Inspections, Compliance, Enforcement, and Criminal Investigations

Noven Pharmaceuticals, Inc. 8/5/16


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

Public Health Service
Food and Drug Administration
Florida District
555 Winderley Place, Suite 200
Maitland, Florida 32751
Telephone: 407-475-4700
FAX: 407-475-4770 


August 05, 2016


Mr. Jeffrey F. Eisenberg
President & CEO
Noven Pharmaceuticals, Inc.
11960 SW 144th St.
Miami, FL 33186-6109
Dear Mr. Eisenberg:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility Noven Pharmaceuticals, located at 11960 SW 144th St., Miami, Fla., from June 22 to July 10, 2015.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
We reviewed your July 31, 2015, response in detail and acknowledge receipt of subsequent responses.
Our investigators observed specific violations including, but not limited to, the following.
1.    Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods (21 CFR 211.165(e)).
During the inspection, we observed that your methods for measuring (b)(4) are not scientifically sound. (b)(4), or movement of adhesive past the edges or through the slit in a release liner, is a quality concern in transdermal drug delivery systems (TDDS) such as Minivelle and Daytrana. Excessive (b)(4) can lead to product detachment, expose the drug to other people, and other safety issues.
We are concerned that your unsound methods could be masking product failures. The complaint rate for Minivelle increased by 50 percent from your 2013 reporting period (October 2012 – September 2013) to your 2014 reporting period. However, you failed to determine why. The following examples illustrate deficiencies with your testing methods.
a.  Your qualitative (b)(4) method (b)(4) for Minivelle relies on an analyst’s subjective visual interpretation. On June 24 during our inspection, your analyst demonstrated this method for us and concluded that there was no (b)(4). However, we observed adhesive residue on the pouch and around the edge of the product which is indicative of (b)(4).
b.  Also during our inspection on June 29, we observed an analyst test a sample from Minivelle lot (b)(4) using the quantitative (b)(4) method (b)(4). To prepare the sample for this test, the analyst handled the sample repeatedly, possibly resulting in unintentional (b)(4) adhesive removal. We advised you at that time that excessive sample manipulation could affect the accuracy of the test.
Your written responses state that you would assess the testing methods and product specifications for Minivelle by September 2015. You indicated that you would implement a new (b)(4) method for (b)(4) by (b)(4).
Your response is inadequate because you continued to use method (b)(4) and (b)(4) for release testing to analyze (b)(4) prior to implementation of a suitable method.
c.  During the inspection, we discovered that you still have not validated test method (b)(4) for (b)(4) of your Daytrana TDDS. The test method is intended to detect adhesive transfer from the TDDS to the removable release liner. When this adhesive transfer occurs, the drug is removed from the TDDS and thus the product is rendered unusable. 
From April 2014 to March 2015, 45 percent (1,734) of your firm’s complaints for Daytrana were for tight release (hard-to-remove liners) and adhesive transfer that impeded users from removing the liner. You did not detect this problem during your quality control testing or when you tested samples from (b)(4) for stability monitoring.
In your response you stated that you misplaced the method validation package and that you will attempt to locate the original at your off-site storage facility. You also stated that you will assess method (b)(4) to determine how it can be improved to reliably detect adhesive transfer. 
Your response is inadequate because you have not demonstrated that you validated method (b)(4) or that it can reliably detect adhesive transfer.
In response to this letter, provide the following:
  • For distributed Minivelle and Daytrana lots that you tested with unsound methods, details of interim action you will take, including enhanced complaint monitoring and trending. Also specify other action you will take, such as notifying customers and recalling products if data indicate defective products are in the marketplace.
  • The timeframe by which you will submit your new (b)(4) method to the Agency for evaluation.
  • Your current version of method (b)(4) for testing Daytrana, the original validation package, and any revalidation that you have performed.
2.    Your firm failed to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).
On June 29, our investigator watched an analyst testing Minivelle lot (b)(4) for peel adhesion. The investigator observed that the analyst failed to follow your procedures. For example:
a.  The analyst aborted testing of two TDDS because the pulley detached from the TDDS during the peel test. The analyst tested two additional TDDS but did not document the aborted tests as required by your SOP (QC-0009). The analyst told our investigator that you record only completed tests.
b.  Our investigator also observed that your analyst did not adequately calibrate the adhesive testing machine used as required by your SOP (QC-0138). Specifically, the analyst failed to use the appropriate range of weights to bracket expected results for the TDDS. Using appropriate calibration weights is important for assuring accuracy over the range of expected test results.
A review of the logbooks for the instrument since November 25, 2014, found that analysts always used weights that did not bracket the expected results. Therefore the adhesive tack testing results may not be accurate due to improper calibration of the instrument.   
In your response, you stated that you purchased a new calibrated digital level and that you will use a larger weight for the upper calibration limit. Your response is inadequate because you did not indicate whether you have retrained and recertified your technicians and analysts. You also did not indicate whether you are using an appropriate weight for the lower calibration limit in order to accurately detect adhesive failure below or at (b)(4).
In response to this letter, provide information about your calibration weight limit for the lower end of your test scale. Also provide details about your global corrective action and preventive action plan including remediation of laboratory procedures, methods, training and staffing improvements, and other appropriate steps.
3.    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).
We also note that previous FDA inspection in May 2010, February 2009, and June 2007, observed inadequate investigations in your firm.
You invalidated out-of-specification (OOS) results without clear evidence of laboratory error. You obtained OOS assay results during the (b)(4) release-rate analysis for Minivelle finished product stability lots 76654, 76510, 76509, 69857, and 69858. 
You attributed the OOS results to (b) (4) response. Your analyst prepared new standards, repeated the analyses, obtained passing results, and then invalidated the OOS results. However, your analyst did not thoroughly investigate whether the original standard was the root cause for the OOS. For example, you did not analyze the original standard against the new standard. It is possible that the OOS results were true failures that you should have considered in your decision to release those drug product lots.
In your response you stated that you retrained and recertified analysts. You also stated you revised SOP QC-0010 to improve your firm’s root cause analyses.
Your response is inadequate. You have not provided information about your evaluation of any other OOS results to determine the root causes. Furthermore, your response does not address whether you reopened the investigation for lots 76654, 76510, 76509, 69857, and 69858.
In response to this letter, provide a summary of the comprehensive retrospective evaluation of all OOS results to ensure they are adequately investigated. This analysis should include evaluation of whether sound scientific rationale was used for subsequent drug product disposition. If you determine that your original conclusion was flawed, provide an action plan for unexpired lots of Minivelle, including steps such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability program, and enhanced complaint monitoring.
4.    Your firm failed to maintain written records so that data therein could be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures (21 CFR 211.180(e)).
You failed to analyze product and process data for commercial batches of Minivelleto identify adverse trends. Our review of the stability summary data for the 15 lots of Minivelle produced in 2014 identified quality attributes that are inconsistent with the specifications in your approved new drug application for Minivelle (NDA 203752). For example:
a.  You manufactured commercial batches using the raw material silicone with significantly (b)(4) values than that used in clinical batches. You updated the (b)(4) specification in June 2014 due to (b)(4) failures of Minivelle lots (b)(4) and (b)(4). However, the (b)(4) and adhesion data to support this change in specification was unreliable, and you continue to have (b)(4) failures.
b.  Probe tack tests found average adhesion of Minivelle commercial batches to be much higher than the values specified in your new drug application. Test results for your commercial batches were between (b)(4) and (b)(4) grams. The specification in your application is no less than (b)(4), based on tack values between (b)(4) and (b)(4) grams for the clinical investigation and registration batches. Your firm failed to identify and investigate this shift in probe tack results.
Your response stated that you will develop and validate a (b)(4) test method, develop specifications based on (b)(4), and will initiate a change control to update your procedure.
Your response is inadequate because you failed to provide sufficient details of your corrective action and preventive action plan. It is imperative that you fully understand your products and processes, in part, to ensure that variation in tack and other adhesion properties is detected and properly controlled to prevent unpredictable drug delivery.
In response to this letter, provide the following:
  • A summary of your retrospective review of all drug products considering the new requirements in your revised (b)(4) product review procedure SOP-QA-0076.
  • A timeframe for submitting a (b)(4) supplement to (b)(4) with new specifications. These new specifications should be based on additional product and process knowledge, including a full understanding of your adhesive manufacturer’s process capabilities and raw material properties (such as (b)(4) and (b)(4)) and the influence of these properties on finished product and other critical components.
5.    Your firm failed to follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product including provisions for review by the quality control unit of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 21 CFR 211.192 (21 CFR 211.198).
We also observed this violation during our February 2009 inspection.
Your complaint handling system was deficient. You did not adequately investigate Daytrana adhesive-related complaints. You failed to consistently seek information on the percentage of adhesive transfer from defective units, which is critical to product performance.
Additionally, you failed to routinely examine and test (b)(4) samples in response to these consumer complaints.   Failure to do so left your quality unit with insufficient information to make appropriate complaint disposition decisions.
Your response is inadequate. You conducted a retrospective review of complaint trends, but did not identify sufficient corrective and preventive actions to improve the effectiveness of your complaint system and to prevent distribution of defective products.
Violations cited in this letter are not intended to be an all-inclusive list. You are responsible for investigating, for determining the causes, for preventing their recurrence, and for preventing other violations.
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at, so that FDA can work with you on the most effective way to bring your operations into compliance with the law.  Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) 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.
After you receive this letter, you have 15 working days to respond to this office in writing. Specify what you have done since our inspection to correct your violations and to prevent their recurrence.
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
If you cannot complete corrective actions within 15 working days, state your completion date and reasons for delay.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may also refuse requests for export certificates. We may re-inspect to verify that you have completed your corrective actions.
If you need additional information or have questions concerning any products distributed through your website, please contact the FDA. You may respond in writing to Randall L. Morris, Compliance Officer. If you have any questions about the contents of this letter, please contact Randall L. Morris at 407-475-4741 (phone) or 407-475-4768(fax).
Susan M. Turcovski
Director, Florida District
Naruhito Higo
Chairman of the Board
Hisamitsu Pharmaceutical Co. Inc.
Marunouchi Bldg. (30F, 31F)
2-4-1 Marunouchi
Chiyoda-ku, Tokoyo Japan, 100-6330                          

Page Last Updated: 04/24/2018
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English