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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Jerome Stevens Pharmaceuticals, Inc


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

Public Health Service
Food and Drug Administration
  New York District
158-15 Liberty Ave.
Jamaica, NY 11433

October 23, 2008



Ref: NYK 2009-03

Mr. Jerome Steinlauf
Jerome Stevens Pharmaceuticals, Inc.
60 Da Vinci Drive
Bohemia, New York 11716

Dear Mr. Steinlauf:

During an inspection of your drug manufacturing facility located in Bohemia, New York, conducted on August 27, 2007, through September 12, 2007, our investigator documented deviations from the Current Good Manufacturing Practice (CGMP) Regulations for Finished Pharmaceuticals (21 Code of Federal Regulations (CFR), Parts 210 and 211). Such deviations cause your drug products, Aspirin 325 mg., Butalbital 50 mg, Caffeine 40 mg., Codeine Phosphate 30 mg. Capsules USP, approved on August 31, 1998, under ANDA number 74-95l; Digoxin .125 mg. Tablets USP; Digoxin 0.250 mg. Tablets USP, approved on July 26, 2002, under ANDA number 76-268; and Unithroid (Levothyroxine Sodium) Tablets, approved on August 21, 2000, under NDA number 21210, in 0.025 mg, 0.050mg., 0.075 mg., 0.088 mg., 0.100 mg., 0.112 mg., 0.125 mg., 0.150 mg., 0.175mg., 0.200 mg. and 0.300 mg. strengths, 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)]. The inspection also revealed deviations from Adverse Drug Experience Reporting Regulations, and other Postmarketing Reporting Regulations for these products (21 CFR Parts 314.80 and 314.81), as required by Section 505(k)(1) of the Act [21 U.S.C: § 355(k)(1)]. Failure to comply with Sections 501(a)(2)(B) and 505(k) of the Act are prohibited acts under Section 301 of the Act [21 U.S.C. § 331].

You received notice of these deviations upon receipt of the form FDA-483, which listed the agency's inspectional observations. You then provided a written response to the form FDA-483 by correspondence dated September 25, 2007. We apologize for the amount of time that has passed since your correspondence. For the reasons explained below, we have determined that your written explanations are inadequate and that some of the deviations constitute repeat violations noted during previous inspections.

The deviations observed during the inspection demonstrating your firm's failure to comply with 21 CFR parts 210, 211, 314.80 and 314.81 include, but are not limited to, the following:

1) Failure to conduct adequate annual reviews in accordance. with 21 CFR § 211.180(e)(1). For example, review of the 2006 annual product review reports for Aspirin 325 mg, Butalbita150 mg, Caffeine 40 mg, Codeine Phosphate 30 mg, capsules USP; Digoxin 0.125 mg tablets USP; Digoxin 0.250 mg tablets USP; and Levothyroxine Sodium tablets in 0.025 mg, 0.050mg, 0.075 mg, 0.088 mg, 0.100 mg, 0.112 mg, 0.125 mg, 0.150 mg, 0.175mg, 0.200 Mg, and 0.300 mg strengths, failed to address such issues as trends in complaints, investigations, rejected or reprocessed batches, and other manufacturing issues that warrant corrective action.

Your response indicated that a procedure does exist and included corrective actions regarding the annual-review. However, the proposed corrective actions did not include review of complaints received, manufacturing deviations, change controls, and out-of-specification events. Furthermore, we note that the procedure was not included as an attachment as you had indicated. Please note that failure to conduct annual reviews was documented in a previous inspection of your facility on April 12-21, 2005.

2) Failure to conduct and document a thorough investigation of any unexplained discrepancy or failure of a drug product batch to meet its specification as required by 21 CFR § 211.192. For example, lot #012107 of Aspirin 325 mg, Butalbital 50 mg, Caffeine 40 mg, Codeine Phosphate 30 mg, capsules was reprocessed on July 30, 2007; two weeks after the testing of the initial blend sample detected an out-of-specification result for the assay of Butalbital, reported as 108.9% (b)(4) during an in-process check. This deviation was not properly assessed and documented, including consideration as to the need for corrective and preventative action.

Your response indicated that "upon completion of the blend process, the batch blend weight was over what is normally observed" and that (b)(4) of Butalbital was discovered missing-from the inventory on July 17, 2007." However, there is no record of any discrepancy observed in the weight of the batch during the blending procedure dated July 17, 2007, and the calculated yield is within specifications. In addition, your response reported that an investigation was conducted immediately after completion of the blend procedure, but a record of an investigation was not available either during the inspection or with your response. The only records of an investigation provided were annotations to the batch record dated July 18, 2007, indicating that-an additional (b)(4) of Butalbital was added to the batch by mistake. This does not suffice as a record of investigation. An investigation must extend to other batches of drug products that may have been associated with this type of problem and include adequate investigational conclusions and appropriate corrective actions to prevent recurrence of the problem.

Please note that failure to conduct adequate investigations was documented in two previous inspections of your facility on July 15-18, 2002 and March 6-23, 2006.

3) Failure to establish and follow written procedures prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics as required by 21 CFR § 21l.115. For example, your firm did not have a reprocessing procedure when lot #012107 of Aspirin 325 mg, Butalbita 150 mg; Caffeine 40 mg, Codeine Phosphate 30 mg, capsules was reprocessed on July 30, 2007. Also, your firm only conducted routine batch release testing on the reprocessed lot, which did not allow for a determination of the cause of the out-of-specification result, and the lot was not placed on stability.

Although your response included the submission of a written procedure for reprocessing, the procedure is inadequate. The procedure simply states that the QCU will determine when reprocessing will be required and the steps that will be taken at the time. You still lack a specific procedure that includes a description of the testing to be performed on the reprocessed lot, including tests to ensure the tot meets appropriate standards, specifications, and any other relevant criteria (including stability); the process that will be followed to ensure uniformity of the reprocessed batches; and, the scientific rationale that will be used to determine the reprocessing parameters.

4) Batch production records do not include complete information relating to the production and control of each batch as required by 21 CFR § 211.188. For example, failures were noted in the accuracy of documenting each production step in a real-time manner. For example:

a. On August 27, 2007, our investigator observed that the A check and a approval-for-use steps of the line clearance form entitled (b)(4) or the compression of Levothyroxine Sodium, 0.075 mg. tablets, lot #013307; were omitted and not approved prior to the start of the operation. When the form was reviewed again on August. 29, 2007, the investigator noted that the QA check column for review and approval-for-use had been completed and back-dated as, of the start of the operation, August 22, 2007.

b. On August 28, 2007, our investigator observed the blending of Levothyroiine Sodium 0.088 mg, lot #013907. He observed steps 1 and 2 on the batch record sheet entitled "Blending Procedure" had been in fact completed and initialed by the performing operator, but the check spaces for quality approval remained blank. The operator informed our investigator that he went to look for the Scientific Director to sign the record-for quality approval in order to proceed with the next step. However, the operation had already been completed.

c. On September 12, 2007, our investigator noted two intermediate blend lots, IB9307 and IB-9407, granulated on September 10 and 11, 2007, in the quarantine area. Batch records were requested for these lots which showed blank check spaces for the verification of steps 4 and 5. However, when copies of these batch records were received, these blank spaces had been filled (signed for "QA" by the Laboratory Scientist Director next to the manufacturing date of "9/11/07"). This verification should have been performed on the actual granulation date.

Your response described these observations as inaccurate and stated that all employees have been instructed in the proper method of "Clerical Error Correction." Your, explanations for the discrepancies-observed by the investigator included: "the machine was checked but the supervisor forgot to sign;" "clerical error," or "the firm does verify all processes and controls" and "the method of verification used at the firm has been performed in the same manner for decades." However, your response did not propose any corrective actions to avoid these discrepancies in the future. For example, you did not propose increased supervisory or QC/QA oversight of employee practices to ensure that proper checks are performed and batch records are complete:

5) Failure to provide employee training on a continuing basis to assure their knowledge and understanding of the drug CGMP regulations as they relate to their assigned functions as required by 21 CFR § 211.25 and failure to have the responsibilities and procedures applicable to the QCU in writing as required by 21 CFR § 211.22. For example, the Laboratory Scientist Director has not been given training in the particular operations he performs. This individual signs and approves the release and/or rejection of finished products and components, but he was observed approving documents related to other operations, such as manufacturing, packaging, and laboratory, for which he was not trained. In addition, a procedure that delineates the responsibilities of the QCU has not been established.

Your response stated that this individual has been employed by the firm for (b)(6) and has access to various references. However, training is required on a continuing basis and with sufficient frequency to assure that all employees remain familiar with CGMP requirements applicable to them. In addition, your response included a procedure titled (b)(4). The procedure you submitted is inadequate and is simply a duplicate of the regulations at 21 CFR § 211.22 without any specifics regarding how these provisions will be implemented.

6) Failure to establish and follow written procedures for the preparation of master production and control records as required by 21 CFR § 211.186.

Your response did not include a written procedure, but indicated only that a procedure will be created (no specific date given) to address the preparation of Master Production and Control Records. Adequate procedures for the preparation of Master Production and Control Records are a fundamental control to consistently produce drugs of acceptable quality because these records provide the detailed step-by-step instructions for completing every operation in the manufacture of a drug.

7) You failed to submit a periodic adverse drug experience report as required by 21 CFR § 314.80(c)(2). Specifically, you did not submit the periodic adverse drug experience report that was due by October 21, 2006 for NDA 21-210, Unithroid (Levotliyroxihe Sodiurn), approved on August 21, 2000. The submission date of the last report was August 1, 2005. Your firm received adverse event data on January 12, 2006, which was the subject of a 15-day Alert report (control number 011206).

Your response did not indicate that a periodic adverse drug experience report was submitted to the Agency for this product as required by 21 CFR § 314.80 (c)(2). In accordance with 21 CFR § 314.80(c)(2)(ii); holders of approved drug applications are required to submit to the Agency a periodic adverse drug .experience report containing a narrative summary and analysis of the information in the report and an analysis of the 15-day Alert reports submitted during the reporting interval, a FDA Form 3500A for each adverse drug experience not reported as a 15-day Alert report, and a history of actions taken since the last report because of adverse drug experiences.

8) The following Annual Reports were not submitted to the Agency within the required timeframes as required by 21 CFR § 314.81 (b)(2):

a. The Annual Report that was due by October 21, 2006 for NDA 21-210, Unithroid (Levothyroxine Sodium), approved on August 21, 2000, was not submitted to the Agency until November 20, 2006.

b. The Annual Report that was due by September 26, 2006 for ANDA 76-268, Digoxin, approved on July 26, 2002, was not submitted to the Agency until October 25, 2006.

Your response stated that the report for the following year would be submitted on time. However, your response did not include any information indicating the cause of the late Annual Reports from 2006, nor did it provide any specific information concerning what actions you have taken or will take to ensure Annual Reports are submitted within the required timeframes in the future.

In addition to these reporting deficiencies, a review of your firm's Adverse Drug Reporting Standard Operating Procedure, SOP Section 14(A), found this procedure to be deficient. 21 CFR § 314.80(b) requires written procedures to be developed for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA. Deficiencies noted with your Adverse Drug Experience (ADE) written procedures include, but are not limited to the following:

• Your written procedure does not contain definitions of "seriousness" and "nonseriousness" or "expectedness" and "unexpectedness" for the purpose of determining whether adverse event reports should be submitted on an expedited basis.

• Your written procedure does not contain timeframes within which follow-up to serious and unexpected adverse events is to be performed and reported to FDA.

• Your written procedure does not contain any instructions on the preparation and submission of periodic reports, including required elements and submission schedule.

• Your written procedure contains the incorrect address for submission of ADE reports to the Agency.

• Your written procedure states that "ADE's received by a 2nd party marketer of JSP products will be responsible for the filing of any ADE's received." However, you do not appear to have any written procedures for how these firms will perform surveillance, receipt, evaluation, and submission of adverse drug experiences, or how you, as the holder of the approved drug application, will ensure that ADE reporting for your products is being performed in accordance with the FDA requirements.

The above identification of violations and the observations on the form FDA-483 issued at the end of the inspection are not intended to be an all-inclusive list of violations. It is your responsibility to assure adherence with each requirement of the Current Good Manufacturing Practice Regulations, Adverse Drug Experience Reporting Regulations, and other Postmarketing Reporting Regulations. Federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when considering 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.

You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action without further notice. These actions include seizure and/or injunction.

You should notify this office in writing, within 15 working days of the 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 action cannot be completed within 15 working days, state the reason for delay and the time within which corrections will be completed.

Your reply should be sent to Compliance Branch, Food and Drug Administration, 158-15 Liberty Avenue, Jamaica, NY 11433. Attention: Lillian C. Aveta, Compliance Officer.



Otto D. Vitillo
District Director
New York District

Enclosure: Form FDA 483 dated September 12, 2007