Warning Letter: Inadequate validation (ucm164129)

Failure to observe, standardize, and maintain equipment and failure of equipment to perform in the manner for which it was designed so as to assure compliance with the official requirements for blood and blood components [21 CFR 606.60(a)]. Specifically, the following observations were made during review of your firm’s validation of the interface between the automated blood testing instrument [redacted] and the database system, [redacted]

• Validation sample testing and data collection was conducted on December 9, 2008, prior to approval of the validation test plan on. December 19, 2008;
• The validation pass/fail criteria was not met;
• The validation test plan was not followed; and
• The validation data was incomplete.

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Warning Letter: Database validation (ucm162745)

Failure to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, or electronic equipment, including computers, used in the manufacture, processing, packing and holding of a drug product. [21 CFR 211.68]

The Enterprise Resource Planning System known as the firm’s Systems Applications and Products (SAP) computer database allows rejected batches of drug product to be in Unrestricted Status (to be released for distribution).

During the inspection, you provided our FDA investigators a spreadsheet that you stated contained data for calibration of [(b)(4)], however, you were not able to provide the raw calibration data. In addition, the calibration data for the [(b)(4)] that you provided in your December response in Attachment #9 do not correspond to the [(b)(4)] observed by our FDA investigators.

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Warning Letter: Failure to establish procedures (s7186c)

Failure to establish and maintain 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, the [redacted] used in the manufacturing of [redacted] products was changed from [redacted] to [redacted]. However, your validation records indicate [redacted] was used as the [redacted]. There are no records of design validation using [redacted] as the [redacted] furthermore, verification activities related to using [redacted] are not complete.

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Warning Letter: Failure establish and maintain records (ucm166530)

Failure to evaluate and select suppliers, contractors, and consultants on the basis of their ability to meet specified requirements, including quality requirements, as required by 21 C.F.R. 820.50(a)(1). 17) Failure to establish and maintain records of acceptable suppliers, contractors, and consultants, as required by 21 C.F.R. 820.50(a)(3).

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Warning Letter: Failure to maintain procedures, documentation (s6881c)

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).

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Warning Letter: Lack of controls and audit trails (ucm1048180)

The [redacted] data acquisition system for the [redacted] UV/Visible spectrophotometers allows your analysts to modify, overwrite, and delete original raw data files. The spectrophotometers are used for dissolution testing of finished product, stability samples, and process and method validation studies. All laboratory personnel were given roles as [redacted] Managers, which allowed them to modify, delete, and overwrite results files. This system also does not include an audit trail or any history of revisions that would record any modification or deletion of raw data or files. Your laboratory computer system lacks necessary controls to ensure that data is protected from tampering, and it also lacks audit trail capabilities to detect data that could be potentially compromised.”

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Warning Letter: Failure to Comply (s6876c)

• Failure to adequately validate manufacturing processes with a high degree of assurance, and approve and document the results of the validation activities, to ensure that product specifications can be consistently met, as required by 21 C.F.R. § 820.75(a). Specifically, your firm has not validated the milling process and documented the validation results to ensure that the brass rounds are correctly milled to patients’ programmed [redacted] files [redacted] codes).
• Failure to revalidate manufacturing processes in response to changes or process deviations, and document the results of the revalidation activities to ensure that product specifications can be consistently met, as required by 21 C.F.R. § 820.75(c). Specifically, your firm has not documented the results of the revalidation of the milling process after your firm repaired a loosened bushing on the tooling plate and [redacted] without established procedures in place for implementing these changes.
• Failure to establish and maintain procedures for verifying or validating, approving, and documenting changes to a specification, method, process, or procedure, before implementation, as required by 21 C.F.R. § 820.70(b). Specifically, your firm has not established written procedures describing how changes to your milling process are to be verified or validated, approved, and documented.

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Warning Letter: Failure to establish procedures (s6788c)

Failure to establish design change control procedures for the identification, documentation, validation and/or verification, review, and approval of design changes before implementation. [21 CFR § 820.30(i)] Specifically, between 2003 and 2006, design changes were made to the Secure Safety Insert System. The molding operation was changed to improve the visibility of the biohazard symbol on the cap; the interlock of the cap into the tube was changed to improve the pull strength testing; and short caps were added to accommodate different size syringes.  Verifications and/or validations, design reviews, design releases, and design approvals were not performed for any of these changes.

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Warning Letter: Failure to establish and maintain adequate procedures (s6752c)

Failure to establish and maintain adequate procedures for validating the device design to include software validation and risk analysis, as required by 21 CFR 820.30(g). For example, [redacted] Software Development Manager, indicated the diagnostic algorithm system for the PAD software was enhanced to version [redacted] from [redacted] in September 2007, to include the Arabic and Persian languages. The pediatric capability transfer for the PAD device was conducted on 1/18/07, and 2/19/07. Your validation protocol ( [redacted]) failed to document how you validated the software upgrade or how you validated the pediatric capability transfer. 2. Failure to establish and maintain adequate procedures for acceptance of incoming product to include inspection, testing, or other verification as conforming to specified requirements, as required by 21 CFR 820.80(b). For example: a) The Heartsine Samaritan AED System Traveler form ( [redacted]) indicates that Internal Inspection and In QAT testing was not performed for serial numbers [redacted] and [redacted]. Additionally, the required Monitoring Mode for steps [redacted] through [redacted] was not performed for serial number [redacted] b) The Heartsine Samaritan PAD Unit [redacted] form ( [redacted]) indicates that Internal Inspection and In QAT testing was not performed for serial number [redacted] c) The Heartsine Samaritan PAD [redacted] Page ( [redacted]) indicates that [redacted] Inspection and Inspection of [redacted] were not performed for serial numbers [redacted] and [redacted]”

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Warning Letter: Incomplete documentation of validation (s6741c)

Failure to adequately establish and maintain procedures for validating the device design, as required by 21 CFR820.30(g). For example:

a. Device software validation is incomplete. For example, the documentation of the external validation testing for the [redacted] Scanner conducted by a Canadian site in 2005 reveals incomplete sections rating the effectiveness of the scanner.

b. Discrepancies that were noted at the completion of design validation are not addressed. For example, the final validation report for the [redacted] noted an issue regarding “streak” artifacts at one of the clinical sites; however, there was no further documented evaluation of this artifact to include significance and potential risk prior to the finalization of the design validation and commercial distribution.

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