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InfoCard #: COMM-QA-042 Rev. 14 Effective Date: 13 May 2019

DUKE

DOCUMENT NUMBER: COMM-QA-042

DOCUMENT TITLE:

Deviations and Investigations

DOCUMENT NOTES:

Document Information

Revision: 14

Status: Release

Date Information

Creation Date: 03 Aug 2017

Effective Date: 13 May 2019

Control Information

Author: RB232

Previous Number: COMM-QA-042 Rev 13

Vault: COMM-QA-rel

Document Type: COMM-QA

Release Date: 13 May 2019

Expiration Date:

Owner: RB232

Change Number: CCBB-CCR-1348, COMM-CCn

CONFIDENTIAL - Printed by: ACM93 on 13 May 2019 10:18:28 am


COMM-QA-042DEVIATIONS AND INVESTIGATIONS

1 PURPOSE

1.1 To describe the procedure for reporting, documenting, approving, and trackingevents occurring outside of Standard Operating Procedure (SOP), current GoodManufacturing Practices (cGMP), current Good Laboratory Practices (cGLP),Good Tissue Practices (cGTP), and/or current Good Clinical Practices (cGCP).

2 INTRODUCTION

2. 1 An event management system is necessary to promptly alert the Quality SystemsUnit (QSU) and applicable parties of the event, document details of the eventincluding root cause, risk assessment, investigation, and action(s) taken, andfacilitate timely closure of events.

3 SCOPE AND RESPONSIBILITIES

3. 1 This procedure is referenced when reporting, investigating, documenting,approving, and tracking the event(s) via MasterControl, for the Carolinas CordBlood Bank (CCBB), Stem Cell Laboratory (STCL), Adult and Pediatric Bloodand Marrow Transplant Programs (APBMT), and the Robertson GMPLaboratory.

3. 2 Refer to Program specific OOS procedures (e. g., CCBB-QA-020 Handling Out ofSpecifications (OOS) and Unexpected Results; STCL-QA-007 Non-ConformingProducts - Receipt, Processing, Distribution, and Disposition; GMP-QA-003Non-Conforming Products and Out of Specification Results - Receipt,Processing, Distribution, and Disposition) for details on evaluating anddocumenting these types of events.

3. 3 Refer to Program specific procedures on handling Adverse Experiences (AEs)(e. g., CCBB-QA-026 Postmarketing Receipt of Adverse Experiences; GMP-QA-005 Evaluation of Complaints and Adverse Experiences).

3.4 Program personnel are responsible for promptly notifying theirSupervisor/Manager when an event or deviation from a policy, process, orprocedure is identified.

3. 5 Trained personnel are responsible for completing the MasterControl Deviationand Investigation Report form (COMM-QA-042 FRM4 Deviation andInvestigation Report) and modifying step routes as needed to ensure applicableSupervisor/Manager, Medical/Program Director, and approving physician areincluded. This includes bracketing ofproduct(s) with input from QSU andMedical Director, as necessary.

3.6 The Medical/Program Director reviews and approves or rejects allDeviations/Investigations via electronic signature.

3. 7 QSU responsibilities include:

3.7. 1 Review and approval of all Deviations/Investigations for completenessand appropriate level of detail.

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3. 7. 2 Verify bracketing as necessary to assess quality impact to product(s).

3.7.2. 1 Verify appropriate quarantine of associated product(s), asapplicable, until the investigation is complete and theproduct(s) are approved by QSU to be released fromquarantine.

3. 7. 2.2 Utilize available databases (i. e., EMMES, CordSource,MasterControl) to prevent release/upload of associatedproduct(s), as necessary, while an investigation is ongoing.No quarantined product(s) shall be released by QSU until allassociated investigations are appropriately closed and theproduct is determined acceptable for release, unlessotherwise directed in facility-specific SOPs.

3. 7. 3 In rare time sensitive situations, QA may release a product with anassociated Deviation/Investigation if it has been appropriatelydocumented, including a product impact assessment, prior to issuingfinal QA approval for release. If applicable, facility-specific SOPsdefining requirements for the specific product should be followed. AMasterControl event must be initiated for reference, and QSU should beconsulted to identify an appropriate way to document the situation andassessments in real time.

3. 7.4 Monitor the Deviation/Investigation system to facilitate timely closureof reports.

3. 7. 5 Perform quarterly tracking and trending and initiate investigations basedon identified trends, as applicable.

3. 7. 6 Provide status updates to applicable Supervisor/Managers, ProjectCoordinators, and Medical/Program Directors, in an effort to facilitatethorough and timely closure ofDeviations/Investigations and CAPAsand to communicate identified trends.

4 DEFINITIONS/ACRONYMS

4. 1 AEs: Adverse Experiences

4. 2 APBMT: Adult and Pediatric Blood and Marrow Transplant

4. 3 BPDR: Biological Product Deviation Report

4.4 Bracketing: The practice of performing an expanded product impact assessmenton all products that were manufactured during the timeframe in which thedeviation occurred; e.g., failures in critical equipment, such as leaks and repairs toa HEPA filter: Bracketing will include tracking of products manufactured back tothe last successful equipment monitoring to determine impact on product.

4. 5 CAPA: Corrective and Preventive Action

4. 6 Corrective Action: Action taken to eliminate the cause of a detected event or

deviation. Corrective action is taken to prevent the recurrence of a problem.Please note that any action taken to address the cause of a problem is part of aCAPA (ex. additional training or changes to procedures, processes or systems).

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4. 7 cGCP: current Good Clinical Practices

4. 8 cGLP: current Good Laboratory Practices

4. 9 cGMP: current Good Manufacturing Practices

4. 10 cGTP: current Good Tissue Practices

4. 11 CBUs: Cord Blood Units

4. 12 CCBB: Carolinas Cord Blood Bank

4. 13 Complaint: An event in which customer expectations are not met. Complaintsare also documented when a vendor or supplier fails to meet the expectations ofthe program/manufacturer. Complaints may or may not also be classified asdeviations.

4. 14 Correction: Action to eliminate a detected nonconfoiTnity.

4. 15 DCO: Document Control Operations

4. 16 Deviation and Investigation Report: Form used to document the findings of aninitiated deviation

4. 17 Events: Examples may include planned and unplanned deviations from SOP,customer complaints, out of specification or unexpected results, internal andexternal audit findings, or reoccurring problems/trends.

4. 18 External Reporting: The dissemination of information to an outside party asrequired by any applicable regulation, standard, contract or quality agreement.This could include reporting to FDA, an external sponsor, or another entity.

4. 19 Final Quality Approval: The point in the review process after which an eventreport is considered to be complete/final and in a form that may be disseminatedto an outside party as a complete/final document.

4. 20 HEPA: high-efficiency particulate air

4.21 Investigation: A thorough and comprehensive collection of information toaddress a trend associated with a product, process, and/or quality system. Thegoal of the investigation is to identify the root cause of the event.

4.22 ISBT label: is a standard labeling format that ensures a consistent layout ofcritical information for product labels.

4.23 MasterControI: An electronic 21 CFR compliant data management system

4. 24 Nonconformity: A departure of a quality characteristic from its intended level orstate that occurs with severity sufficient to cause an associated product or servicenot to meet a specification requirement. A nonconformance may or may not beclassified as a deviation.

4.25 Out of Specification Result: Any measurement or assay result that falls outsideof established specifications or other established acceptance criteria as defined bythe Program.

4.26 PBMT: Pediatric Blood and Marrow Transplant

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4.27 Planned Deviation: A deviation from a policy, process, or procedure that isanticipated and requires prior approval by a designated Physician orMedical/Program Director and QSU.

4.28 Preventive Action: An activity or step implemented to prevent the initialoccurrence of a problem, based on an understanding of the product or process.Please note that any action taken to prevent initial occurrence of a problem is partof a CAPA (ex. additional training or changes to procedures, processes orsystems)

4.29 QA: Quality Assurance. The sum of activities planned and performed to provideconfidence that systems and their elements that influence the quality of a productare functioning as expected and relied upon.

4. 30 QC: Quality Control. Includes the activities and controls used to determine theaccuracy of the establishment's equipment and operations in manufacturing andproduct release.

4.31 QSU: Quality Systems Unit

4. 32 Root Cause: An identified reason for the presence of a defect, problem,deviation, or nonconformity, the most basic reason which, if eliminated, wouldprevent recurrence. The root cause can also be defined as the source or origin ofan event.

4.33 SOP: Standard Operating Procedures

4. 34 SQIPP: Safety, Quality, Identity, Purity, Potency

4. 35 STCL: Stem Cell Laboratory

4.36 Unplanned Deviation: An unexpected event or error that deviates from a policy,process, or procedure; e. g., written procedure or instructions not followed, failureto sample and test, improper material storage, use ofequipment/reagents outsideofcalibration/expiration date.

5 MATERIALS

5. 1 Supporting reports/documents; e. g., product recall notification, emailcorrespondences.

6 EQUIPMENT

6. 1 Computer access to MasterControl

7 SAFETY

7. 1 N/A

8 PROCEDURE

8. 1 Event Notification

8. 1. 1 Personnel notify their Supervisor/Manager upon discovery of an eventor deviation from a policy, process, or procedure.

8. 1. 2 Supervisor/Manager ensures immediate correction(s) are initiated andnotifies the QSU and Medical/Program Director, as necessary.

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8.2

8.3

Time Requirements and Report Monitoring

8. 2. 1 Trained personnel initiate a Deviation and Investigation Report(COMM-QA-042 FRM4) via MasterControl in a timely manner uponthe discovery of a deviation.

8. 2. 1. 1 For CCBB, cord blood units will be quarantined asappropriate per CCBB-QA-032 Tracking and Traceability ofCBUs concurrently with initiation of adeviation/investigation report, and a copy of the quarantinereport will be attached to the deviation/investigation prior tosubmission for QA review.

8.2.2 Deviation and Investigation Reports should be completed and submittedfor review expediently, unless extenuating circumstances delaythorough investigation to identify root cause. The target timeframe fordeviation and investigation resolution is 30 days.

8. 2. 3 Deviation/Investigation progress will be actively monitored by the QSUthrough a variety of mechanisms, which may include but are not limitedto regular QA meetings discussing open events, monthly eventmanagement tracking meetings, and/or regular reports that are sent toapplicable Department Managers, Quality Director and MedicalDirector(s). These meetings and reports will highlight key statisticssuch as discovery/initiation date and report duration.

Planned Deviations

Refer to COMM-QA-042 Appendix A for instructions on completing aplanned deviation.

Refer to COMM-QA-077 Risk Assessment Procedure for assistancedetermining if a CAPA is required due to risk.

Refer to procedure COMM-QA-076 Corrective and Preventive Actionsfor additional information and instructions on completing a CAPA, ifdeemed necessary. If a CAPA is implemented, please ensure that thecorrective and/or preventive actions are noted in the designated CAPAsection of the Deviation and Investigation Report. Details and theeffectiveness check will be documented and monitored per COMM-QA-076 Corrective and Preventive Actions.

;. 3.1

. 3.2

.3.3

8.4

8. 3.4 Approval by the Supervisor/Manager, Medical/Program Director ordesignated physician, and QSU should be documented prior toimplementing the planned deviation from policy, process, or procedure.

8. 3. 5 An electronic version of the planned deviation is maintained in theMasterControl system, and a reference to the approved planneddeviation report is added within the associated file, such as product filesor batch records, as applicable.

Unplanned Deviations

Refer to COMM-QA-042 Appendix A for instructions on completing anunplanned deviation.

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8. 6. 2 If the initiator of a Deviation and Investigation Report is not theSupervisor/Manager, modify step routes, as applicable, to include theSupervisor/Manager for review and approval.

8. 6.3 Verify that the appropriate Medical/Program Director or physician, asapplicable, is selected for review and approval routes. Modify steproutes as necessary.

Review Process

8. 7.1

8. 7.2

8. 7.3

As part of the review process, QSU completes an assessment on allsubmitted deviations/investigations to determine the necessity forBiological Product Deviation Reporting (BPDR) as well as any externalreporting to outside vendors/sponsors per applicable quality agreement.QSU also designates an event code.

QSU assesses step routing for completeness and accuracy and modifiessteps as necessary to ensure thorough review.

Review and approval routes include, at a minimum: Initiator,Medical/Program Director, and QSU Representative.

8. 7. 3. 1 Reviewers may reject any route step during the review andapproval process to ensure consistent and accuratedocumentation.

8. 7.4

8.8

8.9

QSU will ensure any associated lots and batch records units areremoved from quarantine, if applicable, upon resolution of a deviation.

Tracking and Trending

8. 8. 1 QSU generates trending data (e. g., type and frequency of event) andprovides this in quarterly reports to applicable Supervisor/Managers,Project Coordinator, and Medical/Program Directors.

8. 8.2 QSU initiates investigations and any associated CAPAs, if deemednecessary, in response to identified trends.

Maintenance of Records

8. 9. 1 Deviation and Investigation Reports, and associated forms aremaintained in MasterControl and are accessible for printing and review.Reports may be generated by Document Control Operations (DCO) orQSU upon request.

8. 9.2 For events impacting or potentially affecting product, QSU will helpensure the MasterControl Deviation and Investigation Report isreferenced appropriately within the associated file/batch record to alertfile reviewers of the event.

8. 9. 3 In the event that a Deviation and Investigation Report is found to needadditional documentation after closure; e. g., missing data such as ISBTproduct identifiers, relevant attachments, or other pertinent information,an additional Deviation and Investigation Report may be opened as asupplement to the initial report.


8. 9.4


8.9.3. 1 The title of the report should be populated as "Supplement to(insert Deviation and Investigation number)".

All records are maintained according to the associated Program RecordsManagement or Records Retention procedure(s).

RELATED DOCUMENTS/FORMS

9. 1 CCBB-QA-011 Licensed Biological Product Deviations (BPD)

9.2 CCBB-QA-020 Handling Out of Specifications and Unexpected Results

CCBB-QA-026 Postmarketing Receipt of Adverse Experiences

CCBB-QA-032 Tracking and Traceability of Cord Blood Units

COMM-QA-042 FRM4 Deviation and Investigation Report

COMM-QA-076 Corrective and Preventive Actions

COMM-QA-077 Risk Assessment Procedure

9.3

9.4

9.5

9.6

9.7

9.8 STCL-QA-007 Non-Conforming Products - Receipt, Processing, Distribution,and Disposition

9.9 GMP-QA-003 Non-Conforming Products and Out of Specifications Results

9. 10 GMP-QA-005 Evaluation of Complaints and Adverse Experiences

10 REFERENCES

10. 1 21 CFR 211.22(a)-Responsibilities of a Quality Control Unit

10.2 21 CFR 211. 100 - Written Procedures; Deviations

10. 3 21 CFR 1271 - Human Cells, Tissues, and Cellular and Tissue-Based Products

10.4 FACT-JACIE International Standards for Cellular Therapy; Current Edition

10.5 FACT Common Standards for Cellular Therapies; Current Edition

10. 6 NetCord-FACT International Standards for Cord Blood Collection, Banking andRelease for Administration; Current Edition

11 REVISION HISTORY

Revision No.

14

Author

R. BryantDescription of Change(s)

Added instruction for external reporting. Added appendixinformation. Procedure revised to combine deviation form

with issue review form, previously discussed in COMM-QA-077 Risk Assessment procedure. Revisions madethroughout to align with use by multiple departments.



Appendix A

Deviation and Investigation Report (COMM-QA-042 FRM 4) Instructions:

. Complete the Deviation and Investigation Report, filling in all required information.

. Record N/A in any section that does not apply.

Data Field

Deviation/InvestigationNumber

ProgramInitiated By

Date Discovered

Date(s) Affected

Supply/ReagentEquipment ReferenceDeviation and InvestigationTitleProblem Statement

Correction(s)/ImmediateAction(s)

Investigation

Instructions

Event number is auto-populated by MasterControl.

Select applicable program in which deviation occurred.This field is auto-populated by MasterControl to indicate which user initiatedthe deviation.

Enter the date the issue being investigated/documented was discovered .This is the time period in which the deviation may have affected product. Forplanned deviation, enter time period for which the planned deviation is needed.If a specific date range does not apply, enter N/A.Enter name and lot number of supply reagent, if applicable.Enter name and serial number of equipment, if applicable.Enter a title that clearly identifies what the Deviation and Investigation Report isabout.

Clearly describe the situation.Identify the problem being addressed at the start of the narrative.If applicable, state the requirement/procedure not met and describe the deviationfrom the requirement.State the date the event occurred.

Include a description of how and when the event was identified.

Note: If deviation is planned, inchtde jiistificationfor action^Detail all immediate actions taken, in chronological order to resolve theproblem. Include dates completed.Examples: Containment, Stop ofshipment/supply. Destruction of Product orProduct Recall, Suspend production process.

Note: Action(s) taken to address the root cause of a problem or to prevent initialoccurrence of a problem is not typically an immediate action/correction. This isa CAPA (ex. additional training or changes to procedures, processes orsystems.)

If deviation is planned, specify:What the action(s) will beWho will do itWhen it will be done

Define the scope of the event in greater detail and include applicable dates onwhich events/actions occurred. If investigation is conducted over time,update/refine the investigation as new information is discovered:

o What information was gathered, reviewed and/or evaluatedo Include and explain all applicable dates/date rangeso Results of the reviews/evaluations of the information

o Summary of information gathered to help identify root cause(s) and/orcontributing factors

o Consider if the event may have impact to other processes, documents,COMM-QA-042 Deviations and InvestigationsOffice of Regulatory Affairs and Quality, DUDurham, NC CONFIDENTIAL-Printed by: ACM93 on 13 May 2019 10:18:28 am Page 9 of 10


Data Field

Root Cause

Deviation Identification

External Reporting

Event report(s) associatedwith This

Deviation/InvestigationRisk Assessment

Risk Assessment Score

Detail Rationale for Risk

Assessment

CAPA Number

Summary ofCAPA

Was product associated withthis report quarantined?If all other specifications forlicensure are met, is thereany reason that product(s)associated with this event

cannot be released under thelicense?

Unique Product Identifiers)Affected

[Lot Number/ISBT]QA Assessment(Completed by QSU)Event Code

(Completed by QSU)Attachments

Instructions

samples, results, etc. If other programs/departments will be impacted,notify the department/management, as appropriate.

Note: This section is not required for planned deviations.Statement of Root Cause identified during investigation.Note: If deviation is planned, please still include a root caitse.Complete this section to document, by listing SOP numbers, if any deviationfrom SOP was identified. This section also used to differentiate betweenplanned and unplanned deviations.This section is completed to determine if additional regulatory or other externalreporting such as to a vendor or sponsor may be required. If notification isrequired prior to event closure, then documentation, such as email, FAX etc.,should be attached to the document in the Attachments section. This section to

be populated by author/initiator if known at time of report and/or QSU at time ofreview.

Enter any report number(s) associated with this Deviation/Investigation (otherDeviation(s), Adverse Events, complaint(s)).

Reference procedure COMM-QA-077 to assess risk and determine ifCAPA isrequired. CAPA may still be appropriate even if not required due to risk.Use the Risk Assessment Matrix to assign a numerical value for risk assessment.Summarize the rationale for the risk assessment and include clarification aboutwhich risk severity and frequency were chosen for the risk matrix (and why).Enter number ofCAPA generated. Enter N/A if no CAPA.

Give an overview ofCAPA(s) to be implemented in associated CAPA report (ifapplicable).As a best practice, please route any associated CAPA (first routing) concurrentlywith the corresponding Deviation and Investigation Report.Select radial button to indicate applicable quarantine of product and describeselection.

Select appropriate toggle to indicate any change to license status. Use text fieldto explain if yes. Select N/A ifnon-CCBB or licensed MC3 GMP product.

Add associated product identifier(s) as applicable.

QSU will reference program specific SOPs for BPDR assessment.

Select the event code from the data set that most closely matches the root cause.

Use this function to attach all applicable documents.



Signature Manifest

Document Number: COMM-QA-042

Title: Deviations and Investigations

Revision: 14

All dates and times are in Eastern Time.

COMM-QA-042 Deviations and Investigations

Author

Name/Signature

Patrick Killela (PK37)

Medical Director

itle Date ^^^jMeamng/Reaspn07 May 2019, 09:47:56 AM Approved

Name/Signature

Joanne Kurtzberg(KURTZ001)

Quality

I Title Date Meaning/Reason

07 May 2019, 11:16:56 AM Approved

; Name/Signature

Amanda Parrish (AKB8)Taylor Orr (TS04)LisaEddinger(LE42)

Document Release

Title Date J Me a ni ng/Reason

07 May 2019, 11:44:16 AM Approved

[Name/SignatureSandy Mulligan (MULL1026)

Title Date Meaning/Reason08 May 2019, 09:45:35 AM Approved

Quick Approval

Approve Now

Name/Signature I Title

Sandy Mulligan(MULL1026)

Date, iiMeaning/Reason

i May 2019, 09:54:27 AM Approved

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