Guest Column | April 1, 2016

Data Integrity: Understanding Global Regulations & Past Enforcement Actions

By Barbara Unger, Unger Consulting Inc.

In Part 1 of this three-part series, we reviewed the history that brought us to this point of global regulatory focus on data integrity in the pharmaceutical industry. In this article, we will address the regulations and guidance published in this area, and review data integrity-related enforcement actions taken over the past 10+ years.

Applicable Regulations And Guidance

An official definition of “data integrity” is not found in the regulations. FDA and other regulatory authorities expect that data will have attributes described in the acronym ALCOA. This acronym was first referenced in the September 2013 guidance Electronic Source Data in Clinical Investigations and addresses the attributes of clinical “source data.” As applied to GMP, that means data is expected to be:

  • Accurate: Data must be accurate. Where appropriate, correctness should be second-person verified. Data accuracy extends, for example, to data/information that is presented in multiple locations — such as an equipment log, laboratory notebook, and electronic chromatography records — where data should be in agreement.
  • Legible: Data and results must be legible/readable. Electronic data must also have the capability to be made human-readable.
  • Contemporaneous: Thus, data is recorded at the time of the event/action, not transcribed at a later date. Data is not transcribed from sticky notes or scrap paper to the official documents, such as batch records or laboratory notebooks.
  • Original: Original data is similar to “raw data.” The following is taken from the MHRA guidance and appears to also represent FDA’s opinion: “Original record: Data as the file or format in which it was originally generated, preserving the integrity (accuracy, completeness, content and meaning) of the record, e.g. original paper record of manual observation, or electronic raw data file from a computerized system.” The paper printout of a chromatogram is no longer considered the official raw GMP data because it does not include the complete information, including but not limited to meta-data, audit trails, and system configuration for the analysis in question. FDA addresses this in its GMP Q&A.
  • Attributable: This term requires the ability to determine who logged into the system, who collected the data, when it was collected, from which instrument it was collected, who processed the data, and who made any data modification or data manipulations. For example, for HPLC chromatography, this includes all integration events. Use of shared passwords renders makes it impossible for the reviewer to attribute the data to a specific person.

Requirements meant to ensure data integrity preceded Part 11 and are found in 21 CFR 211 and in other parts of 21 CFR governing GxP areas. The two regulations that are most frequently cited in warning letters are 21 CFR 211.194 and 21 CFR 211.68 (Unger Consulting Inc. data, available upon request). These require maintenance of complete laboratory records and adequate controls over computer systems, respectively. 21 CFR 211.188 is frequently cited and requires that production and control records include complete information in addition to 21 CFR 211.100(b), which requires that actions are documented at the time they are performed.

The first regulation that specifically addressed electronic records and electronic signatures became effective as 21 CFR Part 11 in 1997. Interpretation and enforcement of this new rule resulted in confusion among both FDA investigators and the regulated industry. In 2003, FDA published a guidance meant to clarify its interpretation. Current interpretation and actions that prompt enforcement may be found in FDA presentations given at industry symposia, the Q&A on its website, forms 483, and warning letters. This information is valuable to read because it will always have greater specificity than the text in regulations and guidance.

FDA is not unique in establishing and updating requirements and guidance regarding data management meant to ensure data integrity. EMA revised and expanded Annex 11 of its GMP Guide in 2011 to provide additional clarification for computer system requirements. This same annex was adopted by PIC/S. MHRA took the lead in the EMA region to identify and detail its requirements for data integrity. In December 2013, MHRA announced that the pharmaceutical industry is expected to review data integrity during self-inspections. In January 2015, the agency published a guidance document on the subject, and a revised version of the guidance was published in March 2015.

MHRA defines terms commonly used in the data integrity area and provides detailed examples of expectations. MHRA expects that a “robust data governance” approach will ensure that data iscomplete, consistent, and accurate, regardless of the format in which data is generated, used, or retained. An important statement in the guidance is that manufacturers “… are not expected to implement a forensic approach to data checking…”.

The World Health Organization (WHO) recently published a 35-page draft document on its website, Guidance on Good Data and Record Management Practices for GxP regulated activities. This also addresses both paper records and electronic records. The guidance includes a detailed set of examples for each and seems closely aligned with the MHRA guidance from March 2015.

Armed with the knowledge of the background for data integrity, and understanding the regulations and guidance on the topic, we proceed to evaluate inspection observations and warning letters. Again, these are primarily FDA-focused enforcement actions because they are most readily available.

Inspection Observations, Warning Letters, WHO Notices Of Concern, And EU Inspections

As mentioned earlier, enforcement actions for deficiencies in data integrity span more than the past 10 years, include both the GMP and GCP sectors of the industry, and have been made by FDA, EMA authorities, and WHO. The summary reports of noncompliance written by the MHRA and other EU authorities and published on the Eudra GMDP website appear very similar to FDA forms 483 and warning letters. WHO published at least two notice of concern announcements in 2015 (in June and September) that also appear similar. Obviously, firms that are still receiving these observations in forms 483 and deficiencies in warning letters missed opportunities to learn from publicly available information. Many have suffered expensive consequences, both financial and in reputation. It is worth noting that enforcement actions have been taken simply when conditions exist where it is not possible to identify invalid or altered records. Regulators do not need to identify actual data falsification before they take action.

“Audit trails” are frequently cited in enforcement actions. It is important to remember that audit trails in electronic records are the equivalent of the “line-out, initial and date, explain” process used to identify and correct mistakes made in paper records. In the absence of appropriately configured and enabled audit trails it is impossible for a reviewer or auditor to ensure the data is valid and has not been altered or deleted. Warning letters have been issued for permitting conditions to exist where data may be changed or deleted; inspectors do not need to identify confirmed examples of inappropriately modified or deleted data.

As early as 2000, a warning letter issued to Schein Pharmaceuticals cited lack of control over computerized laboratory systemsi including lack of password control and broad-ranging staff authority to change data. Table 1 shows that selected enforcement actions based on data integrity have continued into 2015, with similar inspection observations, warning letter deficiencies, EMA findings, and WHO actions. This is not meant to be a complete listing but rather to demonstrate ongoing, consistent enforcement actions in this area over 10-plus years. The Comment column provides an abbreviated listing of some of the deficiencies that were identified. I encourage readers to evaluate the original document at the links provided.

 Table 1: Selected Enforcement Actions for Data Integrity Problems

Fiscal Year




Schein Pharmaceuticals

Warning letter to Schein Pharmaceuticals cites inadequate control over laboratory computer systems including password control and authority to change data. See specifics in Endnote i.


Able Laboratories, Cranbury NJ

The 15-page form 483 was among the early forms 483 addressing the broad category of data integrity. The inspection resulted in withdrawal of ~50 ANDAs, and the firm is no longer in business.


Ranbaxy, Paonta Sahib

Failure to maintain documentation of operation conditions and settings, and complete raw data were not retained; SOP provides for discarding of data.



Failure to maintain complete and accurate records is a repeat deficiency cited at previous inspections; logbook did not contain complete and accurate information; data was not documented at the time of performance.


Actavis Totowa LLC, NJ

Electronic data files are not checked for accuracy; data discrepancies between electronic data and data documented in laboratory notebooks.


Ranbaxy, Paonta Sahib

Written records were signed by individuals who were not present in the facility on the day of the signing.


Ranbaxy, Ohm Laboratories in Gloversville NY

Analysts were given access to delete data; user account privileges were inadequate.


Cetero Research

This untitled letter was issued to a firm located in the U.S. that conducted BA/BE studies in support of NDAs and ANDAs. As part of follow up, FDA sent a letter to the firms that contracted with Cetero Research for BA/BE studies requesting specific information to establish validity of the BA/BE information in the drug application. We also include one of the forms 483.


Wockhardt Ltd

This letter was the second one in 2013 to cite the new FDASIA power to deem product adulterated if they are manufactured at a site that “delays, denies or limits” an inspection; investigators found batch records for 75 lots torn in half in the waste area; HPLC raw data files can be deleted from the hard drive using the common PC login used by all analysts.


Wockhardt Ltd

Practice of performing trial injections before the “official” injection; documentation entries not made as the activities were performed; HPLC data could be deleted from standalone instruments.


Fresenius Kabi Oncology

This represents the first warning letter to cite the FDASIA definition of adulteration to include products made in a facility that “delays, denies or limits” an inspection; electronic data could be altered or deleted; use of “test” or “trial” injections.


Trifarma S.p.A.

The firm does not retain laboratory raw data; there is a lack of access control to computer systems.


Apotex Pharmachem India Pvt Ltd.

Lack of raw data; batches were tested until they passed; OOS events were not reported or investigated.


Hospira S.p.A

Chromatography systems did not have adequate controls to prevent deletion or modification of raw data files; audit trails were not enabled for the “Test” folder, and the firm was unable to verify what types of test injections were made, who made them, or the date or time of deletion.


Apotex Research Private Limited

Data used to release product did not agree with the original data; “trial” injections were identified; failure to document activities as they occurred; failure to investigate and report OOS results.


GVK Biosciences

The French Medicines Authority inspected this site in Hyderabad, India and identified apparent data manipulations conducted in clinical studies, particularly with EKG data. The manipulations were reported to have been ongoing for five years.


Quest Lifesciences Pvt. Ltd.

This WHO notice of concern addressed deficiencies in documentation in the GCP clinical trials area.


Svizera Labs Private Limited

This WHO notice of concern addressed deficiencies in documentation.

Now that we’ve covered the deficiencies that global authorities have addressed in the GMP and GCP areas, Part 3 will explain what you can do to identify data management and data integrity shortcomings within your own company.


  1. The warning letter is not available on the current FDA web site and must be requested under FOI. Following is the specific deficiency, #6 among the deficiencies listed in the warning letter:
    1. Failure to maintain the integrity and adequacy of the laboratory's computer systems used by the Quality Control Unit in the analysis and processing of test data. For example:
      1. There was a lack of a secure system to prevent unauthorized entry in restricted data systems. Data edit authorization rights were available to all unauthorized users, not only the system administrator.
      2. The microbiology departments original reports on sterility test failures of Penicillin G Potassium for injection, lots 9804024 and 9811016 due to environmental mold, which were sent via electronic mail to the Quality Assurance Management, differed significantly from the versions included in the Quality Assurance Management's official reports.
      3. The network (b) (4) module design limitations, which can only support up to four chromatographic data acquisition systems, had up to five chromatographic systems connected. There was no validation showing this configuration to be acceptable.

System testing was not conducted to insure that each system as configured could handle high sampling rates. Validation of the systems did not include critical system tests such as volume, stress, performance, boundary and compatibility.

About The Author

Barbara Unger formed Unger Consulting, Inc. in December 2014 to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry. She has extensive expertise in this area having developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen Inc. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Barbara was the first chairperson of the Rx-360 Monitoring and Reporting work group (2009 to 2014) that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. She also served as the chairperson of the Midwest Discussion Group GMP-Intelligence sub-group from 2010 to 2014.

Before Amgen, Barbara worked for the consulting firm Don Hill and Associates, providing regulatory and quality services to the pharmaceutical industry, and for Eli Lilly and Company in quality and CMC regulatory affairs positions. She began her career in the pharmaceutical / device industry with Hybritech Inc. and received a bachelor's degree in chemistry from the University of Illinois in Urbana Illinois.