Manual – 029 Manufacturing Deviation Management Pharmaceuticals quality assurance & validation procedures GMPSOP

1. Purpose

The purpose of this guideline is to outline the requirements for the reporting, investigation and handling of individual deviations, and to outline a systematic approach for the trending of deviations, to enable ongoing improvement in deviation performance.

2. Scope and Applicability

This document applies to all cGMP activities performed by the manufacturing sites. It applies to all facilities, processes, systems, and procedures used during manufacturing and quality control, that may directly or indirectly affect product quality. The objective is to facilitate investigations into individual deviations and the reduction of deviations across Operations, through a systematic and collective approach.

Prospective (or planned) deviations are out of scope. Out-of-Specification (OOS) analytical results are not covered by this document.

3. Definitions

3.1 Investigation

A formal and documented review of an issue, deviation, incident or problem, to identify its root cause and determine the actions required to address it.

3.2 Deviation

Departure from a process/procedure OR an unexpected result.

3.3 Root Cause

The basic cause of a deviation, from which effective actions can be defined to prevent recurrence.

3.4 Corrective Action

An action taken to correct or eliminate the causes of an existing deviation, issue, incident or problem.

3.5 Preventive Action

An action taken to prevent recurrence or pre-empt a potential deviation, issue, incident or problem.

3.6 Repeat Deviation

A deviation that re-occurs, after the identification of actions identified from a previous deviation. This would indicate that the root cause of the previous deviation had not been correctly identified and/or that the actions determined, had either not been taken in a timely manner, or effectively addressed the root cause.

3.7 Incident

Something that occurs that is not anticipated. These incidents should be acted on and an immediate response and assessment should be done to judge if it should be treated as a deviation.

3.8 Deviation

3.8.1 Level 3 Deviation

A deviation from GMP or procedure with no impact on product quality.

3.8.2 Level 2 Deviation

An isolated event or deviation from an agreed/approved procedure or process that normally results in a rapid corrective action or establishment of such corrective actions. Alternatively, a level 2 deviation may arise as a consequence of numerous repeated level 3 deviations.

3.8.3 Level 1 Deviation

A deviation that may have an actual or potential adverse effect on product quality (inc. purity and identity) safety or efficacy. Alternatively, a level 1 deviation may arise as a consequence of numerous repeated level 2 deviations.

4. Responsibilities

It is the responsibility of each site to implement a deviation management system.

This system should include the following:

* Tracking of investigations and logging system

* Documentation of the deviations

* Investigation including Root Causes

* Analysis

* Definition of and tracking of appropriate and timely corrective and preventative actions.Quality Assurance approval of deviation reports prior to making any product release decision

* Each site should set up cross-functional teams to manage the process outlined in this guideline, for the systematic handling of deviations.

N.B. See Appendix 1 for guidance on minimum responsibilities during the lifecycle of a deviation.

5. Guideline

5.1 Reporting of individual deviations

There must be a local procedure to describe the steps to be followed to investigate and document deviations and to prevent premature batch release.

The local system must ensure that all deviations are adequately addressed according to the seriousness of the deviation and that the appropriate corrective and preventative actions are taken. The originating area and

Quality Assurance must agree the corrective and/or preventative actions. Deviations must be classified and investigated according to their seriousness as, Level 1, 2 and 3.

Appendices 1 and 2 identify the minimum reporting requirements and the key steps in the lifecycle of a deviation.

For Level 1 deviations, the root cause must be identified wherever possible and a formal root cause analysis should be done if the root cause cannot be readily identified. If, following analysis, the root cause cannot be identified, the most probable root cause should be identified. The identified root cause, or the most probable root cause should be used as the basis for defining preventative actions to prevent recurrence.

For Level 1 and 2 deviations, a formal investigation should be performed and the root cause identified. Level 3 deviations are at minimum usually only documented in routine batch or test related documentation and records.

The process and timing in which agreement and approval are achieved may vary depending on the level of the deviation. The exact approach should be described in local procedures. For example, for a Level 3 deviation a retrospective review by QA in connection with batch release is acceptable. However, for a Level 1 deviation, corrective and preventative actions should be agreed with QA as soon as reasonably practicable after the incident.

5.1.1 Deviation Reporting

Electronic or paper records of all deviations must be kept, together with a record of the investigation (if applicable) and remedial action taken. The degree of documentation required may vary according to the level of the deviation. For example, minor deviations (Level 3) can be recorded in batch or other GMP documentation, whereas more significant deviations (Level 1 and 2) are usually recorded using a specific proforma. Batch related deviations must be referenced and/or filed with the relevant batch records.

The following minimum requirements must be included in the deviation documentation, as appropriate:

Figure:

Appendix 1 gives additional guidance around reporting responsibilities.

5.1.2 Deviation Timings

Deviations and their investigations must be completed in a timely fashion. The following timescales should routinely be applied. Deviations should be documented immediately.

The formal investigation of level 1 and 2 deviations should be initiated within 2 working days of the incident. An investigation report should be issued within 30 working days of the incident. The completion of some preventative actions may extend beyond 30 days, planned completion dates and any subsequent extensions to these must be agreed by QA. Batch related corrective actions must be completed prior to batch release.

5.1.3 Stability Testing of Batches Subject to Process Deviations

Additional stability studies can be carried out to support release of batches subject to a process related deviation when the product is known to have either:

Significant batch to batch variability in stability characteristics in normal manufacture; and/or

One or more stability parameters that show adverse trends at long term storage conditions giving data that normally approach the lifetime specification limits in the year before expiry; and/or Quality control test results that are frequently near the lifetime specification limits at time of manufacture

If the nature of the deviation raises questions about its impact on stability, then a special stability study should be considered.

These studies may be conducted as part of the postproduction surveillance program. This should not be used on a regular basis and it is important to know beforehand how to act on the results from the study. Comparison of stability data generated at accelerated conditions may be useful in predicting atypical adverse stability characteristics providing that data on typical manufacture have been generated under similar conditions. In this eventuality the person responsible for releasing the affected batches should consider appropriate corrective actions

Note: stability OOS results (or adverse stability trends) are not regarded as process deviations.

5.2 Systematic approach for the trending of deviations

In addition to the identification of specific actions identified through individual investigations, a formal periodic review of all deviations will enable the identification of any trends and the definition of improvement actions where appropriate. This pro-active approach, in addition to the re-active approach used for individual investigations and an appropriate set of Key Performance Indicators (KPI’s), should result in the elimination of specific types of deviations and on-going improvement in deviation performance (e.g. reduction in the number of deviations occurring; elimination of repeat deviations).

Depending on site size, the formal periodic review of all deviations may be a one step process looking across the whole site, or a multi step process built up from logical groupings (e.g. functional areas such as processing, packaging, distribution, quality assurance). Typically, this work is performed in cross- functional teams including Production, Quality Assurance and Process Technology (the function with knowledge of the process). The full process and a systematic approach to classification and trending is outlined below in section 5.3 and 5.3.1.

5.3 Classification and trending, overview

The quality system covering deviations should facilitate the identification of trends (including any emerging trends), their communication to management and identification of areas for improvement. Therefore the system should include a periodic review and analysis of all deviations, to identify recurring incidents and trends. For Level 1 and 2 deviations, this formal review should be at least annual and may be performed as part of the periodic and/or annual product quality review. It may be appropriate to trend Level 3 deviations on a less formal basis.

To support the formal and systematic trending of deviations, measurement and trending processes need to be in place. The review frequency should be linked to the numbers of deviations raised and other relevant factors, such as process capability. The tools typically used to facilitate this, are Process Behavior Charts (sometimes called Statistical Process Control Charts), histograms and categorization/classification schemes. The following parameters should be trended:

– Number of deviations raised

– Number of repeat deviations

– Timeliness measures (e.g. elapsed time between the deviation occurring and the approval and closure stages)

– Root causes against the classification scheme in section 5.3.1.

The outcome of the ongoing product quality review process should also be taken into account during the periodic review of deviations.

5.3.1 Classification and trending – detailed process description

The detailed process for the formal and systematic trending of deviations, is divided into six steps. To realize the maximum benefit from the process it is essential to engage personnel with the right experience and knowledge.

This may vary between steps in the process and specific problem areas. Sufficient time must also be allowed, particularly on the first two steps.

Step 1

Understand the overall deviation ‘picture’ across the site and define any major problem areas. Generally this is facilitated by grouping deviations according to a local categorization/classification scheme.

Dependant on the size of the site, it may be necessary to apply the scheme to individual functional areas and to develop the overall site ‘picture’, from these. Application of the local categorization/ classification scheme, should enable different views of the raw data (the individual deviations) ‘picture’ and the identification of any major problem areas. The root cause scheme below is applicable to any function and any site. Other common categorization/classification areas that can be used are: location (where the deviation was found – e.g. which line); activity (what was happening when the deviation was found – e.g. primary packing); and symptom (how the deviation was recognized – e.g. fails limit). Tools that can be used are Pareto charts, histograms, process mapping and brainstorming. (See appendix 4).

Root cause categories are defined as:

– Man (Human/Manual mistakes leading to a deviation)

– Machine (Mechanical malfunction and breakdowns leading to a deviation)

– Method (Complicated and/or unclear guidance in procedures, guidelines, manufacturing methods, batch records, process or control records)

– Manufacturing (Non-robust or established processes).

– Material

– Environment

Local categorization/classification schemes may find that sub-division of these root causes (or other groupings), will aid understanding of the overall ‘picture’ and should therefore be used (e.g. sub-division of the ‘Man’ root cause, into ‘Procedure not followed’, ‘No available procedure’).

Record the outcome.

Step 2

Prioritize any defined problem areas and define what is causing them. Where multiple (>3) problem areas have been defined, use simple risk management tools to prioritize the areas which will most improve product quality, compliance and/or improvement in deviation performance measures. Analyze the cause(s) of each priority problem area. The tools, which can be used to do this, include:

– Fishbone diagrams

– Spider diagrams

– Pareto charts

– Histograms

– Brainstorming

In some cases, the need for additional or supporting data may be identified during this stage. This data should also be collected, in order to complete the analysis and prioritization step.

Record the outcome.

Step 3

Generate solutions. Identify the actions required to address the cause(s) of the priority problem areas. Use tools such as the 4-box model; road of choice analysis/FMECA (failure mode effect and criticality analysis against different solutions).

Record the outcome as a detailed action plan against each priority problem area.

Step 4

Track all actions to completion. Periodically review the action plan and make amendments as appropriate. Look for evidence, to determine if specific actions have/have not been effective. If the expected result has not been realized, re-visit the previous step, to determine if any amendment of the action plan is required. Update the action plan as appropriate

Step 5

Evaluate the impact of the actions taken, on product quality, compliance and/or improvement in deviation performance measures, to determine if the desired outcome(s) have been achieved. If a desired

outcome has been achieved, ensure that the benefits are consolidated for the long term (e.g. by ensuring that any related process and procedural documents are updated and personnel trained in them). If a desired outcome has not been achieved, determine why not and define any additional actions to address this. This may require going back to Step 3, or starting again from Step 1.

Step 6

Communicate the outcome of the improvement actions across the site, to ensure that the learning is shared and can be applied elsewhere, where appropriate. As appropriate, communicate the outcome of the improvement actions with other sites, to ensure that the learning is shared and can be applied elsewhere, where appropriate. Start a new review of the deviation profile and run the process again.

See appendix 3 for process scheme.