INVESTIGATING AND DOCUMENTING DEVIATIONS

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Peter Jasper Palmer
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1 INVESTIGATING AND DOCUMENTING DEVIATIONS

2 AGENDA! What is a Deviation?! Capturing Essential information! Deviation vs Event! Classify the Deviation how bad is it?! Remediate and Escalate! Investigation! Root Cause Analysis! Go fishing! Why, why, why, why, why?! HER! CAPA - What to do about it! Closing! Tracking and Trending

3 WHAT IS A DEVIATION?! de vi a tion /,dēvē āshəәn/! The action of departing from an established course or accepted standard! An unplanned event that has been assessed as having a potential to impact material or product in terms of quality, patient/customer safety and regulatory compliance! Any occurrence that is not in conformance with established SOPs, Master Batch Records, regulatory filings, test methods, specifications or other standards, that may affect the purity, potency, quality, efficacy or safety of products or components

4 CAPTURING ESSENTIAL INFORMATION

5 CAPTURING ESSENTIAL INFORMATION! To make any assessment, basic information needs to be captured on the what, when, why, where and who! Develop a standard template or checklist that prompts this initial data gathering phase! This should be available so anyone can raise a deviation when they detect one! Information should be recorded in a clear and concise manner! Stick to the basic facts! Unless it is obvious a root cause does not need to be stated

6 CAPTURING ESSENTIAL INFORMATION! When was it discovered?! When did it happen?! Where did it happen?! Building / Room / Functional location! Who was involved?! Who discovered it?! Where there any witnesses?! What is the extent of problem/time period (quantities/areas)! A description of the deviation i.e. what is immediately obvious! The identity of any process, equipment or system implicated by the deviation.

7 CAPTURING ESSENTIAL INFORMATION! Why it is a deviation?! What should have occurred?! What are the expected results or outcome?! Which part of your QMS is it not compliant with! Is there an obvious root cause?! Details of other batches affected if known! What Immediate action taken was taken?! Any initial actions taken to stop the deviation

8 DEVIATIONS VS EVENTS

9 DEVIATIONS VS EVENTS! An initial assessment mechanism is needed! This mechanism needs to determine if there is potential to impact material or product in terms of quality, patient/customer safety and regulatory compliance! If there is no potential impact then is can be treated as a simple unplanned event or comment! For both deviations and events an appropriate level of documentation is required to document the facts and assessment outcome

10 DEVIATIONS VS EVENTS! Yes or Maybe to any of these questions then manage as a deviation:! Has a deviation from a procedure that controls a process which may affect product quality or regulatory compliance occurred?! Has an atypical event occurred which may affect product quality or regulatory compliance? e.g. process, equipment failure! Has a deviation from Good Manufacturing Practice occurred?! Has a deviation from official protocols, or validation protocols occurred?! Has a process or system been operated outside of validated conditions?! Is key prime information (including documentation) missing or incorrect?

11 DEVIATIONS VS EVENTS! Is there a failure to meet process specifications?! Is there a QC test result which fails to meet specifications or criteria?! Has material been rejected / reworked?! Has material of incorrect quality or identity been detected by chance?! Is it an atypical event for which corrective actions are not covered by a procedure?! Has an atypical event occurred which may contravene registered or legal requirements?! Is there a need for Quality Assurance to be aware of this event at batch disposition?! Have issues relating to the above been identified as a result of trend analysis?

12 CLASSIFY THE DEVIATION

13 CLASSIFY THE DEVIATIONS! Some deviations are worse than others! Some deviations require escalation to senior management or regulatory bodies! Use a standard scheme against which to classify! Classification in turn:! Prioritizes attention to most critical deviations! Facilitates timely response to remediate or restrict impact! Err on the side of caution! On investigation the classification can always be amended (downgraded)

14 CLASSIFY THE DEVIATIONS Factor Cri*cal Cri*cal / Major Major Minor Informa*on Consequence Detec*on Implica*ons Priority Impact or poten,al impact for pa,ent safety, including product efficacy. Non- compliance with label claim or regula,ons Detected by chance. Systema,c failure - no system in place Implicated batches are already released Inves,ga,on required to determine if further batches are affected High. Immediate ac,on is required. Incident management procedures invoked to ini,ate assessment processes to determine the need for recall or no,fica,on. High. Immediate ac,on is required. Poten,al for further batches being implicated. A serious failure of process/ controls has occurred and requires immediate inves,ga,on. Detected by rou,ne check at a later stage Product safety or efficacy not directly affected. Impact on product release. Poten,al regulatory compliance implica,ons, adverse comments from inspectors, or major business cost Impacts appearance of the product or be related to minor document irregulari,es Detected at or close to point of error Implicated batches are s,ll within your control & quaran,ned. Resolu,on may be required before forward manufacture. No immediate implica,ons for other batches Medium. Prompt ac,on is advised. Devia,on has been contained, an incident of this severity should be resolved as soon as possible. Low. Poten,al for reoccurrence and subsequent cost implica,ons Timeline to Address Inves,ga,on and iden,fica,on of root cause should be completed within 1 week. The target to complete within 1 to 2 weeks Target to complete within 1 month so lessons can be learned and implemented

15 CLASSIFY THE DEVIATIONS Error Cri*cal Cri*cal / Major Major Minor Informa*on Packaging error. Misprinted labels on finished product Example Ac,ons Rogue cartons with distributor. Not detected on line (no bar code reading system present). Noted by chance by distribu,on centre Recall impacted batch. Launch inves,ga,on to determine other impacted batches Establish root cause and implement CAPA Rogue cartons within final batch. Detected by chance by line operator (no bar code reading system present). Quaran,ne impacted batches. Launch inves,ga,on to determine other impacted batches Establish root cause and implement CAPA Rogue cartons detected by online bar code checking machine. Erroneous labels not detected at issuance Quaran,ne impacted batches. Establish root cause and implement CAPA Incorrect batch number placed on labels. Error noted as part of QA document review process Establish root cause and implement CAPA Cosme,c marks noted on final carton during In Process Control checks. Establish root cause and implement CAPA

16 ESCALATE IF NECESSARY! Critical Deviations should invoke product recall assessment processes! This process should assess the need for product recall! Manage the product recall! For MNCs, assessment should also consider wider implications to other sites or management of the issue at above site level

17 PERFORM REMEDIAL ACTIONS! Action to address the immediate quality and compliance issues associated with the deviation.! Stop line / clean down! Batch reprocessing / reworking! Batch destruction! Re-packaging / re-labeling

18 ROOT CAUSE ANALYSIS

19 ROOT CAUSE ANALYSIS We are looking for Root Causes that:! Have Specific underlying reasons.! The more specific about why an event occurred, the easier to provide suggestions to prevent recurrence! Can be reasonably identified.! Investigations must be cost beneficial.! It is impractical to keep valuable manpower occupied indefinitely! Hypotheses can be tested! Using a structured RCA approach gets the most out of the time invested.

20 ROOT CAUSE ANALYSIS! Management has control to fix or influence.! Look further than general cause classifications such as operator error, equipment failure! Severe weather is not controlled or influenced by management.! Causes should be specific enough to allow management to make effective changes.! Management needs to know exactly why a failure occurred before action can be taken to prevent recurrence.! Effective recommendations for preventing recurrences can be generated.! Recommendations should directly address the root causes identified during the investigation.! Improve adherence to written policies and procedures is too vague. A basic and speific enough cause has not been found - more effort is need in analysis

21 ROOT CAUSE ANALYSIS! A structured approach to the investigation process should be used with the objective of determining the root cause. - ICH Q10! Problems are prevented by addressing, correcting or eliminating root causes, as opposed to merely addressing immediately obvious symptoms! RCA determines Why the deviation happened! Only if the why is know can effective corrective measures be identified that will prevent it from ever recurring

22 ROOT CAUSE ANALYSIS! To be effective, RCA must be performed systematically as part of an investigation! Conclusions and root causes identified should be backed up by documented evidence.! The analysis should establish a sequence of events to understand the relationships between:! contributory (causal) factors! root cause(s)! the defined problem or event to prevent in the future.

23 ROOT CAUSE ANALYSIS! There may be more than one root cause! Root causes identified depend on the way in which the problem or event is defined! Effective problem statements and event descriptions are required! Various tools can be used to gather data:! Cause and Effect / Fishbone! 5 Whys! Questioning! Brainstorming! Human Error Reduction! Usually a team effort is required.

24 ROOT CAUSE ANALYSIS! Without a structured investigation process:! An erroneous or incomplete conclusion is reached too hastily without considering all the facts.! The full extent of the failure and its impact upon other processes, products and batches is not realised.! The cause of failure is determined in only general terms, and the true root-cause lies more deeply hidden and unidentified.! The time taken to reach a conclusion is extended, causing interruptions to supply.! The failure is subsequently repeated

25 GATHERING DATA! 4 Key Steps:! Gather Data! Identify Contributing Factors! Identify Root Causes! Identify CAPA

GATHERING DATA! Provide a simple Process Flow Chart.

process Start of Process Step 1 Decision Step 2 Step 3 End!

Often discrepancies are clearly identifiable between

26 GATHERING DATA! Provide a simple Process Flow Chart. It helps the whole investigation team understand the process Start of Process Step 1 Decision Step 2 Step 3 End! Tip: Compare the chart with the procedures. Often discrepancies are clearly identifiable between different operators understanding of the process, and or the procedures that govern it

27 GATHERING DATA! Cause and Effect / Fishbone Diagram:! Assemble a team possessing knowledge about the area to be analysed! Write the Problem Statement at the end of a back bone.! Identify the main categories of possible causes and place these at the ends of the branches emanating from the back bone.! For physical processes, some common main categories are: Manpower, Machines, Materials, Methods, Measures, Environment.! Brainstorm all possible causes and place these in the suitable area of the chart.! Use predefined questions to support brainstorming! Analyse the identified causes to determine the most important ones, the ones that should be addressed further.

28 CAUSE AND EFFECT / FISHBONE DIAGRAM Manpower Materials Machines Problem Statement Environment Measures Methods

29 GATHERING DATA! Questioning! Predefined questions are used as an initial tool for gathering back ground data, brainstorming and understanding the process! Use the questions to build up a picture of events and circumstances and extrapolate data on all aspects! Questions can be open or closed! Don t stop at the first negative response! There could be multiple factors! Initial questions can lead to more questioning and investigation

30 EXAMPLE INVESTIGATION QUESTIONS! Measure:! Did processing occur within established parameters?! Are all entries correct?! Calculations correct and verified?! Is there any previous atypical results or trending history leading to the failure?! Is the supplier assessed as suitable for the material in question?! Do previous inspection or maintenance results indicate potential problems?! Recent documentation history?

31 EXAMPLE INVESTIGATION QUESTIONS! Method:! Is the process validated?! Is the process operating within its validated parameters?! Any deviations from standard operating procedures?! Is the right procedure used?! Is the procedure accurate/clear?! Samples pulled at appropriate steps?! Any sampling issues?! Were processing steps properly verified?

32 EXAMPLE INVESTIGATION QUESTIONS! Machine:! Has equipment been recently replaced or repaired?! It is within calibration?! Is preventative maintenance completed?! Maintenance records reviewed?! Any equipment cleanliness issues?! Equipment capacity or availability an issue?! Is equipment being used for its intended purpose?

33 EXAMPLE INVESTIGATION QUESTIONS! Materials:! Were materials/ Components adequate?! Were materials available?! Properly segregated?! Materials properly stored temperature / humidity?! Within expiration dating?! Labeled adequately?! Properly issued and released?

34 EXAMPLE INVESTIGATION QUESTIONS! Environment:! Were there any environmental conditions that contributed to issue?! Was room or product temperature an issue?! Was equipment/ room properly cleaned?! Is this documented?! Is cleaning validated?! Approved cleaning sanitization solutions used?! Any Air Flow / Pressurization Issues?! Any activities occurring at the same time that could be an issue?! Was Personnel Monitoring within limits?

35 EXAMPLE INVESTIGATION QUESTIONS! Manpower! Were personnel properly trained in the procedures?! Are the operators familiar with the activity?! Were an adequate number of personnel utilized for the particular procedure? (cover for breaks / shift change etc)! Is adequate oversight of operators possible?! Are procedures available to operators conducting the activity?

36 GATHERING DATA! 5 Whys Used in connection with the Cause and Effect Diagram to probe more deeply into the root cause of a deviation.! Determine the starting point, either a problem or a high-level cause that should be further analysed.! Use brainstorming to find causes at the level below the starting point.! For each identified cause, pose the question, "why is this a cause for the original problem?"! For each new answer to the question, ask the question again and again until no new answers results. This will probably be one of the root causes for the problem.! This often requires five rounds of the question "Why?

37 5 WHYS Contribu,ng Cause Contribu,ng Cause Why? Contribu,ng Cause Why? ROOT CAUSE Why? Why? Effect or Problem Why? Direct Cause Why? Contribu,ng Cause Why? Contribu,ng Cause

38 GATHERING DATA! Human Error Reduction! Human error reduction is applicable in situations where an initial investigation may highlight an aspect of human failure as the root cause.! Used when the initial investigation highlights operator error, failure to follow procedure, or human error as the outcome.! Used to eliminate or minimise the range of factors that impact on the performance of an individual! The technique is based upon the premise that:! Every time a task is performed there is a possibility of failure! An accumulation of factors results in human error! The probability of the failure is affected by one or more Error Producing Conditions (EPCs)! that by removing or reducing EPCs factors the likelihood of error will also be reduced.

39 HUMAN ERROR REDUCTION Individual Task Interpersonal Infrastructure Organisa*on Independent Experience Intelligence Fa,gue Stress Illness Medica,on Senses Memory Priori,sa,on AZen,on span Age Gender Structure Sequence Layout Defini,on Environment Ergonomics Documenta,on Complexity Equipment Familiarity Deadlines Conflicts Clear Objec,ves Suitable team Group Characteris,cs Decisions/ Assump,ons Communica,on Peer Pressure Compe,ng priori,es Equipment/ Standards Loca,on IT Space Building Change in responsibili,es Communica,on Management style Culture Training Constraints Resource Security Economic climate Poli,cal climate Physical proper,es of an area! Key words are used to identify EPCs that led to an event! Traditional approaches focus on changing the operator to fix the error! Retraining / coaching! In HER, to prevent reoccurrence consideration is given to eliminating the factor and thus changing the circumstance

40 SUMMARIZING AND CONCLUDING

41 SUMMARIZE THE INVESTIGATION! Pull together the data and potential root causes! Eliminate possible root causes that are not impacting! Provide rational for why not! Conclude on the root cause(s) that are deemed to have given rise to the deviation

42 IDENTIFYING CAPA! The purpose of identifying all solutions to a problem is to prevent recurrence at lowest cost in the simplest way.! Multiple root causes may have different solutions! A single root cause may have multiple solutions! If there are alternatives that are equally effective, then the simplest or lowest cost approach is preferred! Once the Root Causes are established, CAPA can be identified! A CAPA is intended to eliminate or mitigate a root cause, and prevent reoccurrence of the deviation! The CAPA should have an objective and a series of related tasks

43 IDENTIFYING CAPA! A CAPA objective should:! define the problem to be solved! state the actual or most probable root cause! outline the required end result! include the criticality assessment from the initial assessment process to allow timescales to be determined! Tasks should be SMART (Specific, Measurable, Achievable, Realistic and Time-based)! It should be remembered when defining the CAPA, the person executing the task may not be involved in its initial establishment.! The objective and task definition needs to be clear, concise and understood by all.! Responsibility for the CAPA should be clearly defined with timelines for resolution

44 COMPLETE BATCH IMPACT ASSESSMENT! Revisit the deviation criticality and based on the detailed RCA determine if the initial assessment remains valid! Provide an assessment of the affected batch(s) impact and provide a disposition recommendation based on the impact of this deviation, with rational

45 CLOSE THE DEVIATION! Ensure the report is properly written up! All people involved in the investigation are listed! Comments are signed and dated in a GMP compliant manner! All investigation areas are documented (including those which do not result in the root cause being identified)! The cause and effect tools used are recorded! Details are recorded in a factual and concise manner! Remedial actions which have been taken are detailed together with a statement of whether these are considered to have resolved the root cause of the incident

46 CLOSE THE DEVIATION! Additional data/reports are referenced on the main report! Where appropriate a clear statement is made regarding the impact on batch release! A clear statement identifying root cause is made. Where this is not possible a most probable root cause can be stated based upon analysis of the investigation! CAPA objectives are stated! The section of the QMS related to the incident is identified to allow trending of incidents! All required signatures are in place

47 DEVIATION TRENDING

48 DEVIATION TRENDING! It is useful to track metrics and trend data on deviations! Collect the data in real time! Trends should be reviewed periodically! Minimum as part of Annual Product Review process! Patterns can be observed and wider issues with underlying quality management system can be identified! This is what inspectors like to do! Identified trends should be investigated and appropriate CAPA implemented

What to Trend Type of Devia,on Possible Categories Equipment Failure Human Error Material Issue Environmental Process Failure DEVIATION TRENDING What it might tell you Underlying problem with

49 What to Trend Type of Devia,on Possible Categories Equipment Failure Human Error Material Issue Environmental Process Failure DEVIATION TRENDING What it might tell you Underlying problem with equipment maintenance procedures / frequency Unsuitable equipment / old technology Poor procedures Inadequate training or assessment Reliance on manual processes where a machine might do bezer Raw Material Quality Issue Inadequate supply chain or warehouse prac,ce Inadequate QC tes,ng Inadequate clean room prac,ces Poor clean room design Inappropriate alert levels Inadequate environment for opera,on Inappropriate process control limits too,ght Inappropriate alert levels too loose

What to Trend Time to Close Number of Devia,ons Possible Categories On,me Later than target Low High DEVIATION TRENDING What it might tell you Process is well managed Inadequate resources to

50 What to Trend Time to Close Number of Devia,ons Possible Categories On,me Later than target Low High DEVIATION TRENDING What it might tell you Process is well managed Inadequate resources to inves,gate Lack of ownership of devia,on Process is very well controlled, everyone knows exactly what they are doing People do not understand the devia,on process Devia,on process may not be used properly other mechanisms may be employed Process is out of control Devia,on process is well understood Devia,ons may be raised where a remark might do

51 DEVIATION SOP

52 DEVIATION SOP! What to include! Responsibilities and clear escalation routes for handling of deviations! A generic list of information required to support initial assessment! Methods of initial assessment (extent & potential impact on product quality and regulatory compliance)! How to contain the impact of the event! Suitable instructions for different types and different scales of event! Evaluating the nature & potential seriousness of the deviation (priority, time-scale to resolve, communications)

53 DEVIATION SOP! What to include (cont)! A fast-track process, where required for serious events! The classification of deviations! How to plan, execute and document of root cause investigations! Approval required for reports in each category of deviation! Handover to CAPA and batch release processes! Periodic trending of deviations to confirm successful resolution of identified root causes! Mechanism to ensure that appropriate data on deviation handling is gathered to assess successful operation of the Deviation Handling process! A standard template for recording it all

54 DEVIATION SOP! What to avoid! Too many specific mandated examples! Decision trees should go into standard operating procedures and be used to tailor processes to avoid the deviation in the first place! Reliance on human error and retraining! Drill down and investigate and eliminate

55 Questions?

Top Annual 483 Observations: The Cycle of Quality June 2017 Presented by: Susan Schniepp

Top Annual 483 Observations: The Cycle of Quality June 2017 Presented by: Susan Schniepp 2016 Regulatory Compliance Associates Inc. Top Observation for 5 years Year Drugs #1 citation Device #1 citation