Improved Utilization of Self-Inspection Programs within the GMP Environment A Quality Risk Management Approach

Improved Utilization of Self-Inspection Programs within the GMP Environment A Quality Risk Management Approach Barbara Jeroncic Self-inspection is a well-established and vital part of the pharmaceutical quality system. The development of the International Conference on Harmonisation (ICH) Q9 and Q10 guidance documents have introduced an opportunity to improve the design of the self-inspection program by application of the quality risk management (QRM) principles and concepts. Selfinspection can be designed as a QRM tool used to assess the management of current and potential risks to quality and to drive forward continual improvement. The application of QRM also allows more efficient inspection workload and resource management focusing on those areas within the quality system that present higher risk to quality. This article provides examples of how QRM could be introduced to main activities within the self-inspection program. The article also explores the application of QRM in the area of self-inspection by pharmaceutical companies based in Ireland. INTRODUCTION Self-inspection is a well-established part of the pharmaceutical quality system. Companies have traditionally been using it as a method for monitoring the implementation and compliance with good manufacturing practice (GMP) principles, as well as for introducing appropriate corrective measures. This role of self-inspection is promoted by the current GMP legislation and guidance (1). Development of the International Conference on Harmonisation s (ICH) Q10 guide has expanded the role of self-inspection to that of an important performance indicator used for monitoring the effectiveness of processes and activities within the pharmaceutical quality system. ICH Q10 promotes the use of self-inspection results as an important input for periodic management review performed to manage, evaluate, and continually improve the quality system s performance (1, 2). An interview with a senior GMP inspector at the Irish Medicines Board (IMB) published in the Journal of GXP Compliance (3) identifies some of the issues with current self-inspection programs of pharmaceutical manufacturing companies. A major issue discussed was that significant and critical deficiencies observed during regulatory inspections were not identified and corrected by the companies themselves via their own self-inspection programs. This could be due to the fact that for many companies self-inspection comprises little more than a review of compliance with current standard operating procedures (SOPs). Furthermore, its low priority is coupled with insufficient resources and lack of commitment from senior management. The interview (3) identifies the opportunities for self-inspection to be designed as a formal quality risk management tool capable of identifying and managing risks and driving forward tangible and realistic continual improvement. Selfinspection programs designed in this way can help to demonstrate the effectiveness of the quality system, and thus can play an important role in the achievement of the reduced regulatory oversight in the inspection area (3). This article introduces an innovative self-inspection program design, as a part of quality risk management, aimed at risk identification and management as tools for continual improvement. As a part of the design process, a survey of pharmaceutical manufacturing companies in Ireland was conducted; 84 Journal of GXP Compliance

Barbara Jeroncic the findings are reported in this paper. The survey goal was to explore the practical application of quality risk management to self-inspection programs and the pharmaceutical industry interest in seeking reduced level of direct regulatory oversight in the area of regulatory inspections. REALIGNING SELF-INSPECTION AS A QUALITY RISK MANAGEMENT TOOL Many parts of the European GMP guide (1) are currently undergoing revision to incorporate the principles and concepts of the quality risk management, such as chapters one, three, and five. There is a similar opportunity with respect to chapter nine ( Self-inspection ). ICH Q9 is already taking initiative in its drive to define the frequency and scope of inspections by taking into account various risk indicators. ICH Q9 also provides guidelines for the application of quality risk management to regulatory inspections aimed to assist with: resource allocation including inspection planning, frequency, and intensity; evaluation of quality defect significance, recalls, and inspection findings; assessment of the scope and type of post-inspection follow-up; and identification of risks that should be communicated between inspectors and assessors to facilitate better understanding of risk control (4). ICH Q9 states, quality risk management is a systematic process comprising of assessment, control, communication, and review of risks impacting the drug (medicinal) product quality across the product lifecycle. Organizations manage risk through identification, analysis, and evaluation of the most suitable risk mitigation strategy. This process further encompasses risk monitoring and review aided by communication and consultation with stakeholders in order to ensure that no further risk control/treatment is required (4, 5). There is a potential to apply a quality risk management approach to the area of self-inspection that can be integrated into the organization s quality risk management framework. The purpose is two-fold as follows: To design self-inspection as a quality risk managment tool that can provide the objective evidence to the management about whether or not the current and potential risks to quality are effectively managed to acceptable levels. Management then can judge the effectiveness of processes and functions within the quality system Efficient inspection workload and resource management focusing on those areas within the quality system that present higher risk to the quality of medicinal product, with aim of meeting the quality objectives. Benefits Of The Application Of Quality Risk Management To Self-Inspection Programs ICH Q9 lists the following main benefits of the application of an effective quality risk management approach to various processes and activities within the quality system, including self-inspection (4): Ensuring high quality of the medicinal product by proactively identifying and controlling potential quality issues Improving decision making if a quality issue arises Facilitation of better and more informed decisions that can provide the regulators with greater assurance of a company s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight. ISO 31000 standard entitled Risk Management Principles and Guidelines provides even further detail of benefits of the application of effective quality risk management (5), as follows: Increasing the likelihood of achieving quality objectives Encouraging proactive management Awareness of the need to identify and treat risks throughout the organization Improving the identification of opportunities and threats Improving compliance with legal and regulatory requirements and international norms Improving governance Improving stakeholders confidence and trust Establishing a reliable basis for decision making and planning Summer 2010 Volume 14 Number 3 85

Improving controls Effectively allocating and use of resources Improving operational effectiveness and efficiency Improving loss prevention and incident management Minimizing losses. Elements Of Quality Risk Management The following are elements of quality risk management. Risk assessment. Risk assessment is the process of risk identification, analysis, and evaluation (4, 5). Its application within the self-inspection program can be tailored to the risk assessment output purpose, the desired level of detail, and the available information. For example, the estimate of risk associated with an area within the quality system, for the purpose of defining a scope and frequency of selfinspections, can be based on the general evaluation of risk factors, without a detailed risk assessment, as this will be performed during self inspections. ISO 31010 standard describes different methods and tools that could be used when performing risk assessment. Examples of the methods and tools are provided in the following sections. Risk identification. The purpose of the risk identification process is to identify the causes and sources of hazards, events, situations or circumstances that could have an impact upon the quality of the medicinal product, the quality objectives, and the nature of that impact (4, 5, 6). There is a variety of tools and techniques that could be chosen for risk identification, such as: reviews of historical data, checklists, theoretical analysis, systematic team approaches (e.g., structured what-if technique [SWIFT]), primary hazard analysis, hazard operability analysis (HAZOP), fault tree analysis (FTA), cause and effect analysis, and supporting techniques (e.g., brainstorming, Delphi method) (4, 6). Risk analysis. Risk analysis is an estimate of the risk associated with an identified hazard. It consists of linking the consequences and their likelihoods for the identified hazard (can also link detectability of the hazard) to determine the level of risk. The purpose of the risk analysis is to develop risk understanding (4, 6). The analysis of consequences determines the nature and type of impact that could occur (6). It can involve the following (6): Relating the consequence to the achievement of the quality objectives Taking into consideration existing controls to mitigate the consequence, together with all relevant contributory factors Considering both immediate consequences and those that may arise after a certain time has elapsed, if this is consistent with the scope of assessment Considering secondary consequences (i.e., those impacting on associated processes, activities, equipment, etc.). The examples of methods and tools that are suitable for consequence analysis are: HAZOP, hazard analysis and critical control points (HACCP), failure mode effects analysis (FMEA), cause and consequence analysis, cause and effect analysis, etc. (6). The probability analysis estimates the likelihood of a particular hazard, using one of the following approaches (6): Use of relevant historical data to extrapolate or predict the probability of occurrence of similar events or situations in the future. It should be noted that if historically there is a very low frequency of occurrence, the estimate of probability will be very unreliable Probability forecasts using predictive techniques such as fault tree analysis and event tree analysis. When historical data are unavailable or inadequate, the probability can be estimated by analysis of a relevant process, activity, equipment, etc. and its associated failure or success states Expert judgements that can be facilitated by formal methods (i.e., Delphi approach, category ranking, paired comparison, etc.). The consequence and likelihood can be linked by using a variety of qualitative, semi-quantitative, or quantitative methods to determine the level of risk. The degree of detail depends upon the particular ap- 86 Journal of GXP Compliance

Barbara Jeroncic plication, the availability of reliable data, and the decision-making requirements. Examples of methods and techniques are: consequence-probability matrix, SWIFT, FMEA/FMECA, etc. (6). Risk evaluation. Risk evaluation involves comparing the identified and analyzed risks against established risk criteria in order to determine their significance. The purpose of risk evaluation is to assist in making decisions, based on the outcomes of risk analysis, on the requirements and priorities of treatment implementation (4, 5, 6). Risk criteria should reflect the organization s values and objectives, legal, regulatory, and other requirements (5). ISO 31000 standard suggests consideration of the following factors when defining risk criteria: The nature and types of causes and consequences of risks that can occur and their measurement Definition of likelihood The timeframe(s) of the likelihood and/or consequence(s) How the level of risk is to be determined The views of stakeholders The level at which risk becomes acceptable or tolerable Whether combinations of multiple risks should be taken into account, and how and which combinations should be considered. Risk control/treatment. Risk control/treatment is the process of decision making in order to reduce and/ or accept risks, identify risk control/treatment solutions and implement these solutions aiming to reduce the risk to an acceptable level. Decisions can take into account a wider context of the risk and include consideration of the risk tolerance borne by stakeholders, cost-benefit analysis and the legal, regulatory, and other requirements (4, 5, 6). Risk communication. Risk communication refers to information sharing regarding risks and risk management between stakeholders. It is important that this information is accurately and regularly communicated through reporting channels established by the organization in order to ensure the success and effectiveness of the quality risk management process. This can take place at any stage of the quality risk management process (4, 5, 6). The communication and reporting mechanisms should ensure that key components of the quality risk management approach to self-inspections, and any subsequent modifications, are appropriately and timely communicated to all interested parties; that there is adequate reporting of the risk assessment outcomes; that relevant information on the application of quality risk management is available at appropriate levels and times; and that there are established processes for consultation with stakeholders (6). Communication between stakeholders can assist the development of appropriate quality risk management approach to self-inspection and integration of self-inspection into the organization s quality risk management framework. It can further ensure that the interests of stakeholders are understood and considered when developing self-inspection programs; bring together different areas of expertise to ensure that the risks are adequately identified and analyzed through the use of risk assessment methods and techniques; ensure that different views are appropriately considered when defining risk criteria and in evaluating risks; and can help to secure endorsement and support for a mitigation plan (5, 6). Risk review and monitoring. Regular review of the quality risk management ensures that any new knowledge and experience is taken into account (4, 5, 6). For example, it ensures verifying that the assumptions about risks remain valid, obtaining further information to improve risk assessment, analyzing and learning from events, including near-misses, changes, trends, successes and failures, verifying that risk assessments are properly applied, verifying that risk treatments are effective, detecting changes which could influence risk criteria and upon which risk treatments need to be revised, identifying emerging risks, etc. (5, 6). Application Of Quality Risk Management To The Activities Within The Self-Inspection Program The following sections discuss quality risk management applications to main activities. Examples of quality risk management within the self-inspection program include the following: Summer 2010 Volume 14 Number 3 87

Self-inspection planning defining the scope (inspection units), frequency, and level of selfinspections, and allocation of the inspectors Detailed plan preparation for self-inspections of the individual inspection units Conducting self-inspections Adequate response to self-inspection results determining the type of actions for the issues identified within self-inspections, determining the timeframe for the implementation of actions, and assessing the associated risks. Planning Of Self-Inspections Risk management can be applied to self-inspection planning with the intent to direct the inspection effort to the areas within the quality system that represent higher risk to the quality of the medicinal product and the achievement of the quality objectives. The application of the quality risk management allows the estimation of the risk associated with areas within the quality system and determining the scope (inspection units), frequency and level (time, number of inspectors) of self-inspections, and allocation of inspectors to particular self-inspections (considering their experience and skills) based on the estimated levels of risk. This forms the basis for a risk-based inspection planning and enables better utilization of available resources. The risk associated with an area can be estimated by analysis of selected risk factors that indicate or identify the risk. ICH Q9 suggests the following various risk factors that can be used: Complexity of the site, manufacturing process, and product The number and significance of quality defects Results of previous audits/inspections The overall compliance status and history of the company or facility Robustness of a company s quality risk management activities Major changes of building, equipment, processes, and key personnel Experience with product manufacturing process Existing legal requirements Official laboratory test results. Some additional factors the companies could consider might be the following: Criticality of an area. This factor considers the effect of failure of a particular area and the influence of potential or identified issues with this area on areas downstream Coupling of an area. Tightly-coupled processes or systems could be those having time dependent processes/activities that cannot wait; those having rigidly ordered processes or activities (i.e., sequence A must follow sequence B); those having only one path to a successful outcome; those having very little slack in the system, as the system requires precise quantities or specific resources for successful operation, etc. (3) Adequacy of resources associated with an area. The risk associated with an area can be estimated by using different risk ranking methods or tools. For example, a simple approach could be assigning a numerical descriptive value of 1 (low) to 3 (high) to established categories for the selected risk factors. An example is provided in Table I. The estimated values for all risk factors can then be linked together in an appropriate way to yield a risk level associated with an area (e.g., low, medium, and high). The estimated values for risk factors could also be multiplied by significance-weighting factors to give a total. This assessment of risk associated with the areas within the quality system can be seen as a preliminary risk screening with the intention to direct the inspection effort to those areas that represent higher risk. It is important that this evaluation of risk is appropriately communicated to the interested parties (e.g., management, inspectors, etc.). Furthermore, it should be regularly reviewed to take into account any new information including the results of self-inspections and the risk control/treatment process. Based on this information, the frequency of self-inspections can be reviewed and adjusted if required. Preparation And Conduct Of Self-Inspections Preparation for self-inspections of a particular inspection unit can include preparing detailed plans 88 Journal of GXP Compliance

Barbara Jeroncic TABLE I: Example of categories for a risk factor and their numeric values. Risk factor Results of previous self-inspections Number and significance of deviations Category (impact X likelihood) (based on data for a given time period) < 5 minor observations, no major or critical observations 1 < 15 minor observations, no major or critical observations 2 > 15 minor observations or any major or critical observations 3 < 20 minor deviations not affecting the number of released batches 1 per month. No major deviations affecting batch release > 20 minor deviations not affecting the number of released batches per month 2 < 10 major deviations resulting in delay of batch release 2 no major deviations resulting in batch reject or reprocessing > 10 major deviations resulting in delay of batch release 3 Any major deviations resulting in batch reject or reprocessing Value for individual self-inspections with the intention to direct self-inspection activities. These plans could be based on the risk assessment of the inspection unit with the purpose to focus on those elements that represent higher risk to the quality and the achievement of the quality objectives and can, therefore, have a higher impact on the effectiveness of the activity, process, or function of that unit. The elements with higher associated risk can be inspected more thoroughly during self-inspections and can be included into future assessments more frequently. Risk assessment performed at this stage can be seen as the initiation of assessment of risks associated with elements of the inspection unit based on the available information. Risk assessment can then be completed during conduct of self-inspections based on the additional information gathered during selfinspections. Risk assessment of the inspection unit can be continuously updated during subsequent inspections of the inspection unit based on new knowledge and experience. The purpose of the risk assessment is to provide an understanding of risks, including their causes, consequences, and probabilities, and the understanding of the adequacy and effectiveness of existing controls to mitigate these risks (6). After the conduct of each self-inspection, an objective report can be presented to the management regarding the adequacy and effectiveness of risk management of the inspection unit. The level of risk depends on the adequacy and effectiveness of existing controls, which can be addressed using following criteria (6): What are the existing controls for a particular risk? Are those controls suitable for adequate risk mitigation, resulting in a tolerable risk levels? In practice, are the controls operating in the intended manner and can they be demonstrated to be effective when required? For example, during the assessment of the inspection unit production process A, it was identified that there were several occasions of the delays in the process A as the purified water was not available due to out-of-specification test results. Table II provides an example of how risk associated with this hazard could be assessed. The assessed risk increased from Category 3 to Category 4 in a given time period, thus it was decided that purified water system would be inspected more frequently and new potential controls would be assessed. Summer 2010 Volume 14 Number 3 89

TABLE II: Example of the initial risk analysis of one of the identified hazards associated with an inspection unit. Identified hazard: Purified water (PW) not available due to out-of-specification results of conductivity, TOC, microbial content or endotoxin Impact factors: Number of days PW was out of use in a given time period Impact on batch release delay, reject, or reprocessing Impact categories: 1 PW out of use < 2-day intervals interruptions and delay in process A No impact on the number of batches released per month 2 PW out of use >2-day intervals Reduced number of batches released per month for < 2% 3 Reduced number of batches released per month for > 2% Any batch rejects or reprocessing Likelihood factors: Number of out-of-specification results in a given time period conductivity, TOC, microbial content, endotoxin Existing controls: UV disinfection system, series of water filters (purified water system map) Risk analysis: Risk category Impact X Likelihood 1 < 15 out of specifications resulting in interruptions and delay in process A but not impacting the number of batches released per month 2 > 15 out of specifications resulting in interruptions and delay in process A but not impacting the number of batches released per month 3 Reduced number of batches released per month for < 2% 4 Reduced number of batches released per month for > 2% < 2 batch rejects or reprocessing 5 > 2 batch rejects or reprocessing The output of the risk assessment performed during the preparation of detailed plans for self-inspections of the inspection unit could include the following elements to help ensure the effectiveness of self-inspections: A process map of the inspection unit providing visibility of the inspection unit elements and their interaction, and the interaction with other areas of the quality system A list of identified hazards coupled with description of methods and type of data used for hazard identification An analysis of consequences of those hazards and their likelihood, including a description of methods and type of data used for this analysis Estimated levels of risk associated with the inspection unit elements Criteria for risk evaluation based on the management tolerance of risk Objectives for self-inspections of the inspection unit (or their recommendation) to direct inspection effort to those elements that represent higher risk for the achievement of the quality objectives associated with the unit. Detailed plans can be prepared just before the individual self-inspections, or can be prepared pe- 90 Journal of GXP Compliance

Barbara Jeroncic Figure 1. Example of vertical and horizontal self-inspection. Warehouse Produc on Process 1 Produc on Process 2 Devia on Inves ga on Produc on Process 3 QC department 1 QC department 2 examination of all aspects of the quality system that contribute to the output (result) within a particular area, function, or department. It examines all inputs and activities required to produce an output. Selection of this approach is useful when performing departmental or functional self-inspections. Horizontal approach to self-inspection involves examination of an aspect of the quality system that is applied to, or involving, different functions, areas, or departments. This type of approach is useful when performing self-inspections of systems implemented across various areas or processes, involving different areas or functions (e.g., change management system, deviation investigation, training of personnel, and calibration of equipment). It is also useful for self-inspection of projects and products. Horizontal approach can be a powerful tool to test the interfaces between different parts of an organization involved in the system, process, project, etc. Ver cal self-inspec on approach: Example, self-inspec on of ac vi es within a QC department. Horizontal self-inspec on approach: Example, self-inspec on of devia on inves ga ons in the produc on area. riodically, in which case the risk assessment should be revisited just before individual self-inspections to include any relevant new information. It is very important that the relevant information is appropriately communicated to inspectors who are conducting selfinspections (if not the same person) to ensure the effectiveness of the risk assessment. Based on the outputs of the initial assessment, the inspectors can identify additional information required for efficient completion of risk assessment of the inspection unit, and identify methods for obtaining this information including various inspection techniques (e.g., interviews, observation, review of documentation, etc.) and approaches. For example, the inspectors could decide to use vertical or horizontal approach to self-inspection, as follows (7) (see Figure 1): Vertical approach to self-inspection involves an The inspection unit risk assessment outputs after the conduct of self-inspections could include the following: The updated list of hazards The updated analysis of risk, based on the information obtained during the self-inspections, including analysis of risk associated with any identified issues or non-conformances Evaluation of risks against established risk criteria A self-inspection report including the findings and conclusions that allow the management to judge the adequacy and effectiveness of the inspected unit risk management, recommended actions for identified issues, and identified opportunities for improvement of risk management and efficiency of the inspected unit elements. The common approach that can be used when evaluating analyzed risks against the established risk criteria is to divide risks into the following tree bands (6): An upper band, where the level of risk is regarded as intolerable and risk treatment is essential A middle band, where the management can Summer 2010 Volume 14 Number 3 91

decide, based on the established treatment criteria (e.g., As low as reasonably practicable [ALARP] criteria system), as to whether or not take any actions A lower band, where the level of risk is regarded as negligible, or so small that no risk treatment measures are needed. The results of risk assessment of the inspection unit should be appropriately communicated to the responsible management, enabling appropriate actions. They should also be communicated to those responsible for planning of self-inspections to allow review of the risk levels associated with the inspection unit. Risk assessment of the inspection unit can be revisited, reviewed, and updated before and during each subsequent self-inspection. Results of selfinspections are also important input into periodic senior management review as they provide objective evidence of suitability, adequacy, and effectiveness of the quality system and identification of opportunities for improvement of the quality system and the performance of the organization (2, 8, 9). Response To The Self-Inspection Results Based on the results of self-inspections, the responsible management can make decisions on whether the identified risks can be accepted or reduced and how to reduce the risks. If self-inspection identifies opportunities for improvement of the inspection unit, these decisions could also include the assessment of the identified opportunities and plans for their realization. Risk control/treatment process could be seen as a cyclical process involving the following (5): Review of self-inspection findings, including issues (e.g., a non-conformity or an ineffective control) or identified opportunities for improvement Risk assessment of the identified issues to facilitate decision on their mitigation, for example: An immediate correction eliminating an existing non-conformity or undesirable situation simple tools can be used to investigate the cause for the non-conformity or undesirable situation, such as brainstorming, 5 Whys, etc. A corrective or preventive action eliminating the cause(s) of an existing or potential nonconformity or undesirable situation in order to prevent recurrence or occurrence. For corrective actions, tools for root cause analysis can be used to identify the cause(s) of the issue. For the potential issues, the prevention can include FMEA or FTA analysis to determine potential risk associated with the identified issue A trend that will be monitored Selection of possible risk control/treatment solutions for the identified issues or improvements in areas where the opportunity has been identified: Identification of possible risk treatment solutions or improvement solutions (i.e., use of simple tools such as brainstorming, etc.) Assessment of risks associated with the risk treatment solutions or improvement solutions (i.e., residual risks, new introduced risks, etc.) Determining the criteria for selecting or prioritizing a particular risk treatment solution or improvement solution (e.g., risk context, stakeholders concerns, cost-benefit analysis, legal, regulatory, and other requirements) Solution confirmation providing proof, through objective evidence, that the selected risk treatment solution will solve the problem, or that improvement solution will improve the effectiveness of the inspection unit and will not adversely affect the quality of the medicinal product and achievement of the quality objectives Defining the project plan for the implementation of the selected risk treatment or improvement solution, including the following: Project goal and responsibilities (e.g., specific, measurable, attainable, relevant, time-specific [SMART] criteria can be used to define a project goal) Verification. How will the effectiveness of the selected risk treatment solution/improvement solution be verified? How frequently and for how long before the implementation? Implementation. How will the risk treatment solution or improvement solution be implemented and in what timeframe? 92 Journal of GXP Compliance

Barbara Jeroncic How will the effectiveness of the implemented risk treatment solution or improvement solution be monitored, how frequently and for how long? Implementation of the selected risk treatment solution/improvement solution Monitoring and assessment of the risk treatment solution and improvement solution (i.e., including through subsequent self-inspection) effectiveness. It is important that the outcomes of the risk control/treatment process are appropriately communicated to the interested parties; including those responsible for planning of self-inspections and those responsible for planning and conducting self-inspections of the inspection unit; as any actions taken can influence the risks associated with the inspection unit. The output of risk control/treatment process should also be input into the periodic senior management review. SURVEY OF PHARMACEUTICAL MANUFACTURING COMPANIES IN IRELAND ON THE QUALITY RISK MANAGEMENT APPLICATION IN SELF-INSPECTIONS A survey was sent to the quality assurance managers or audit managers of 40 pharmaceutical manufacturing companies based in Ireland with the intent to explore whether and how the pharmaceutical companies apply quality risk management to their self-inspection programs. The survey also assessed the companies understanding of, and their interest in, reduced level of direct regulatory oversight in the area of regulatory inspections. The survey included drug product manufacturers and manufacturers of active pharmaceutical ingredients. Eighteen companies responded to the survey (45%), and the results are presented as follows. The Role Of Self-Inspection Within The Quality System In 50% of the companies who responded to the survey, self-inspection is structured as a stand-alone and independent component of a quality system used to monitor compliance with current GMP regulations Figure 2. Application of formal quality risk management in high-level aspects of the quality system. and standard operating procedures. In 31% of the companies it is structured as a part of quality risk management used to proactively and systematically identify, evaluate, and manage current and potential risks to quality and non-compliances. The structure in the remaining 19% is in between the previous two. The majority of the companies, 63%, do not use selfinspection as one of the main activities for identifying the opportunities for continual improvement. The Application Of Quality Risk Management To Self-Inspection The survey tried to establish whether companies apply the quality risk management principles and tools outlined in ICH Q9 in the various high-level areas of the quality system. According to the survey, 44% of the companies apply them in the area of self-inspection (see Figure 2). The most commonly used formal quality risk management tools are failure mode effects analysis (FMEA) and process mapping and cause and effect diagrams, used by 69% of respondents. Furthermore, 50% of the respondents use hazard operability analysis (HAZOP) and flow charts; 44% use risk ranking and filtering; 38% apply hazard analysis and critical control points (HACCP); 31% implement fault tree analysis (FTA); and 19% use failure mode, effects and criticality analysis (FMECA). Companies were asked to estimate to what extent their self-inspection program was risk based, and Summer 2010 Volume 14 Number 3 93

Figure 3. Estimate of how much is self-inspection risk based. the results are presented as follows. The majority of the companies design their self-inspection programs based on assessed risks at least to some extent (see Figure 3). When planning the frequency and the scope of self-inspections, the results of previous self-inspections and regulatory inspections are the factors most frequently taken into account by the companies who responded to the survey (88%). In addition, 81% of the companies take into account the number and significance of quality defects associated with an activity/process; 69% consider the specific areas mentioned in chapter nine of the European GMP guide and the complexity of the specific activities and processes; and 63% of the surveyed companies take into account major changes in building, equipment, processes, key personnel, etc. Only 38% of the companies consider experience with the activity or process and just 19% take into account specific arrangements and agreements associated with the activity or process. Half of companies report that the same amount of time and personnel are typically devoted to all selfinspections included in the annual self-inspection program. Fifty-six percent of the companies who responded to the survey do not have documented guidance for different types of self-inspections (e.g., horizontal, vertical, systems-based, process-based, departmental-based, etc.). Only half of the respondents review results of self-inspection as a part of the periodic management review. The Potential For Reduced Level Of Direct Regulatory Oversight In The Area Of Regulatory Inspections ICH Q9 and Q10 promote the potential for reduced regulatory oversight. There is an opportunity to increase the use of risk-based approaches for regulatory inspections for companies that can demonstrate an effective quality system is being in place, including effective use of quality risk management principles. In the inspection area, reduced regulatory oversight can take a form of less frequent or less intensive regulatory inspections, or inspections where some areas are not inspected or are less thoroughly inspected based on the risk considerations (2, 3). Of the companies who responded to the survey, 56% are familiar with the potential opportunities for a reduction in the level of direct regulatory oversight that may be applied as envisaged by the ICH Q8, Q9, and Q10 guidelines. Further 38% are partially familiar and only 6% are not familiar at all. Importantly, 44% of the companies are interested in seeking some level of reduced regulatory oversight from the Irish Medicines Board, and the same percentage of the companies are not interested. The remaining 12% of the respondents have not answered this question. A significant majority, 81%, of the companies think that the best way to demonstrate to the regulatory inspectors that an effective quality management system is in place within the company is proactive discussion of the company s quality management system elements with the regulatory inspectors. Furthermore, 75% of the companies consider a good regulatory inspection outcome (e.g., no major or critical deficiencies) an important factor in demonstration of an effective management system; 50% assign equal significance to no recalls and a low number of complaints over a certain period, whilst 44% are satisfied with no for-cause regulatory inspections carried out at their company. The majority of respondents, 63%, would like to see a formal program of communications with regulators with respect to the potential applications of regulatory flexibility and reduced regulatory oversight. A considerable 31% are not interested in this, and 6% did not answer this question. The majority of the respondents, 88%, are willing to consider open 94 Journal of GXP Compliance

Barbara Jeroncic sharing of self-inspection reports with a regulatory inspector in some way, in order to demonstrate that an effective quality management system is in place within their company, whilst 12% of the companies would not be willing to do so. CONCLUSION ICH Q10 and ISO 9000 standard series view selfinspection as a vital and integral part of the quality system, providing an independent tool for monitoring and assessment of the effectiveness of the activities and processes within the quality system, and for driving forward their continual improvement. In order to be efficient and complete, this process should include the evaluation of the risks hindering the achievement of the quality objectives placed on activities and processes potentially affecting the quality of the medicinal product. There is an opportunity to design self-inspection as a quality risk management tool identifying and assessing risks associated with areas of the quality system and providing objective evidence on the effectiveness of their management. Self-inspection designed in this way could potentially identify issues and non-conformances before they occur by allowing the management to take the appropriate risk-reducing actions; and further recognise the opportunities for improvement of risk management and effectiveness of the quality system areas. Application of principles and concepts of quality risk management also enables more efficient organization and planning of self-inspections by directing the inspection effort to those areas of the quality system that represent higher risk to the quality of the medicinal product and the achievement of the quality objectives. The application of quality risk management in different areas of the pharmaceutical industry, including self-inspection, is strongly supported by ICH Q9. This article presents innovative approaches to self-inspection as a quality risk management tool, with the potential for introduction of a risk-based approach to self-inspection planning in pharmaceutical manufacturing. The results of the survey of the pharmaceutical manufacturing companies in Ireland demonstrate that the companies have started to apply quality risk management to their self-inspection programs. Whilst half of the companies still view self-inspection as an isolated and independent component of the quality system used to monitor compliance with current GMP regulations and standard operating procedures, the remaining respondents have structured it as a part of the quality risk management used to identify and manage current and potential risks to quality and non-compliances, at least to some extent. The majority of the companies estimated that their self-inspection program was based on the assessed risk at least to some extent. The most frequently used factors for determining the frequency and scope of self-inspections envisaged by ICH Q9 are the results of previous self-inspections and regulatory inspections, and the number and significance of quality defects associated with an activity or process. The survey identified three main areas of self-inspection program improvement within the pharmaceutical companies: structuring self-inspection as an integral and vital part of the company s quality system and risk quality management strategy; designing self-inspection in a way it could be used as one of the main activities for identifying the opportunities for continual improvement; and including self-inspection results as an input into periodic management review. With respect to the potential for reduced level of direct regulatory oversight in the area of regulatory inspection promoted by ICH Q10, the results of the survey showed that the majority of companies are interested in this idea and would welcome a formal program of communications with regulators. The surveyed companies consider proactive discussion of the company s quality management system elements with the regulatory inspectors to be the best way to demonstrate that an effective quality management system is in place within the company. The majority of the companies are willing to consider some form of open sharing of self-inspection reports with regulatory inspectors in order to demonstrate that an effective quality management system is in place. The survey identified a need for further regulatory guidance and recommendation in the area of the reduced regulatory oversight, as envisaged by ICH Q8, Q9, and Q10. Summer 2010 Volume 14 Number 3 95

REFERENCES 1. EudraLex, GMP Directive 2003/94/EU, Good Manufacturing Practice (GMP) Guidelines, Vol. 4, Part I-Basic Requirements for Medicinal Products, Chapter 9-Self-inspection. Retrieved from: http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/eudralex/vol-4/pdfs-en/cap9_en.pdf. 2. ICH Q10 Pharmaceutical Quality System, 2008. 3. O Donnell K., Self-Inspection and its Potential Benefits via ICH Q9, Journal of GXP Compliance, Summer 2008, Vol.12 No. 4. 4. ICH, Q9 Quality Risk Management, 2005. 5. ISO 31000 Risk Management Principles and Guidelines, First Edition, November 13, 2009. 6. ISO 31010 Risk Management Risk Assessment Techniques, first edition, 2009-12-01. 7. Wealleans D., The Quality Audit for ISO 9001:2000: A Practical Guide, 2nd edition, Gower Publishing, 2005. 8. ISO 9001 Quality Management System Requirements, Third Edition, December 15, 2000. 9. ISO 9004 Quality Management Systems Guidelines for Performance Improvements, Second Edition December 15, 2000. GXP ARTICLE ACRONYM LISTING ALARP As Low As Reasonably Practicable FMEA Failure Mode and Effects Analysis FTA Fault Tree Analysis GMP Good Manufacturing Practice HACCP Hazard Analysis and Critical Control Points HAZOP Hazard Operability Analysis ICH International Conference on Harmonisation IMB Irish Medicines Board ISO International Organization for Standardization QP Qualified Person QRM Quality Risk Management SMART Specific, Measurable, Attainable, Relevant, Time-Specific SWIFT Structured What-If Technique TOC Total Organic Carbon ABOUT THE AUTHOR Barbara Jeroncic has worked in the pharmaceutical industry for several years in different roles, including working in quality departments. She may be reached by e-mail at barbara.jeroncic@ imb.ie. 96 Journal of GXP Compliance