1. 2013 PROCESS FAILURE MODES AND EFFECTS ANALYSIS

2.  Risk based thinking is not industry dependent!  Airline (1,895 air traffic control errors in 2012)  Device (48 recalls in 2012)  Pharma (45 recalls in 2012) BASIC PHILOSOPHY  To control risk, you need to know where it exists  Dynamic tool = control  Static tool = waste of time  Brainstorm, the more brains the better  You can never eliminate all risk

3. 1.Map all ACTUAL steps of your process a)Best practice: Brainstorm with the actual hands on people b)Pitfalls: Don’t just go off of SOP steps, may loose detail STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What are the steps in the process?

4. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

5. 2.List all things that could go wrong with the step a)Best practice: Put it all down, even if crazy! Include human factors. b)Pitfalls: Don’t avoid putting it down because of low risk STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What could go wrong with that step? What environmental or human factors could contribute (stress, flow of work, concentration)?

6. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

7. 3.List the effects of each failure mode identified a)Best practice: Put it all down, even if crazy! b)Pitfalls: Don’t avoid putting it down because of low risk STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What effects could result from the failure occurring?

8. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

9. SCORING Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism(s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Recommended Action(s) Responsibility & Target Completion Date Action Results ActionsTaken SevSev OccurOccur DetecDetec R. P. N. How bad could the effect of the failure be? Severity of Effect 10May result in safety issue or regulatory violation without warning 9May result in safety issue or regulatory violation with warning 8Primary function is lost or seriously degraded 7Primary function is reduced and customer is impacted 6Secondary function is lost or seriously degraded 5Secondary function is reduced and customer is impacted 4Loss of function or appearance such that most customers would return product or stop using service 3Loss of function or appearance that is noticed by customers but would not result in a return or loss of service 2 Loss of function or appearance that is unlikely to be noticed by customers and would not result in a return or loss of service 1Little to no impact

10. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16 Note: We only scored regulatory risk since the patient wouldn’t use a compromised device. You may want to also assess business risk

11. 4.List the causes of each failure mode identified a)Best practice: Remember human factors b)Pitfalls: Don’t avoid putting it down because of low occurrence STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What caused the failure to occur?

12. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

13. STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. How often does this failure mode occur? Probability of Occurrence 101 in 2 91 in 10 81 in 50 71 in 250 61 in 1,000 51 in 5,000 41 in 10,000 31 in 50,000 21 in 250,000 11 in 1 Million

14. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

15. 5.List any current controls you have to prevent that failure a)Best practice: List only what is driven by the procedure b)Pitfalls: Don’t include personal best practices STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What do you currently have in place to prevent the failure?

16. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

17. 6.List all the ways you can currently detect the failure a)Best practice: List only what is driven by the procedure b)Pitfalls: Don’t include tribal knowledge or personal best practices STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What do you currently have in place to detect occurrence of the failure?

18. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

19. STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What is the probability of detecting the failure? Likelihood of Detection 10Absolutely uncertain that failure will be detected 9Very remote chance that failure will be detected 8Remote chance that failure will be detected 7Very low chance that failure will be detected 6Low chance that failure will be detected 5Moderate chance that failure will be detected 4Moderately high chance that failure will be detected 3High chance that failure will be detected 2Very high chance that failure will be detected 1Almost certainty that failure will be detected

20. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

21. 7.Calculate the Risk Product Number (Severity x Occurrence x Detection) STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What is an acceptable threshold for your process?

22. EXAMPLE: EO CLINICAL BATCH RELEASE PROCESS Item / Function Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanism( s) of Failure OccurOccur Current Design Controls Prevention Current Design Controls Detection DetecDetec R. P. N. Prep for sterilization by stacking them directly into the sterilizer or containing them in a basket in the sterilizer Compromise integrity of primary packaging (pouches, trays) Unit unsuitable for use 1 Stuff too many units into basket or sterilizer, depends on how many runs client wants 3 Sponsor could double pouch or sterilize in secondary packaging or use additional sterilizers Analyst and Sponsor visual inspection of units 927 EO penetration variance due to loading configuration Inconsistent SAL 3 Stuff too many units into basket/cham ber and/or stacking of full baskets in chamber 2 EO sterilizer qualification PQ incorporates a uniformity verification by Bis throughout fully loaded chamber with dunnage. Chamber size is small. PCDs placed throughout chamber, then BI tested for sterility to verify 16

23. 8.Calculate the Risk Product Number (Severity x Occurrence x Detection) STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. What, if any, actions need to be taken to reduce the risk? Who is going to do them and when?

24. RISK MITIGATION PLAN R. P. N. Recommended Action(s) Responsibility & Target Completion Date Action Results ActionsTaken SevSev OccurOccur DetecDetec R. P. N. 27 Sterilization agreement should delineate client's responsibility for final package inspection prior to use 6none

25. 9.Close the loop from actions taken and calculate your new RPN STEPS Item / F unction Potential Failure Mode Potential Effect(s) of Failure SevSev Potential Cause(s)/ Mechanis m(s) of Failure OccurOccur Current Design Controls Preventio n Current Design Controls Detection DetecDetec R. P. N. Recommen ded Action(s) Responsi bility & Target Completio n Date Action Results ActionsTa ken SevSev OccurOccur DetecDetec R. P. N. Did your actions taken bring you to an acceptable risk?

26.  PFMEA is a useful tool when:  You are trying to change an existing process  You are designing a new process  You are performing root cause analysis (CAPA)  PFMEA must be the horse – not the cart  Procedural/Process changes after PFMEA can negate efforts or add new risks  Use dynamically to sync with current procedure  PFMEA is an excellent training tool  People performing the process learn the “WHYs” behind control points and “What” can happen if it is not done right LESSONS LEARNED

27.  Controls fail – redundancy is better  For high risks, don’t just rely on one control. Have a safety net!  Think outside the scope of your process  Consider defects of the process prior and how that effects yours  Audit process after actions  You typically discover new failure modes you missed the first time around  Use constant input from quality system (complaints, CAPAs, etc.)  Don’t rush, this takes time to do right  Some have taken me up to 5 meetings to complete LESSONS LEARNED

28. QUESTIONS?