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FDA 2013- APOTEX 2013

Inspections, Compliance, Enforcement, and Criminal Investigations

Apotex Inc. 2/21/13
   
 Department of Health and Human Services
Public Health Service
Food and Drug Administration
  Silver Spring, MD 20993

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Warning Letter

WL: 320-13-09

February 21 , 2013

Jeremy B. Desai, PhD
President and Chief Operating Officer
Apotex, Inc.
150 Signet Drive
Toronto, ON, Canada M9L 1 T9

Dear Dr. Desai:

During our August 13, 2012 through August 24, 2012, inspection at your pharmaceutical manufacturing facility, Apotex, Inc., located at 150 Signet Drive, Toronto, Canada, and our October 18, 2012 through October 26, 2012, inspection of your pharmaceutical manufacturing facility, Apotex, Inc., located at 380 Elgin Mills Road East, Richmond Hill, Ontario, Canada, investigators from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Part 210 and 211. These violations cause your drug product(s) 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.

We have conducted a detailed review of your firm' s responses of September 14, 2012 and November 16, 2012, and note that they lack sufficient corrective actions. We also acknowledge receipt of your firm's additional correspondence dated October 11, 2012 and December 14, 2012.

Our investigators observed specific violations during the inspections, including, but not limited to, the following:

A. Apotex, Inc., 150 Signet Drive, Toronto, Canada

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

For example, you failed to perform adequate unidirectional airflow pattern studies (i.e., smoke studies) for the aseptic filling line used for the production of (b)(4) Injection. The smoke studies did not include examination of airflow during set-up and at points of process intervention. Moreover, your airflow patten studies for the class 100 area of the (b)(4) filling line show clear evidence of turbulent airflow in your filling line located in Room (b)(4) both above the (b)(4) just prior to entry into the filling zone and over the stopper bowl adjacent to the filling zone. Although this lack of unidirectional airflow can compromise sterility, you failed to take appropriate action to ensure that your parenteral drug products were protected from these contamination hazards.
An in situ air pattern analysis should be conducted in all critical areas under dynamic conditions, to demonstrate unidirectional airflow and sweeping action at critical work areas.
These studies should evaluate the impact of aseptic manipulations (e.g., interventions) and equipment design, document the activities performed, and include written conclusions. In your response to this letter, provide a copy of your new smoke study recordings along with supporting documentation.

According to your September 14, 2012 response, you committed to conduct smoke studies by December 31, 2012. In your response to this letter, provide an update of all airflow pattern studies conducted, your evaluation of the results, and your proposed corrective and preventive actions. In addition, provide your risk assessment for all sterile products within expiry that were manufactured under these unacceptable conditions.

In addition, your firm failed to establish maximum holding times for vials used in media fills, prior to incubation. Your media fill protocol for batch (b)(4) does not establish a set timeframe between completion of filling vials and placing filled vials in the incubators. Our investigator found that, during a media fill operation you filled the vials on July 24 and July 25, 2012, and did not incubate them until July 30, July 31, and August 1, 2012. Your manager attributed the delay to lack of space to perform the visual inspection and to personnel resource constraints. Upon completion of filling the media fill vials, the vials should be incubated under conditions (time and temperature) adequate to allow detection of microorganisms that might otherwise be difficult to culture. Data should be maintained to show monitoring of, and conformance to, those conditions.

Your response indicates that you initiated a change control to have a maximum hold time of (b)(4) from end of filling to start of incubation of the media fill vials. In your response, provide your justification for the (b)(4) maximum hold time. In addition, specify the required storage conditions for the media vials during this hold period and their justification. In you response please also provide a summary of your assessment regarding whether the vial hold conditions between filling and incubation for batch (b)(4) affected the conclusions of your media fill studies, including whether you plan to repeat the studies and the rationale supporting this decision.

2. Your firm failed to thoroughly investigate any unexplained discrepancy or 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).

Our investigator found that your firm released partial batches to the U.S. market without specific criteria for the partial release decision and without appropriate investigations. You have been cited for the same practice in previous warning letters. Indeed, your firm released at least 76 sublots from January 2011 to August 2012 without adequate investigations.

For example, on April 13, 2011, while (b)(4) the (b)(4) during the (b)(4) step for (b)(4) tablets, batch (b)(4), your operator noticed five tablets with breached (b)(4) in (b)(4), a critical defect. The documentation available indicates that the (b)(4) used for (b)(4) of the tablets was (b)(4) prior to the start of (b)(4), and your firm re-sampled (b)(4) and found that (b)(4) had one critical defect. Your firm permits zero critical defects at the (b)(4) step. Your firm rejected (b)(4). On May 4, 2011, your firm released the tablets from (b)(4) to market as batch #(b)(4). Your investigation and your response indicate that the breached (b)(4) was attributed to the use of a (b)(4) with rough edges and variation of the (b)(4) technique. However, your firm failed identify the control to be used during the (b)(4) step in the future to ensure that the (b)(4) condition does not affect product quality. Please explain the basis for your conclusion that the only affected part of the batch was the rejected portion.

In addition, on May 25, 2011, during the compression of (b)(4) tablets batch #(b)(4), your Quality Control Unit rejected a portion of the batch due to black specks observed on the tablets. However, your firm failed to identify the contaminant(s) found in this lot, and according to your investigation report, you were not able to determine a definitive root cause. In your September 14, 2012 response you indicated that the specks may have been linked to punches and punch seals, and that you released for distribution the remaining sublot, as #(b)(4).

In the foregoing and many other investigations, you did not identify the true root cause(s) of the various deficiencies. Accordingly, the actions taken often did not prevent recurrence of the problems. Your September 14, 2012 response indicates that you will further define and update sublot disposition procedures. During a TCON held on November 7, 2012 between the FDA and Apotex, you made a commitment to discontinue the practice of partially releasing batches that could be potentially affected by a quality issue, as in the referenced examples. We remain concerned about the lots affected by this practice and released into distribution; your response did not provide information to show that a thorough investigation to determine the cause of each unexplained discrepancy or failure to meet specifications had been conducted. Your response also lacks a description of appropriate corrective and preventive actions implemented, along with any risk assessment conducted prior to the release of each sublot. 

Your firm’s practice of rejecting portions of drug product batches is an indication that your firm does not have well-controlled manufacturing processes. In addition, it raises concerns about the quality of the portions of those batches that you released. In your response to this letter, please describe how you intend to address these concerns. It is important that your firm’s investigation procedures ensure that you perform a full investigation extending to all associated lots, including determining root cause(s), prior to distribution. We will verify the implementation of your revised investigation procedures during a future inspection.

Additionally, we are concerned about your approach to process validation. Your experience with the manufacture of (b)(4) mg and (b)(4) mg tablets suggests that product and process development studies were not comprehensive enough to sufficiently understand the interaction between material properties, equipment, and processing parameters in order to establish the right control strategy. The failure of your first commercial scale validation attempt for these products necessitated significant equipment and in-process material changes. While these changes may have improved the compression and (b)(4) issues, you still observed defects related to tablet capping in the second validation effort. Your investigation concludes - “…reduced tablet hardness during compression contributed to generate a small number of tablets that were prone to capping.� We reviewed the Process Validation Report PVS-12-056-FR and associated investigation but important questions still remain. Regarding (b)(4) mg tablets, please address the following points and questions in your response:

a) The appropriateness of the current lower hardness limit. Also, what is the target hardness value?

b) You included no analysis or characterization of the hardness variability in your process validation report. Provide the summary of the in-process hardness data, an appropriate statistical analysis of the data and characterization of the hardness variability in the individual validation lots and overall.

c) Do factors other than (b)(4) affect tablet hardness, e.g., (b)(4) operation and (b)(4) characteristics? How have you evaluated this?

d) Your analysis of root cause(s) and plans for both corrective and preventive actions.

e) With regard to batch (b)(4), the (b)(4) acceptable quality level (AQL) failure and partial release: If the compression process was stable, softer tablets would be present throughout the tablet core batch and not limited to only one of the (b)(4). We understand you collected an AQL sample from each of the (b)(4)and only one (b)(4) failed. Based on this result you rejected that (b)(4) and released the other (b)(4) of tablets. Because you believe the (b)(4) AQL failure was related to hardness, an attribute created in the previous unit operation, you should have thoroughly evaluated the compression operation, the tablet core batch as a whole, and the final (b)(4) tablet batch as a whole to ensure that the problems present in the failed batch were not also present in the released batches.

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

For example, on August 22, 2012, an FDA investigator observed your microbiologist reading an environmental monitoring (personnel) plate. The microbiologist reported the result for that plate as zero; however, our FDA investigator observed one (1) colony forming unit (CFU) on the plate. Your microbiologist corrected this observation on the form WI-MI-150-108-J Microbiology Laboratory after the FDA investigator pointed it out to him. Your firm did not take further action to investigate and determine the impact of inaccurate reporting of your microbiological plate readings on the release of your batches. 

The failure to document positive results for a microbial plate that was confirmed as containing microbial growth raises concerns about the accurate reporting of results in your records. Accurate and reliable microbial data management is essential to support the reliability of your aseptic manufacturing of finished drug products intended for distribution in the United States.

B. Apotex, Inc., 380 Elgin Mills Road East, Richmond Hill, Ontario, Canada

1. Your firm failed to thoroughly investigate any unexplained discrepancy or 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). 

For example, (b)(4) Injection (b)(4) lot #(b)(4) failed its sterility test on April 19, 2012. Your firm rejected all manufactured batches of (b)(4) Injection (b)(4) up to the resumption of commercial production on June 28, 2012. However, you did not recall the lots of (b)(4), manufactured on the same filling line, and still within expiry. In your response of November 16, 2012, you indicated that one of the probable root causes was the lubricant used on a (b)(4) for the (b)(4) filling line. In addition, you indicated that the last shipment of (b)(4) was January 21, 2011, and that all distributed batches but that one had expired. Your response was inadequate because it did not address all products within expiry as of the date of the sterility failure.

2. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)). 

For example, your firm failed to record the incubation dates of the microbiological plates in the validation study of the (b)(4) of (b)(4) for (b)(4) Solution, (b)(4) Solution, (b)(4) Solution, and (b)(4) Spray. Your procedure for the validation study requires the incubation of the (b)(4) plates to be (b)(4) to (b)(4) and the incubation of the (b)(4) plates to be (b)(4) to (b)(4). You indicate in your response that you have revised procedures, conducted a risk assessment, and will re-execute the validation of the (b)(4) of (b)(4). Your response is inadequate because the risk assessment did not assess the impact of your failure to document the incubation period on the released batches. 

In addition, your firm failed to record and maintain the raw data to support your conclusions regarding the effectiveness of the (b)(4) used in (b)(4) Solution, (b)(4) Solution, (b)(4) Solution, and (b)(4) Spray. Your firm recorded the (b)(4) test results from (b)(4) plates for each time point rather than recording the actual observed colony count for each plate. In your response, you indicated that you will revise procedures, conduct a risk assessment, and re-execute (b)(4) effectiveness testing. However, you failed to include an assessment as to how the lack of raw data supporting (b)(4) effectiveness affects batches that you released to the market.

We note that some of the CGMP violations cited above are repeat violations; that is, we cited Apotex in previous warning letters for violating the same regulations, often in very similar ways. For example, in WL #320-09-06, dated June 25, 2009, we cited violative practices at your Etobicoke, Ontario, Canada facility, including a charge for inadequate investigations under 21 CFR Part 211.192. In WL #320-10-003, dated March 29, 2010, we cited violative practices at your Signet, Toronto, Canada facility, again including a 21 CFR Part 211.192 charge for inadequate investigations. In the March 29, 2010 warning letter, we also identified violations similar to those cited here and indicative of your firm’s failure to have an overall quality management system (QMS) (e.g., a citation for violation to 21 CFR Part 211.22, supported by documented instances of unjustified release by your quality control unit of contaminated batches, noting your practice of repackaging, reassigning batch numbers, and releasing products for distribution notwithstanding their failure of the acceptable quality level (AQL) test).
   
The evidence suggests that Apotex has failed to implement adequate global and sustainable corrective and preventive actions, and that it continues to manufacture and distribute pharmaceutical product without upholding its legal obligation to comply with CGMP. FDA’s inspections continue to find repeated deficiencies in your quality systems. We highly recommend that appropriate resources be used to conduct a thorough retrospective evaluation of past deficiencies and that appropriate permanent changes be implemented to ensure that your corporation manufactures pharmaceutical products using a sustainable quality platform in all your facilities. Fundamental to this responsibility is your assurance of timely investigation and resolution of the issues, prevention of distribution of defective product, and implementation of an effective quality management system across all facets of your pharmaceutical manufacturing operations. 

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facilities. 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, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing the admission of articles manufactured at Apotex, Inc., located at 150 Signet Drive, Toronto, Canada; and Apotex, Inc., located at 380 Elgin Mills Road East, Richmond Hill, Ontario, Canada into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles may 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 CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).  

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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3002906944 for the Signet facility, and FEI # 3001617666 for the Richmond Hill facility.

Please send your reply to: 

  Maan Abduldayem
  Compliance Officer
  U.S. Food and Drug Administration
  Center for Drug Evaluation and Research
  Office of Manufacturing and Product Quality
  Division of International Drug Quality
  White Oak, Building 51
  10903 New Hampshire Ave
  Silver Spring, MD 20993
  Tel: (301) 796-3916
  Fax: (301) 847-8741


Sincerely,
/Michael Smedley/ 
 Michael Smedley 
 Acting Director
 Office of Manufacturing and Product Quality
 Office of Compliance
 Center for Drug Evaluation and Research 


Department of Health and Human Services
Public Health Service
Food and Drug Administration
  Silver Spring, MD 20993 
ADDENDUM to Warning Letter 

Re: WL 320-13-09

Date: March 19, 2013
Subject: Warning Letter 320-13-09 from the Food and Drug Administration

Warning Letter (WL: 320-13-09) was issued on February 21, 2013 with the incorrect date of February 21, 2012. The Warning Letter was amended to reflect the correct issuance date of February 21, 2013.
​====================================================================================================

 Department of Health and Human Services
Public Health Service
Food and Drug Administration
  Silver Spring MD 20993
Warning Letter

VIA FEDERAL EXPRESS MAIL 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:


CGMP VIOLATIONS

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. § 211.22(d)].

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 events.

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 States.

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.

FIELD ALERT REPORTING VIOLATIONS

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, 2009.

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 § 351(a)(2)(B)].

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

Sincerely,
Teddi Lopez for
/Richard L. Friedman/
Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research

​==================================================================================================


FDA 2009 – APOTEX

Inspections, Compliance, Enforcement, and Criminal Investigations
Enforcement Actions
• Warning Letters
• 2013 


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

Pc:
Ron McArthur - Apotex’s Senior Vice President

During news media interview (2002 ) Apotex’s Senior Vice President , Operations Ron McArthur offered a very liberal description / assessment of internal situation / non compliance as a Standard Operational Procedure ( SOP ) WITH IN THIS Organization ( Apotex ) which by its nature invalidated all Good Manufacturing Practices (GMP). All ingredients (actives, controlled substances and every thing else together on the floors in manufacturing (MFG) / Packaging (PKG) areas / all over. Apotex for years sacrificed own employees AND FOR MANY YEARS very negatively impacted unfortunate, afflicted, and very much suffering vulnerable people / health products consumers.
Scores of them were pushed over the edge by contamination, over dose (luck of actives) etc.
Justice was not served for those affected those who perished in agony / their families / General Public (somebody’s loved ones) often spending last pennies on meds which suppose to help.
Construction / expansion created mayhem for 6 + years.
Ron McArthur actually provided some real matrix / matrices.