Inspections, Compliance, Enforcement, and Criminal Investigations

Wyeth Lederle S.p.A 3/27/13


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD  20993 


Warning Letter
WL: 320-13-10
CERTIFIED MAIL                                                                        

Mr. Giuseppe Galizia
Wyeth Lederle S.p.A.
Via Franco Gorgone
Zona Industriale
Catania, Italy
Dear Mr. Galizia:
During our July 9, 2012 through July 20, 2012 inspection of your pharmaceutical manufacturing facility, Wyeth Lederle S.p.A. located at Via Franco Gorgone - Zona Industriale, Catania, Italy, investigator(s) 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, Parts 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. 
In addition, our investigator(s) identified significant violations of Section 505(k) of the Act, 21 U.S.C. 355(k), and Title 21, Code of Federal Regulations, Section 314.81, promulgated in accordance with Section 505(k)(1) of the Act, 21 U.S.C. 355(k)(1), which requires an applicant to establish and maintain records, and to report data relating to clinical experience, along with other data or information, for drugs in which an approved application is in effect.  Failure to comply with regulations promulgated under Section 505(k) is a prohibited act under Section 301(e) of the Act. 21 U.S.C. 331(e).  
We have conducted a detailed review of your firm’s response dated August 10, 2012, and note that it lacks sufficient corrective actions. We also acknowledge receipt of your firm’s correspondence dated November 9, 2012.
Our investigator(s) observed specific violations during the inspection, including, but not limited to, the following:
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).
Your firm failed to conduct an adequate investigation that should have resulted in your implementation of corrective actions to prevent recurrence of the problem and evaluate other potentially affected lots.  Specifically, on April 17, 2012, your (b)(4) site reported that out-of-specification (OOS) endotoxin results were at or above the (b)(4) EU/ml limit in Torisel Diluent batch AGMV/1. We note that a portion of batch AGMV/1 was shipped to a contractor, (b)(4), for distribution to the U.S. market, on January 5, 2012.
Your investigation into the (b)(4) Torisel Diluent batch AGMV/1 failures began on April 17, 2012, and you continued to test and re-test samples from this lot through August 14, 2012. In an attempt to find the root cause of the OOS results, your firm used different endotoxin testing platforms, tested at three different laboratories, wiped external vials with (b)(4), and used (b)(4) to try to mitigate endotoxin failed results.  Subsequently, your firm tested nine Catania AGMV/1 retain samples and six (b)(4) AGMV/1 samples on multiple dates with several failures. In addition, your firm sent one Catania AGMV/1 retention sample and one (b)(4) AGMV/1 sample to an external testing laboratory.  The extensive repeat testing of (b)(4) Torisel Diluent batch AGMV/1 samples resulted in inconsistent passing and failing results. At no point did you conduct quantitative endotoxin testing to determine the extent of the endotoxin specification failure.
In your August 10, 2012 response, you outlined your manufacturing controls and stated that only the samples returned from (b)(4) exhibited (b)(4) interference, and that the deviation investigation is still in progress. You further stated that the samples from (b)(4), when tested with (b)(4), did not fail the endotoxin specification, and you concluded that this indicates the failing results were false positives caused by (b)(4) interference.  You have suggested that (b)(4) from secondary packaging components (i.e., cardboard) are the interfering components but have proposed no credible explanation as to how these (b)(4) may have entered the samples.  In particular, you have not explained why the (b)(4) sample vials, which were externally sanitized with (b)(4), resulted in inconsistent passing and failing results.  Your response is inadequate because it does not provide scientific justification that (b)(4) interference was the source of the endotoxin OOS results. Based on the testing data we believe your root cause hypothesis is not probable due to continued inconsistent results, and we do not find that you have established a justifiable root cause. Additionally, your initial response did not address the portion of the batch distributed to the U.S. market.  We acknowledge that your firm decided to recall this portion of the batch after discussions with our office.  We are concerned that you did not originally extend your investigation to include the U.S.-marketed portion of the batch when you initiated your investigation into the reported endotoxin failures.
In your response to this letter, provide additional evidence to support your conclusion that the repeated endotoxin failures were the result of (b)(4) from the secondary packaging. If no further compelling evidence exists, then please provide an updated manufacturing investigation outlining potential sources for endotoxin contamination in the lot, and your proposed preventive actions. In addition, provide assurance that in the future, your firm will thoroughly investigate problems relating to products manufactured for the U.S. market.
2. Your firm failed to submit NDA/ANDA Field Alert Reports (FARs) within three working days of receipt of 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 the drug product to meet the specification established for it in the application (21 CFR 314.81(b)(1)(ii)).
Specifically, on April 17, 2012, your (b)(4) site reported OOS endotoxin results in Torisel Diluent batch AGMV/1 released from your Pfizer Catania site on January 4, 2012.  However, the FDA did not receive the initial Field Alert Report (FAR) concerning the OOS endotoxin results until August 9, 2012.  As mentioned above, your firm shipped a portion of Torisel Diluent batch AGMV/1 on January 5, 2012, to a packaging facility, which then shipped (b)(4) vials of the batch to the United States on April 3, 2012.  In your response to this letter, please explain why your firm failed to file the FAR within the required timeframe and what actions your firm has taken to prevent recurrence. 
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 appropriate FDA district office within three working days of receipt by the applicant. Field Alert Reports help to ensure 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 to prevent potential hazards from drug products manufactured in the future. For problems meeting the definition of the regulation, whether confirmed or unconfirmed, firms must submit FARS within three working days of becoming aware of the problems.­­­­­­­­­­­­­­­­­­­­­­­­­­­­

The violations cited in this letter are not intended to be an all-inclusive list 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, 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 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 admission of articles manufactured at Wyeth Lederle S.p.A. located in Catania, Italy into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). 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 CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B). 
You should take prompt action to correct the violations cited in this letter.  Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure, and injunction.  Other federal agencies may take this warning letter into account when considering the award of contracts.  Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected.  FDA may re-inspect to verify corrective actions have been completed.
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, including further scientific justification for the endotoxin out-of-specification root cause. In addition, 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 Torisel Diluent, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3002806766.
Please send your reply to the following address: 
Diane Raccasi, Microbiologist
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, room 4335
Silver Spring, MD 20993
Tel: (301) 796-3927
Michael Smedley                                                                                                                                                                                                                                                                                                                                Director (Acting)
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research

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