FDA WARNING LETTERS
A selection of miscellaneous FDA comments taken from 483’s and FDA warning letters. Some are so basic, it is alarming that there are persons in the industry so poorly informed. Others are pure complacency, with a drop of arrogance mixed in.
Details from a FDA warning
letters dated 10th November 2009
1) You have failed to establish and maintain
procedures to control the design of the device in order to ensure that specified
design requirements are met, as required by 21 CFR 820.30(a).
2) You have failed 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).
3) You have failed to adequately establish and
maintain the procedures for receiving, reviewing, and evaluating complaints by a
formally designated unit, as required by 21 CFR 820.198(a).
4) You have failed to review, evaluate, and
investigate any complaint involving the possible failure of a device to meet any
of its specifications, as required by 21 CFR 820.198(c).
5) You have failed to establish and maintain
procedures for finished device acceptance to ensure that each production, run,
lot or batch of finished devices meets acceptance criteria, as required by 21
6) You have failed to validate computer software
for its intended use according to an established protocol, when computers or
automated data processing systems are used as part of the production or the
quality system, as required by 21 CFR 820.70(i).
7) You have failed to document maintenance
activities, including the date and individuals performing those activities, as
required by 21 CFR 820.70(g)(1).
8) You have failed to establish and maintain
adequate procedures to ensure that device history records for each batch, lot,
or unit are maintained to demonstrate that the device is manufactured in
accordance with the device master record, as required by 21 CFR 820.184.
9) You have failed to maintain a device master
record to include device specifications, as required by 21 CFR 820.181(a).
10) You have failed to establish procedures for
quality audits and conduct such audits to assure that the quality system is in
compliance with the established quality system requirements and to determine the
effectiveness of the quality system, as required by 21 CFR 820.22.
11) You have failed to appoint and document such
appointment of a member of management who, irrespective of other
responsibilities, ensures that quality system requirements are effectively
established and effectively maintained and reports on the performance of the
quality system to management with executive responsibility, as required by 21
12) Your management with executive responsibility
failed to review the suitability and effectiveness of the quality system at
defined intervals and with sufficient frequency according to established
procedures to ensure that the quality system satisfies the requirements of this
part and the manufacturer's established quality policy and objectives. The dates
and results of quality system reviews shall be documented, as required by 21 CFR
13) Failure to provide adequate resources
including the assignment of trained personnel, for management, performance of
work, and assessment activities, including internal quality audits, as required
by 21 CFR 820.20(b)(2).
FDA Warning Letters Continued.Failure to validate with a high degree of assurance, and approve according to established procedures, the results of a process that cannot be fully verified by subsequent inspection and test, and failure to document the validation activities and results. [21 CFR § 820.75(a)]. FDA Warning Letters 1.
Failure to implement procedures to ensure the device history records (DHR's) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Master Record (DMR) and the Quality System regulation. [21 CFR § 820.184]
During the investigator's visual inspection of the manufacturing facility, layers of dust and dried white powder were observed on the surface of the lyophilizer, tables, compounding tanks, water storage tanks, filter housing, water purification equipment and the walls of the building. This dust was also observed on various components of the water purification system. FDA Warning Letters 3.
Cobwebs were observed between the [redacted] C freezer, the walls surrounding it and the water purification system. FDA Warning Letters 4.
The investigator noticed a white dried crystallized powder on the top opening of the tanks as well as the outside wall of the tanks. The firm had no designated area for the tanks to be cleaned properly. The firm gave no reply when asked the last time the facility was cleaned. FDA Warning Letters 5.
Prior to performing process validation of the lyophilizer in 2004, the firm noticed there was damage to the equipment. More specifically, the firm's process validation report indicated that the wires on the lyophilizer were damaged. This physical damage was observed by the investigator during the current inspection. FDA Warning Letters 6.
The firm failed to establish procedures to ensure that all equipment was appropriately designed, constructed, placed, and installed to facilitate use. FDA Warning Letters 7.
Failure to document acceptance activities including the acceptance activities performed, the date acceptance activities are performed, the results, the signature of the individual conducting the acceptance activities, and, where appropriate, the equipment used. [21 CFR § 820.80(e)] FDA Warning Letters 8.
Failure to implement procedures for quality audits and conduct such audits to assure that the quality system is in compliance with quality system regulation. [21 CFR § 820.22] FDA Warning Letters 9.
Failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has been already distributed [21 CFR 211.192]. For example: FDA Warning Letters 10.
Failure to fully establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product. [21 CFR 211.198(a)]. For example: FDA Warning Letters 11.
Failure to establish and follow written responsibilities and procedures applicable to the quality control unit [21 CFR 211.22(d)]. For example: Written procedure 2-032, In-House Reference Standards, dated 8/27/04, is not followed. In house reference standards, which are used in testing finished product samples, are not retested annually as required by step 7.3 of the SOP. Examples include: FDA Warning Letters 12.
There is no written procedure that describes the visual examination of reserve samples of finished drug products for deterioration. A report titled, "2005 Annual Product Inspection (Visual / Odor)," indicates that all inspected products passed. However, there is no written procedure that describes how the examination is done or that defines the pass/fail criteria. In addition, the lot numbers and number of units examined are not documented in the report. FDA Warning Letters 13.
Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product [21 CFR 211.110(a)]. FDA Warning Letters 14.
During the inspection, the FDA investigator asked how the bulk samples can be considered to be representative of the complete manufacturing process, including the filling operation. Our investigator was told that sampling procedure is used because First Priority has performed process validation testing on all products. However, our inspection revealed that none of the process validation studies reviewed, particularly for suspension and powder products, established a hold time between compounding and filling. FDA Warning Letters 15.
The testing and release of drug products for distribution do not include appropriate laboratory determination of satisfactory conformance to the identity and strength of each active ingredient prior to release. Specifically, identity tests are not done on all drug products prior to release [21 CFR 211.165(a)]. For example, batches of the following drugs were released without identity testing: FDA Warning Letters 16.
Device history records are not maintained and written procedures have not been developed that ensure that device history records (DHRs) for each batch, lot or unit are maintained to demonstrate that the device was manufactured in accordance with the device master record (DMR) and the Quality System regulations, as required by 21 CFR 820.184.
Your firm failed to maintain device master records (DMRs) that include or refer to the location of device specifications as required by 21 CFR 820.181(a). For example, your firm lacks device master record including but not limited to a full list of materials and diagrams of finished devices with specifications or procedures covering in-house manufacturing processes such as gluing or inspections of its medical devices.
Your firm failed to formally designated unit for complaint evaluation to maintain records of investigations conducted under 21 CFR 820.198, as required by 21 CFR 820.198(e).
Your firm failed to establish and conduct quality audits to verify that your quality system is effective and in compliance with an established quality system, as required by 21 CFR 820.22.
Your firm has not established procedures to control the design process, as required by 21 CFR 820.30(a).
Your firm has not established procedures for implementing corrective and preventive actions, as required by 21 CFR 820.100(a).
Failure to establish an adequate and effective quality system that has been fully implemented and maintained at all levels of the organization, as required by 21 C.F.R. 820.20(a).
Failure to establish procedures for quality audits, as required by 21 C.F.R. 820.22. For example, your firm does not have any quality audit procedures in place to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system. To date no audits have taken place.
Failure to establish and maintain procedures for implementing corrective and preventative action (CAPA) and to document all CAPA activities and their results, as required by 21 C.F.R. 820.100.
Failure to evaluate complaints to determine whether the complaint represents an event which is required to be reported to FDA under part 803, Medical Device Reporting, as required by 21 C.F.R. 820.198(a)(3).
Failure to assure that a process whose results can not be fully verified by subsequent inspection and test, has been adequately validated and approved according to established procedures, as required by 21 C.F.R. 820.75(a).
Failure to establish and maintain procedures to control all documents, as required by 21 C.F.R. 820.40.
Failure to establish and maintain procedures for receiving, in-process, and finished device acceptance activities, as required by 21 C.F.R. 820.80(a).
Failure to document the equipment identification, calibration dates, the individual performing each calibration, and the next calibration date, as required by 21 C.F.R. 820.72(b)(
Management with executive responsibility did not ensure that an adequate and effective quality system was fully implemented and maintained at all levels of the organization [21 C.F.R. 820.20].
Production processes were not developed to ensure that a device conforms to its specifications [21 C.F.R. 820.70(a)].
Not all of the actions needed to correct and prevent the recurrence of nonconforming product and other quality problems were identified. Specifically, your firm documented decreasing [redacted] Spinalscopics, lot #46170, during the accelerated stability testing for extending the expiration date and there was no nonconformance prepared for the decreasing [redacted] [21 C.F.R. 820.100(a)(3)].
A process, with results which cannot be fully verified by subsequent inspection and test, was not adequately, fully validated and approved according to established procedures [21 C.F.R. 820.75(a)].
Employee training was not fully documented [21 C.F.R. 820.25(b)]. Specifically, There was no documented training for the CEO, President, or Quality Control Manager in the firm's current quality manual (includes the firm's quality policy).
There was no documented training for the Lead Auditor [redacted] or 2006 auditors, [redacted] and [redacted] in the firm's Internal Audit Procedure, QSP-17.
Employees were not adequately trained [21 C.F.R. 820.25(b)]. Specifically, Only 16 out of approximately 60 employees received training in cGMP on 1/11/05 and no additional group training was held in 2006.
Out of 11 initial training records reviewed, only 1 person ([redacted] was documented as receiving cGMP training on 1/11/05 and again on 9/9/05. This employee was not documented as receiving the group training on 1/11/05.
Employees were not always trained on changes to procedures and records.
Employees were not made aware of device defects that could occur when they improperly perform their jobs [21 C.F.R. 820.25(b)(1)].
Quality audits were not conducted at sufficient regular intervals as prescribed by internal procedure to verify that the quality system is effective in fulfilling the quality system objectives [21 C.F.R. 820.22]. Specifically, the Internal Audit Procedure states the audit schedule is based on ensuring all elements of ISO 13485, IVD Directive and CMDCAS ISO 13485 are audited for not less than [redacted]
Individuals who conduct quality audits have direct responsibility for the matters being audited, in violation of 21 C.F.R. 820.22. Specifically, one [redacted] of the individuals who audited manufacturing on 3/6/06 had direct responsibility over the area he audited.
The Design History File was not established or maintained for the Liproprint LDL and HDL Subfraction System [21 C.F.R. 820.30(j)].
The Design History File does not demonstrate that the design was developed following the approved design plan and the design control requirements of 21 CFR 820. Specifically, the design history file (DHF) for GlycoHemosure, Hemoglobin Alc (HbAlc) Control is incomplete or procedures were not followed. [21 C.F.R. 820.30(j)].
The Design History File does not demonstrate that the design was developed following the approved design plan and the design control requirements of 21 CFR 820.
There was no design plan in the DHF, there were no approved design inputs, and the risk analysis was not performed according to the firm's procedure, which requires the use of the [redacted] approach. The DHF also lacks documentation of design design validation, design review, and design transfer activities.
Acceptance records did not include the results of certain acceptance activities [21 C.F.R. 820.80(e)(1)]. Specifically, real time stability tests are not conducted according to the firm's Stability Procedure.
Software used as part of the production quality system was not validated for its intended use according to an established protocol [21 C.F.R. 820.70(i)].
Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements were not established [21 C.F.R. 820.50].
Corrective and preventive action activities were not documented, including the actions needed to correct or prevent recurrence of nonconforming product and other quality problems, and implementation of corrective and preventive actions [21 C.F.R. 820.100(b)].
There was no corrective and preventive procedure to determine when verification can be conducted in lieu of validation [21 C.F.R. 820.100(a)(4)].
Appropriate sources of quality data were not adequately analyzed to identify existing and potential causes of nonconforming product and other quality problems [21 C.F.R.820.100(a)(1)].
A justification for not reporting the correction or removal action to FDA that included conclusions and reviews by a designated person was not included in the correction or removal records [21 C.F.R. 806.20(b)(4)]. Specifically, there was no justification maintained for not reporting to FDA:
Complaint handling procedures for complaints were not implemented [21 C.F.R. 820.198(a)]. Specifically, [redacted] of [redacted] complaints reviewed exhibited failures of the device, its labeling, or packaging to meet specifications. These complaints were not investigated.[redacted] of [redacted] complaints did not include the reason for no investigation.
Records of a complaint investigation did not include appropriate corrective action [21 C.F.R. 820.198(e)(7)]. Specifically, microbial testing of Synovialscopics Control was performed on 4/19/05 as part of an investigation into a complaint of microbial contamination. Although there were no positive/negative controls run when the microbial test was performed, no corrective action was taken.
Written MDR procedures were not developed [21 C.F.R. 803.17]. Specifically, SOP 12-004, Medical Reporting, effective date 04/04/06, was developed to comply with reporting to the Competent Authority, not to FDA.
Schedules for the adjustment, cleaning and other maintenance of equipment were not implemented [21 C.F.R. 820.70(g)(1)]. Specifically, two instrument S/N [redacted] and S/N [redacted] used during testing of finished devices were observed on 11/27/06 as requiring preventative maintenance.
Failure to validate software used as part of production and quality system for its intended use according to an established protocol, and failure to document the results of the software validation, as required by 21 C.F.R. § 820.70(i). warning letters and 483 Item 8. Specifically, your firm has not maintained documentation of the validation of the computer software used to (a) receive encrypted patient treatment data and decrypt/encrypt it; (b) convert decrypted patient treatment data into (b)(4) codes that are converted into b)(4) codes that are then sent to your contract manufacturer's (b)(4) milling machine to produce the compensators.
FDA WARNING LETTERS