FDA Warning Letters


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  1. Warning Letter: Data Integrity Issues (ucm495778)

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    Notification to Pharmaceutical Companies: Clinical and Bioanalytical Studies Conducted by Semler Research Are Unacceptable

    “FDA is notifying sponsors of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) that clinical and bioanalytical studies conducted by Semler Research Private Limited (Semler) located in Bangalore, India, are not acceptable as a result of data integrity concerns, and need to be repeated… The inspection found significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples.

    “Specifically, the WHO examined company computer servers and found a spreadsheet file containing detailed instructions for manipulating drug samples that were used in clinical trials for its clients.”

    View the original warning letter.


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  2. Warning Letter: Unauthorized Access (ucm496623)

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    Failure of computerized systems to have sufficient controls to prevent unauthorized access or changes to data.

    Your firm’s computer system for entering test results and storing certificates of analysis (CoA), which document whether a drug meets specifications, does not have sufficient controls to prevent unauthorized changes to a CoA after quality unit approval.

    During the inspection, our investigator reviewed [redacted] CoA stored on computer #16, all of which were approved by the quality unit. A manager demonstrated for our investigator how results on an already finalized CoA could be manipulated after the formal quality unit approval. Also, the quality unit’s electronic signatures on these CoA were uncontrolled images of signatures rather than certificate-based electronic signatures.

    View the original warning letter.


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  3. Warning Letter: Data falsification and manipulation (ucm489735)

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    Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

    During our inspection, we observed multiple examples of incomplete, inaccurate, or falsified laboratory records.

    View the original warning letter.


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  4. Warning Letter: Validation not documented (ucm489358)

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    There is no change control procedure or documentation for moving from Computer Numeric Control process.

    Failure to establish and maintain procedures for changes to a specification, process, or procedures, as required by 21 CFR 820.70(b). Specifically,

    On or about 5/12/2014, you had your contract manufacturer change from using Computer Numeric Control process to a hydroforming process to manufacture the ONE TRAY. You have not established process change procedures nor has this change been documented and verified/validated.

    Your November 10, 2015 response cannot be assessed at this time. Your response states that you will fully document the validation activities performed to support the new manufacturing process; and will update your agreement with the contract manufacturer to address process changes. Please provide an update on the progress of these corrective actions.

    View the original warning letter.


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  5. Warning Letter: Failure to establish and maintain adequate procedures (ucm515974)

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    Failure to establish and maintain adequate procedures for implementing corrective and preventive action (CAPA), as required by 21 CFR 820.100(a). For example:

    a. Your firm’s CAPA procedure, [redacted], only requires that nonconformances will be reviewed every [redacted]. However, the procedure does not require analysis of quality data, including quality records, complaints and returned products, for potential CAPA.

    View the original warning letter.


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  6. Warning Letter: Firm has not validated or documented software changes (ucm516079)

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    Failure to establish and maintain adequate procedures for the identification, documentation, validation, or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). For example: your firm has not validated or documented software changes for the Omega XP Laser System; Omega XP-Clinic Laser System; and Omega Excel Laser System.

    View the original warning letter.


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  7. Warning Letter: Failure to validate computer software for its intended use according to an established protocol (ucm515647)

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    Failure to ensure that when computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i). For example, your firm has not validated the software, [redacted], used to manage various activities such as complaints, CAPAs, repairs, servicing, internal and external audits, and warranty service. Your firm has been utilizing this software since January 2011

     

    View the original warning letter.


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  8. Warning Letter: Lack of Audit Trails and other deficient computerized system controls (ucm478393)

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    “Your firm failed to establish appropriate controls over computers and related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel (21 CFR 211. 68(b)).

    You lacked audit trails or other sufficient controls to facilitate traceability of the individuals who access each of the programmable logic controller (PLC) levels or Man-Machine Interface (MMI) equipment. You had no way to verify that individuals have not changed, adjusted, or modified equipment operation parameters.”

    View the original warning letter.


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  9. Warning Letter: Device software has not been fully validated (ucm466204)

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    “Failure to adequately establish procedures for design validation, as required by 21 CFR 820.30(g). Specifically, QS-57532 (Rev. 2.0, “WI-Customer Validation Process”) allows for devices that have not yet fully completed design validation, including software validation, to be shipped to end users for clinical use on patients in a “Limited Availability” basis for the purpose of collecting additional feedback prior to the completion of design validation activities. Further, the Merge HEMO V10.0 was shipped to [redacted] end users for clinical use in cardiac catheterization procedure labs as part of the firm’s design validation plan as a “Limited Availability” release; these devices had not been fully validated. Additionally, document number HEMO-6830 (Rev. 1.0, “Customer Validation Plan Merge Hemo 10.0) describes the customer validation process conducted at the two end user facilities during the “Pre-Release/Limited Availability” release timelines where it is indicated the software will be used in a “production environment,” i.e. for patient use….”

    View the original warning letter.


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  10. Warning Letter: Failure to maintain complete data (ucm465626)

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    “2. Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

    Your laboratory systems lacked access controls to prevent raw data from being deleted or altered. For example:

    a. During the inspection, we noted that you had no unique usernames, passwords, or user access levelsfor analysts on multiple laboratory systems. All laboratory employees were granted full privileges to the computer systems. They could delete or alter chromatograms, methods, integration parameters, and data acquisition date and time stamps. You used data generated by these unprotected and uncontrolled systems to evaluate API quality.

    b. Multiple instruments had no audit trail functions to record data changes.

    3. Failure to maintain complete data derived from all testing, and to ensure compliance with established specifications and standards.

    Because you discarded necessary chromatographic information such as integration parameters and injection sequences from test records, you relied on incomplete records to evaluate the quality of your APIs and to determine whether your APIs conformed with established specifications and standards. For example:

    a. During the inspection, the investigator found no procedures for manual integration or review of electronic and printed analytical data for [redacted] stability samples. Electronic integration parameters were not saved or recorded manually. When the next samples were analyzed, the previous parameters were overwritten during the subsequent analyses.

    i. Your HPLC 14 computer files included raw data for undocumented [redacted] stability samples analyzed on December 30, 2013, but no indication of where these samples came from and why they were tested.

    ii. In a data file folder created on May 22, 2013, 23 chromatograms were identified as stability samples for [redacted] lots [redacted], and [redacted]. Results were not documented. More importantly, the acquisition date was July 7, 2013, more than six weeks after the samples were run.

    iii. (b)(4) lots (b)(4) and (b)(4) were not in your stability study records at the time of inspection. Additionally, there were no log notes of any samples from the three lots removed from the stability chamber.

    In response to this letter, provide your revised procedures and describe steps you have taken to retrain employees to ensure retention of complete electronic raw data for all laboratory instrumentation and equipment. Also, provide a detailed description of the responsibilities of your quality control laboratory management, and quality assurance unit for performing analytical data review and assuring integrity (including reconcilability) of all data generated by your laboratory.”

    View the original warning letter.


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