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Table 1 Categories and Remedies for Issues Raised by the FDA
Category Description Examples of Issues Remedies

Problems with inadequate • Paper-based test results did not contain all analytical • Regulatory requirements should be interpreted
1
recognition data. correctly.
• There were no audit trail functions. • Systems should be updated to enable compliance
Functional deficiencies, inadequate
2 settings, and usage issues • Login IDs and passwords were being shared. with regulations.
• Data deletion was not restricted using user rights. • System settings should be specified appropriately.
• Tests were repeated until acceptable results were obtained.
3 Testing process reliability issues • Out-of-specification (OOS) data was neither investigated • Operations should be checked for any improper actions.
nor reported.

5. Categories and Remedies for 6. Relationship Between Inputs
6. Relationship Between Inputs
5. Categories and Remedies for
and Outputs
Issues Raised by the FDA
Issues Raised by the FDA and Outputs
There are multiple data integrity issues that have been raised by the Using HPLC analysis as an example, consider what is lacking in cur-
FDA, however, they can generally be categorized as indicated in Table rent practices, in terms of data integrity. Based on the prerequisites
1. Category 1 includes issues that result from a fundamental lack of indicated in Fig. 1, it appears that current practices are acceptable as
recognition, which requires properly interpreting regulatory require- long as security settings, such as login IDs, audit trail settings, and
ments. Category 2 includes issues related to functional deficiencies, user rights for deleting data, are configured in compliance with es-
setting inadequacies, or usage factors. These issues require updating tablished regulations. Normally, only the printed chromatograms are
systems to be able to comply with regulations or specifying proper checked, the instrument conditions (instrument parameters) used for
settings. Category 3 includes issues related to the reliability of the the analysis, the data analysis conditions (data processing param-
testing processes. These issues require verification to confirm that no eters), the batch analysis conditions, or other factors. However, reli-
invalid operations are being performed. Because FDA investigations ability can be ensured only by checking all these factors in addition to
are currently focused on data integrity, importance has shifted the chromatogram report. 7)
toward providing evidence that no improper operations were per- It is easier to understand this as a relationship between the input and
formed with respect to analytical results. This approach of the investi-
output processes. Fig. 2 shows that, even if stronger security mea-
gators based on suspicion, which is a major departure from the ap- sures are implemented for outputs (analysis data), they are meaning-
proach used in previous investigations. 6)
less without proper inputs (such as acquisition and data analysis con-
ditions). While computers can apply security measures, they cannot
judge the malicious intent of humans.

Implementation of Generation and storage of
analysis analytical data Chromatogram reports
Preparation of
samples (Print-out)

Login Logout
Check Approval Storage
Analytical condition settings

Instrument
Instrument
parameters
parameters
Check Approval
Peak integration
Peak integration
parameters
parameters
Prerequisites
Security settings, such as login IDs, audit trail settings, and user rights for
Batch settings
Batch settings deleting data, are presumably already configured in compliance with established
regulations.

Fig. 1 HPLC Analysis Process Flowchart

2