Warning Letter: Failed to exercise appropriate controls (ucm 355294)

Additionally, during an audit of the data submitted in support of the [redacted] regarding [redacted] tablets USP [redacted] mg, our investigator requested to review the electronic analytical raw data to compare the values for [redacted] assay and degradation products. However, your firm provided only the printed copies of the raw data because your firm did not have the software program available to view the electronic raw data.
Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

During the inspection, our investigator also identified a backdated QC worksheet in the analytical report of [redacted] API raw material batch [redacted]. When your analyst affixed the related substance and IR weight printouts to the Format for Blank Sheet for Printout (Format No. F2/QCD/F/026-00), he signed and dated this worksheet as July 29, 2011. A second analyst, who reviewed this worksheet, also signed and dated it as July 29, 2011. However, your QA department did not issue this worksheet until July 31, 2011. Your analyst acknowledged during the inspection that he backdated this worksheet on July 31, 2011.

Your response stated that the analyst incorrectly dated the worksheet as July 29, 2011, instead of July 31, 2011, and that there was no intention to deliberately backdate the document. However, your response contradicted your analyst’s backdating admittance during the inspection. In addition, your response did not explain the reviewer’s signature which was also dated July 29, 2011.
Backdating documents is an unacceptable practice and raises doubt about the validity of your firm’s records.
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Warning Letter: Lack of spreadsheet controls (UCM 311326)

Specific violations observed during the inspection include, but are not limited, to the following: Your firm has not established appropriate controls designed to assure that laboratory records include all data secured in the course of each test, including graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, drug product container, closure, in-process material, or drug product, and lot tested [21 CFR 211.194 (a)(4)]. Specifically, the inspection revealed that your firm has not established written procedures to control and account for electronically generated worksheets used by analysts to record analytical test results. Analysts in your QC laboratory print an uncontrolled number of worksheets from computers throughout the QC laboratory without supervision.

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Warning Letter: No contols over computer system (ucm278262)

Your firm has failed to exercise appropriate controls over computer or related systems to assure that the input to and output from the computer or related systems of formulas, other records, or data, are checked for accuracy [21 C.F.R. § 211.68(b)]. For example, your firm’s custom software for your Master Batch Production record, referred to as the “I-131 Database,” has not been validated. This software is responsible for generating the batch production record, performing calculations to produce varying concentrations of drug product, and generating label information for customer vials and lead pigs.

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Warning Letter: Compliance training (ucm2275453)

“Your firm also failed to establish SOPs to ensure the following: (1) that all ADE information obtained from all sources are promptly conveyed to appropriate Jazz personnel and reviewed, in particular information obtained by your contracted central pharmacy and call center; (2) that all ADEs are evaluated against the U.S. package insert for seriousness and expectedness; (3) that all ADEs are reported accurately from source documentation to the FDA Form 3500A; and (4) that all ADEs that are the subject of 15-day Alert reports are promptly investigated and that all attempts to obtain additional information about the adverse experiences are recorded (as required by 21 CFR 314.80(c)(1)(ii)).

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Warning Letter: Failure to exercise appropriate controls (ucm253467)

Your firm has failed to exercise appropriate controls over computer or related systems to assure that changes in master production and control records, or other records, are instituted only by authorized personnel [21 C.F.R § 211.68(b)]. For example, your firm lacks control of the [redacted] computer system which monitors equipment, room differential pressure, room humidity, and stability chambers. Although the system is password protected for temperature and humidity set points, all employees have access to the room where the [redacted] computer system is located and the external hard drive is not password protected. During the inspection we observed that an employee was able to alter or delete data without a password and save the changed file.

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Warning Letter: Failure to conduct complete validation (ucm255936)

Failure to check input to and output from the computer or related system of formulas or other records or data for accuracy [21 CFR 211.68(b)]. For example, your firm went live with version 2.0.0 of the Hemocare Lifeline (HCLL) Donor Module on March 2, 2009, however, the validation of Module 15, Product Labeling, was incomplete in that it was not reviewed, accepted, or signed off by a responsible individual.

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Warning Letter: No documentation of software validation results (ucm247475)

Documentation of all software validation results  for the i.v.STATION was not completed per your firm’s Design Control, (D R&D 33.00) and the Design and Development Planning (P R&D 01.01) procedures. For the [redacted]  software validation test, the output is to verify that the procedure was completed correctly and that the “bag contains the requested volume of the drug.” The test completion date and the volume of the drug were not recorded. Additionally, successful completion of the [redacted]software validation test is to verify “that the syringe contains the required volume of drug.” The completion date and the volume of the drug in the syringe were not recorded, per procedure, for this test as well.

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Warning Letter: System not validated (ucm243585)

In addition, we remain concerned that your [redacted] adverse drug experience reporting system has not been fully validated, and may have resulted in inaccurate assessment and untimely submission of 15-day alerts. The current application was released into production on November 9, 2009 using an Interim Validation report (IVR) that is still not final. Critical issues (deviations) identified in your interim validation report during the inspection included the following, but is not limited to: lack of training for your [redacted] support team, incomplete SOPs and Work Instructions, and inaccurate data migration of legacy adverse experience cases from your previous adverse drug experience database, [redacted]. Currently, your [redacted] system does not display accurate clock dates on MedWatch forms for cases which were initially entered in [redacted] and later entered into [redacted] due to the receipt of additional information (follow-up) for the same cases. MedWatch forms printed out from [redacted] for these migrated cases are documented as initial 15-day reports, instead of follow-up reports. Also, the report date in Block B5 of the MedWatch form is the print date, not the actual date of submission. Shortcomings such as these affect the accuracy, reliability, consistency of the system and your firm’s ability to discern invalid or altered electronic records or make timely submissions to FDA as required.

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Warning Letter: Spreadsheet data entry cells not locked (ucm229262)

We observed 8 of 9 worksheets where one or more tabs with formula cells were not locked. These worksheets were used for analyzing raw data from drug component and product samples, including [redacted]. Your firm’s SOP 100-G-0110, “Creation and Use of Templates,” stated that cells, in which data is entered, must be locked within their electronic template.

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Warning Letter: Failure to Follow Procedures (ucm216889)

Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process shall be validated with a high degree of assurance and approved according to established procedure [21 C.F.R. § 820.75(a)]. “Specifically, the procedure “Validation of the Aseptic Filling Process Utilizing the Media Fill Method,”[redacted], states that initial validations should be conducted consecutively and prior to routine production fills and subsequent re-qualifications should be performed [redacted] as appropriate. In addition, the procedure states that routine production may not resume until acceptable qualification or validation runs are achieved or until all appropriate investigations and/or repeat media fills have been performed with acceptable results. However, validation of the aseptic filling process in filling suite [redacted] for [redacted] bottles was inadequate in that the [redacted] re-qualification of the [redacted] Aseptic Filling Process utilizing the Media Fill Method [redacted]performed on March 23, 2009 failed. The failure produced [redacted] contaminated units out of approximately [redacted] units inspected. In addition, the subsequent validation of [redacted] for filling [redacted]and [redacted] bottle [redacted performed on May 20, 2009 also failed.

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