Luciana Mansolelli Group Compliance and Audit Group Quality Assurance

1. Palestra: Quality of Investigations: Reliable Supply Chain, Manufacturing Deviations and the Human Factor Luciana Mansolelli Group Compliance and Audit Group Quality Assurance Novartis Pharmaceuticals Corporation

2. Some of the information contained in this presentation is confidential. Accordingly, Novartis respectfully requests confidential treatment with respect to this presentation and any related materials under the U.S Freedom of Information Act. Further, if any person (including any governmental employee) should request the opportunity to inspect, copy or otherwise obtain Novartis confidential information, Novartis requests that it be immediately notified of any such request, furnished with a copy of all written materials pertaining to such request (including the request itself) and given advance notice of any intended release so that it may, if deemed necessary or appropriate, pursue available remedies.

3. Quality of InvestigationsObjectives • Process and requirementsfor handling deviations and Out of Specification Test Results. • Productive strategy meetings • Driving logical thinking • Operate in a team environment • Drive toward agreements and conclusions. • Soft data and hard data. • Effective and efficient techniques for data collection • Evaluation of data - techniques to analyze and challenge conclusions in order to correctly identify the root cause(s). • Human Error as a root cause. • Appropriate corrective and/or preventive actions. • Investigation report.

4. Why is it important to improve the quality of Investigations? William Edwards Deming • Patient Risk • Compliance • Health Authority Requirement • Continual Quality Improvement • Effectiveness • Eliminate recurrence – (focus on deviation reduction) • Identify root cause/most probable cause • Identify adequate/appropriate Corrective and Preventive Actions • Efficiency • Economics

5. Quality of Investigations Health Authority Requirements (examples) • ANVISA RDC 17 of 16.04.2010 Chapter V • Art. 26. All complaints and other information related to products with possible deviations in quality should be carefully investigated and recorded in accordance with written procedures. • Sole paragraph. Preventive and corrective actions should be taken when quality deviation is proved.

6. Quality of Investigations • 21CFR - Part 211 (Section 211.192) • “Any unexplained discrepancy(including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meets any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may be associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.”

7. Quality of Investigations • 21CFR - Part 820 - Quality System Regulation Subpart I - Control of nonconforming product.“Each manufacturer shall establish and maintain procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented.”

8. Quality of Investigations • Guidance for Industry: Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production, 2006 • “FDA Regulations require that an investigation be conducted whenever an OOS test result is obtained(211.192). ………Even if the batch is rejected based on the OOS result, the investigation is necessary to determine if a result is associated with other batches of the same drug product or other products. Batch rejection does not negate the need to perform an investigation.The regulations require that a written record of the investigation be made, including conclusions and follow-up(211.192).”

9. Quality of Investigations • EU Guide to Good Manufacturing Practice for Medicinal Products - Chapter 6 Section 6.5 • “Written procedures should be established and followed for investigating critical deviationsor the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.” • ISO 9001:2000 – Section 8.3 “Control of Nonconforming Product” • “The organization shall deal with nonconforming product by one or more of the following ways • by taking action to eliminate the detected nonconformity; • by authorizing its use, release or acceptance under concession by a relevant authority and, where applicable, by the customer; • by taking action to preclude its original intended use or application.”

10. Quality of Investigations • ISO 13485:2003 Section 8.5.3 “Preventive Action” • “The organization shall determine action to eliminate the causes of potential nonconformities in order to prevent occurrence. Preventive action shall be appropriate to the effects of the potential problems. • A documented procedure shall be established to define the requirements for: • by taking action to eliminate the detected nonconformity; • by authorizing its use, release or acceptance under concession by a relevant authority and, where applicable, by the customer; • by taking action to preclude its original intended use or application.”

11. Quality of Investigations Question: How do the regulations differ? They don’t……………… • The requirements, expectations are the same, only worded differently.

12. Quality of Investigations There is an expectation: • Action • To investigate deviations from procedures, process, etc. • Demonstrate “due diligence” • Dig “deep” enough • Ensure an understanding as to why the “event” occurred and how to prevent recurrence • Identify the root cause or most probable cause • Identify, implement and monitor effectiveness of corrective and preventive actions • Quality Oversight • Notification to Quality in a timely manner • When to notify, how to notify, what information to document • Appropriate Site Management/Quality...... review and approval

13. Quality of InvestigationsDefinitions

14. Quality of Investigations Definitions (1/3) • Deviation: Unplanned departurefrom an approved instruction or established standard or an unexpected observation. • Nonconformity: Non-fulfillment of a requirement. • Out-of-Expectation Results (OOE): A test result that falls outside historical, expected or previous trends/limits. • Out-of-Specification Results (OOS): A test result that does not meet established specifications or acceptance criteria. In stability testing the test result does not meet shelf life specifications. • Out of Trend (OOT): A stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during the stability study. • Human Errors are errors or mistakes caused by humans in theGMP environment or which may have effect on GMP. Errors and mistakes might or might not lead to a GMP related incident.

15. Quality of Investigations Definitions (2/3) • Incident is an event that may adversely affect the quality, safety, identity, strength, purity, availability (supply) or efficacy of a commercial product or clinical trial material and/or may compromise the Novartis Quality System and the global Novartis reputation. Any such incidents must be brought to the attention of the management through a system of sequential or concurrent notifications. • Unintentional errors against approved and communicated norms. The action (or lack of action) can be accidental or caused by lack of correct knowledge or be a consequence of incorrect knowledge. This category also includes situations where the approved norms were communicated but for some reason the individual was not aware or capable of properly executing the process or using the machine (for example not understanding the training, disturbing environment or complicated interface).

16. Quality of Investigations Definitions (3/3) • Intentional mistakes (misconduct) require conscious decision (fault) of acting against approved and communicated norms which the individual had or should have had knowledge of. The mistakes can be active or passive, including situations where the individual should have known the right procedures or use of the machine/device but didn't understand the consequences of their actions or negligence. Mistake can be caused by misjudgment, carelessness, or forgetfulness. This category also includes covering-up unintentional errors. • Enforced misconducts are when individual is ordered, forced or otherwise pressured against individuals will to act against approved and communicated norms. • Hypothesisis an idea or theory that is not proven but leads to further study or discussion.

17. Quality of InvestigationsThe Overall Process

18. Quality of InvestigationsThe Investigation – Key points to consider • The investigation process is a simple process. • It consists of: • Evaluate situation • Collect and evaluate information • Draw a conclusion • Compare information • Revisit conclusion • Challenge conclusion • Challenge outcome • Re-evaluate, etc.

19. Quality of InvestigationsKey points to consider Key Steps……… A. STOP!!!! B.Assess/Evaluate C.Determine Next Steps

20. Quality of InvestigationsKey points to consider You also stop because…… • Allows for a “preservation” of the “scene.” • Documents (Batch Records, Data Sheets, etc.) • Equipment/instruments • Glassware • Materials/Excipients • Reagents • Sample • Standard and sample solutions • Anything related to the activity • Note: It is critical that all solutions, glassware, etc. everything used in the process/analysis are retained.

21. Quality of InvestigationsKey points to consider • Considering Laboratory OOS investigations • Level 1 – Preliminary Investigation • Allows for the elimination of obvious errors, i.e., Laboratory Assigned Cause • MUST be completed with 5 working days from discovery • Level 2 – Full Scale Investigation (Quality Oversight required) • Notification to Quality and Manufacturing • MUST be completed within 30 calendar days • Important to remember • Cannot perform investigational testing, such as retests in Phase 1. • Those activities are performed in a Phase II Investigation activity and typically require an approved plan/protocol.

22. Quality of InvestigationsStrategy Meetings – Critical Success Factors • Problem statement – clearly define the issue (DEVIATION) • Team Membership - who should participate • R & D, Laboratory, Operations, Technical Services, Quality Assurance, Engineering, Others? • Appropriate technical experience • Availability • Scope of the meeting must be communicated in advance • At this stage actions should be towards Data collection and Analysis • Share all relevant background information • Results in a more effective meetings by giving the attendees the opportunity to be prepared • Facilitation of the meeting to enable productive problem solving analysis

23. Quality of InvestigationsData Collection & Analysis • In order to determine if the conclusion is appropriate, we must first review the objective evidence (data) that supports the conclusion. Data Collection and Analysis Objective & Subjective Hard information Soft Information (data/facts) (no data) Hard plus Soft plus Experience = Judgment

24. Quality of InvestigationsData Collection & Analysis Fact versus Theory Facts • Can be measured or photographed Judgments, Opinions, Assumptions are not facts! Exception: Eye Witness Reports Example: too much, insufficient, poor …

25. Quality of InvestigationsData Collection & Analysis • Manufacturing Records (examples) • Batch records • Applicable SOPs • Equipment records • Temperature Charts , etc. • Training Records • Other? • Laboratory Records (examples) • Notebook pages/data sheets • Test Methods • Applicable SOPs • Sample Receipt • What do I look at? • Sample characteristics • Chromatograms, data printouts, temperature charts, etc. • Training Records • Equipment/Instrument Records • Other? DATA

26. Quality of InvestigationsData Collection & Analysis The Interview • An interview is so important to an investigation as it may: • Provide information that has not been recorded in the notification to Quality or • Add clarity to what was recorded • Eye Witness.................. • Provide historical data or information

27. Quality of InvestigationsDocumentation of Investigation Activities Ensure there is no “testing into compliance”………. • Capture all information • Be Accurate • Document every step of your investigation.

28. Root Cause AnalysisOverview • Basic Problem Solving Tools • Quality Control Tools: Run Chart, Pareto Chart, Control Chart, Flowchart, Cause and Effect Diagram, Process Mapping • Creativity Tools: Brainstorming, Picture and Word Associations • Management and Planning Tools: Affinity and Tree Diagram

29. Root Cause AnalysisBrainstorming

30. Root Cause AnalysisProcess Mapping • Process Map • A method for displaying processes that illustrates how a product or transaction is processed • It is a visual representation of the work flow either within a process or an image of the whole operation • Comprises a stream of activities that transforms a well defined input or set of inputs into a predefined set of outputs • Process mapping is useful in instances when there is a need to evaluate multiple processes, and in instances of a parallel evaluation of an analytical test method and a batch record.

31. Root Cause AnalysisProcess Mapping – Visual Mapping – Example 1 • Process Mapping - Test Method (word document) • Buffer Solution: Transfer 3.48g of K2HPO4 into a 1000mL volumetric flask, dissolve, dilute with HPLC grade water to volume and mix. Filter through 0.45um PTFE filter prior to use. • 10 mol/l KOH Solution: Weigh 56.1 of KOH pellets into 100mL volumetric flask, add 70 mL of water and shake to dissolve. Use flowing water to prevent solution from heating. Fill flask to mark with water and shake. Filter solution with 0.45um PTFE filter. Transfer 3.48g to 1000mL volumetric Dilute to volume with HPLC water Filter using 0.45um PTFE filter Weigh 56.1 KOH into 100mL volumetric, add Water…mix Use flowing water, to prevent heating Filter using 0.45um PTFE filter

32. Root Cause AnalysisProcess Mapping – Visual Mapping – Example 2 Air Dispensing Fluidized Bed Dryer Sieving Scale Granulation Air Magnesium Stearate Blending Sieving Tableting Packaging Coating

33. Root Cause AnalysisRoot Cause Analysis – Cause & Effect • What is a Fishbone diagram? • Invented by Dr. Kaoru Ishikawa • It is an analysis tool that provides systematic way of looking at effects and the causes that may create or contribute to those effects • Creates a picture of the possible causes of the problem • Prevents the team from jumping to conclusions without evaluating and challenging the possible causes • Helps to build support for the identified corrective and preventive action(s) that will address the problem • When should it be used? When the “team” : • Needs to study a problem and determine the cause • Needs to study all possible reasons why a process is beginning to have difficulties, problems or breakdowns • Needs to identify areas for data collection • Wants to study why a process is not performingproperly or producing the desired results

34. Root Cause Analysis Cause & Effect – Site Example

35. Root Cause Analysis 5 Whys

36. Root Cause Analysis Other Tools • The qualitative tools we have just discussed are examples of those most commonly used when performing root cause analysis • There are other “Problem Solving” tools as well. • For example: • Failure Mode and Effects Analysis (FMEA) • Interrelationship Diagrams • Map out relationships between all possible causes • Kepner Tregoe (KT) • Others?

37. Root Cause Analysis Kepner Tregoe Basics KT Matrix - Helpful Questions What IS the deviation ? What could be the deviation, but IS NOT ?

38. Gather additional data Identify new potential causes Eliminate unreasonable causes Compare causes against the facts Quality of Investigations Root Cause Analysis Decision Making Continue to search for root causes until possibilities are exhausted!

39. Quality of Investigations Root Cause Analysis seeks to identify the CAUSE of the deviation • There are generally three types of causes: • Physical - Tangible, material items failed in some way (for example, an equipment failure occurs). • Human - People do something incorrectly, or did not doing something that was required. Human error typically leads to physical causes (for example, no one checked the fluid level, which led to the failure). • Organizational - A system, process, or procedure is faulty (for example, no one person was responsible for maintenance, and everyone assumed someone else had performed the required maintenance).

40. Quality of InvestigationsHuman Factor • Human error is typically not the root cause • Human errors are symptoms of deeper causes (symptom versus the disease) • We must perform in depth investigations to determine the cause of the “Human Error” • Interviewing is the most critical step in the investigation • Key points to consider: • Poor design of facility and/or equipment • Inadequateprocedures and processes • Ineffective training • Inadequate supervision • Inadequate staff and resources • Ineffective communication • Roles and responsibilities not clearly defined

41. Quality of InvestigationsContributing factors of Human Error • Processes • Inadequate checks, verification, control • Change in process • Lack of robust design • Not user tested • No user centered design • People • Fatigue • Lack or loss of focus • Stress • Automatism • Superman syndrome (It won’t happen to me) • Not understanding the impact of their actions • State of mind • Ignore a suspected issue • Disregards established procedures • Circumvents the process (workarounds) • Organization • Training • Right people in the right roles • Peer Pressure • Proper Resourcing • Governance / Metrics • Speed is more important than right • Quantity over Quality • Performance Pressures • Unclear accountability and responsibility • Deadlines • Budget • Unclear / insufficient communication • Procedures • Unclear Instructions • Procedure doesn’t match the process • Overly complicated • No user-centered design • Tools • Improper tools and equipment • Unnecessarily complex • Physical Environment • Noise • Climate • Lighting • Interruptions & Distractions • Workspace design • Cleanliness / Order • Product

42. Quality of InvestigationsHuman Factor • Stepwise approach for Human Factor investigations: • Detectionof potential HFs including evaluation • Skill Based Errors • Rule Based Errors • Knowledge Based Errors • Investigation leading to identifying most probable root cause and contributing factors. • Individual • Environmental • Process/interface • Non Human Factors • Consequencesincluding CAPAs and disciplinary or administrative actions • Follow-up

43. Quality of InvestigationsHuman Factor • Key elements of an Error Free Workplace: • Speak up about errors • What behaviors are we driving (and how) that increase human error? • Strive for perfection in order to achieve excellence • Eliminate repeat human errors • Personally recognize and reward success

44. Corrective and Preventive ActionIntroduction Effective Corrective & Preventive Action (CAPA) and remediation management of quality, compliance and risk related issues is essential for a closed loop, continuous improvement process. Relying on stand-alone solutions or paper-based processes to manage CAPA and remediation processes may fail to address systemic problems due to limited reach and visibility.

45. Quality of InvestigationsDefinitions • Correction/Remedial Action – Actions taken to eliminate the existing nonconformity • Corrective Action - An action taken to eliminate the cause of an existing deviation, non-conformity, defect, or other undesirable situation in order to prevent recurrence. (REACTIVE) • Preventive Action – An action taken to detect and eliminate the causes of potential deviations, non-conformity or defect in order to prevent occurrence. (PROACTIVE) • Preventive actions are actions to reduce the probability that a potential problem will occur. • Effectiveness Check – An action taken to verify that the expected results are achieved I.e., that the corrective and or preventive actions prevent occurrence or recurrence of the event. (Has the root cause of the problem been solved?)

46. Quality of InvestigationsThe Investigation Package • What does it look like? • Must be a “stand alone” document • A “Table of Contents” is a bonus! • What is the expectation? • All relevant documentation must be included and/or referenced as to its location • The Report • Must be clear and concise • Contain all supporting Documentation • Raw Data • Analytical Test Methods • Metrics/Charts • Batch Records • Maintenance/Calibration Records • Training Records, etc.

47. Quality of Investigations