FDA warning letters highlight CAPA concerns

Amidst numerous warning letters distributed by the US Food and Drug Administration (FDA) to pharmaceutical manufacturers in recent months, in July this year, the US regulatory body published its analysis on drug product quality in 2022.

In this paper, the US FDA highlighted that between 2018 and 2022, the quantity of warning letters issued were highest in the US in 2019 (55) and 2022 (47). Eight FDA warning letters were handed to European companies in 2018. In subsequent years, up to 2022, half this number or less were issued.

Failure to implement appropriate CAPA

Within warning letters given to manufacturers including RemedyRepack, Inc., Edge Biologicals Inc., Baxter Healthcare Corporation and Intas Pharmaceuticals Limited earlier this year, numerous corrective and preventive action (CAPA) compliance concerns were reported.

Intas Pharmaceuticals Limited

The FDA delivered a warning letter to Intas Pharmaceuticals Limited on 28 July 2023. It shed light on the company’s aborted chromatographic sequences in its QC laboratories between January 2020 to November 2022.

Although the incidents were investigated by its QC laboratory, the company “lacked adequate trending and CAPA systems to evaluate and identify recurring issues that should be targeted for laboratory improvements,” FDA stated.

Intas Pharmaceuticals Limited did acknowledge the need to enhance its processes and practices for applying CAPAs, but this was inadequate, FDA noted. It asserted that in its response, the company did not adequately address how it will implement systems to identify and address adverse laboratory incident trends, “or provide an overall management strategy for improving all phases of your laboratory investigations.”

Baxter Healthcare Corporation India

On 25 July 2023, the FDA issued a warning letter to Baxter Healthcare Corporation India. It warned: “You failed to conduct adequate investigations into endotoxin testing and your 100 percent automated visual inspection system… You did not identify and implement appropriate corrective actions and preventive actions (CAPA).”

“You did not definitively identify the source or sources of the particulate matter [in one or more wells used to perform the kinetic-turbidimetric assay (KTA) method], define the scope of potentially impacted operations (including potential manufacturing causes), and implement scientifically justified CAPA in a timely manner.”

In the FDA warning letter from July, it considered Baxter Healthcare Corporation India’s response as inadequate. The company did previously commit to evaluate and implement improvements to its procedures and practices. For example, on 17 February 2023, in relation to the Form FDA 483 issued after its most recent inspection.

However, this did not “adequately address your failure to conduct timely investigations into recurring and persistent issues,” FDA wrote in response. To remedy these deficiencies, FDA established that “all necessary CAPA to prevent recurrence of endotoxin result invalidations” must be implemented.

Cleaning validation concerns – FDA warning letter

Edge Biologicals Inc. 

An FDA warning letter delivered to Edge Biologicals Inc. on 27 June 2023 highlighted that the company “failed to validate the cleaning process for controlled environmental areas used for the aseptic processing of Mueller Hinton Agar antimicrobial susceptibility test culture media and other culture media devices.”

The FDA also noted a repeated observation cited during inspections done in 2015 and 2018 as well as in a warning letter issued in 2012. In its letter delivered on 27 June 2023, the US regulatory body conveyed that Edge Biologicals Inc failed to “adequately establish procedures for corrective and preventative actions, as required by 820.100(a).”

Based on its findings, the FDA cited several examples, stating that the company:

• Failed to analyse sources of quality data to identify existing and potential causes of nonconforming product or other quality problems
• Does not conduct analysis of environmental monitoring data for aseptic processing operations
• Failed to adequately investigate and identify actions needed to correct and prevent the recurrence of product sterility failures of (b)(4), Lot (b)(4), identified on 04/29/2021 and Lot (b)(4), identified on 05/07/2021, as required by your procedure QA-008/L, Product/Process Quality Incidents (PQI’s).

The FDA acknowledged that while Edge Biologicals Inc.’s response promised to implement corrective actions, it “was not comprehensive to address the systemic deficiencies identified including a corrective action plan and corrective actions to address the concerns along with timeframes to correct them.”

Root cause analysis – FDA warning letter

RemedyRepack, Inc.

In a warning letter sent to RemedyRepack, Inc. on 11 May 2023, the company’s investigations were found to lack “sufficient root cause determinations, CAPA, and assessment of all potentially affected batches” regarding multiple deviations for numerous broken tablets caused by the company’s packaging equipment between 20 October 2021 and 8 November 2021.

FDA stated: “You treated these similar deviations as individual occurrences and did not address this adverse pattern.” In the letter, the FDA shared an example from the company’s investigation which recorded: “these tablets ‘are tiny and do not run well’ [on its repackaging equipment]”. FDA emphasised this was despite a lack of adequate root cause determination and no implementation of CAPA.

While RemedyRepack, Inc. responded that it would provide adequate employee training to resolve this, the FDA deemed this inadequate. It called for RemedyRepack, Inc. to provide an “action plan [to remediate this system, which] should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures.”