The Top 10 Reasons Why Drug, Device, Biologic, Research and Veterinary Facilities Fail FDA Inspections
Posted 07 February 2014 | By
The US Food and Drug Administration (FDA) conducts tens of thousands of inspections of pharmaceutical, medical device and biological manufacturing facilities each year, resulting in thousands of subsequent reports noting deficiencies.
But as data released by the agency shows, some problems are far more common than others, illustrating areas where the industry can make outside improvements.
Data taken from FDA's inspectional database between 1 October 2012 and 30 September 2013 showed a total of 5,211 FDA Form 483s, the form FDA uses to note deficiencies at a manufacturing facility.
But as we said before, some violations tend to pop up more than others, in some cases hundreds of times each year. In the medical device sector, for example, 378 inspections showed that corrective and preventive action (CAPA) procedures had not been put into place, raising FDA's concerns that problems might occur over and over again.
Below are the top 10 inspection violations found during inspections of medical device, pharmaceutical, biologic, veterinary and bioresearch facilities.
Medical Device: Top 10 Inspection Violations
21 CFR 820.100(a)
Lack of or inadequate procedures
Procedures for corrective and preventive action have not been [adequately] established.
21 CFR 820.198(a)
Lack of or inadequate complaint procedures
Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been [adequately] established. Specifically,***
21 CFR 820.100(b)
Corrective and preventive action activities and/or results have not been [adequately] documented.
21 CFR 820.75(a)
Lack of or inadequate process validation
A process whose results cannot be fully verified by subsequent inspection and test has not been [adequately] validated according to established procedures.
21 CFR 803.17
Lack of Written MDR Procedures
Written MDR procedures have not been [developed] [maintained] [implemented].
21 CFR 820.50
Purchasing controls, Lack of or inadequate procedures
Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements have not been [adequately] established.
21 CFR 820.90(a)
Nonconforming product, Lack of or inadequate procedures
Procedures have not been [adequately] established to control product that does not conform to specified requirements.
21 CFR 820.30(i)
Design changes - Lack of or Inadequate Procedures
Procedures for design change have not been [adequately] established. Specifically,***
21 CFR 820.181
DMR - not or inadequately maintained
A device master record has not been [adequately] maintained.
21 CFR 820.22
Quality audits - Lack of or inadequate procedures
Procedures for quality audits have not been [adequately] established.
Drugs: Top 10 Inspection Violations
21 CFR 211.22(d)
Procedures not in writing, fully followed
The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed].
21 CFR 211.192
Investigations of discrepancies, failures
There is a failure to thoroughly review [any unexplained discrepancy] [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 211.100(a)
Absence of Written Procedures
There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.
21 CFR 211.160(b)
Scientifically sound laboratory controls
Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity.
21 CFR 211.67(b)
Written procedures not established/followed
Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.
21 CFR 211.113(b)
Procedures for sterile drug products
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not [established] [written] [followed].
21 CFR 211.67(a)
Cleaning / Sanitizing / Maintenance
Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product.
21 CFR 211.165(a)
Testing and release for distribution
Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release.
21 CFR 211.110(a)
Control procedures to monitor and validate performance
Control procedures are not established which [monitor the output] [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 211.166(a)
Lack of written stability program
There is no written testing program designed to assess the stability characteristics of drug products.
Veterinary Medicine: Top 10 Inspection Violations
Treatment records were not [maintained] [complete]. Specifically,***
21 CFR 530.11(d)
Causing a residue of an approved human or animal drug above an established safe level, safe concentration, or tolerance, through use of the drug contrary to its labeling.
You lack an adequate inventory system for determining the quantities of drugs used to medicate your [cows] [calves] [livestock].
Expired drug(s) were observed in the drug storage area.
Extra label use w/o veterinary client-patient relationship
Use of [a human] [an animal] drug in a manner contrary to label directions without benefit of a valid veterinary client-patient relationship.
Identity of animals
Failure to [identify] [maintain records regarding the identity of] [record the existing identification of] the animal(s) that you [purchased] [transported] and delivered for [sale] [consignment] at [an auction yard] [a slaughter plant].
21 CFR 530.11(a)
Rx not followed
Failure to follow your veterinarian's prescription for [dosage] [frequency and duration of treatment] [route of administration] [species or class of animal] [pre-slaughter withdrawal time] [special cautionary directions].
Records review prior to slaughter
Failure to systematically review treatment records prior to offering an animal for slaughter for human food, to assure that drugs have been used only as directed and that appropriate withdrawal times have been observed.
21 CFR 530.20(a)(2)(iv)
Causing an illegal residue in a food-producing animal of an approved human or animal drug through [prescribing the use of] [using] the drug contrary to its labeling, and failing to take appropriate measures to assure that [assigned timeframes for withdrawal were met] [no illegal residue would occur].
21 CFR 530.41(a)
Drugs prohibited for extralabel use in food producing animal
A prohibited [drug] [substance] was administered in an extralabel manner to [a] food-producing animal(s).
Bioresearch Monitoring: Top 10 Inspection Violations
21 CFR 312.60
FD-1572, protocol compliance
An investigation was not conducted in accordance with the [signed statement of investigator] [investigational plan]. Specifically***
21 CFR 312.62(b)
Case history records- inadequate or inadequate
Failure to prepare or maintain [adequate] [accurate] case histories with respect to [observations and data pertinent to the investigation] [informed consent].
21 CFR 56.115(a)(2)
Minutes of IRB meetings
Minutes of IRB meetings have not been [prepared] [maintained] in sufficient detail to show [attendance at the meetings] [actions taken by the IRB] [the vote on actions, including the number of members voting for, against and abstaining] [the basis for requiring changes in or disapproving research] [a written summary of the discussion of controverted issues and their resolution].
21 CFR 312.62(a)
Investigational drug disposition records are not adequate with respect to [dates] [quantity] [use by subjects].
21 CFR 56.108(a)(1)
Initial and continuing reviews
The IRB [has no] [did not follow its] written procedure for conducting its [initial] [continuing] review of research.
21 CFR 56.115(a)(5)
List of members
A list of IRB members has not been [prepared] [maintained], identifying members by [name] [earned degrees] [representative capacity] [indications of experience sufficient to describe each member's chief anticipated contribution to IRB deliberations] [any employment or other relationship between each member and the institution].
21 CFR 50.27(a)
Consent form not approved/signed/dated
Informed consent was not properly documented in that the written informed consent used in the study [was not approved by the IRB] [was not signed by the subject or the subject's legally authorized representative at the time of consent ] [was not dated by the subject or the subject's legally authorized representative at the time of consent].
21 CFR 312.66
Failure to report promptly to the IRB all unanticipated problems involving risk to human subjects or others.
21 CFR 312.50
General responsibilities of sponsors
Failure to [select qualified investigators] [provide investigators with the information needed to conduct the study properly] [ensure proper monitoring of the study] [ensure the study is conducted in accordance with the protocol and/or investigational plan] [ensure that FDA and all investigators are promptly informed of significant new adverse effects or risks].
21 CFR 312.60
Failure to obtain informed consent in accordance with 21 CFR Part 50 from each human subject prior to [drug administration] [conducting study-related tests] . Specifically***
Biologics: Top 10 Inspection Violations
21 CFR 606.100(b
Maintained and followed
Written standard operating procedures including all steps to be followed in the [collection] [processing] [compatibility testing] [storage] [distribution] of blood and blood components for [homologous transfusion] [autologous transfusion] [further manufacturing purposes] are not always [maintained] [followed] [maintained on the premises].
21 CFR 606.100(c)
Failure to [perform a thorough investigation] [make a record of the conclusions and follow-up] of [an unexplained discrepancy] [a failure of a lot or unit to meet any of its specifications]. Specifically,***
21 CFR 606.160(a)(1)
Person performing, test results, interpretation
Records fail to [identify the person performing the work] [include dates of the various entries] [show test results] [include interpretation of the results] [show the expiration date assigned to specific products] [be as detailed as necessary] so as to provide a complete history of the work performed.
21 CFR 606.160(a)(1)
Records are not concurrently maintained with the performance of each significant step in the [collection] [processing] [compatibility testing] [storage] [distribution] of each unit of blood and blood components so that all steps can be clearly traced.
21 CFR 606.160(b)
Failure to maintain [donor] [processing] [storage and distribution] [compatibility testing] [quality control] [general] records.
21 CFR 606.171
Biological product deviation report
Failure to submit a biological product deviation report [within 45 days from the date you acquired information suggesting that a reportable event occurred].
21 CFR 606.60(a)
Equipment observed, standardized, calibrated
Equipment used in the [collection] [processing] [compatibility testing] [storage and distribution] of blood and blood components is not [observed] [standardized] [calibrated] on a regularly scheduled basis as prescribed in the SOP Manual.
21 CFR 606.60(b)
Equipment calibration frequency
Equipment used in the [collection][processing][compatibility testing][storage and distribution] of blood and blood components is not observed, standardized and calibrated with at least the frequency required.
21 CFR 606.100(c)
Record review prior to release
All records pertinent to a lot or unit were not reviewed before the release or distribution of a lot or unit of final product.
21 CFR 606.100(b)(15)
Schedules and procedures for equipment & calibration
The standard operating procedure fails to include a written description of schedules and procedures for equipment maintenance and calibration.