITUATION / CONDITIONS.
"TorPharm Inc. will provide you with all of your current employment benefits until the end of six weeks from the date of this letter , with your Extended Health and Dental benefit coverage then continuing until May 4 2004 , or until such time as you secure employment with benefit coverage elsewhere etc. TorPharm Inc. will offer you employment services with Right Axmith, help of Mike Sostaric , Manager , Human Resources etc. "
That is an example of how an exceptional long term employee, impaired by side effects of lethal illegal products he was forced to work with , was treated after many years being forced to work on those products in confidentiality etc."
THEN I WAS DEPRIVED OF EVERYTHING UNTIL NOW AND PENDING. I DO NOT DESERVE THAT.
MY TERMINATION LETTER CONTAINS EX - EMPLOYER's COMMITMENT TO LOOK AFTER ME, SEVERELY IMPAIRED LONG TERM EXCEPTIONAL EMPLOYEE DUE TO EMPLOYERS CRIMINAL NEGLIGENCE FOR AS LONG AS IT TAKES, COVERING WHAT NEEDS TO BE COVERED. I DID NOT NEED TO CONTACT CRIMINAL CHARACTERS IN ALL OF THOSE AGENCIES OR BE SUBJECTED TO ANY OF THEIR "PERVERTED" BUREAUCRATIC WAYS FOR 19 + YEARS AND PENDING WHILE MY EMPLOYER WAS PERMANENTLY ABSENT AT THE WORKPLACE, PLAYING "LOBBYIST" IN SOMEONE's OFFICE INSTEAD OF BEING AT OWN PLACE OF WORK etc. I SUPPOSED TO BE TAKEN CARE OF ME BY MY EX- EMPLOYER FOR AS LONG AS IT TAKES WITHOUT ANY PARTICIPATION OF THIRD PARTY's INVOLVEMENT TO GRATIFY THEMSELVES A SPECIALLY FOR SUCH A LONG PERIOD OF TIME DEPRIVING ME OF EVERYTHING FOR PERMANENT OCCURRENCE AND CAUSING SO MUCH DAMAGE TO ME AND TO SO MANY.
MY EX - EMPLOYER DESTROYED MY HEALTH BY CRIMINAL NEGLIGENCE AND WITH HELP / PARTICIPATION OF HIS UNABLERS IN GOVERNMENT AGENCIES WCHICH I LIST ABOWE DID DEPRIVE ME AND MANY OF EVERYTHING FOR 19 + YEARS AND PENDING. I AM AWAITING CORRECTION OF HIS ACTIONS.