Apotex - contamination   www.apotexterror.homestead.com         www.pharmaholocaust.com
I live like a walking death in twilight zone / some where in between death and a life being deprived of all Human Rights and Constitutional / Law 
protection by habitual offenders. I was assessed by three (3) independent psychiatrists to eliminate offender's speculations about my insanity 
prompting "delusions" etc. All psychiatrists stated clearly, that I am sane /I do NOT have/had any mental illness. No family history of any.
Apotex got second Warning Letter from FDA
Apotex Inc. 3/29/10
Department of Health and Human Services Public Health Service
Food and Drug Administration
Silver Spring MD 20993
Warning Letter
WL: 320 - 10 - 003
March 29, 2010
Mr. Jack M. Kay
President and COO
Apotex Inc.
150 Signet Drive
Toronto, Ontario, Canada M9L 1T9
Dear Mr. Kay:
During our July 27- August 14, 2009 inspection of your pharmaceutical 
manufacturing facility, Apotex Inc. located at 150 Signet Drive, Toronto, 
Ontario, Canada, investigators from the Food and Drug Administration (FDA) 
identified significant violations of the Current Good Manufacturing Practice 
(CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal 
Regulations, Parts 210 and 211. These violations 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)] in that 
the methods used in, or the facilities or controls used for, their 
manufacture, processing, packing, or holding do not conform to, or are not 
operated or administered in conformity with CGMP. In addition, our 
inspection revealed that you failed to submit NDA Field Alert Reports (FARs) 
to FDA as required by 21 C.F.R. § 314.81(b)(1) and section 505(k) of the Act 
[21 U.S.C. § 355(k)].
The July - August 2009 inspection uncovered several violations that are 
identical to those found during a December 10 - 19, 2008 inspection of your 
Etobiocoke, Canada site that resulted in the issuance of a Warning Letter to 
the Etobiocoke site in June 2009. These identical CGMP violations 
demonstrated a lack of adequate process controls and raised serious 
questions regarding your corporation's quality and production systems. This 
prompted the FDA to place both sites under import alert on August 28, 2009, 
whereby all finished drug products offered for entry into the United States 
and manufactured at the Etobiocoke and Signet Drive, Ontario facilities are 
detained without physical examination. Your firm has voluntarily recalled 
approximately 659 batches of different products manufactured at this site, 
and remains under Import Alert 66-40. However, this Warning Letter is being 
issued because of serious and repeat violations from the 2008 and 2009 
inspections and because your response, dated September 3, 2009, and 
discussed below, is inadequate and lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not 
limited, to the following:
1. Your firm's quality control unit failed to follow the responsibilities 
and procedures applicable to release of the drug product [21 C.F.R. § 
For example, (b)(4), an Active Pharmaceutical Ingredient (API), batch 
#HY2470, was found to be contaminated with (b)(4) materials. You rejected 
part of this lot. However, you used a portion of this contaminated API to 
manufacture Cetirizine HCl Film Coated Tablets, 10 mg batches #HY2910 and 
#HY2912. These batches were released for distribution and shipped to the 
United States.
Additionally, Metformin HCl (b)(4) batch #HT2731 was found contaminated with 
(b)(4) particles identified as (b)(4) material, and charred material. This 
batch was not rejected. Instead, it was used to manufacture Metformin HCL 
(b)(4) tablets batch #HT2657, film coated into batch #HT2526, and packed 
into finished drug product batch #HR7670. Batch #HR7670 was subsequently 
released for distribution and shipped to the United States under batch 
#JC2151 on March 4, 2009.
The inspection also documented your practice of repackaging and assigning 
new batch numbers to products that failed the Acceptable Quality Level (AQL) 
test. Your firm lacks a scientific rationale and documentation to support 
this practice. For example, desiccant batch #HK8805 was used in 
approximately 76 different products, 11 of which failed the AQL desiccant 
leaking test. These 11 lots of contaminated Ranitidine Film Coated tablets 
150 mg were initially rejected. However, 10 of these 11 lots were repackaged 
into 500 count bottles using a new lot of desiccant, and assigned a new 
batch number. These lots were then released for distribution without 
assessing the potential impact the leaking desiccant could have on product 
quality. You stated in your response that examination of retain samples for 
the 11 lots did not confirm the presence of leaky desiccant. However, it is 
possible that the absence of defective desiccant may be related to the 
limited number of retain samples examined. In your response to this letter 
please include a justification for the sample size and the corrective 
actions you have implemented to prevent reoccurrence of these types of 
Your response reports that for the period of July 2007 to August 2009 your 
firm had voluntary recalled all products associated with: a) deviation 
reports, b) investigations of foreign components and material, and c) 
products included in opened Field Alert Reports. This corresponds to the 
immediate corrective action addressing this deficiency. However, your 
response does not address other unacceptable practices such as returning 
defective material back into inventory, or re-releasing failed material that 
was inadequately reprocessed or retested without a scientifically sound 
rationale and an assessment of potential impact to product quality.
Your corrective and preventive actions should include specific instructions 
for reprocessing and conditions under which failed material can be 
reprocessed and returned to inventory.
2. Your firm does not have adequate written procedures for production and 
process controls designed to assure that the drug products you manufacture 
have the identity, strength, quality, and purity they purport or are 
represented to possess [21 C.F.R. § 211.100(a)].
For example, three initial process validation batches (#HP0793, #HP0706, 
#HP0794) for Oxcarbazepine 300 mg tablets failed the dissolution test 
specification (Q=NLT (b)(4)% at 30 minutes) and the batches failed to meet 
the 30 minutes dissolution specification. Dissolution out of trend (OOT) 
results were also obtained for Oxcarbazepine 150 mg and 600 mg tablets. The 
same (b)(4) was used for the process validation of Oxcarbazepine 300 mg, 150 
mg, and 600 mg tablets.
During your second attempt to perform the process validation, three batches 
of Oxcarbazepine tablets 300 mg (lot #HT8606, #HT8607, and #HT8608) were 
made from one (b)(4) that failed to meet the 30 minutes dissolution 
specification. You released Oxcarbazepine 150 mg and 600 mg tablets that 
were manufactured from the same (b)(4) that was used to manufacture the 300 
mg strength. Your investigation Q-note 200071071 concluded that the 
dissolution results were affected by the order in which the excipient 
(b)(4), USP was added during the (b)(4) process. Appropriate process design 
studies were not conducted to scientifically establish the correct order of 
adding excipients, e.g., (b)(4), during the (b)(4) operation to ensure 
proper dissolution of the drug product.
In addition, please explain your rationale for releasing different lots of 
product (Oxcarbazepine 150 mg, 300 mg, and 600 mg) manufactured from the 
same defective (b)(4).
3. Your firm fails to thoroughly investigate unexplained discrepancies or 
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 
C.F.R. § 211.192].
For example, on March 31, 2008, during the preventive maintenance of the 
(b)(4), yellow powder identified as residue of (b)(4) active materials and 
several excipients were found behind the (b)(4) seals. Subsequently, on May 
12, 2008, a yellow contaminant was found during the production of Ranitidine 
HCL (b)(4) batch #HV9588 that led to the rejection of the batch. Your 
investigations of these incidents are inadequate because the investigations 
were not expanded to other lots manufactured in the same equipment prior to 
March 31, 2008.
The inspection revealed several other examples of inadequate investigations 
that did not extend to other batches of the same drug product, or other 
products that may have been associated with the failure or discrepancy. 
Specifically, investigation Q-note 200070632 involved the contamination of 
Metformin HCl API batch #HP8402 with particles identified as (b)(4) 
material, and charred material. You failed to assess all batches of finished 
product manufactured with this contaminated API. Metformin HCl tablets batch 
#HT2569, manufactured using the contaminated API, was released to the United 
States without an evaluation into the potential impact to product quality.
Furthermore, your investigation (Q-note 200068475) into the appearance 
failure of Lithium Carbonate 300 mg capsules (batch #HM6665) for missing 
imprint on the capsules, did not include an evaluation of related batches 
manufactured using the same batch of capsules lacking the imprint. In 
addition, the remaining empty capsules in your inventory were not evaluated 
for lack of imprint. Instead, they were used in the production of seven 
other batches of Lithium Carbonate capsules and distributed to the United 
In addition, your product Metformin HCl (b)(4) lot #HL4695 was produced 
using (b)(4), batch #HL8373. This batch of raw material was found to be 
contaminated with charred (b)(4) and (b)(4).
It was used to produce 20 lots, including Metformin HCl 500 mg tablets and 
Gemfibrozil 600 mg tablets that were released for distribution to the United 
States. Your response lacks appropriate corrective actions to prevent the 
use of contaminated raw materials in product manufacturing. We are concerned 
with your organizational unit's lack of appropriate oversight in assuring 
that procedures are followed during production and release, resulting in the 
use of contaminated raw materials in the manufacturing process.
FDA's inspection of your Etobicoke, Ontario, Canada manufacturing site 
during December 10 - 19, 2008 uncovered significant CGMP violations and the 
failure of your quality unit to carry out its responsibilities. This 
resulted in issuance of a Warning Letter on June 25, 2009. In your response 
to the FDA-483 you reported that your Etobicoke and Signet facilities are 
managed by the same quality unit. The violations found during the July - 
August 2009 inspection at Signet Drive, Ontario are an indication that your 
quality unit continues to fail to perform its responsibilities regarding 
control and review, and to release products that meet specifications. Your 
response to the FDA-483 is inadequate in that it does not address the 
inability of your quality unit to conduct adequate investigations, determine 
the root cause, or establish adequate preventive and corrective actions for 
the problems found. Please provide a corrective action plan that describes 
your procedures, corrective and preventive actions and controls to ensure 
product quality. This plan should also include a comprehensive retrospective 
review of your raw material suppliers, equipment adequacy, cleaning and 
maintenance procedures implemented to ensure that all products produced and 
released by your quality unit meet specifications.
4. Your firm fails to have an adequate equipment cleaning and maintenance 
procedure or program to prevent contamination that would alter the safety, 
identity, strength, quality, or purity of the drug product beyond other 
established requirements [21 C.F.R. § 211.67(a)].
For example, a field alert report (FAR) involving Eplerenone Tables (ANDA 
78-482) reported the presence of powder residues during a preventive 
maintenance check of the (b)(4) (asset #5001-PR31-(b)(4)). Based on your 
investigation, the root cause was determined to be an inadequate cleaning 
procedure because the procedure did not provide for complete disassembly of 
the (b)(4) lines, as well as use of the clean-in-place system. Your 
investigation also concluded that your preventive maintenance program was 
not robust enough to detect the potential contamination. In December 2009, 
two other FARs were reported regarding the same situation. Although the 
first notification about cross-contamination was in September 2009, it was 
not until December 2009 that other equipment and products were implicated 
because of cross-contamination. As part of this investigation, you used 
placebo batches (instead of product) in a study to determine if the cleaning 
procedure was adequate and the product was fit for release. This study is 
inadequate in that it did not reproduce the scenario and conditions that 
specifically lead to the problem nor predict the level of the contamination 
that may exist. Your cleaning procedure should be robust enough to ensure 
that no residue from previous lots remains in the manufacturing equipment.
Furthermore, a FAR investigation initiated on October 2, 2009, for Diltiazem 
capsules manufactured in (b)(4)), indicated that a powder residue was 
present on some of the (b)(4) units used in your facility. The (b)(4) 
piping, connected to the (b)(4) to provide (b)(4) to the units, came in 
contact with the product. Your investigation is inadequate because it does 
not provide assurance that the powder particles in (b)(4) did not 
contaminate the product manufactured in this equipment. Your actions did not 
include a global approach of corrective actions in that all (b)(4) were not 
examined for powder residue.
Additionally, an investigation into a FAR initiated on December 8, 2009, for 
Clonazepan tablets (0.5 mg, 1 mg, and 2 mg) in 100 and 500 bottles, revealed 
that foreign materials were found in the (b)(4) (asset #750) above the 
(b)(4) of the (b)(4) (asset #5001-PR25-KE209). Your investigation indicated 
that the presence of the foreign material was due to incorrect sizing of the 
(b)(4) and seal during equipment modification. Also, you indicated that the 
contaminated products were Clonazepam tablets and (b)(4) capsules. This 
investigation is inadequate because it did not include when the modification 
occurred, or identify all the lots manufactured with the (b)(4) since the 
modification. The investigation report also fails to include whether the 
modification occurred in other (b)(4) used in your facility, or if the other 
(b)(4) were examined for similar issues. The FAR only included Clonazepam 
tablets lots. It did not list the lots related to (b)(4) capsules.
We are concerned about your inadequate preventive maintenance and cleaning 
procedures and your failure to conduct a timely investigation into all 
equipment and products potentially affected by the deviations.
The NDA/ANDA Field Alert reporting requirements in 21 C.F.R. § 
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 appropriate FDA district office within three working days of receipt 
by the applicant. The intent of the 21 C.F.R. § 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 and also 
to prevent potential safety hazards with drug products manufactured in the 
future. Field Alert Reports must be submitted for confirmed and unconfirmed 
problems meeting the definition of the regulation within three working days 
of becoming aware of the problem.
In addition to the aforementioned CGMP violations, your firm is in violation 
of the Field Alert reporting requirements set forth in 21 C.F.R. § 
314.81(b)(1)(i) and (ii). For example, during November and December 2009, 
your firm submitted two FARs due to contamination found in your 
manufacturing equipment. Your quality unit was notified of one of the two 
FARs that pertains to Eplerenone tablets (ANDA 78-482) on September 16, 
2009. However, the FAR was not submitted to FDA until November 20, 2009. The 
second FAR, pertaining to the (b)(4) (asset #5001-PR29-(b)(4)) equipment 
used in manufacturing room (b)(4), was submitted to FDA on December 7, 2009. 
However, your quality unit was aware of this information on November 26, 
We remain concerned with the continuing CGMP violations demonstrated at your 
facilities and failure to report FAR related events within three days of 
becoming aware of a problem. Please include in your written response the 
corrective action you plan to take regarding distributed products 
manufactured at these facilities that may be affected by the violations.
The violations cited in this letter are not intended to be an all-inclusive 
statement of violations that exist at your facility. You are responsible for 
investigating and determining the causes of the violations identified above 
and for preventing their recurrence and the occurrence of other violations. 
If you wish to resume shipping products to the United States, it is the 
responsibility of your firm to ensure 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 violations and your firm's compliance with CGMP, this office will 
recommend withholding approval of any new applications or supplements 
listing your firm as a drug product manufacturer. In addition, failure to 
correct these violations will result in FDA continuing to deny entry of 
articles manufactured at Apotex Inc., Toronto, Canada into the United 
States. Because your firm is currently under Import Alert, the articles are 
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 § 
Within fifteen working days of receipt of this letter, please notify this 
office in writing of the specific steps that you have taken to correct 
violations. Include an explanation of each step being taken to prevent the 
recurrence of violations and copies of supporting documentation. If you 
cannot complete corrective action within fifteen working days, state the 
reason for the delay and the date by which you will have completed the 
correction. Please identify your response with FEI #3002906944.
If you have questions or concerns regarding this letter, contact Maan 
Abduldayem, 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 Branch
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3916
Fax: (301) 847-8741
Teddi Lopez for
/Richard L. Friedman/
Richard L. Friedman
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research