Inspections, Compliance, Enforcement, and Criminal Investigations

Heritage Pharmaceuticals, Inc. 11/5/15

  

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

Public Health Service
Food and Drug Administration
 New Jersey District
10 Waterview Blvd., 3rd Floor
Parsippany, NJ 07054
Phone: 973-331-4917
Fax: 973-331-4969 

November 5, 2015

WARNING LETTER
 
VIA UNITED PARCEL SERVICE
 
Mr. Jeffrey A. Glazer
Vice Chairman, Chief Executive Officer
Heritage Pharmaceuticals, Inc.
12 Christopher Way Ste 300
Eatontown, NJ 07724
16-NWJ-01
Dear Mr. Glazer:
 
Between May 12, 2015 and May 27, 2015, the U.S. Food and Drug Administration (FDA) inspected your firm, Heritage Pharmaceuticals Inc., located at 12 Christopher Way, Eatontown, New Jersey. The inspection revealed serious violations of Postmarketing Adverse Drug Experience (PADE) reporting requirements under Section 505(k) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355(k)] and Title 21, Code of Federal Regulations (21 CFR) 314.80 and 314.98. Failure to comply with Section 505(k) is a prohibited act under Section 301(e) of the Act [21 U.S.C. § 331(e)].
 
We acknowledge receipt of your written response dated June 16, 2015 to the Form FDA 483, Inspectional Observations, issued to your firm on May 27, 2015. From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your firm's written response, we conclude that your firm did not adhere to the applicable statutory requirements and FDA regulations governing PADE reporting. Specific violations include, but are not limited to, the following:
 
1.    Failure to report each adverse drug experience not reported under 21 CFR 314.80(c)(1)(i) at quarterly intervals for three years from the date of approval of the application, and then at annual intervals, as required by 21 CFR 314.80(c)(2)(i) and 21 CFR 314.98(a).
 
As the holder of abbreviated new drug applications (ANDAs), you are required to submit Periodic Adverse Drug Experience Reports (PADERs) for each application. PADERs are required to include all adverse experience reports not reported as 15-day Alert reports. Between 2010 and 2014, your firm failed to submit approximately (b)(4) individual case safety reports (ICSRs) required to be submitted with their respective quarterly and/or annual PADERs, affecting at least (b)(4) applications held by your firm.
 
For example, for (b)(4), the annual PADERs for the time periods 06/2010 through 06/2014 state, "No adverse drug experience reports were received for this product during this reporting period." However, there were approximately ten ICSRs reported to your firm during that period of time that should have been included in the corresponding PADERs. This omission was not discovered by your firm until it was pointed out by the FDA investigator during the inspection.
 
Your management indicated that PADERs were prepared for your approved applications by a regulatory affairs contractor and that the contractor should have known to include ICSRs in their respective PADERs. As the application holder, you are ultimately responsible for all PADE submissions and recordkeeping requirements under the Act and implementing regulations. The complete omission of ICSRs required to be submitted with PADERs for a period of over four years raises concerns about your firm's ability to monitor the safety of drug products.
 
Your response to this observation has been reviewed and determined to be inadequate. In your response, you committed to submitting to the Agency amended PADERs for the affected applications to include the non-expedited ICSRs omitted from your PADERs. Your response is inadequate because we cannot determine whether you have implemented adequate preventative measures, such as adequate SOPs, work instructions, database access, and staff training, to prevent recurrence of your failure to submit non-expedited ICSRs in their respective PADERs in the future. This is particularly concerning as we note that your firm's Standard Operating Procedures (SOPs) in effect at the time of the inspection fail to include any provisions on the completion, evaluation, and submission of accurate PADERs.
 
2.    Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences from all sources as required by 21 CFR 314.80(b) and 21 CFR 314.98(a).
 
Your firm does not have adequate written procedures to ensure that adverse drug experiences are correctly assessed and reported to FDA in accordance with postmarketing regulations. During the inspection you provided your firm's two SOPs pertaining to PADE requirements: (b)(4)
 
Your firm's SOPs fail to ensure that: (1) all ADE information obtained from all sources is promptly conveyed to the appropriate Heritage personnel and reviewed, (2) all ADEs are evaluated against the U.S. package insert for seriousness and expectedness, (3) all ADEs are reported accurately from source documentation to the FDA, (4) all ADEs that are the subject of 15-day Alert reports are promptly investigated and all attempts to obtain additional information about the adverse experiences are recorded, and (5) a Form FDA 3500A for each ADE not reported as a 15-day Alert report under 21 CFR 314.80(c)(1)(i) is timely submitted in the correct format.
 
We also note that your (b)(4) states that you will retain ADE records for not less than three years.  A three-year record retention period is inconsistent with the ten-year record retention period required by postmarketing regulations under 21 CFR 314.80G). We believe the inadequacy of your SOPs contributed to your firm's failure to submit over (b)(4) ICSRs with their associated PADERs, affecting at least (b)(4) ANDAs. We acknowledge that this violation, as written, was not included on the Form FDA 483 that you received.
 
Without adequate written procedures, we cannot be assured that you will accurately capture and report important safety information about your drug products to FDA. Failure to report ADEs to FDA at the required intervals raises concerns about your firm's ability to monitor the safety of drug products, as well as the reliability and integrity of the information submitted to FDA.
 
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your firm. It is your responsibility to ensure 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, including injunction, without further notice. Federal agencies are advised of the issuance of all Warning Letters about drugs and devices so that they may take this information into account when awarding contracts. FDA may re-inspect your firm to verify corrective actions have been completed.
 
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of active pharmaceutical ingredients and/or finished products produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Staff immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov 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 Staff also allows you to meet any obligations you may have to report discontinuances in your drug manufacture 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. In appropriate cases, you may take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.
 
Within fifteen working days of your 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 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. You may wish to include dates for when each corrective action will be fully implemented.
 
Your response should be sent to the following address: U.S. Food and Drug Administration, 10 Waterview Blvd., Parsippany, New Jersey 07054. If you should have any questions regarding any issue in this letter, please contact Andrew Ciaccia, Compliance Officer by telephone at 973-331-4904.
 
 
Sincerely,
/S/
Craig W. Swanson
Acting District Director
New Jersey District

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