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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on November 26, 2025

In November 2025, the USFDA issued a Warning Letter to Bangalore-based Cdymax India following an inspection in April 2025 by investigator Arsen Karyapaten. The citation highlights significant lapses in the investigation of laboratory incidents, handling of Out-of-Specification (OOS) results, and the validation of analytical methods.

Key Findings

1. Lapses in Laboratory Investigations

The Warning Letter notes that the firm recorded over 1,500 laboratory incidents, including OOS results and equipment failures. However, Cdymax failed to adequately investigate these incidents, often lacking appropriate root cause analysis or Corrective and Preventive Actions (CAPA). Even when laboratory errors could not be conclusively identified, the firm failed to initiate manufacturing investigations.

Testing into Compliance
Incident of unknown peak in stability sample

The warning letter cites an example of a stability sample where unknown peaks were observed. However, after testing a third sample and receiving passing result, the initial result was invalidated citing possible contamination during sample preparation. There was no identification of the contaminant, its origin and reason for its presence in the sample.

Lapses in Response to FDA

The FDA also flagged discrepancies in the firm’s response. While Cdymax claimed no batches were released by repeating the analysis using new sample solution, the data tables indicated otherwise

Training as CAPA

FDA warning letter also criticized the CAPA of refresher training on GLP practices to personnel, noting it contradicted the Firms own initial finding that the analysts were trained and qualified.

2. Lapses in Validation of Test Procedures

The inspection revealed a failure to validate in-house methods for raw materials, starting materials, and finished APIs, as well as a failure to verify compendial methods.

In response to FDA, Cdymax committed to validate /verify test methods and also provided a completed method validation for a starting material. But FDA found this was lacking with insufficient robustness, precision, suitability studies to demonstrate method is adequately validated.

Comprehensive Assessment and Remediation

FDA has asked the Firm for a comprehensive, retrospective, independent review of Firm’s systems and procedures and remediation plan addressing:

  • System for investigation of deviations, laboratory incidents, discrepancies, complaints, OOS results, and failures
  • Remediation plan for the CAPA program and investigation competencies and procedures,
  • Retrospective review of all laboratory incidents of the past four years and whether the incident conclusively or inconclusively demonstrate causative laboratory error
  • Extension of CAPA: where laboratory error is route cause, review all other methods vulnerable to similar route cause
  • Manufacturing investigations where root cause is inconclusive
  • Review of chemical and microbiological specifications of materials, supplier CoA acceptance processes, and a commitment to perform at least one identity test for all incoming lots.

QC lapses – What should have been done?

OOS Investigations

USFDA regulations (21 CFR 211.192) require a scientifically sound investigation into any OOS result to determine the cause of the OOS and implement appropriate corrective actions. Several USFDA 483s and Warning letter citing’s highlight this.

The USFDA guidance on Investigating Out-of-Specification (OOS) Test Results define a phased approach:

  • Phase I – Laboratory Investigation
  • Phase II – Full scale investigation

The MHRA guidance on Out-of-specification investigations gives a very usable framework for phase wise investigation which aligns well with the USFDA expectations.

  • Phase 1A: Obvious Laboratory error (E.g.: Instrument failure, power failure, incorrect method / instrument parameters, other obvious errors like contamination from glassware, spillage, wrong glassware etc).
  • Phase 1B: Extended laboratory investigation to identify other possible errors
    • Errors in performing the different steps of the test procedure (weighing, dilutions, extractions, injections and so on)
    • Instrument errors, chromatography issues like baseline drift, spikes etc
    • Standard related issues
    • Contamination, sample degradation, other handling errors,
    • analyst knowledge and skills and performance of the test

Phase IB may also involve hypothesis testing, to evaluate what would have happened.

  • Phase II: Full-Scale Investigation. When evidences from the Phase 1 (A&B) investigations are unclear a full-scale manufacturing investigation should be taken up to determine what caused the OOS result. This should include (but not limited to):
    • Review of manufacturing documents
    • Review of process steps, process capability, process development records
    • Suitability of equipment, facility
    • Variability of materials, adequacy of specifications
    • Failure and deviation history

Phase II also may involve a hypothesis testing including retesting a portion of the same sample or additional sampling and testing to evaluate and confirm projected causes

The whole investigation process – progress from one phase to the next, rationale for additional testing should be well documented. Hypothesis testing must follow a predefined plan rather than testing till acceptable results are obtained or testing into compliance.

After Phase 1 investigations if the projected laboratory error is not clear and conclusive (for e.g. a possible laboratory error), a manufacturing investigation must be performed. FDA has highlighted this in several warning letters.

See other USFDA 483s / Warning letters citing OOS

The USFDA guidance also emphasizes that there shall be no preconceived assumptions as to the cause of the OOS result. It should be the outcome of an objective investigation.

The Training “Trap”

How many times personnel will be trained on GLP or analytical processes as a CAPA for OOS incidents. If for every laboratory incident, training is a CAPA, then training program itself is flawed! Regulatory agencies are increasingly being wary of laboratory error-human error as root cause of OOS and training as the CAPA; FDA has flagged this many times.

What is needed is to develop competencies for OOS investigations to identify the root cause and appropriate CAPA. And strengthen process of building competencies and skills of analysts and analyst qualification. Enhance the program with explanations and practical demonstration of each unit tasks in an analytical process and qualify analysts for each unit task. This is what can help in reducing laboratory incidents and errors.

Read Qvents post – Strengthen Analyst Qualification, Reduce Human Errors

Method Validation

FDA guidance on Analytical Procedures and Methods Validation require that analytical methods should be validated and validation studies shall cover:

  • Specificity
  • Linearity
  • Accuracy
  • Precision (repeatability, intermediate precision, and reproducibility)
  • Range
  • Quantitation limit
  • Detection limit
  • Robustness studies (to evaluate effect of changes in method parameters)

Compendial procedures should be verified covering validation characteristics such as specificity, LOD, LOQ, precision and accuracy.

Test method should be validated / verified to show they are suitable for intended purpose:

  • Inhouse Test Methods: Full validation,
  • Compendial Methods: Verification

The extent of validation / verification efforts shall depend on the criticality of material and should be documented and justified. For raw materials validation / verification of the test method must demonstrate fit-for-purpose.

Conclusion

The Cdymax Warning Letter serves as a reminder that “testing into compliance” and weak investigations are critical compliance risks. A robust Quality System should ensure comprehensive Investigation of laboratory events, identify root cause(s) and CAPA. Analytical test procedures must be fit for the purpose and this should be demonstrated through validation.

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