Manual – 025 Conducting Investigations

5.1 General Written procedures must be established describing how investigations should be performed, as well as the roles and responsibilities for performing, documenting and approving them. The need for a timely and thorough investigation of an incident, problem or deviation must also be included in the procedures. Appendix 1 outlines a general recommended process for conducting investigations.

5.2  Problem Identification and Determination of Whether an Investigation is Required Incident, problems or deviations may be identified at any time during normal activities; through feedback from existing monitoring systems (e.g. Internal/external auditing, stability programs, product complaints); or from notification from outside parties (e.g. suppliers, regulatory authorities).

Once an incident, problem or deviation is identified, the need for an investigation and the nature and depth of the investigation will be dependent upon the many surrounding circumstances, including the degree of risk that it presents.

Written procedures must provide guidance regarding the circumstances under which investigations will be or will not be required. Following evaluation of the incident, problem or deviation, if an investigation is not to be performed, the rationale for this decision must be documented, unless procedures exclude the requirement for investigation of the specific incident or if it falls into pare-defined category that excludes the need for an investigation.

5.3 Notification of Management and Management Review Written procedures must ensure management are notified of incidents, problems or deviations and kept informed of investigation status. Formal review and evaluation by management and/or the quality assurance unit must take place for any action that may result in notification of a regulatory agency or recall of material.

5.4 Investigation Approach Once the need for an investigation is identified, the investigation approach should be clearly defined and documented.  Depending upon the extent of the investigation, this may be outlined in an investigation protocol to state the scope, timescales, and responsible individuals. To execute the investigation, a team should be established to include experts from relevant local functions as well as remote functions as necessary. The investigation may be coordinated by centrally based organizations via Issue Management Teams.

5.5 Root/Assignable Cause Analysis Investigations must include steps to identify the root or assignable cause of the incident, problem or deviation. Where a root cause is not identified, the most probable cause(s) must be identified and corrective and preventive actions initiated on this basis. Investigations should be detailed, focused and logical in pursuit of the cause of an incident, problem or deviation.

Investigation procedures should outline the general approach to be taken in conducting an investigation and require review of relevant information including records, data, past issues, and any events/circumstances leading to, surrounding and/or associated with the incident, problem or deviation.  Where the initial investigation results do not lead to identification of a root cause, further investigation may be required.

5.6 Identification of the Scope of the Problem Investigations must include the identification of the scope of the incident, problem or deviation.  Documentation must demonstrate that the potential for a broader scope is evaluated throughout the course of the investigation.

If considered isolated, the investigation report must document the rationale for limiting the investigation. Investigation procedures should provide guidance in this respect and require consideration of whether the particular incident that initiated the investigation was isolated or whether it may have gone undetected in or have the potential to affect other lots/batches, time periods, etc.

5.7 Identification and Implementation of Corrective and Preventive Action Investigations must include the identification and implementation of immediate corrective action.  Determination of the need for preventive actions must also be included.  Where preventive action is identified to prevent reoccurrence of the problem, it must be outlined and implemented. Once an incident, problem or deviation is identified, immediate corrective action may be necessary (e.g. to hold batches from further distribution).

Upon investigation, further corrective action should be outlined to isolate the problem, to minimize impact on compliance and to ensure the safety of consumers and/or study participants, (e.g. product recall). Actions should also be identified to prevent reoccurrence of the problem. These are considered preventive actions and may include such things as revision of processes or procedures, creation of new systems, training or re-training of personnel. An implementation plan for corrective and preventive action (where necessary) must be established with identified actions, persons or groups responsible, and timing for completion of the actions.

The timing for implementation must be agreed and take into account the relative risk to ongoing and future activities.

Any preventive actions must be completed as soon as possible.  In the event that a preventive action may take some time to implement (e.g. purchase and commission a new piece of equipment), the corrective actions identified must take into account such things as additional oversight to minimize the occurrence of similar incidents while the preventive action is being completed.

5.8 Investigation Conclusions and Approval an investigation must include documented conclusions.  Conclusions should include identified or probable root cause(s), scope of the incident, problem or deviation, recommendations for disposition of the product batch(is), including any actions taken on other related product batches identified as a result of the investigation. The investigation, conclusions, corrective and preventive actions taken and/or proposed must be approved by management and by the Quality Assurance function.

5.9 Investigation Closure Investigation procedures must outline requirements that must be met tallow an investigation to be closed. Investigations must involve a formal step for closure. Investigation closure should be performed at the point where conclusions have been drawn, dispositions made, corrective actions taken and preventive actions taken or identified.

In the case of longer term preventative action identified (i.e. Beyond 30 working days to implement), the investigation may be considered closed, with agreement of the approving parties, provided outstanding actions are included in an action plan or compliance improvement plan (or similar system), with identified completion dates, and that follow up is monitored to completion.

5.10 Preventive Action Follow Up Although an investigation may be considered closed, additional, longer-term preventive actions may have been identified. A process must be in place to monitor the preventive action plan and ensure documented closure of actions.  If, through the course of the implementation, it is deemed unnecessary to proceed or if additional or alternate action is taken, this must be documented and agreed by those responsible for approving the original investigation conclusions and actions.

All action taken must be documented separately, or as an addendum to the original investigation report and filed with the original investigation documentation or traceable to it.

5.11 Trending/Preventive Action Monitoring Trending of incidents, problems and deviations must take place in order to monitor that corrective and preventive actions have been effective. Where trends identify that actions have not been effective, systems must been place to investigate the trends, including further root cause analysis and implementation of further corrective and preventive actions.  Trending and resulting investigations must be documented.

5.12 Timing Regulatory authorities view the prioritization and conduct of investigations as well as the timely implementation of corrective and preventive actions as critical elements in a Quality System. The timeliness of an investigation is critical.  Procedures should require that investigations take place in as timely a fashion as possible.  Important information and evidence related to events can be lost if investigations are delayed.

This delay can have a negative impact on identification of the cause and implementation of the appropriate corrective and preventive actions.  Procedures should establish priorities for investigations.  For example, an out-of-specification test failure on a stability sample should take priority over other activities.  Immediate action should be required for those incidents, problems or deviations of the highest priority.

Those of lesser priority should be documented on discovery with an investigation commenced as soon as reasonably possible. Investigations must be closed and a report finalized within 30 working days of discovery of the incident.  If an investigation is not closed within 30working days, an interim report must be written detailing the justification for this, including additional actions taken to ensure that ongoing studies or production is not impacted or continuing at risk. A new closing date must also be indicated.

5.13 Documentation All elements of an investigation must be documented in a report. Appendix 2 entitled “The Investigation Report” provides recommendations for content and preparation of an investigation report. The investigation report should include the reason for the investigation, the areas investigated, key decisions made, actions taken/to be taken, by whom and when. Documentation should be thorough and be prepared throughout the course of an investigation.

Protocols, investigation documentation and reports should be assigned reference numbers to facilitate tracking. Where applicable, cross-reference to an original issue report/deviation/complaint, etc. should be made tallow for full traceability. The investigation report (interim report if appropriate) should be circulated tother impacted sites/functions as appropriate.

The Quality System must also ensure that links exist to provide visibility of the existence of an investigation to those making critical decisions that maybe impacted by the investigation underway – e.g. batch release. The security and retention of documentation should be in accordance with local practice and corporate guidance.