QP s experience with QRM. Fergus O Connell QA Manager AMS Laboratories

Transcription

1 QP s experience with QRM Fergus O Connell QA Manager AMS Laboratories December 2011

2 Risk Management in a QPs role Validation Master Plan Risk Review Early issues Human Error Risk Influencing Factors

3 EU implementation of ICHQ9 Chapter 1 updated February 2008, In force July Questions: Risk Assessments in QP role? Risk Assessments in Quality System? What situations fall outside RA?

4 Annex 16 (not adopted by PIC/S) describes the duties of a Qualified Person. QP is responsible for product release in EU. Legislated education & experience. Approved by Regulatory Authority. Listed on Manufacturing License. Legally accountable. Risk does not appear in Annex 16 Annex currently under review. Concept paper out for comment references ICHQ8, Q9 and Q10.

5 RA in Finished product release? Very limited! EMA reflection paper on the use of QP discretion for minor deviations. January 2009 One-off, minor event (in context of compliance). Principles of ICH-Q9 to be employed. MA specifications must be met (there is no discretion here).

6 Issues: If the final decision on quality is left to the Qualified Person. Quality System is failing. Decisions on quality should be addressed elsewhere. Is it a One-off event or the first time the issue was noticed? would the Quality System have caught it previously? RAs should NOT be a standard practice at the product release stage. Beginning to manage risks post manufacturing is too late. EMA reports that the Reflection Paper on QP discretion has been misinterpreted in some cases. Many questions now exist regarding its status.

7 Are any areas out of bounds for risk assessment? MHRA: Risk assessments cannot conclude that statutory, regulatory or GMP requirements should not be followed or are not appropriate. eg risk assessment could not conclude that it was appropriate for licensed products to be released by someone who was not a qualified person (QP). Other Illegible expiry date on some packaging cartons after batch has been packaged. RA tools applicable to find root cause. Inspection would be required to further reduce the risk.

8 where do we start? Cleaning Validation Equipment Matrix Approach Selection of high risk products for cleaning validation Define common product contact surfaces Calculate cross-over limits Individual Risk Assessments as appropriate E.g. assess each Packaging line» Entrapment areas» Risks with upgrades» Risks with Like-for-like changes

9 Process & Packaging Validation Master Plans Define Low, Medium and High Risks. Define & justify validation approach for each category Pre-validation assessments and trial/characterization batch data Use data to justify or change risk level Risk Review Points in the process Pre- & Post-characterisation/trial batch Post validation Challenge the initial Risk Assumptions Expand and/or redefine risk questions

10 Risk Review Points - overlooked something important?

11 Risk Review Points Remember: Risk questions will change over time. As our knowledge of a product or process increases. High risk changes in a validation master plan will remain high. Low/medium risk changes - If initial risk assumptions not met - Raise risk level. - Perform additional validation activities as necessary.

12 Risk Review Points Associated with product & process knowledge increases. Present across entire product life-cycle (ICHQ8, Q10). Validations Investigations Complaints Pharmacovigilance Change Control Revisiting original risk assessment May not always be necessary Should always be considered Option to define when in procedures QP s do request for investigations to include: review of validation data information from RAs

13 General rule of thumb: If on a steep learning curve for a product/process review risks Predicted reviews e.g. Validations Unpredicted reviews e.g. Investigations Frequent Reviews Life-cycle

14 Some early issues with Risk Assessments: Misunderstanding of RA uses & benefits Perceived as another regulatory hurdle Preconceived conclusions, Within Incident Investigations Looking only for evidence to support conclusions Root cause - Human error

15 Investigations Failure to identify multiple contributing factors Root causes which do not explain results or observations Conclusions not critically assessed before QP review Procedures not assessed. Ineffective Corrective And Preventative Actions introduced. Failure to start with a detailed process map Important steps overlooked Reassessment/review criteria not agreed Conclusion of there is no risk. A degree of risk exists in all situations.

16 Two types of RAs (ICHQ9) Prospective Validations Retrospective/Root cause assessments Investigations

17 Investigations: Tools - used for identification of root causes FDA - investigations are not being progressed to completion. Investigation Risk Assessment Root Causes identified One or two steps after

18 After root causes identified Look beyond the current batch or issue The same risks may be present elsewhere Assess impact to other processes or products If issues noted: post validation as part of Investigations Corrective actions may introduce new risks Risks in other products/processes can be overlooked

19 Human Error as a Root Cause Typical response to human error RETRAIN

20 Why does this tried & tested reaction keep failing? Human error is NOT a root cause Look beyond it Underlying system has failed Procedures may not be adequate/detailed enough Correct checks may not be in place Operator failed to follow procedure ask why? Original training may have been insufficient. Unless the failure is identified, Corrective Actions will also fail. Updates to a procedure Will this prevent human error? Add a retraining session? FDA citation in Singapore: "Your SOP and batch [ ] instructions are in English (the official language in Singapore). However, one operator who works in the processing of the plaster line for the finished product of [ ] cannot read English."

21 IMB: root cause of human error is not considered justified when: multiple people have made the same type of error on a single batch, same type of error has occurred on several other occasions. Recommends that the term human error be formally defined in deviation and complaint procedures. How do we address human error?

22 Risk Influencing Factors Frequently omitted The effect of human behaviour and characteristics are enhanced. ~15% errors conscious processes ~85% errors largely automatic behaviour 2 groups Environmental/Structural Stressor

23 Environmental/Structural factors: Poor documentation layout Poor lighting Confusing instructions Stressors: Fatigue/poor concentration Distractions Critical steps performed in a noisy room. Interruptions do you have a policy? Using visual cues to indicate a critical step/personnel are not to be interrupted is an option. Excessive workload Time of day (lunchtime, shift changes etc) Boredom - - automatic behaviour being used

24 If all factors have been removed or minimised, the likelihood of an error will also be minimised. Identifying good practices is essential to minimising RIFs. Not all RIFs can be addressed Address those that can be. A difference will be made.

25 Risk Assessment Part 1: Detailed Flow Chart of individual steps Part 2: Associated Risks For each step Part 3: Risk Influencing Factors for each step (especially major & critical steps) Examples include: -Interruption - Space - Lighting - Concurrent activities - Time of day

26 Good Risk Assessments Can direct investigations quickly to what failed. Detailed process map. Concurrent activity charts. RIFs have been considered. Many mitigation strategies applicable elsewhere. E.g. for new products, equipment introductions. No need to reinvent the wheel. Provides strategic justifications & direction. Validation is a good example Allows a QP to release batches with confidence.

27 Thank you

28 References: EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines. Annex 16 - Certification by a Qualified Person and Batch Release Medicines and Healthcare products Regulatory Agency (MHRA) Good Manufacturing Practice (GMP) - Quality risk management: Frequently asked questions ingpractice/faq/qualityriskmanagement/index.htm Reflection paper on a proposed solution for dealing with minor deviations from the detail described in the Marketing Authorisation for human and veterinary Medicinal Products (Rev1) Doc. Ref. EMEA/INS/GMP/227075/ Concept paper on Revising Annex 16 of the Guide to Good Manufacturing Practice: Certification by a Qualified Person and Batch Release WC pdf International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) - Quality Guidelines Q8, Q9 & Q10

29 QP Discretion Workshop Day Hilton Airport Hotel, Dublin Monday 5 th October 2009 Run by Ann McGee Consulting Ltd Pharmaceutical Quality, Compliance and Training Specialists Presentation by John Evans Human Error and RIFs Human Error and Retraining An Interview With Kevin O Donnell, Ph.D., Irish Medicines Board Journal of GXP Compliance Autumn 2009, Volume 13, Number 4, 2-15 Irish Medicines Board Presentation: PharmaChem Skillnet & PharmaChemical Ireland Conference Cork, March 31st, 2010 Deviations, Inspection Observations & Issues to Consider Kevin O Donnell, Ph.D. Market Compliance Manager Irish Medicines Board FDA Warning Letters