FDA Warning Letter to Abbott Diabetes Care: Inspection Findings, Response Failures, and Compliance Lessons

This is a review of the FDA warning letter to Abbott Diabetes Care, Inc. with comments about the inspection findings and FDA comments to the responses provided by Abbott following their inspection.

In the warning letter, the FDA noted that devices were adulterated with four failures provided as rationale.

Failure 1: Inadequate Design Transfer Procedures (21 CFR 820.30)

The first failure was a “failure to adequately establish and maintain procedures to ensure that the device design is correctly translated into production specifications, as required by 21 CFR 820.30.” An example provided was that the company had not established and maintained procedures for design transfer of a particular product, specifically regarding transfer of performance specifications to a third-part manufacturer. The design transfer process did not ensure that performance specifications identified in the design process were translated into manufacturing specifications for the third-party manufacturer. 

I have seen this occur when a design team was working with a third-party contractor to produce the design specifications and production processes, but no formal documentation was created and released through a document control process. The contract manufacturer continued to build the product based on internal notes they created and expected at some point they would get official copies of controlled documents but did not insist upon having them before starting production. 

I have even seen a situation where, after several years of being in production, it was discovered that an assembly drawing, BoM, and specifications had never been released and in the haste of releasing the formal documentation, an error was introduced into the subassembly that caused the new assemblies to fail. The error in the original design documentation had been discovered by the third party manufacturer years earlier and they had obtained written approval by a design engineer to make a correction to the prototype units. However, the error was never corrected in the manufacturer’s files. No one at the manufacturer had cross checked the full documentation package against the third-party’s documentation to catch the differences so the error was reintroduced by the formal release of the faulty documentation. 

To add to the headache, because the assembly was used in significant quantities and was needed for production, no first articles were ordered and a full production lot of nonconforming assemblies required costly rework and added further delays in production. Chances of this type of issue can be minimized through tighter documentation controls during the design process to make sure that design changes and corrections are properly recorded and a thorough review of released documentation at the completion of the development stage of the design process.  It is also very helpful to have an independent reviewer go through design documentation to catch items that have been missed due to a familiarity blindness of the material being reviewed.

Failure 2: Inadequate Finished Device Acceptance Procedures (21 CFR 820.80(d))

The second failure listed in the letter was the failure to adequately establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria, as required by 21 CFR 820.80(d). As an example of this failure, the inspection found that the company releases finished “integrated continuous glucose monitoring system (iCGM) devices without performance-testing the finished, fully assembled, sterilized, programmed, and packaged devices for accuracy prior to distribution.”

FDA Comments on iCGM Accuracy Requirements

The FDA noted that “iCGM special controls require that manufacturing and product release controls be established to ensure that released devices meet validated accuracy performance requirements (21 CFR 862.1355(b)(3)). Reliance on upstream, component-level testing performed prior to critical manufacturing steps does not ensure that finished, sterilized, and packaged devices meet accuracy performance requirements at the time of releases.” The FDA continued, “In addition, inspectional evidence documents that contract manufacturers responsible for final assembly and release were not provided accuracy performance specifications and were not required to verify finished-device accuracy performance prior to release. As a result, your firm has not established final acceptance activities to ensure that only conforming finished devices that meet the accuracy performance requirements are distributed, as required by 21 CFR 820.80(d).”

Commentary: Why Finished Device Testing Matters

Someone reviewing this warning letter might ask themselves, “how could they have overlooked acceptance criteria for a finished device? The user requirements for the device that were tested as part of the design validation would be the starting point. Could they have believed that if function testing was performed at subassembly levels, final testing would not be necessary?” I’ve worked for a couple companies that manufactured single use, disposable sterile consumables that worked with a device and in those cases, we obviously couldn’t perform 100% testing of those finished goods but we still had acceptance criteria, still performed incoming inspections to make sure the labeling was accurate, the sterilization records were correct, and that the product and packaging wasn’t damaged in shipping. For products that were produced in any significant numbers, there was random sampling from each lot.

Failure 3: Inadequate Statistical Techniques (21 CFR 820.250(a))

The third failure was a “failure to adequately establish and maintain procedures, where appropriate, for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics, as required by 21 CFR 820.250(a).” An example given was, “our inspection revealed that your firm failed to establish statistically valid acceptance criteria and sampling plans to ensure that only conforming finished devices are released to distribution.”

Failure 4: Inadequate Design Validation Procedures (21 CFR 820.30(g))

The fourth failure was “failure to adequately establish and maintain design validation procedures to ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions, as required by 21 CFR 820.30(g).” The example stated that although the product previously demonstrated compliance with accuracy performance requirements during premarket review, the inspection revealed that the firm “failed to adequately validate” that the product, “as implemented, is an appropriate manufacturing and release control to ensure preservation of that validated performance.”

FDA Evaluation of Abbott’s Responses to Inspection Findings

After reviewing the failures, we can consider the FDA’s comments about the company’s response to the initial findings. For many of the failures, the FDA found that the responses were inadequate and provided explanations for their findings.

Response to Failure 1: Missing Details on Device Master Record Documentation

In regard to the response to the first failure, the FDA noted that the “response does not identify whether finished-device accuracy performance release testing will be performed by Abbott or contract manufacturers, nor where these requirements are documented within the Device Master Record (DMR).” The FDA also points out that monitoring documents focus on general manufacturing parameters but “inadequately address sensor glucose accuracy performance requirements.

As a general rule, responses to observations must completely address the root causes of the problems identified in the initial inspection findings. In this case, the inspectors had specifically pointed out an issue with specifications not being provided to the third-party manufacturer, so any solution that did not directly address that problem and define specific documentation that will be created to provide objective evidence of compliance in the future will be viewed as inadequate by the FDA.

Response to Failure 2: Temporary Measures Are Not Sufficient

The FDA stated that the responses to the second failure were inadequate because they described temporary interim inspections and monitoring activities, which “do not ensure that finished devices released to distribution meet validated accuracy performance requirements at the time of release”. Also, some of the proposed device testing had not yet been implemented and did not demonstrate that the devices that had already been released to distribution conformed to accuracy requirements. The FDA also took issue with the proposed use of testing that had not been properly validated.

Best Practices for Responding to FDA Inspection Findings

When companies respond to FDA inspection findings, it is critical that the response address preventive actions being taken to ensure that the failure will not occur in the future. Temporary solutions do not ensure long-term prevention of re-occurrence. Proposed solutions that have not been validated to be effective do not provide objective evidence that they are effective. If observations have been made regarding product that has already been manufactured, then responses must include evidence that corrective actions and corrections have been or are being taken to ensure conformance of existing products in inventory. If actions need to be taken in connection with products that have already been distributed, such as a recall, then those actions should be included in the response.

Responses to Failures 3 and 4: Lack of Objective Evidence

The FDA also concluded that responses to the third and fourth failures did not adequately address the causes of those failures. They failed to provide “objective evidence demonstrating that proposed sampling strategies are sufficient to ensure detection of nonconforming finished devices” and objective evidence validating a testing method used for manufacturing or release control, was “capable of ensuring that finished devices continue to meet validated accuracy performance requirements.” The FDA concluded that the company had “not adequately validated its manufacturing and release controls, as required by 21 CFR 820.30(g) and 21 CFR 862.1355(b)(3).”

Key Takeaways: Responding to an FDA Warning Letter

When responding to an FDA Warning Letter, it is critical that not only should containment measures, corrections, corrective and preventive actions taken with regards to nonconforming product be properly documented, but also any and all process deficiencies be corrected with objective evidence that the updated procedures will not result in repeated nonconformances in the future.