Inspections, Compliance, Enforcement, and Criminal Investigations
Warner Chilcott Company, LLC 3/8/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|466 Fernandez Juncos Avenue|
San Juan, PR 00901-3223
Telephone: (787) 474-9500
Fax: (787) 729-6658
MAR 8, 2012
Mr. Roger Boissonault
Chief Executive Officer
Warner Chilcott Company, LLC
100 Enterprise Drive
Rockaway, NJ 07866
Dear Mr. Boissonault:
During our June 22 to July 29, 2011 inspection of your pharmaceutical manufacturing facility, Warner Chilcott Company, LLC, located at Road 195, Km. 1.1, Union Street, Fajardo, Puerto Rico, an investigator from the 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 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.
We have reviewed your firm's response of August 18, 2011, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. §211.192].
For example, since 2006 to present, 7 of 9 lots of Ovcon (Norethindrone (NE) 1 mg and Ethinyl Estradiol (EE)) 50 mcg tablets, laced on stability, failed to meet the assay test specification for Ethinyl Estradiol (EE) at (b)(4) condition at different stability testing intervals. We are concerned that the current stability data does not support your labeled expiration date. Significantly, your firm failed to identify the root cause of the problem and has been unable to implement appropriate corrective and preventive actions. In addition, during this same time period, your firm has continued to manufacture and release Ovcon 50 tablets, although these may be subpotent.
In your response, you indicated that the (b)(4) EE assay stability failures are due exclusively to (b)(4). During the manufacture of optimization lot #02260T, your firm implemented a process change to (b)(4) (a potential source of (b)(4) of EE) by using an (b)(4) procedure. In your response, you also indicated that you will package all future lots of Ovcon 50 using a new configuration under a (b)(4). However, you have not conducted a comprehensive evaluation of these corrective actions and assured that these have adequately addressed the persistent Ovcon 50 tablets quality problems. For example, on November 10, 2011, you submitted a Field Alert Report (FAR) to the agency reporting that Ovcon 50, lot 02260T (the above mentioned optimization batch produced using the (b)(4) procedure), failed to comply with the (b)(4) EE assay specification at the (b)(4). You also have not provided documentation to support how the new packaging configuration and (b)(4) within the package will prevent the degradation of the drug product.
Please provide information on the equipment that you will use for the (b)(4) (e.g., name of the equipment and documentation regarding whether it is capable and has been qualified to provide a (b)(4) to your new packaging configuration), in-process controls that will ensure that the packages contain a (b)(4), details of this process change, and stability data that support the effectiveness of the process change. In addition, you should contact CDER to determine the need to file these modifications relating to manufacturing and packaging process changes to your approved NDA, in accordance with 21 CFR 314.70.
2. Your firm has failed to ensure that your quality control unit fulfills its responsibilities as required by [21 C.F.R. § 211.22(a)].
For example, the stability history of your drug product (Ovcon 50) suggests that since your acquisition of the product in 2005 from (b)(4) your quality control unit has failed to exercise its responsibility to assure that your product meets its predetermined specifications throughout its shelf life.
When you acquired the product, you changed the manufacturing drying parameters from requiring a drying time of (b)(4) (the criteria used at (b)(4) to ending the drying process once the product reaches a temperature of (b)(4). Your firm performed validation studies of this altered process, however, while the validation batches met all the product release specifications, two of the three validation batches failed (b)(4) EE assay specification on stability.
Although all stability samples held at the (b)(4) conditions were analyzed with the same assay test method and passed, you attributed the failing (b)(4) EE assay test results to the lack of robustness of this same analytical method. Your decision to rely on the method appears to have been result-dependent and without scientific justification. Given the background of the change in the drying process and knowing there were other factors that should have been evaluated to reduce variability of the drying process, in 2006 you should have revisited the drying process as a root cause of the stability failures when the first validation batch failed. Instead, you continued to manufacture and release batches to the marketplace for five years (2006-2011) by assigning the root cause of the stability failures to a problem with the analytical method. It was not until June 21, 2011, during the recall of Ovcon 50 lot 01150F, due to a failing EE assay detected at the (b)(4) storage condition, that your firm performed a more rigorous evaluation of the manufacturing process and other possible root causes.
Your quality unit failed to ensure that the drug product quality issues were adequately evaluated. Specifically, your quality unit failed to effectively evaluate available developmental and technical transfer data that may impact the quality attributes of products that you manufacture. It is essential that the quality unit review relevant process design data including process knowledge and understanding obtained during technical transfer activities in order to assure an overall understanding of the process impact on the quality attributes (e.g., assay) of your drug product. In your response, please provide appropriate evidence that you have changed your quality system . and that you have identified steps that you will take to ensure that your quality unit personnel understand their responsibilities, and have the necessary scientific and technical qualifications and the appropriate authorities to effectively execute their quality functions to ensure that your drug products are safe and effective.
In addition, you stated in your written response to the FDA-483 of August 18, 2011, that you did not take market action for Ovcon 50 prior to June 21, 2011 because you considered the (b)(4) stability condition more appropriate for assessing the stability of the product. Both the (b)(4) and (b)(4) conditions are approved requirements in your stability commitment to the agency. Your product must meet its approved stability specifications under both storage conditions, and your assertion to the contrary is incorrect.
Please conduct a comprehensive retrospective review of your stability program for all approved products to ensure that your marketed products are in compliance with approved application commitments. If any of the products released to the marketplace do not meet your firm's stability commitments, please inform this office of additional corrective actions you intend to implement.
The agency acknowledges your decision to recall the affected lots of Ovcon 50 tablets from the market. However, we remain concerned regarding the quality problems that have gone unresolved for the last five years without you fully understanding the reason for the failures and without assurance that the product will meet its quality attributes throughout the product's shelf life. We would recommend that you place all lots of Ovcon 50 on stability until you verify that your corrective actions are effective. In addition, please provide your plan for how you intend to ensure that other products that you manufacture will meet the required specifications through their expiration dates.
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. It is your responsibility to assure compliance with all 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 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 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.
Your reply should be sent to the following address: Food and Drug Administration, Attention: Carlos A. Medina, Compliance Officer, 466 Fernandez Juncos Avenue, San Juan, Puerto Rico 00901-3223.
San Juan District
Enclosure: FDA 483
Mr. Frank Rodriguez
Senior VP and Plant Manager
Warner Chilcott Company LLC
P.O. Box 1005
Fajardo, PR 00738-1005