Practical Strategies for Improving Quality Risk Management activities in GMP environments

Transcription

1 Practical Strategies for Improving Quality Risk Management activities in GMP environments Kevin O Donnell, Ph.D. Market Compliance Manager & Senior GMP Inspector, Irish Medicines Board, Ireland CMC Strategy Forum, Quality Risk Management Conference Bethesda, July 27-28, 2009 Slide 1

2 Topics for today What ICH Q9 offers the GMP Environment and its limitations The role of Quality Risk Management in Qualification, Validation & Change Control How value-adding are current practices? Opportunities for Improvement Practical Strategies for improving Quality Risk Management activities in GMP Environments Considerations for future work to improve how we apply Quality Risk Management principles and tools Slide 2

3 Some thoughts on ICH Q9 ICH Q9 provides an internationally accepted framework in which to apply Quality Risk Management principles and concepts in our work environments But it provides only high level, conceptual guidance on QRM Not designed as a solution for carrying out, at a practical level, QRM exercises within a pharmaceutical company or Competent Authority Much of the guidance on methods and tools is largely conceptual It does not offer any substantial guidance on how the various tools differ from each other, or how to chose one tool over another Or how to apply the formal Quality Risk Management tools at a practical level in our day-to-day work activities It also offer no guidance on how to address the problems of subjectivity and uncertainty that are often experienced during QRM exercises Slide 3

4 Quality Risk Management in the EU GMPs Several references to Risk Assessment & QRM One of the main references for some time (since 2001) has been in Annex 15 A risk assessment approach should be used to determine the scope and extent of validation, and the likely impact of changes should be evaluated, including risk analysis. But how value-adding are current Qualification, Validation & Change Control activities in terms of addressing patient and animal risk? Despite ever increasing work on Q&V activities, there is evidence that defective and non-compliant medicinal products continue to be manufactured As discussed in ISPE s 2005 White Paper on Risk-Based Qualification for the 21st Century, Qualification practices are often document-intensive, expensive and time-consuming, but do not necessarily add value, or lead to clear patient-risk mitigation strategies or process understanding Slide 4

5 How value-adding are current Q, V & CC practices? On inspection, we sometimes find that despite extensive qualification work having been carried out on an item of equipment, key areas and issues are often overlooked For example, In a QC lab, extensive qualification was documented for the computerised system components of a particle size analyser but no qualification tests were performed on the vacuum pump on the instrument, and vacuum was critical when running the particle size method with this instrument Slide 5

6 How value-adding are current Q, V & CC practices? Likewise, process validation activities sometimes do not adequately address the critical and important aspects of processes Many GMP deficiencies still relate to validation activities For example: During the validation of a rework process for a high ROI batch of X, the design of the process validation protocol and the homogeneity tests to be carried did not ensure that the high ROI problem would be corrected, and it was noted that no ROI homogeneity tests had been carried out during the testing of the reworked batch During the reprocessing of batch Y (as a result of a freeze drying problem), no consideration was given to whether any validation testing was required to demonstrate dryness effectiveness or dryness homogeneity For a concurrent process validation exercise, no review of the outcome of the validation exercise had been carried out, and no conclusions had been documented on the suitability or otherwise of the process. In the Cleaning Validation Protocol for Filter Dryer A and Glovebox B, swab locations were not adequately specified with respect to worst case locations. Slide 6

7 How value-adding are current Q, V & CC practices? In change control, planned changes often involve substantial capital expenditure, large project teams and a significant use of resources but sometimes fail to identify important patient risks introduced by the change In 2006, one company decided to redesign its product artwork/livery to harmonise the appearance of its products across the product range Dispensing errors began to be reported shortly after the changed packaging hit the market, and the company decided to revert to the original packaging Adequate risk-based Change Control might have triggered the need to consult pharmacists groups as a key stakeholder for the change A recent change in the product contact material used to produce a cassette device for administering morphine sulfate solutions resulted in an incompatibility with the solution, and a sharp reduction in ph was observed This resulted in a patient level recall in Ireland and other countries Adequate risk-based Change Control might have allowed for better consideration of the potential risks presented by the new material Slide 7

8 Opportunities for Improvement As acknowledged in ICH Q9, the use of formal Risk Management methodologies in the pharmaceutical industry has, to date, been limited The full benefits of Risk Management, as a valuable component within a pharmaceutical quality system, have yet to be realised When one compares the current level of application of formal Quality Risk Management methodologies in the pharmaceutical manufacturing industry with that of other manufacturing industries - Automotive, semi-conductor manufacturing industries It is evident that the pharmaceutical manufacturing industry has a way to go to achieve a similar state of knowledge about risks and their contributing factors Slide 8

9 Opportunities for Improvement For example: In the Semi-conductor manufacturing industry High focus placed on process and product reliability. High degree of process understanding & detailed knowledge about the causative pathways that lead to important failure modes, such as electrostatic discharge This is indicative of the extent to which RM methodologies have been applied in that industry to better understand and control risk In the Nuclear power generation industry High emphasis on the use of formal quantitative Probability Risk Assessment methodologies, to understand possible accident pathways for loss of containment events, and how the control systems that are in place might fail e.g. quantitative Event Tree Analysis coupled with quant. Fault Tree Analysis In the Aeronautics industry The use of formal RM methodologies coupled with the use of lessons-learned databases & capturing near-miss data is often a formal requirement of their quality management systems Slide 9

10 Opportunities for Improvement The pharmaceutical industry is still at an early stage in its application of formal Quality Risk Management methodologies across the broad spectrum of its areas and activities. This presents opportunities Current approaches to Qualification, Validation & Change Control can be modified to benefit from the use of more formalised and scientific approaches to Quality Risk Management Several useful strategies can help as we move towards the use of more formal Quality Risk Management methodologies in our day-to-day work, especially as part of Qualification, Validation & Change Control activities Slide 10

11 Strategy 1 learn from other industries In Change Control, the Pharmaceutical GMP Industry should strive to learn from the experiences of other industries that are mature in their application of Risk Management Aeronautics, Nuclear Power Generation, Semi-conductor manufacturing In GMP environments, CC is of course often used to manage new projects While current CC procedures often evaluate the impact of the change on validation, cleaning, documentation, training etc they often rely on check-list approaches to Change Control This sometimes means that the company fails to ask in the broader (and more rigorous sense) what can go wrong if we implement this change or if we implement this new project? NASA has experienced and learned from this problem Slide 11

12 Strategy 1 cont d Like the GMP environment, NASA uses Risk Management and Validation NASA s Mars Climate Orbiter mishap 1999 the spacecraft was lost as it entered the Martian atmosphere at a lower then expected trajectory The investigating team highlighted serious flaws in NASA s approach to Risk Management and validation activities generally These were considered to be among the most important and frequent contributing factors to the failure of the Orbiter and other spacecraft a lack of systematic analyses of what could go wrong with the Mars missions, and that no fault tree or other a priori analyses of what could go wrong had been performed the Mars Climate Orbiter project failed to introduce sufficient discipline in the processes used to develop, validate and operate the spacecraft greater attention be paid to risk identification and management. Slide 12

13 Strategy 2 take learnings from key research areas into account When writing QRM procedures, the GMP Industry should make use of research in areas that relate directly & indirectly to QRM activities A central feature of Risk Assessment activities concerns the need to make decisions and judgement calls about problem areas and issues that are uncertain, such as the probability of an event occurring. Experimental psychologists such as Kahneman, Tversky, Fischhoff, Slovic, Lichtenstein know a lot about how experts and others make decisions about uncertain events, and what can affect human judgements during brainstorming Expert opinion elucidation and brainstorming are often key parts of the QRM process, but how well are these areas understood in GMP environments? What factors should a Team Leader take into account when seeking strength of evidence when opinions are offered during brainstorming sessions? Slide 13

14 Strategy 3 Use more GMP-tailored QRM tools QRM methodologies that are tailored for GMP-based applications, and that address pharmaceutical-related problems, should be developed: This is important in many respects. For example: When planning to use a QRM methodology in qualification and validation activities, the role played by GMP controls in the assessment of risk should be a central feature of that methodology Many QRM methodologies were not designed for GMP applications, and they often pay too little rigor and attention to the evaluation of GMP controls in these areas This is especially the case when assigning Severity, Probability of Occurrence and Detection ratings to a particular failure mode The following are some practical and science-based strategies that can be implemented to address the above concerns Slide 14

15 Practical Strategy 3.1 Design Quality Risk Management worksheets that ensure that the value of the currently in-place GMP controls is assessed before risks are assessed Often, Probability of Occurrence and Severity ratings are assigned to a potential negative event or failure mode without first considering the currently-in-place GMP controls that may influence the probability of occurrence of that potential negative event, or the Severity of its effects. This can result in a high level of guesswork, subjectivity and uncertainty in the P and S ratings assigned during the QRM exercise It is highly beneficial to require the team performing the QRM exercise to formally consider, classify and critically evaluate any currently in-place GMP controls, in terms of how they might influence the Probability, Severity and Detection of a potential failure mode or negative event, before ratings in these areas are assigned Well designed QRM worksheets can help ensure that this happens The way that many generic FMEA worksheets are designed contributes to the above problem, & this can lead to an overreliance on detection-based controls, not preventative controls Slide 15

16 Practical Strategy 3.2 Ensure that the outcomes of QRM exercises are formally linked with the company s Qualification & Validation programmes, & with Change Control Many QRM methodologies and exercises we see on inspection do not clearly link the outcomes of the risk assessment & risk control activities with the company s qualification & validation programme (e.g. via their VMP) It is often then unclear how qualification and validation protocols took into account the results of QRM exercises performed on the process This presents a risk of overlooking the qualification or validation requirements for GMP controls that are important for controlling or reducing particular risks This situation can be avoided by simply designing QRM worksheets that include formal qualification & validation considerations, e.g. Q&V status, Q&V requirements, etc., for the GMP controls that were identified as being important in risk control or mitigation. Slide 16

17 Practical Strategy 3.3 Avoid a false sense of security in Quality Risk Management work - design QRM worksheets so that the qualification and validation requirements for current controls are not overlooked To achieve true risk-based qualification or validation, QRM methodologies should ensure that the qualification or validation status of all the GMP controls that were determined to be useful for controlling or mitigating risk is determined Often not addressed in existing methodologies, as often, only the Q/V requirements for new controls are assessed, if at all The Q/V requirements for already-in-place GMP controls are often overlooked. (It is often assumed that these controls have already been qualified or validated, but this may not be the case.) Also, there can be times when a risk (or an RPN) is deemed acceptable on the basis of current controls only - meaning that no new risk control measures are required. Again, the Q/V requirements for those current controls are often not formally assessed. This can result in a false sense of security in the process under study It is not appropriate to assume that those currently-in-place controls have already been properly qualified or validated Slide 17

18 Practical Strategy 3.4 Ensure that risk detection issues are dealt with in a manner that is appropriate to the principles of QA and the GMP environment How Detection controls are dealt with in a GMP environment sometimes has to be very different from how another industry might deal with detection, even when the exact same Quality Risk Management methodology is being used (e.g. FMEA) In GMP environments, a high detectability for a potential negative event or failure mode should not automatically allow one to conclude that a risk is acceptable or adequately controlled There should not be an over-reliance on detection controls to ensure quality at the end of the process Such a reliance is contrary to the concepts of Quality Assurance (good design, training, validation, etc.) Detection is important, but controls that prevent negative events, or controls that reduce the severity of their effects, are better for achieving QA Quality Risk Management methodologies in GMP environments should apply formality and rigor to how detection is dealt with Slide 18

19 Considerations for future QRM work Developing GMP-tailored Quality Risk Management methodologies presents an opportunity to tackle certain problem areas that, if left unchecked, will limit the benefits to be gained from the use of QRM in GMP environments The extent of subjective guesswork associated with QRM exercises when identifying potential failure modes, their causes and associated risks (e.g. when severity, probability of occurrence and detection ratings are being estimated) Strength of evidence is important to consider The potential adverse influences of human heuristics (cognitive rules of thumb) on the outcomes of QRM exercises, e.g., during brainstorming and other teambased decision-making activities How to deal with the Heuristic of Availability How to deal with the Heuristic of Anchoring & Adjustment How to deal with the Heuristic of Representativeness Slide 19

20 Considerations for future QRM work In relation to the above problems: The lessons learned by other industries in their use of Quality Risk Management methodologies should be taken into account The GMP environment can benefit from research conducted in fields such as: Uncertainty Analysis (for understanding probability of occurrence estimations) Experimental Psychology (for understanding expert opinion elucidation techniques) Human Factors Engineering (for understanding the factors that influence risk perception). Practical strategies can be developed in relation to each of the problems listed above Slide 20

21 Considerations for future QRM work The importance of Good Science Good science should always be a feature of the Quality Risk Management methodologies in use This is sometimes lacking in current Quality Risk Management methodologies. Four key areas that could benefit from better science-based thinking are: 1. The selection and use of Risk Priority Number (RPN) cut-off values in FMEA-based tools This can be aided by the use of science-based confidence intervals, but inspection experience shows that this is often not a feature of such methodologies. 2 The way in which the Quality Risk Management methodology deals with differences of opinion that can arise during team-based QRM activities such as assigning probability of occurrence, severity and detection ratings to potential failure modes. Averaging is sometimes used as a way out but often this is not an appropriate, scientific strategy. Slide 21

22 Considerations for future QRM work Four key areas cont d 3. The way in which the methodology deals with the requirement to assign a probability of occurrence rating to a potential failure mode when there is a poor knowledge or understanding of how often the potential failure mode is likely to occur Some methodologies require the highest available rating to be assigned, but this is not a scientific approach, and may lead us down a path in qualification and validation which has little meaning. 4. The way in which human error is assigned to the cause to a failure mode, when human error may often represent a symptom rather than the cause It is useful to have clear and documented rules in place before human error may be assigned as the cause of any failure mode or potential negative event Slide 22

23 Some Useful References Kahneman, D., Tversky, A., Subjective Probability: A Judgement of Representativeness, Cognitive Psychology, 3: , (1972) Kahneman, D., Tversky, A., On the Psychology of Prediction, Psychological Review, 80, No 4, , (1973) Fischhoff, B., Slovic, P., Lichtenstein, S., Fault trees: sensitivity of estimated failure probabilities to problem representation, J. Exp. Psychol. Human Perception Perf. 4:330-44, (1978) Hoch, S. J., Availability and Interference in Predictive Judgement, Journal of Experimental Psychology: Learning, Memory and Cognition, 10, No. 4, 1984 Mars Climate Orbiter Mishap Investigation Board, Report on Project Risk Management at NASA, March 13, 2000, available from ftp://ftp.hq.nasa.gov/pub/pao/reports/2000/mco_mib_report.pdf, accessed November 28th, 2007 A White Paper on Risk-Based Qualification for the 21st Century, ISPE s Qualification Task Team Steering Committee, ISPE, 9th March 2005, available at Slide 23

24 Some Useful References Stamatis, D. H., Failure Mode and Effect Analysis: FMEA from Theory to Execution, 2nd edition, ASQ Quality Press, 2003 Hickman, J. W., et al., PRA Procedures Guide A Guide to the Performance of Probabilistic Risk Assessments for Nuclear Power Plants, American Nuclear Society, NUREG/CR-2300, Vols. 1 and 2, January 1983 Morgan, M. G., Henrion, M., Uncertainty A Guide to Dealing with Uncertainty in Quantitative Risk and Policy Analysis, Cambridge University Press, 1990 Coburn, J., Weddle, G., Risk-Based Regulation, Learning from the Experience of Others, BioProcess International, September 2006, pp FDA Guidance for Industry Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management, July 18, 2000, available at Slide 24

25 Questions / Discussion? Slide 25