Company: McNeil Consumer and Specialty Pharmaceuticals
Subject: CGMP Regulations for Finished Pharmaceuticals/Adulterated
Issuer: San Juan District Office
Issued: Jan. 15, 2010 Closed:
Not Issued
Source ucm197811 Archive Code:

McNeil Consumer and Specialty Pharmaceuticals 1/15/10

Department of Health and Human Services

Public Health Service
Food and Drug Administration

San Juan District
466 Fernandez Juncos Avenue
San Juan PR 00901-3223

Telephone: (787) 474-9500
FAX: (787) 729-6658

January 15, 2010



Mr. Peter Luther, President, NA OTC
McNeil Consumer Healthcare
7050 Camp Hill Road Mb # 204
Fort Washington, PA 19034

Dear Mr. Luther:

This is regarding an inspection of your pharmaceutical manufacturing facility, McNeil Healthcare LLC, located at Road 183, Km. 19.8, Sector Montones, Las Piedras, Puerto Rico 00771, conducted by investigator J. Lopez and chemist R. Gonzalez and concluded on January 8, 2010. The inspection identified significant violations of the Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (C.F.R.), 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 regulations. In addition, our inspection revealed that you failed to submit NDA Field Alert Reports (FARs) to FDA in compliance with 21 C.F.R. § 314.81 (b)(1)(ii), as required by section 505(k) of the Act [21 U.S.C. § 355(k)].

Specific violations observed during the inspection include, but are not limited, to:

1. Failure to thoroughly investigate any unexplained discrepancy 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. In addition, you failed to extend the investigation to other batches of the same product and other products that might have been associated with the discrepancy as required by 21 C.F.R. § 211.192.

Your company has determined that the "uncharacteristic odor" complaints, some of which were associated with adverse event reports (gastrointestinal distress), for several of your OTC drug products are due to 2,4,6 Tribromoanisole (TBA) contamination in the product and/or bottles. TBA, which has a musty, mildew-type odor, is a known degradant of 2,4,6, Tribromophenol (TBP). TBP is a pesticide and flame retardant used to treat wooden pallets for transporting packaging materials and finished product. TBA is organoleptically detectable at parts per trillion. You are currently attributing the cause of the uncharacteristic odor to be contamination of the drug product containers from TBP treated wooden pallets. You have concluded that TBP from the wooden pallets degraded into TBA, which contaminated product containers and the finished product in those containers.

The contamination, first noted in 2008, occurred again in 2009, leading to recalls of several lots of Tylenol Arthritis Relief caplets, 100 count bottles, 650 mg. More recalls are being conducted including multiple other OTC drug products.

We are aware of the complaint information available to your company, the sequence of events, and the extent of your firm's follow up measures during this period. We have concluded that your company did not conduct a timely, comprehensive investigation.

Your initial investigation into the root cause of the odor was unjustifiably delayed and terminated prematurely. Numerous complaints were received over a four month period in 2008 before they were considered a trend and before actions were initiated to determine the root cause. When microbiological testing in August 2008 did not support an initial speculation that microbial contamination was the root cause of the odor, the investigation was closed. No other possible root causes were pursued. Your firm lacked adequate justification for this decision.

Complaints of uncharacteristic odor were reported again in April 2009. Approximately 112 similar complaints were received by August 3, 2009. Although your firm had test results indicative of contamination with TBA as the source of the off odor on the complaint samples since September 2009, these results were not shared with FDA until after the initiation of the inspection and following several requests for this information made by the district office.

In October 2009, you concluded that the most probable root cause of the odor in the Tylenol Arthritis Relief caplets was the exposure of drug product bottles to wood pallets chemically treated with TBP. You did not expand the scope of the investigation to other lots and products potentially affected by this deviation. This would include, for example, products packaged in bottles from the same supplier that used the same type of wooden pallets, and other products manufactured by your facility for which odor complaints were received.

2. Failure of your Quality Control Unit to ensure a thorough investigation in accordance with 21 C.F.R. § 211.192 with conclusions and follow up accomplished as required by 21 C.F.R. § 211.198. As described above, the timing and depth of your investigative efforts regarding
uncharacteristic odor complaints were insufficient to meet good manufacturing practice. Your firm's management, including the Quality Control Unit, was not proactive in response to consumer complaints. In addition, during the 2008 examination of complaint samples, your
firm's analysts noted that the tablets, once removed from the bottle, did not have an unusual odor but the bottle retained a strong odor. Nonetheless, you did not pursue chemical testing at that time.

Your firm's quality management should have ensured the start of chemical testing far earlier. Failure to do so prolonged identification and resolution of the problem, resulting in continued consumer exposure. Quality problems must be thoroughly investigated, root cause determined, and appropriate corrective and preventive actions implemented as quickly as possible to limit exposure of the public to substandard drugs.

3. Failure to submit NDA-Field Alert Reports (FARs) within three (3) working days of receipt of information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug products as required by 21 C.F.R. § 314.81 (b)(1)(ii).

Your firm received numerous uncharacteristic odor consumer complaints during the period of April 2008 through September 2008 for your product Tylenol Arthritis Relief caplets. Nevertheless, you failed to submit a FAR to FDA within three working days to inform the
Agency of the nature of the problem and the steps that you were taking to address it. You did not submit the FAR until September 18, 2009, after again noting an adverse, continuing trend of numerous complaints over the course of a several month period.

The Agency is concerned about the response of Johnson & Johnson (J&J) to this matter. It appears that when J&J became aware of FDA's concerns about the thoroughness and timeliness of McNeil's investigation, whether all potentially affected products had been identified, and whether the recall was adequate in scope, J&J did not take appropriate actions to resolve these issues. Corporate management has the responsibility to ensure the quality, safety, and integrity of its products. Neither upper management at J&J nor at McNeil Consumer Healthcare assured timely investigation and resolution of the issues.

Neither this letter nor the observations noted on the FDA-483 is intended to be an all-inclusive list of the deficiencies that may exist at your facility. In addition, the Agency may send further correspondence based upon continued review of the inspectional findings. It is your responsibility to ensure that your operations at this facility and all other facilities under your control are in full compliance with all applicable requirements of federal law and FDA regulations. 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 new drug applications listing your facility as a manufacturer until the above violations are corrected. A reinspection may be necessary.

Within 15 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, as well as copies of related documentation. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction.

Please contact the District Office to schedule a meeting to discuss your proposed corrective actions and time frames, as well as your plan for ensuring timely and meaningful involvement of corporate management (local and global) in resolving significant public health issues in the future. Please contact Margarita Santiago, Compliance Officer, at (787) 474-4789 to schedule a meeting at the FDA, San Juan District Office.

Your reply to the Warning Letter should be sent to the Food & Drug Administration, San Juan District Office, 466 Fernandez Juncos Ave., San Juan, PR 00901-3223, to the attention of Margarita Santiago.



Maridalia Torrres
District Director
San Juan District

Mr. William C. Weldon, CEO, Johnson & Johnson
Ms. Nuria Ramirez Ordonez, General Manager, McNeil Healthcare, LLC, Las Piedras, PR