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Risk analysis by FMEA as an element of analytical validation

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Abstract

We subjected a Near-Infrared (NIR) analytical procedure used for screening drugs on authenticity to a Failure Mode and Effects Analysis (FMEA), including technical risks as well as risks related to human failure. An FMEA team broke down the NIR analytical method into process steps and identified possible failure modes for each step. Each failure mode was ranked on estimated frequency of occurrence (O), probability that the failure would remain undetected later in the process (D) and severity (S), each on a scale of 1–10. Human errors turned out to be the most common cause of failure modes. Failure risks were calculated by Risk Priority Numbers (RPNs) = O × D × S. Failure modes with the highest RPN scores were subjected to corrective actions and the FMEA was repeated, showing reductions in RPN scores and resulting in improvement indices up to 5.0. We recommend risk analysis as an addition to the usual analytical validation, as the FMEA enabled us to detect previously unidentified risks.

Introduction

Analytical procedures must provide reliable results. To ensure the reliability of analytical procedures, e.g. those used in the quality control of registered drugs, it is essential to validate the analytical procedures [1]. This analytical validation covers technical and instrumental aspects. For example, the International Conference on Harmonisation (ICH) Guideline requires validation with respect to Accuracy, Precision, Repeatability, Intermediate Precision, Specificity, Detection Limit, Quantitation Limit, Linearity and Range [1]. In the European Union, the validation of Near-Infrared Spectroscopy (NIR) is described in a separate regulatory document [2], which focuses on technical and instrumental aspects.

However, the reliability of an analytical procedure does not depend solely on technical and instrumental aspects. On the contrary, Kieffer [3] argues that: “Frequently the steps in the process which involve human intervention are the weak links in the process (…) Quite often in validation work the human element is ignored while mechanical and technological aspects are studied in great detail”. In the regulated pharmaceutical industry, this discrepancy might originate from the fact that technical and instrumental aspects are covered by the Registration Dossier whereas human aspects are covered by Good Manufacturing Practice.

Risk analysis can bridge that gap, but up to now few results have been presented in which the human factor is fully taken into account. Cogdill et al. [4] introduced risk analysis into the development of a NIR analytical procedure, but no practical results were included. Dejaegher et al. [5] used Failure Mode and Effects Analysis (FMEA) in combination with other tools to study the reliability of a High Performance Liquid Chromatography (HPLC) analytical procedure, but did not explicitly discuss the human factor. Borman et al. [6] performed FMEA to identify important risks of a NIR analytical procedure for the monitoring of drying. However, only minor attention is paid to the human element as a risk factor. Capunzo et al. [7] applied also FMEA, to a clinical laboratory process. The authors mention the human factor and conclude FMEA to have a high improvement potential.

In our Official Medicines Control Laboratory we use a NIR analytical method for screening drugs on authenticity. In addition to the technical validation of our NIR analytical method, we applied risk analysis to our method using FMEA, taking into account human factors.

Section snippets

Materials and methods

The FMEA was performed according to the principles laid down in The FMEA Pocket Handbook [8]. The FMEA was performed by a team of four people with different competences: a NIR expert, a senior technician, an expert in Quality Assurance with experience in laboratory quality systems and HACCP, and a senior pharmacist who mainly participates in the review of the chemical–pharmaceutical part of registration files. The participants of the team all attended a one-day course on FMEA and the FMEA

Results

Six sessions of two hours each were needed to perform the FMEA.

In the process steps subjected to FMEA, a total of 31 failure modes were identified, with RPN scores ranging from 12 to 320. Table 2 shows the six failure modes with the highest RPN scores, the corrective actions taken, the RPN after these corrective actions were taken, and the improvement indices.

When evaluating the methodology, a team of a NIR expert and more general pharmaceutical experts was reported to work well, as the

Discussion

Several tools are available for the risk analysis. ICH Q9: QUALITY RISK MANAGEMENT [9] describes FMEA, Failure Mode, Effects and Criticality Analysis (FMECA); Fault Tree Analysis (FTA); Hazard Analysis and Critical Control Points (HACCP); Hazard Operability Analysis (HAZOP); Preliminary Hazard Analysis (PHA) and Risk Ranking and Filtering. We choose FMEA, a tool which, according to ICH Q9, “can be used to prioritize risks and monitor the effectiveness of risk control activities” and also

Acknowledgements

The authors would like to thank D.W. Groot and F. Bakker for their contribution in carrying out the FMEA.

References (10)

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