Data Integrity Warning Letter Summary – August 2018


The U.S. Food and Drug Administration (FDA) recently issued a Warning Letter to a Japanese bio-chemical manufacturing company.  The Warning Letter summarized significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).  The letter cited non-compliance with section 501(a)(2)(B) of the 21 U.S.C. 351(a)(2)(B).

The FDA inspection observed many data integrity non-compliances included retesting and manipulation of data results for system suitability testing performed to qualify equipment used in raw material analysis.  Quality testing was then performed on a previously nonconforming raw product sample which was thereby determined to meet the specification.  The persons involved generated no documentation was to detail these actions.

In their response to inspection findings, the company attributed the root cause to a “lack of awareness of the seriousness” of CGMP deviations, and an “environment where test data could be easily manipulated.”  The company offered no further detail regarding root cause, effect, or corrective actions.  The company also asserted that no out-of-specification (OOS) product was in distribution, but was not able to provide data to support this assertion.

The follow-up Warning Letter cited an inadequate quality system to ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs manufactured.  In a previous Warning Letter, FDA cited similar CGMP deviations related to the quality unit’s failure to thoroughly investigate and document OOS events at multiple sites, demonstrating that executive management oversight and control over the manufacture of drugs is inadequate.

The FDA inspection also observed “Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to have adequate controls to prevent omission of data.”  Findings included the lack of audit trails in software systems that produced data for system suitability testing and the lack of unique user names and passwords.  The company also used unprotected, uncontrolled, and non-validated Excel worksheets to perform calculations and statistical evaluations of production data.  The FDA called into question the reliability of the company’s production data, in general.

In the Warning Letter, the FDA called for the company to conduct a retrospective review of all distributed lots.  It called for the company to make a thorough assessment of their system for investigating deviations, discrepancies, OOS results, complaints, and other failures.  Further, The FDA recommended an immediate, comprehensive CAPA investigation and detailed account of the company’s global manufacturing operations (preferably by a third party) to ensure that systems, processes, and products conform to FDA requirements.  The scope would include all data generated, including analytical data, manufacturing records, and all data submitted to FDA.  It called for an independent (third party) review of controls and procedures for electronic data generated from all of your laboratory equipment, and a corrective action and preventive action (CAPA) plan to resolve any findings along with a detailed account of the implemented CAPA process.  Qualified third party consultants would be required to audit and assist in identification and remediation of the data integrity issues.  This process would include interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies.  Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) would need to be put in place to ensure the future integrity of the company’s data.

The CAPA plan would need to detail interim measures to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to their stability programs to assure stability, drug application actions, and enhanced complaint monitoring.  An assessment of the potential effect of observed compliance failures would be required to determine risks to patients, including distributed product and ongoing operations.  Any further plans for distribution of product are currently under scrutiny and at the discretion of the Center for Drug Evaluation and Research (CDER).

Until the company remediates these CGMP deviations, and the FDA confirms full remediation, the FDA may withhold approval of any new applications or supplements submitted for approval by the manufacturer.  The FDA may also refuse the company’s requests for distribution rights in the United States.

As you can see, the scope of this Warning Letter is enormous.  Whether through ignorance or disregard of regulatory compliance requirements for data integrity, not only has this company placed the patient at risk through their non-compliance with FDA regulatory requirements, but has placed their company’s future in financial and legal jeopardy by failing to actively ensure the compliance of their data systems.  As you may infer, due to the global standardization of regulatory agency requirements under the ICH, their risk extends to their global market.  This company will now pay an unimaginable price to remain viable in the bio-chemical market.

It is not enough to assume the quality of products distributed by our health-care, pharmaceutical, medical-device, and cosmetic manufacturers.  That is why the regulatory agencies are there to enforce that these products meets the quality standards for safety, efficacy, and dosage.  Quality systems need to be an integral consideration in development, manufacture, and distribution of products in these industries.  Data integrity is vital in ensuring that these quality systems are used accurately, efficiently, and honestly, and will continue to be subject to attention by the FDA. For more information on data integrity assessment, take a look at our project summary on the topic.

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