Warning letter / DuPont Nutrition USA Inc. / MARCS-CMS 627211/ 627211/ DECEMBER 02, 2022/ Observation 3

Failure to ensure the test methods used are suitable for their intended use.

Firm is currently using compendial and non-compendial conductivity test methods for in-process and release testing of Avicel lots. Failure to adequately verify and validate compendial and non-compendial conductivity methods, respectively. Firm was unable to provide evidence of method verification and validation prior to April 2021 even though these test methods were used to conduct release testing for Avicel prior April 2021.

A. Firm failed to verify the compendial conductivity test method and evaluate if additional verification parameters or validation were required due to changes in sample preparation. For example:

• failed to have an approved method verification protocol with pre-established requirements for most current (April 13, 2021) test method report; were also unable to locate the testing instructions for precision study.
• compendial method verification failed to evaluate accuracy of the test method.
• lacked scientific rationale to support the range evaluated during the method verification.
• lacked adequate scientific justification to identify an anomalous result obtained during precision study as an “outlier” and to exclude it from the study.
• Review of raw data compared to report indicated discrepancies in the number of samples and the timing of testing.

B. Firm failed to validate the non-compendial method for in-process and packaging testing.

Firm attempted to correlate compendial and non-compendial test methods as part of validation of firms “quick methods.” The results showed a low correlation and a significant difference between the methods. Of concern, the data showed significantly lower conductivity values when compared to the compendial method. However, it was concluded that the methods had good correlation and authorized it for use in production in place of the compendial method. This may have resulted in inaccurately low conductivity results being used to release Avicel that in fact failed USP conductivity requirements.

C. Firm inappropriately used composite sampling.

While the firm utilized non-compendial for individual packaged samples, the certificate of analysis included the result of the composite sample. A review of the data indicated passing composite sample results comprised of samples which included individual failing packaging samples. The use of composite sampling may have allowed the release of OOS Avicel to the market. Additionally, the practice of composite sampling is concerning considering non-compendial tests provided inaccurate results and Firm were using composite samples inappropriately for release testing; lacked an adequate scientific rationale for the use of compendial test methods for composite samples and non-compendial test methods for in-process and packaged samples.

Firms’ response is inadequate. Firm reiterated that it verified the compendial method but failed to provide adequate information to support this. FDA acknowledges Firm’s commitment to validate non-compendial test methods, including conductivity and pH.

In response to the Warning letter, Firm to provide:

• A comprehensive assessment of test methods used for excipients for drug use to determine their suitability (i.e., compendial method verification, or non-compendial method validation). If verification or validation is needed, to provide the corresponding protocols and reports or a plan and timeline for completion of the appropriate activity.
• Improved procedures regarding validation/verification requirements and updated analytical methods.
• A retrospective review of results obtained using unverified/unvalidated compendial and non-compendial methods.
• A summary of the impact assessment for released lots.
• A comprehensive, independent review of Firms laboratory practices, methods, equipment, and analyst competencies. Based on this review, to provide a detailed CAPA plan to fully remediate Firms laboratory system.
• Scientific rationale for the use of the compendial test methods for composite samples and non-compendial test methods for in-process and packaged samples.

As can be seen from the FDA warning letter manufacture of Excipients need to comply with applicable cGMPs as per 21 CFR 210&211 and other applicable regulations just as the drug product and drug substance manufacturers. Companies should have procedures for Qualification of test methods (validation, verification) and adopt test methods only after they are adequately qualified, qualification activities should be well documented, reviewed before approval. Batch testing and release procedures should be established with adequate definition of batch and lots within a batch. Where companies follow an inprocess and packaged sample testing and composite sample testing for release of packed lots and the batch (may be due to large batch sizes, continuous manufacturing process) the lots and the batch can be released only if all the samples (all the individual package samples  and composite sample) is passing.

• Compendial methods should be verified for their suitability, accuracy, range before they are adopted to specific products of firms. This is applicable to all methods (not only the chromatographic or spectroscopic methods, where firms usually perform the method verifications).
• Non compendial methods should be fully validated covering all parameters – Specificity, System suitability, Linearity, Accuracy, Range, Robustness and detection limits (where applicable).
• If non compendial methods are used in place of compendial test methods for batch analysis, release testing, such methods need to be qualified. Method equivalency between compendial and non compendial method should be established unambiguously with appropriate acceptance criteria. The non compendial methods should be equal to or better than the compendial method with reference to defined qualification parameters. (Precision, linearity, accuracy, robustness).
• All method verification, validation and method equivalency studies should be performed against approved protocols defining the test procedure, acceptance criteria.
• All the raw data of the method verification, validation and method equivalency studies should be thoroughly reviewed while approving the reports. Any anomalous /atypical results should be reviewed, investigated and appropriately concluded with scientific rationale and documented in the reports. If necessary methods should be properly updated / modified to ensure the defined criteria are met.
• Concept of batches and lots (for eg packaged lots in case of large batch sizes) should be appropriately defined. For releasing any of the individual lots, results of all lots within the batch as well as composite sample of the batch (if any) should be passing. Any discrepancies from this should be investigated, before concluding on the release of lots or batch. (Refer to the USFDA definition of batch and lot:

USFDA 21 CFR 210.3

Batch: A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits and is produced according to a single manufacturing order during the same cycle of manufacture”.

Lot: A batch, or a specific identified portion of a batch, that has uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures it having uniform character and quality within specified limits.”

• Before responding to agency, there should be a comprehensive    assessment of the FDA inspectional observations, corrective actions.  Response to agency should be supported with objective evidence of actions taken and should address the inspector’s concern. If an observation is countered, challenged or even tried to be explained to remove any misconception it should have adequate scientific rationale and supported with evidence of actions.

In the Warning letter FDA has raised concerns on:

• Potential release of failed (OOS) Avicel batches to market
• Inadequacy of method verification, validation, method equivalency procedures (for adopting non-compendial methods in place of compendial methods). Impact on all other method verifications and validations.
• Practices followed for method verification and validation
• Potential lapses in all other test methods for excipients
• Analytical test results of all other excipients and batches
• Firms’ laboratory practices, equipment’s, analyst competencies

The corrective actions (CAPAs) and remediation actions should comprehensively address all the above concerns:

• Engage competent independent cGMP expert consultant to review and assess the overall system for qualification of methods – method validations, verifications, method equivalency, adoption of non-compendial methods. Based on the assessment enhance the procedures.
• Assessment of all the live Avicel batches (within valid expiry) for potential failure for conductivity against a defined protocol. Take remediation actions (customer intimation, recall)
• Assessment of all the other test methods for all the excipients for status of qualification of methods – method verification, validation, adoption of any non compendial methods, method equivalency and adequacy of activities performed. Based on the assessment plan a remediation for performing the method verifications and validations.
• Assessment of all the test results of each of the excipient for potential lapses (in conjunction with assessment of the adequacy of methods and method qualifications). Based on the assessment take up remediation actions (customer intimation, recall).
• Based on the assessment wherever potential failure is identified, open investigation, evaluate the root cause (Laboratory error, or where the laboratory error is not conclusively established manufacturing investigation to establish potential causes). Evaluate the CAPAs established for adequacy (Based on recurrence of the deviations or OOS, whether CAPA address the root cause). Where there is potential concerns of production process, address the same with improvements of manufacturing process.
• Review the definitions and practices of batch and lot segregation, procedures for testing and release of batches and lots.
• Comprehensive assessment of all laboratory practices with respect to compliance to cGMP requirements (e.g activities such as (but not limited to) sampling, sample handling, qualification and calibration of analytical equipment, standards, release testing of batches, training and qualification of analysts and so on). Corrective actions to address all the gaps identified.
• Hire experienced and competent experts for laboratory (QC), train and coach the laboratory personnel.