Enforcement Spotlight: Retests Prove Key Data Integrity Concern in Recent Warning Letter

On April 24, FDA issued a warning letter to contract testing laboratory International Trading Pharm Lab Inc., located in Paterson, N.J. Consumer Safety Officer Niketa Patel conducted the initial inspection October 15-29, 2019. This inspection resulted in a 483 and an Official Action Indicated classification due to data integrity issues.

Barb Unger provided highlights in her May 26 blog post; a more detailed summary is below. 

[NOTE: Looking to avoid a data integrity citation in a 483?  We can help!  Click here for a free 483 Observation Report using “data integrity” as your keyword.]

FDA cited a number of quality issues at the site to the point of recommending the company hire a qualified consultant “to assist in your remediation.” In addition, FDA also encouraged the company to review its guidance on Quality Agreements for contract manufacturing organizations in addition to a Q&A on data integrity

Why make these recommendations? For one, the Warning Letter points to significant CGMP deviations concerning APIs, explaining that the API tested could be considered adulterated under the requirements of the Food, Drug, and Cosmetic Act. A number of these included data integrity violations.

Data Integrity Tops Citation List

The first item highlighted in the Warning Letter explicitly cited failures by the Quality Unit to appropriately test the drugs and report the results to clients. In particular, the inspectors noted that several out-of-specification results from chromatographic tests were not included in an investigation. These were also not communicated to the client. A review of an onsite OOS investigation conducted by the firm in 2017 found that one out of four samples was retested 14 hours following initial testing. This retest data was not included in the analyst’s notebook. In fact, it was not documented as part of the investigation. The Quality Unit was unaware the testing even occurred—a clear data integrity failure. 

Another sample was also tested a second time but labeled “Experimental.” Again, this was not included as part of the firm’s official OOS investigation. Unsurprisingly, FDA felt concerned these findings could be indicative of “testing into compliance.”

In response to the 483 issued, the company assured that auditors would check to ensure no retesting occurs. The Warning Letter explained that this was “inadequate because you did not conduct a review of electronic chromatographic data to determine the extent and impact of this practice.” In fact, the updated procedure failed to firmly state “that sample injections cannot be used to verify the system equilibrium.”

FDA requested the company:

  • Update the procedure for chromatography analysis to explicitly state that trial injections will not be conducted and only qualified reference standards be used to verify chromatography analysis equipment
  • Inform FDA of any actions and client communications due to “experimental” injection results 
  • Provide FDA with a remediation plan for the Quality Unit

FDA felt concerned these findings could be indicative of “testing into compliance”

More Issues with OOS Investigations Pop Up

Investigations of OOS results were also closed without justification. In one example, data on solution stability was found to be lacking. The company responded to this point on the initial 483 by stating that the client had refused to authorize stability studies of that particular solution. Naturally, FDA pointed out that contract testing laboratories are responsible for CGMP operations regardless of any client demands or lack thereof. 

FDA cited this instance as a significant failure to follow procedures for investigating deviations/batch API failures. In the Warning Letter, FDA requested the company conduct a retrospective review of all invalidated OOS results conducted in the last three years, summarize the findings in a report, and develop a comprehensive CAPA for OOS investigation processes. 

Moving onto analytical methods, investigators found failures to verify methods used to analyze drug samples. Ultimately, FDA requested an independent assessment of all test methods to determine suitability and updated procedures for documenting said determination, method verification and validation timing and training records. 

Concerns About Data Integrity Lapses

The bulk of the Warning Letter concerned data integrity lapses, beginning with the aforementioned undocumented trial injection data. Investigators also found that electronic test data from high-performance liquid chromatography (HPLC) and gas chromatography (GC) systems lacked sufficient controls. Notably, analysts responsible for testing drug samples had the ability to delete raw files in the system. Audit trails were not enabled either. 

The audit trail issue was not addressed in the company’s 483 response. 

In the Warning Letter, FDA requested the company provide a detailed plan to enable audit trails as well as evaluate the effectiveness of the laboratory system, including documentation procedures, and ensure all HPLC and gas chromatography data undergoes Quality Unit review. 

Investigators found failures to verify methods used to analyze drug samples

In more strongly worded language, FDA stated that the quality system does not support good data integrity practice. This is what spurred FDA to recommend hiring a consultant. 

Further remediation requirements include:

  • An investigation into the issues cited above that encompasses a comprehensive methodology
  • Interviews with current and former employees by a third party
  • Assessments and evaluation of all data integrity deficiencies 
  • A risk assessment of the potential impact on test result quality (specifically any risk to patients)
  • A risk management strategy featuring details drawn from the CAPA

While the language is the standard boilerplate data integrity language, it is clear that significant lapses in data integrity occurred. Data integrity has become an increasingly cited issue by the Agency.

Not the First Data Integrity Rodeo

Interestingly, this was not the company’s first data integrity citation by FDA. In April 2016, FDA investigators Helen Verdel and Niketa Patel issued a 483. During an April 18-29, 2016 inspection, investigators found that “laboratory records do not include complete data derived from all tests, examinations and assay necessary to ensure compliance with established specifications and standards.”

In that instance, certain parameters were not saved in a specific analysis software. This meant data in the certificate of analysis could not be reproduced. Investigators cited three incidents of this occurring when analysts were testing raw materials. 

[NOTE: Looking to avoid a data integrity citation in a 483?  We can help!  Click here for a free 483 Observation Report using “data integrity” as your keyword.]

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