Exception Event Training

EXCEPTION REPORTS:

INVESTIGATING AND DOCUMENTING EXCEPTION EVENTS

April 14, 2015

G Habiger Consulting, LLC

Exception Events (investigations/deviations/CAPAs) represent the cost of poor quality and affect us in two critical ways.

Financial Cost Compliance Risk

What’s in it for us?

Financial Costs of Investigations

Performing investigations has a financial cost to the company. Eachinvestigation takes resources away from other projects or from theprocess of manufacturing product and shipping it to customers.

You can perform a rough calculation of the cost to write/review/approveinvestigations by determining the number of investigations that are opened in a month, multiplied by the number of staff hours needed to work on the investigation, multiplied by an estimated hourly wage.

Even for a small company with few investigations, the cost neededto close those investigations can be high.

COMPLIANCE RISK OF INVESTIGATIONS

21 CFR 211, Subpart F:

Sec. 211.100 Written procedures; deviations.

(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

COMPLIANCE RISK OF INVESTIGATIONS

21 CFR 211, Subpart J:

Sec. 211.192 Production Record Review

All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. 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 meet 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 have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.

WHY DO WE WRITE INVESTIGATIONS?

Auditors usually start by asking the company for a list of investigations.• A look back two years is typical• Auditor will ask to review exception files for the more serious

events

If the investigation is not self-explanatory….• Causes the auditor to dig deeper, which may reveal other problems• Draws into question the competency of the investigators and

approvers• The SME explaining the investigation will be very uncomfortable• Frustrates the auditor• Causes the auditor to question the adequacy of the deviation

investigation quality systems – opens the way to a Warning Letter.

THE INVESTIGATION MISSION STATEMENT

Our mission is to manage exceptions to minimize their impact on material and product quality, and patient safety, to ensure that root cause is identified and that corrective and preventative actions are implemented to eliminate the cause of the exception and to ensure that appropriate quality decisions are made for batch disposition.

HOW CAN THIS MISSION BE ACHIEVED?

Training employees to follow a logical, clear, and consistent approach to investigating exception events and documenting them appropriately. This will REDUCE the TIME spent on these investigations.

By identifying the TRUE root cause(s) of exception events and implementing corrective and preventative actions to eliminate the root causes. This will REDUCE the NUMBER of deviations.

ROLES IN THE INVESTIGATION

There are many people involved in an investigation. Each person has specific roles or duties to perform. All are important to make sure the investigation is completed on time, and with a true root cause and CAPA identified.

•Discoverer

•Quality Assurance

•Investigator• Subject Matter Expert

•Reviewer/Approver

THE BASIC ELEMENTS TO INVESTIGATE AN EXCEPTION EVENT

• Identify and describe the problem.

• Investigate the problem to find the root cause(s).

• Identify the Corrective Actions for each root cause to prevent recurrence of the deviation for the current situation (either short term or long term).

• Identify the Preventative Actions for each root cause to prevent occurrence of the deviation from affecting all like situations (global, either short-term or long term).

• Implement the Corrective Action(s) and Preventative Action(s) (CAPA).

“How do I know I have a problem to investigate?”

Your SOP should define a problem that requires an investigation as an “Exception”.

Exception: A non-compliance to regulatory requirements, and/or a confirmed event in which a departure from GMP compliance standards, documented procedures, specifications, and/or in-process controls, has occurred. Minor recording errors within GMP records that can be corrected with simple annotations are not considered exceptions.

THE DISCOVERER’S ROLE

EXERCISE: IS THIS UNUSUAL EVENT AN EXCEPTION?

Your manufacturing group tells you that they did not calibrate a scale correctly, and the scale was off by 0.01 grams.Yes: This results in a deviation from the target weight for the material and needs to be investigated.

You are reviewing a packaging record and notice that a technician wrote the wrong month for the date.No: This is a simple GDP correction and is not an exception.

You are reviewing HEPA certifications for a Grade A/ISO 4.8 room and identify a filter that failed its integrity test.Yes: This is a deviation from the procedure/specification for the unit.

THE DISCOVERER’S ROLE

“OK, I think I have discovered an Exception. What do I do now?”

• As soon as possible discuss with and notify your supervisor/manager.

•Bring with you any documentation or other information that describes what you found.

•Bring the QA rep with you if available. Otherwise, make sure QA is notified within 24 hours.

•Discuss immediate corrections to the batch. Consult with QA and decide what actions need to be taken immediately to interrupt the impact of the exception event on the product and/or segregate the product that could be affected and/or take additional samples for analytical or microbiological testing, etc.

EXAMPLES OF IMMEDIATE CORRECTION

Per the batch record, one container of Sodium Acetate Anhydrous was not added to the mixer. This was discovered before completion of mixing and mixing was stopped.

Correction: After conferring with the Customer, the Customer confirmed that the additional container could be added without any effect on the validated mixing process. The container was then added to the mixing vessel and mixing was completed.

Sometimes an Immediate Correction is not possible.One fill weight did not print on the fill check tape. The missing weight on the tape was noticed during batch record review by comparing the fill weights documented on the BR to the tape. No correction to the lot was possible because the exception was noticed after manufacturing was completed.

At the beginning of the investigation process, the role of QA is generally limited to being notified about the event, and depending on the procedures, issuing the investigation report number.

However, there is one important action that QA must undertake as soon as the investigation is initiated:

•Determine Quality Impact

This will help in determining the scope and severity of the investigation.

QUALITY ASSURANCE ROLE

THE BASIC ELEMENTS TO DETERMINE QUALITY IMPACT

• Identify the possible consequences to the quality of the material or product lot(s) affected and their significance.

• Identify all materials, components, in-process product and/or final product lots affected by the specific exception.

• Extend to other lots of same or different product if necessary.

• Justify whether and to what extent the exception has adversely affected quality characteristics of affected materials or products.

• Evaluate the appropriateness and effectiveness of any immediate correction to the lot(s) affected.

There are 8 steps for the investigator to follow:

Step 1: Define/Describe the eventStep 2: Determine the scopeStep 3: Determine the severityStep 4: Determine the frequencyStep 5: Perform the investigationStep 6: Determine the root causeStep 7: Determine the CAPAStep 8: Final assessment

THE INVESTIGATOR’S ROLE

Step 1: Define and Describe the Exception Event

“I just got notified that I’m assigned to investigate an Exception. How do I get started?”

Gather as much background information as possible surrounding the exception event. Potential sources to consider are:

• Batch Record, inspection and testing results• SOPs, drawings, calibration records, PM records, and other documents that describe the operations as they SHOULD BE.• Perform a visual inspection and/or a walk-through of the area where the deviation occurred.• ASAP collect any physical evidence, such as defective items.


• What happened in terms that are measurable and observable?• Where in the process did the exception occur?• When was the exception discovered (date/times) and by whom?• Did anything unusual happen just before the exception?• Exactly what was happening immediately following the exception?• How did the exception event differ from what should have happened?• What immediate action was taken after the exception to interrupt its adverse impact on product or material batch(s). What was the justification? Who did what, when, where and why? Who else was consulted to determine this course of action (QA)?• From this information, prepare a chronology of events.

As soon as possible, interview those involved after the deviation became known and answer the questions: Who, What, Where and When. Considerthese questions.


Step 2: Determine the Scope of the Investigation

Bracketing: The identification process to isolate where or when the exception specifically occurred and isolate the time and associatedproduct, if applicable, involved in the event.


Sometimes referred to as the “Fence”. The Fence can include an entire Lot, a portion of a lot, or multiple lots. This step is usually performed with assistance from QA.

• What batch(es) was/were in the process when the exception occurred?

• When was the last time (date/batch number) the process and equipment were working properly, and what direct observations (by whom and when), data or rationale support this date? Collect references.

• Did the circumstances leading up to the exception exist prior to this batch?

• If yes, what observations, data or rationale (i.e. PMs, batch records, direct observations, etc.) are relevant to establish the last known good batch or date of last normal operation?

• Based on the data and information collected, is there a rationale to support the conclusion that only a discrete and identifiable portion of the batch was affected?

Be aware that as the investigation continues, the scope or fence may change.

These questions can help you identify the scope:

POINTS TO CONSIDER WHEN DEFINING THE SCOPE

POINTS TO CONSIDER WHEN DEFINING THE SCOPE

Warning!

There is a significant compliance risk if all lots affected by a deviation,

including lots already released to a Customer or for distribution, are not

accounted for in the investigation. Each and every lot within the scope of

the investigation must be evaluated before being released by QA!

EXERCISE: WHERE IS THE FENCE?

A fill volume check taken at 10 am is out of specification. The last check taken at 9:45 am was in specification.

All product filled between 9:45 and 10 am are in the fence.

A 9 mo. stability sample for a product has a failing assay result for potency.The lot on stability is affected, and need to evaluate whether other

lots are also impacted.

A HEPA filter over the filling line fails its 6 month certification test.All product manufactured on the filling line since the last good

calibration test should be considered.

The intermediate API took 12 days to dry and meet the moisture specification. This is am unusual event and appears to be out of trend.

Would need to evaluate every manufactured lot for the intermediate API to see what the trend is, and if any other lots are out of trend.


Step 3 – Determine the Severity of the event.

Severity may also be called risk classification depending on the terms

being used in the procedure.

The severity is a way to assess the impact to patient safety and to product quality. It can allow you to determine how many resources may be needed to perform the investigation or how thorough the root cause analysis should be.

Severity should be defined in your investigation procedure and should involve QA in the decision process. Here is one possible way to define severity:

Minor Exception: A situation that is not likely to impact patient safety and/or product quality.

Major Exception: A situation where there is a remote probability that patient safety and/or product quality are at risk.

Critical Exception: A situation where there is a reasonable probability that patient safety and/or product quality are at risk.

POINTS TO CONSIDER WHEN CLASSIFYING SEVERITY OF EVENTS

• Discuss the severity classification with QA and reach consensus.

• Understand that at the start of an investigation, the severity of the exception may not be obvious. Consider performing an initial and final impact assessment as part of the investigation.

• Search for similar situations and determine if there are parallels or precedents that could be helpful to determine the severity classification. You also want to look for trends that would indicate a more in-depth investigation is needed.

• If severity cannot be determined, procedures may allow you to wait until the investigation is further along before classifying the event.

• Just because the event has not happened before, doesn’t mean that the event should be given a lower severity. Severity should not be tied to the frequency of the event.


Step 4 – Determine the frequency of the event.

The event’s frequency is important to determine if there is a trend for the event. Identifying trends will tell you if a process is in a state of control or not and will help you in identifying what CAPAto put in place.

The frequency is performed by looking at historical investigations for the event. Don’t be too narrow in looking at the frequency. Only looking at the product, or the specific event, can create too narrow a focus and allow you to miss trends that may be hiding in plain sight.


Your procedure should identify how far back to look to determine if a trend exists. A good rule of thumb is to go back 1 year plus 1 day from the date of the event.

If your investigation takes longer than your procedure allows, the frequency search should be performed again to identify any new events that may have occurred.

Look for trends for personnel, process/procedure, equipment, and the identified root cause. Don’t limit yourself to looking at only events for the product involved; the frequency investigation should look at all products to try and find trends.

Be clear in stating what you looked at, the time period examined, and whether a trend was identified or not. Provide examples of similar events.

Step 5 – Perform the Investigation

Your investigation should address the following subjects:•Personnel•Procedures•Equipment•Materials•Environment•Miscellaneous

Be consistent and always address each subject in every investigation, even if the subject didn’t contribute to the event. By being consistent you show an auditor that you have examined the subject to determine whether it impacted the event or not.


Tip: The Investigator can and should call on other knowledgeable personnel from QA, Validations, Regulatory, Manufacturing, Technical Operations, Product Development, Engineering/Facilities, Chemistry, and/or Microbiology! An investigation is always a team effort!

If you rely on personnel from other departments for the investigation, be sure to detail who assisted you in the investigation write up. This isn’t about giving credit, but about assigning responsibility and allows an auditor to know who was involved and they can follow up if needed.

Consider beginning each subject with a clear statement of whether or not that subject was or was not the cause of the event. This provides clarity for the reader and allows you to then explain the reason why/why not the subject is the cause.

A checklist is a useful tool to have to make sure you are consistent in addressing topics in each of the subjects.


Step 6 – Determine Root Cause

The goal of the investigation is to find the TRUE root cause for the exception event. There are several Root Cause Tools that can be used to assist the investigator. 5 Why Analysis Is/Is Not Analysis Fishbone Matrix Process Mapping Risk Assessment FMEA (Failure Mode and Effects Analysis)

Not every investigation will need to use these tools, and usually only one tool is needed. Very complex investigations may require two or more tools to find the root cause. State which tool(s) you used. This allows the reader to understand your thinking and follow the process to find the root cause more clearly. Make sure to document your root cause analysis in the investigation or as an attachment.


Include a clear root cause statement in the investigation. Don’t assume your reader will draw the same conclusions or reach the same decision you made.

You may find multiple root causes, or several probable causes, or a root cause and contributing causes that led to the event. Clearly spell out which is which.

If you are unable to find a root cause (or any probable or contributing causes) clearly state this in the investigation. You will need to explain your reasoning and whether the lack of a root cause needs to be further investigated or not.

Your investigation procedure should define root cause categories in which investigations can be grouped. Try to use the same wording and categories in the root cause statement for consistency and clarity with the procedure. These categories are also important for trending of your investigations.


Step 7 – Determine the CAPA

CAPAOnce the root cause is determined the investigator needs to find a way to keep the event from happening again. This is accomplished by using Corrective Actions (CA) and Preventive Actions (PA) to prevent re-occurrence.

Corrective Action – Actions taken to prevent reoccurrence of an existing event.Preventive Action – Actions taken to prevent the occurrence of a potential nonconformity or trend.

CAPA Plan – investigations into major events will have a formal plan for CAPA, including actions to be taken and ways to measure the effectiveness of the corrective and preventive actions.


Don’t confuse immediate corrections or containment efforts as part of the corrective or preventive action. Immediate corrections should be detailed and listed in the investigation, but they are not part of the CAPA.

CAPAs should be clear and provide specific details of what will be done, by whom, and when it will be done by. Follow your existing procedures for the CAPA process.

Consider whether the CAPA will have an affect on any regulatory commitments, validated states, product quality, or product stability.


Step 8 – Final Assessment

Determine the final product assessment – is there any impact to product quality or patient safety as a result of the investigation?


“I’m not QA and I’ve never released a batch. How do I determine if product quality or patient safety was affected?”

Your procedure should give you guidelines in performing an assessment. Andremember that the investigation is a team effort. Don’t be afraid to call on knowledgeable sources from other departments when making the determination.

The reviewer/approver is critical to making sure the final report is ready to be closed. This goes beyond a simple QA review to make sure that a cause was found and CAPA implemented, but is performed to verify that the exception event procedure was followed and the final report is readable.

•Can the conclusions and decisions in the report be understood clearly?•Is there a logical path to the investigation?•Did the investigator follow the investigation procedure? Were all sections completed to show how the root cause was determined?

THE REVIEWER’S ROLE

Consider using the following tools to make your investigations consistent:

•Investigation checklist•Investigation rubric


Checklist: Tool used to verify that specific requirements or sections are included in the investigation.

Rubric: Tool used to delineate consistent criteria used to grade or score the report. Has different levels of assessment and descriptors. If a minimum score is not reached the document is returned to be re-written.

If the investigation report is acceptable and meets the procedural or rubric requirements, the reviewer then writes a summary/ conclusion for the investigation.

•High level overview of the investigation.•Summarize what happened, what the root cause was.•Make a statement about impact to safety, quality, regulatory, or validated states as appropriate.•Summarize containment, immediate corrections and the CAPA as applicable.


INVESTIGATING EXCEPTIONS - REVIEW

• Why do we write investigations?• Identifying an Exception Event• The Discoverer’s Role

• Immediately correcting the situation• Quality Assurance’s Role • The Investigator’s Role

• 8 Steps to writing the investigationDescription ScopeSeverity FrequencyInvestigation Root CauseCAPA Final Assessment

• The Reviewer’s Role

QUESTIONS

Questions

Documents

Exception Event Training