Inspections, Compliance, Enforcement, and Criminal Investigations
Wyeth Pharmaceuticals Company 08-May-06
Department of Health and Human Services
Public Health Service
San Juan District
May 8, 2006
RETURN RECEIPT REQUESTED
Mr. Robert Essner
Chairman, President &
Chief Executive Officer
Wyeth Pharmaceuticals Company
P.O. Box 310, Five Giralda Farms
Madison, NJ 07940-0874
Dear Mr. Essner :
This letter is in reference to the inspection of your manufacturing facility located at State Road #3 km 142.1, Guayama, PR 00784, conducted between November 7, 2005 and December 15, 2005, by investigators from the Food and Drug Administration (FDA). The inspection revealed that your firm's manufacture, processing, packing or holding of the human drug products Triphasil-21 & 28 tablets, Prempo 0.62512.5mg & 0.45/1.5mg tablets, Advil (liquid Gels, Caplets, Gel Caplets), Effexor tablets, Duofeln tablets, Gestodene tablets, Caltrate 600 mg + D tablets and Inderal LA 60 mg tablets violated the Current Good Manufacturing Practice. (CGMP) Regulations as stated within 21 CFR Parts 210 and 211, rendering the drugs as adulterated within the meaning of 21 U.S.C. 351(a)(2)(B) (Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (the Act)). The inspection also found that your firm failed to comply with 21 CFR 314 .81, regarding the New Drug Application (NDA) - Field Alert Reporting (FAR) regulations, thus violating 21. U.S.C. 355(k) (Section 505(k) of the Act).
Examples of these deficiencies are included as follows:
1. Failure to thoroughly investigate the unexplained discrepancies or out of specification results in batches of Triphasil 21 and Triphasil 28 tablets manufactured at your site as required under 21 CFR 211.192. For example, on June 17, 2005, the [redacted] month stability interval assay test for Triphasil- 21 50/30mcg, 75/40)mcg, and 125/30mcg (Lot # A85822, NDA No. 19-192) detected the presence of an unknown peak at high levels. The duplicate samples confirmed the presence of the peak. The same peak was detected in the June 17, 2005 month stability interval impurity test for Triphasil-28 50/30mcg, 75/40mcg, and 125/30mcg (Lot # A36955, NDA No. 19-192), and in the June 20, 2005 [redacted] month stability interval impurity test for Triphasil-28 50/30mcg, 75/40mcg, and 125/30mcg (Lot # A79903, NDA No. 19-192). On June 21, 2005, aliquots of the original sample from Triphasil 21 50/30mcg (Lot # A85822) were tested using a [redacted] solvent. Also on June 21, 2005, two new samples of Triphasil-21 (Lot # A85822) and of Triphasil-28 (Lot # A79903) were prepared and analyzed. The same unknown peaks were detected in each sample for each lot.
On June 23, 2005, your firm spiked a standard solution and a sample aliquot from Lot A79903 with phenol. Your previous investigations into various unknown peaks occurring in your drug products had identified phenol as a packaging extractable originating from the ink used to print the package insert. However, the correlation between the phenol and the unknown substance did not exist. as the phenol peak and the unknown eluted at different times in your assay. Your Laboratory Investigation Report [redacted] which was signed and approved on August 15, 2005, concluded that the unknown peak was an artifact peak. However, on November 15, 2005, during the FDA's inspection of your facility, and 5 months after the initial unknown peak was detected, your firm identified the unknown peak as Caprolactarn, an extractable that potentially originated from the Nylon components used to pack the Triphasil drug product.
Regarding LIR # [redacted] , we have the following concerns:
a) Although the true root cause had not been determined and samples were sent to Wyeth Labs located at Pearl River on June 23, 2005 to identify the unknown, the LIR was closed on August 15, 2005 (approx. 3 months before the unknown was identified).
b) The investigation makes no reference to any action considered against the affected lots in the market or within expiration. Instead, an effort to identify the unknown peak and to conclude the stability investigation was not made until the issue was raised during the current inspection. This example raises serious concerns regarding the timeliness of your investigations.
c) Although your analysis of the previous stability intervals using turbochrorne system detected the same unknown peak, no action has been taken against lots in the market which are represented by the lots currently under stability. Furthermore, the investigation has not been extended to others lots that are not currently under the stability program.
d) Regarding the June 21, 2005 testing of Triphasil 21 50/30mcg (.Lot # A85822), the LIR states that this sample had already expired. Yet it does not explain the reason for using expired samples.
e) Your LIR did not describe any corrective or preventive measures that your firm will take to address the future occurrence of this impurity.
Furthermore, the identity and the root cause of the peak are still unknown. Although during the inspection and in your written response to the FDA-483 dated December 23, 2005, your firm stated that the unknown was determined to be Caprolactam, no evidence was provided confirming the identity or concentration of the Caprolactam . Additionally, your firm contacted the SJN-DO on February 08, 2006 and stated that the unknown peak was identified as Phenol. However, your telephone call to SJN-DO on February 09, 2006 stated that the peak eluting in batches shipped to Canada appears to be Caprolactam. Finally, on February 13, 2006, you submitted an updated response to the SIN-DO stating that the unknown peak in samples of "non-domestic" product appeared to be Caprolactam. However, in samples of "domestic" products, the peak ". . .is believed to come from a very low level of contamination that has appeared in some cases in the Guayama QC laboratory."
We are concerned that while the investigation has been ongoing for months, the affected lots remain in the market. In addition, there is no assurance that other lots are not affected by the same unknown. We acknowledge the statement in your February 23, 2006 that a toxicological assessment has been performed and that the extractable does not pose a safety concern. Please submit any toxicity information or medical assessment that you may have regarding the presence of the aforementioned peak. Please identify any other action that you have taken or intend to take against the lots of Triphasil containing the unknown peaks at unacceptable levels.
It is noteworthy that our investigators have observed seventeen other examples, occurring between December 2003 and August 2005, where adequate investigations into unknown peaks were not performed. These examples involved several different products that your firm manufactures including Ovrette, Zebeta, Alesse, Loette, Gestodene, Duofem, Velnafaxin, Rapamune, and Lo Gentrol. In each of these cases the most probable cause assigned is external contamination, cross-contarnination, contaminated glassware, or human error. Yet, each of these investigations has failed to determine the root cause or source of the contamination, or propose any corrective or preventive measures to address future occurrence of the contamination.
2. Failure to clean and maintain the packaging equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality of the drug products manufactured at your Guayarrla site, as required under 21 CFR 211.67(a). For example, consumer complaints reporting the presence of a screw and two washers found inside a bottle of Inderal LA Capsules were received at your site. Other complaints reporting the presence of a foreign metal object (ejector pins from the filling/packaging line) found inside a bottle of Protonix tablets and a bottle Effexor tablets were also received. The investigations into these incidents concluded that the equipment was not handled correctly or adequately inspected by your packaging personnel. We are concerned that neither your cleaning procedures nor the line clearance inspections were able to detect that the affected equipment was missing some of its parts.
In your December 23, 2005 response, your firm stated that your analysis of the complaint rate revealed a stable or declining trend. Your response also stated that each complaint is taken seriously and that Wyeth is committed to improvement. Yet, the response failed to provide any details on the specific corrective actions that were taken to address future occurrences of these complaints. Please provide specific details such as updated written procedures, information regarding personnel training, and any other improvements which demonstrate that your firm has taken the appropriate corrective action.
3. Failure to adequately inspect packaging and labeling equipment prior to its use to assure that all drug products have been removed from previous operations as required under 21 CFR 211.130(e). There were several incidents where product from previous lots was found in your non-dedicated packaging lines, while filling and packaging operations were being performed. In each of these cases, a complete line clearance had been performed between the processing of the two different products, and records indicated that discrepancies or deviations were not found. For example:
a) On August 20, 2005 during the packaging of Prempo 0.625/2.5 mg, two tablets of Prempo 0.45/1 .5 mg were round in the filler machine. The 0.45/1 .5 mg strength of Prempo was the last lot to he packaged on the line, prior to filling Prempo 0.625/2.5 mg.
No units of drug product were found during the line clearance that was performed between the processing of these two strengths of Prempo.
b) On August 19, 2005, during a line clearance performed after the packaging of Advil Caplets Lot B20409, two Advil Liquid Gels units were found under the conveyor belt leading to the in-line metal detector. A similar line clearance was performed on this packaging line, prior to the packaging of Lot B20409, but no product was found during this clearance. Your investigation into this incident determined that your procedures did not instruct your operators to clean the conveyors leading to the in-line metal detector. Thus, any product lodged in this section of the line, would not have been discovered during the line clearance.
c) On April 2, 2005, during the packaging of Caltrate 600 + D, one Advil tablet was found in the capper machine. Advil tablets were the processed on this filling line prior to processing the Caltrate 600 + D. Your firm had conducted a complete clearance of this line between processing the Advil tablets and the Caltrate 600 + D tablets, but found no product in the line. Your investigation into this incident determined that the Advil tablet must have hidden in a stand hole within the tableting press, and thus was not detected by your operators during the line clearance.
Your December 23, 2005 response to the FDA-483 stated that as part of the corrective actions, several procedures were updated, equipment was dedicated to specific product lines and training for operators was improved. Your response also stated that an Integrated management Report (IMR) was prepared in 2005 which measured several performance metrics for your filling, tableting and packaging operations. This report concluded that more than 99% of the line clearances were performed successfully. Please provide a copy of the IMR . Also, please specify which equipment was dedicated. Additionally, please specify how each affected procedure was updated (include copies), and provide details on the improved training that your personnel have received.
4. Failure to submit NDA Field Alert Reports (FAR) within 3 working days of becoming aware of information concerning any significant chemical, physical, or other change or deterioration in the distributed drug product as required under 21 CFR 314.81. For example, regarding the unknown peaks that were detected for the Triphasil-21 and the Triphasil-28, your findings from the inspection show that the unknown peak was initially identified in June 2005 and your investigation of this peak was approved and closed by your firm in August 2005. However, the FAR was issued on November 16, 2005, during the FDA's inspection of your facility. Neither the records reviewed by the investigators, nor the information submitted with your response to the FDA-483 includes a justification or rationale for your decision to not submit a FAR to the FDA's San Juan District in a timely manner.
We object to the statement in your December 23, 2005 response to the FDA-483 which stated that, "Subsequently, the [unknown] peak was determined not to be phenol and that a Field Alert was promptly issued during the inspection." The evidence from the inspection indicates that more than 5 months have elapsed between the initial detection of the unknown peak and the submission of the FAR to the Agency. The intent of the 21 CFR 314.81 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 314.81(b) (1) within three working days of becoming aware of the problem.
5. Failure of your quality control unit to review production records to assure that errors have not occurred, and to fully investigate errors that have occurred during the manufacturing of your drug products, as stated under 21 CFR 211.22(a). All of the deficiencies stated above are indicative of your quality control unit's failure to assure that each deviation from your drug manufacturing operations, impacting the identity, strength, quality and purity of your drug products, has been adequately investigated. Furthermore, your quality control unit has failed to assure that corrective actions have been determined and implemented to prevent the recurrence of these deviations.
Neither this letter nor the observations noted on the Form FDA 483 are intended to be an all-inclusive list of the deficiencies that may exist at your facility . 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 the Act. You should take prompt action to correct this deviation and prevent their future recurrence. Failure to make prompt corrections could result in regulatory action without further notice. Possible actions include seizure, injunction and/or prosecution. Federal agencies are routinely advised of Warning Letters issued so that they may take this information into account when considering the award of government contracts.
Please notify this office in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective actions can not be completed within 15 working days, state the reason for delay and provide timeframes or a schedule detailing when these corrections will be completed.
Your reply 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 Carrnelo Rosa, Compliance Officer.
Acting District Director
San Juan District