Investigation and Corrective Action

If the analytical method goes out of control, e.g. as indicated by the control chart maintained for the QCs (Section 2.5.3) repeated run failures without cause, or loss of selectivity 

All of the hardware, software, clever methodologies and validation go for nothing if analysts are unahle to assure the end user of the data that the method was in control throughout sample analysis and that the results can he trusted within the stated uncertainty limits. In addition to within-run acceptance criteria based on analysis of QCs and calibrators within a single batch run, control charts are also often used as a means for assessing whether or not the method is in control. Use of only the former as quality control indicators can often lead to missing problems that affect even the most fully validated methods. 

A recent FDA guidance for industry (FDA 2006) provides the Agency s current thinking on how to evaluate out-of-specification (CX)S) test results. Forpurposes of this document, the term CX)S results includes aU test results that faU outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia or by the manufacturer. The term also applies to aU in-process laboratory tests that are outside of established specifications. This document is intended for GMP studies, but it can be generalized for aU applications. The foUowing discussion represents an attempt to do so, as an adaptation of seven key recommendations (FDA 2006). 

The Principal Investigator and possibly laboratory management should discuss the situation with the analyst(s) responsible for acquiring the suspect data, and confirm that the analysts fully understand and have correctly performed all steps specified in the method and in laboratory SOPs. 

Examine the raw data obtained in the analysis, including visual inspection of chromatograms, and identify anomalous or suspect information. 

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Customer Complaints. A failure in a company s quaUty system often shows up in the form of a customer complaint. These reports of nonconformances, whether for product or service deficiencies, are typically received by the sales or customer service organization and then channeled to QA. Quahty assurance often tracks the progress and coordinates the complaint investigation. Once completed, it is QA that reviews the report of the investigation and corrective action for thoroughness and efficacy. QuaUty assurance then either passes the information along to the sales or customer service organization or contacts the customer direcdy. 

Is there a program for handling customer complaints, complaint investigations, and corrective actions ... 

The laboratory shall have a policy and procedure for the resolution of complaints received from clients or other parties. Records shall be maintained of all complaints and of the investigations and corrective actions taken by the laboratory. The laboratory shall have a policy and procedmes that shall be implemented when any aspect of its testing and/or calibration work, or the results of this work, do not coirform to "... 

If three consecutive mns over action levels occur, a media-fill failure investigation and corrective action report must be issued. 

The laboratory must maintain records of complaints, together with investigations and corrective actions. 

The noncompliance detected is extended for investigation and corrective action (as relevant) ... 

Periodic reviews may also be prompted by reported or suspected problems with GMP compliance. When a periodic review determines a deviation from approved conditions or practices this must be investigated and corrective action approved. If there is a need to redocument or retest the computer system, then the need for revalidation must be assessed and the resulting rationale documented. 

Review the reports of previous inspections, reports of adverse drug experiences and complaints, if any exist, as investigations and corrective action taken by the manufacturer should be verified during inspections. 

Any time the yearly MKT of a facility approaches 25°C, the occurrence should be documented, the cause for such an occurrence should be investigated, and corrective actions should be taken to ensure that the facility is maintained within the established conditions for drug product storage. The FDA recognizes that, when the yearly MKT of a facility begins to exceed 25°C, it may not necessarily have an effect on products that have been stored for less than 1 year at the time, but it should be a warning that the facility itself may not be under adequate control. 

Warnings went unheeded - Findings indicated that most incidents were often preceded by a series of smaller accidents, near misses, or accident precursors. Operations and maintenance procedures must include analysis, root cause investigation, and corrective action. 

When contamination is detected in the laboratory, an investigation and corrective action strategy should be developed to determine the source of the contamination and what procedures will be necessary to control it. No samples should be analyzed until it is shown that the problem has been corrected and that blanks and curves can be generated successfully on a routine basis. Additional procedures or modifications to the analytical method may be required to prevent the reoccurrence of the contamination. If it was determined that the blanks used concurrently did not adequately indicate that contamination existed, an additional investigation should be conducted to determine why, and what additional steps or types of blanks will need to be generated for the method. 

A reductive approach is normally used in addition to one (or both) of the above criteria. It is an important basis for in-service safety monitoring - especially regarding incident investigation and corrective action. 

High noise levels, vibrations, abnormal surface temperatures, strange smells should be looked into, the reasons investigated and corrective action taken to prevent any mishap, environmental pollution, deterioration in product quality and damage to plant equipment. 

Conduct weekly inspections with emphasis on good housekeeping, proper use of personal protective equipment (PPE), condition of critical parts of equipment, and preventive maintenance Determine the root cause analysis of any incident in 24 hours Create a written system for documenting all incidents and near misses (loss-producing events) and all subsequent investigations and corrective actions... 

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