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Risk management and environmental monitoring

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Risk management and environmental monitoring

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Risk management tools and techniques for environmental monitoring:

Application of HACCP for selecting environmental monitoring locations; Use of risk filtering to determine frequencies of monitoring ; Applying FMEA to assess risks from process equipment – a sterility testing isolator.

Risk management tools and techniques for environmental monitoring:

Application of HACCP for selecting environmental monitoring locations; Use of risk filtering to determine frequencies of monitoring ; Applying FMEA to assess risks from process equipment – a sterility testing isolator.

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Risk management and environmental monitoring

  1. 1. Dr. Tim Sandle Pharmaceutical Microbiology Resources: www.pharmamicroresources.com
  2. 2. Introduction  Introduction to quality risk management  Definitions of risk  What is the aim of environmental monitoring?  Risk management tools and techniques for environmental monitoring  Application of HACCP for selecting environmental monitoring locations  Use of risk filtering to determine frequencies of monitoring  Applying FMEA to assess risks from process equipment – a sterility testing isolator.
  3. 3. Risk  In general, risks describe any potential dangers.  We are confronted with risks in our day to day life.  Risks cannot be avoided.  There is no such thing as 'zero risk.’  Risk assessment is not an exact science.  Risks relate to a situation, event or scenario in which a recognised hazard may result in harm.
  4. 4. How to define risk?  Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm i.e.  What might go wrong?  What is the likelihood (probability) it will go wrong?  What are the consequences (severity)?
  5. 5. What is risk assessment about?  Is the risk acceptable and what controls are available to mitigate the risk?  Is the risk above an acceptable level?  What can be done to reduce or eliminate risks?  What is the appropriate balance among benefits, risks and resources?  Are new risks introduced as a result of the identified risks being controlled?
  6. 6. Risk assessment  Risk assessment involves identifying risk scenarios either prospectively or retrospectively.  Prospective = determining what can go wrong in the system and all the associated consequences and likelihoods. Can also be used for process improvements.  Retrospective = what has gone wrong .  Risk assessment can be used to assess the process, product or environmental risk and to aid in formulating the appropriate actions to prevent the incident from re-occurring.  This requires risk analysis.
  7. 7. Basics of risk assessment  Risks relate to a situation where a recognized hazard may result in harm.  A hazard is any circumstance in the production, control and distribution of a pharmaceutical product, which can cause an adverse health effect.  Formal risk approaches normally share four basic concepts:  Risk assessment,  Risk control,  Risk review,  Risk communication.
  8. 8. Microbiological risks  Microbiological contamination in the product, which might cause patient harm.  From:  Equipment  Air e.g. Cleanrooms:  Air filtration  Air direction  Air movement (pressures)  People  Water  Central issue is contamination transfer.
  9. 9. Relationship of risk Level of bioburden Opportunity for bioburden transfer: Airborne Direct transfer Likelihood of transfer
  10. 10. EM: risk assessment and root causes  The process involves:  Risk assessment  Identification of hazards  Severity, probability and detection  To stop things from going wrong  To investigate when things have gone wrong  To find ‘root causes’  To propose CAPA
  11. 11. Biocontamination control  Understanding risk and environmental control leads to a biocontamination control strategy:  Developing plans to minimize microbial contamination for pharmaceutical operations  Understanding manufacturing, quality and contamination control are interconnected  This stratgey is all about risk identification and risk minimisation  Then risk mitigation  Then targeted environmental monitoring
  12. 12. Three case studies  Application of HACCP for selecting environmental monitoring locations  Use of risk filtering to determine frequencies of monitoring  Applying FMEA to assess risks from process equipment – a sterility testing isolator.
  13. 13. Hazard Analysis and Critical Control Points
  14. 14. HACCP  “A systematic, proactive, and preventive method for assuring product quality, reliability, and safety.” Potential Areas of Use(s)  To identify and manage risks associated with physical, chemical and biological hazards (including microbiological contamination)  Useful when process understanding is sufficiently comprehensive to support identification of critical control points (critical parameters / variables)  Facilitates monitoring of critical points in the manufacturing process
  15. 15. HACCP How to perform? 1. Conduct hazard analysis: identify preventive measures for each step of the process 2. Determine critical control points (CCP’s) 3. Establish target levels and critical limit(s) 4. Establish system to monitor the CCP’s 5. Establish corrective actions to be taken, if CCP is out of control 6. Establish verification procedures, that HACCP works effectively 7. Establish documentation of all procedures and keep records
  16. 16. HACCP Risk Review Risk Assessment = H azard A nalysis Target levels & critical limit(s) unacceptable Risk Control: C ritical C ontrol P oints Determine critical control points (CCP’s) System to monitor the CCP’s Identify preventive measures Verification that process works effectively Corrective actions, if CCP is out of control Initiate HACCP Output / Results: process described by HACCP R i s k M a n a g e m e n t t o o l : H A C C P R i s k C o m m u n i c a t i o n T e a m f o c u s e d I n t e r n a l c o n s u l t a t i o n S t a k e h o l d e r i n v o l v e m e n t
  17. 17. HACCP  Benefit  Teamwork in cross functional groups  Use very similar principles in Qualification & Validation  Critical control points (CCPs) are similar to critical process parameters  Limitations of the model  Has to be combined with another tool (e.g. FMEA, statistical tools)  Not good for complex processes  Assumes you know the processes  Most CCPs should be addressed for risk control activities  May need to use other models for quantifying risk
  18. 18. HACCP uses  A route map (where the facility is drawn and the route indicated).  Identification of hazards (which can be divided into biological, physical, equipment, transport and chemical). This will allow an assessment of existing control measures.  Process flow.  Assessment of environmental monitoring. This will determine if the activity is safe to proceed.
  19. 19. Approaching HACCP  Prior to performing the individual risk assessments, the scope and the process should be evaluated.  Obtain a process flow diagram / area map. Where required the process steps can be broken down into process steps or sub steps to help focus the effort.  Walkthrough the area, detailing the process steps / activities based on personnel flow, material flow, storage, waste disposal and product transfer.  A Historical Review of data (12 months) or previous risk assessments, which should be considered.
  20. 20. Approaching HACCP  Define every available contamination hazard from each process step / activity.  The hazard can be assessed and rated based on the likelihood of occurrence and severity.  To determine if the hazard is high medium or low.  The risk rating will determine if a critical control point is required and the level of monitoring which is required.
  21. 21. Approaching HACCP – CCP’s
  22. 22. Approaching HACCP  For each critical control point:  Define what level of risk warrants monitoring i.e. if only high and medium risks require monitoring.  Where monitoring is required based on the risk rating,  The monitoring type should be selected e.g. Settle plate, contact plate etc.  The monitoring type will depend on the hazard.  All critical control points will require critical limits assigned to them.  Define monitoring frequencies.
  23. 23. HACCP example: sampling locations  ISO 14644 grid approach for particles should not be followed  Microbiological sampling sites are best selected with consideration of human activity during manufacturing operations.  From careful observation and mapping of the clean room  The most likely route of contamination (ingress into product):  Airborne  Operators – direct transfer  Materials – direct transfer
  24. 24. Problem statement  Issue :  How to set the frequencies for viable monitoring for a non-sterile manufacturing area?
  25. 25. A risk based method  Using risk ranking and risk filtering  Consideration of 10 risk factors  Assessing the level of risk for each risk factor for:  Severity and Probability  Considering methods of:  Detection
  26. 26. Risk process  The risk assessment process involves:  What are risk factors for microbiological contamination in cleanrooms (risk identification)?  What is the likelihood (probability) that contamination will occur?  What are the consequences (severity) for the product should contamination occur?
  27. 27. Risk process  The process allowed:  An evaluation of multiple factors for each risk:  Identifying factors (risk identification) relating to cleanroom design and processing which could pose a microbiological risk to the environment and to the product  Breaking down a basic risk question into as many components as needed to capture factors involved in the risk.  The factors were combined into a single relative risk score. The score can be compared, prioritized and ranked.
  28. 28. Risk process  Risk factors were divided into two categories:  Severity  The impact upon the product or the environment  Categories:  LOW (unlikely to cause product contamination)  MEDIUM (low possibility of product contamination)  HIGH (high probability of product contamination)  Probability  The likelihood that an environment will have a high recovery of microbial counts  Categories:  LOW (contamination events are rare)  MEDIUM (contamination events are infrequent)  HIGH (contamination events are frequent)
  29. 29. Step 1: Frequencies of monitoring  Frequencies of monitoring:  Review historical data:  For trends  Action level excursions  Review resources  Consideration of costs
  30. 30. Step 2: Assigning monitoring frequencies Criticality Viable Factor Frequency of Monitoring CV1 Weekly monitoring CV2 Fortnightly monitoring CV3 Monthly monitoring CV4 Three-monthly monitoring
  31. 31. Step 3: Scoring range for risk factors  Each factor was scored (0 to 4) for severity and / or probability  A score range was set up for severity and probability Probability Low 0 - 5 Medium 6 - 11 High 12 - 16
  32. 32. Relationship between Severity and Probability Low 0-5 Medium 6-11 High 12-16 Severity Probability High 11-15 Low 0 -5 Medium 5-10 Risk Class ONE Risk Class TWO Risk Class THREE Risk Ranking I Risk Matrix (1)
  33. 33. Step 4: Identify risk factors  The factors selected were considered carefully, using professional judgement:  What, in relation to room design and processing, poses a microbiological risk to the environment and to the product?
  34. 34. Risk factors  A number of risk factors can be selected  Temperature  Ambient  Cold  Warm  Wet or dry areas  Water sources or drains in room  Open or closed processing  Duration of activity  Number of personnel present  Cleaning frequencies  Distance from final formulation  Fixed or mobile equipment  Environmental monitoring history
  35. 35. Risk factors  Risk Factor 1: Room Temperature Freezer 0 Cold (typically 2-8oC) 1 Ambient (typically 18- 25oC) 4 Warm (typically with periods of 30oC, e.g. autoclave preparation area) 3
  36. 36. Risk factors  Detection methods need to be reviewed Factor Group Sub-factors Description and reason Weighting / score DETECTION Room environmental monitoring Room environmental monitoring, examined over time for trends,. Low detection In-process sample test and room environmental monitoring In-process samples, provide a direct assessment of the quality of the material. In addition, the room environmental monitoring as indicated above. Medium detection In-process sample test, room environmental monitoring and a monitored water (WFI) outlet In addition to the room environmental monitoring and in-process tests, the presence of a Water-for-Injection (WFI) outlet affords an additional detection method. WFI is assessed as part of a fortnightly rota. High detection
  37. 37. Example 1  Clean room: P100  Grade D / ISO class 9  A room used for preparing equipment prior to autoclaving  The room is reviewed and scored  It is at ambient (severity = 3)  It is a dry area (probability = 1)  It has no floor drain (probability = 0)  It is not used directly for processing (severity = 0)  The room is used for long periods of time (severity / probability = 3)  It is cleaned at a lower frequency (probability = 3)  The room is more than three steps removed from final formulation (severity = 1)  The room has a low occupancy (probability = 1)  The equipment is fixed (severity = 1)  The environmental monitoring history is good (probability = 1)
  38. 38. Example 2 – risk class Low 0-5 Medium 6-11 High 12-16 Severity Probability High 10-14 Low 0 -4 Medium 5-9 Risk Class ONE Risk Class TWO Risk Class THREE Risk Ranking I Risk Matrix (1) P100
  39. 39. Example 3 - detection THREE TWO ONE Detection Risk Classification High Low Medium HIGH priority MEDIUM priority LOW priority Risk Filtering Risk Matrix (2) EM EM +IP EM, IP + water P100
  40. 40. Example 4 - frequency Risk Filtering Risk Matrix (3) CV4 CV4 CV4 THREE CV3 CV3 CV3 TWO CV2 CV2 CV1 ONE Detection Risk Classification High Low Medium Room P100
  41. 41. Outcomes  Lowest frequency of monitoring:  Freezers  Store rooms  Cold storage areas  Offices  Medium frequency of monitoring:  Wash-up areas  Airlocks  Changing rooms  Areas one step removed from final processing.  Slightly higher frequency:  Corridors  Store rooms  Autoclave rooms  Cleaning areas  Highest frequency of monitoring:  Ultra-filtration areas  Final formulation of product  Open processing areas  Filtration rooms  Poor environmental monitoring history
  42. 42. Review  Review annually  Has the room use changed?  Have the room parameters changed?  Has the room been redesigned  Has the environmental monitoring trend altered?
  43. 43. Failure Modes and Effects Analysis
  44. 44. FMEA  Evaluation of potential failure modes for processes  The likely effect on outcomes and/or product performance  Once failure modes are established, risk reduction can be used to eliminate, reduce or control the potential failures  FMEA relies on process understanding  Summarize the important modes of failure, factors causing these failures and the likely effects of these failures How to perform? Break down large complex processes into manageable steps
  45. 45. FMEA Potential Areas of Use(s)  Prioritize risks  Monitor the effectiveness of risk control activities  Equipment and facilities  Analyze a manufacturing process to identify high-risk steps or critical parameters
  46. 46. FMEA How to perform? 1. Establish a team 2. Identify the known and potential failure modes: Develop lists of known problems and brainstorm other potentials… e.g.  Product not meeting specification  Process not meeting yield requirements  Malfunctioning equipment  Software problems Newly identified failure modes should be added at any time
  47. 47. FMEA How to perform? 3. Characterise the severity, probability and detectability  An equal number of levels is sometimes helpful  Some preference to 3, 4, 5, 6 or 10 levels  But: an even number of levels avoids the mid point  Use different scales  Linear: 1, 2, 3, 4  Exponential: 1, 2, 4, 8  Logarithmic: 1, 10, 100, 1000  Self made: 1, 3, 7, 10 Multiplying different scales will differentiate the outcome
  48. 48. FMEA How to perform? 4. Define actions 5. Revisit the ranking 6. Define residual risk 7. Perform a short summary  Scope  Data from the assessment & control (e.g. No. of identified failure modes)  Level of accepted risk without actions i.e. residual risk (e.g. Risk priority Number < 50)  Recommended actions, responsibilities and due dates (including approval, if appropriate)  Person in charge for follow-up of FMEA
  49. 49. FMEA: severity • 10 Extreme • Predicted to cause severe impact to quality (Product out of specifications, no Expert Statement possible) • 7 High • Predicted to cause significant impact on quality (Failure to meet specifications, no Stability data, Expert Statement possible) • 3 Moderate • Predicted to cause minor impact on quality (Failure to meet specifications, Stability data available) • 1 Low • Predicted to have no/minor impact on quality of the product (Quality within specifications)
  50. 50. FMEA: probability • 8 Regular failures • Expected to happen regularly • 4 Repeated failures • Expected to happen in a low frequency • 2 Occasional failures • Expected to happen infrequently • 1 Unlikely failures • Unlikely to happen
  51. 51. FMEA: detection • 4 Normally not detected • Failure very likely to be overlooked, hence not detected (no technical solution, no manual control) • 3 Likely not detected • Failure may be overseen (manual control, spot checks) • 2 Regularly detected • Failure will normally be detected (manual control, routine work with statistical control) • 1 Always detected • Failure can and will be detected in all cases (monitoring, technical solution available)
  52. 52. FMEA: case study #1  Sterility testing isolator  Identifying the main risks:  Leaks;  Gloves / operator manipulations;  Filters;  Other airborne contamination;  Transfer of material into and out of the Isolator;  The Isolator room;  Decontamination cycle;  Cleaning / environmental monitoring issues.
  53. 53. FMEA: case study #2  Designing the FMEA scheme  FMEA schemes vary in their approach, scoring and categorisation.  All approaches share in common a numerical approach. The approach adopted was to assign a score (from 1 to 5) to each of the following categories: i) Severity ii) Occurrence (or probability) iii) Detection
  54. 54. FMEA: case study #3 i) Severity is the consequence of a failure, should it occur; ii) Occurrence is the likelihood of the failure happening (based on past experience); iii) Detection is based on the monitoring systems in place and on how likely a failure can be detected. Sometimes, a good detection system is described as one that can detect a failure before it occurs.
  55. 55. FMEA: case study #4
  56. 56. FMEA: case study #5  Using these criteria a final FMEA score is produced (sometimes called a Risk Priority Number): x 125  The total of 125 is derived from: severity score x occurrence score x detect score, or: 5 x 5 x 5 = 125
  57. 57. FMEA: case study #6  A score of 27 was the cut-off value: where action was required.  Based on 27 being the score derived when the mid-score is applied to all three categories (i.e. the numerical value '3' from severity (3) x occurrence (3) x detect (3)) and the supposition that if the mid-rating (or a higher number) was scored for all three categories then as a minimum the system should be examined in greater detail.
  58. 58. FMEA: case study #7  An example:  Connection of transfer Isolator to main Isolator and transfer-in / out of material
  59. 59. FMEA: case study #8
  60. 60. FMEA: case study #9 Connection of transfer Isolator to main Isolator and transfer- in / out of material
  61. 61. FMEA: case study #10 FMEA score: 4 x 1 x 1 = 4
  62. 62. Summary  Risk assessment  Risk management  Importance of assessment  What is the aim of environmental monitoring?  Types of risk assessment tools and case studies:  HACCP  Risk ranking  FMEA  Thank you for your attention  References:  Sandle, T: ‘The use of a risk assessment in the pharmaceutical industry – the application of FMEA to a sterility testing isolator: a case study’, European Journal of Parenteral and Pharmaceutical Sciences, 2003; 8(2): 43-49  Sandle, T. Environmental Monitoring Risk Assessment’, Journal of GXP Compliance, Volume 10, Number 2, 2006, pp54-73  Sandle, T. (2012). Application of Quality Risk Management To Set Viable Environmental Monitoring Frequencies in Biotechnology Processing and Support Areas, PDA Journal of Pharmaceutical Science and Technology, Vol. 66, No. 6, November–December 2012: 560 - 579

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