Quality Risk Management (QRM) -Mohammad M Sepahi - 2024.pdf

Riskmanagementprinciplesareeffectivelyutilizedinmanyareasofbusinessandgovernmentincludingfinance,insurance,occupationalsafety,publichealth,pharmacovigilance,andbyagenciesregulatingtheseindustries(ICHQ9(R1)). The importance of quality systems has been recognized in the pharmaceutical industry and it is evident that quality risk management is a valuable component of an effective quality system (ICH Q9(R1)).

1. Pharmaceutical qualitysystem(PQS)Webinars Series
Quality Risk Management (QRM) -
Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools
Mohammad Mahdi Sepahi, PhD
PQS/GMP Consultant
29-January-2024
[email protected]
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2. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
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3. Definition and Concepts
Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments
Agenda
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024

4. Objectives,
Applications and Regulations
Definition and Concepts
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024

5. References
ICH ▪QualityRiskManagementQ9(R1),18January2023
PIC/S ▪Annex 20: Quality Risk Management , PE 009-17 (Annexes), 25 August 2023.
ISO
▪ISO/IEC Guide 73:2002 -Risk management —Vocabulary
▪ISO 31000:2018, Risk management guideline
▪ISO 14971:2019, Medical devices-Application of risk management to medical devices
▪ISO 27005:2018 -Information technology –Security techniques –Information security risk management
▪ISO/IEC Guide 51:2019, Safety aspects -Guidelines for their inclusion in standards
WHO
▪Annex2,guidelinesonqualityriskmanagement,TRS,No.981,2013.
▪Annex7,ApplicationofHazardAnalysisandCriticalControlPoint(HACCP)methodologytopharmaceuticals,TRS,No.908,2003.
PDA
▪Technical Report No. 54 (TR54): Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations
▪Technical Report No. 44, (TR 44): Quality Risk Management for Aseptic Processes
▪Technical Report No. 68, (TR 44): Risk-Based Approach for Prevention and Management of Drug Shortages
ISPE
▪Risk-Based Manufacture of Pharmaceutical Products, 2010
▪GAMP 5-A risk-based approach to compliant GxP computerized systems, 2022
▪Alex Brindle and et al., Risk analysis and mitigation matrix (RAMM)-Risk tool for quality management." Pharmaceutical Engineering 32.1 (2012)
▪Murray, K., and Stephen Reich. "Quality Risk Management (QRM) tool selection: getting to right first time." Pharmaceutical Engineering 31.4 (2011)
▪Díaz, Rodolfo, G. Fernández, and Cristian Muzzio. "Practical application of quality risk management to the filling process ofbetamethasone injections."
Pharmaceutical engineering 31.4 (2011)
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

6. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Quality
Thedegreetowhichasetofinherentpropertiesofaproduct,systemorprocessfulfillsrequirements(seeICHQ6Adefinitionspecificallyfor“quality”ofdrug
substanceanddrug(medicinal)products.)
Risk
▪The combination of the probabilityof occurrence of harmand the severityof that harm(ISO/IEC Guide 51:2014).
▪Effect of uncertainty on objectives (ISO 31000)
Management
Is a systematic process for the assessment, control, communicationand reviewof risks to the quality of the drug (medicinal) product across the product
lifecycle(ICH Q9(R1)).
Lifecycle All phases in the life of a product from the initial development through marketing until the product’s discontinuation (ICH Q8 (R2)).
Hazard The potential source of harm(ISO/IEC Guide 51:2014).
Harm Damage to health, including the damage that can occur from loss of product quality or availability.
Definitions
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

7. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Riskmanagementprinciplesareeffectively
utilizedinmanyareasofbusinessand
governmentincludingfinance,insurance,
occupationalsafety,publichealth,
pharmacovigilance,andbyagencies
regulatingtheseindustries(ICHQ9(R1)).
The importance of quality systems has been
recognized in the pharmaceutical industry and
it is evident that quality risk management is a
valuable component of an effective quality
system (ICH Q9(R1)).
Achievingasharedunderstandingoftheapplicationofriskmanagementamongdiversestakeholdersisdifficultbecauseeachstakeholder
mightperceivedifferentpotentialharms,placeadifferentprobabilityoneachharmoccurringandattributedifferentseveritiestoeachharm.
Inaddition,subjectivitycandirectlyimpacttheeffectivenessofriskmanagementactivitiesandthedecisionsmade.Therefore,itis
importantthatsubjectivityismanagedandminimized(ICHQ9(R1)).
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

8. The Extended Quality Triangle*
Inrelationtopharmaceuticals,althoughtherearea
varietyofstakeholders,includingpatientsandmedical
practitionersaswellasgovernmentandindustry,the
protectionofthepatientisofprimeimportancewhen
managingtherisktoproductqualityandavailability,
whenavailabilityrisksarisefromquality/manufacturing
issues(ICHQ9(R1)).
*van der Spiegel, Marjolein. Measuring effectiveness of food quality
management. Wageningen University and Research, 2004.
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

9. Themanufacturinganduseofadrug(medicinal)
product,includingitscomponents,necessarilyentail
somedegreeofrisk.Therisktoitsqualityisjustone
componentoftheoverallrisk.Itisimportantto
understandthatproductqualityisassuredbasedon
appropriaterisk-baseddecision-makingthroughout
theproductlifecycle,suchthattheattributesthatare
importanttothequalityofthedrug(medicinal)product
aremaintainedandtheproductremainssafeand
effective(ICHQ9(R1)).
QRM in the Product Life Cycle
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

10. Existence and Detection of Nonconformities During The Product
Machac, Jan, Frantisek Steiner, and Jiri Tupa. "Product life cycle risk management." Risk Management Treatise for Engineering Professionals (2017): 51-72.
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

11. Risk from Product/Process
ICH Q9 Link Back To Patient Risk
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

12. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

13. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

14. ❑Aneffectivequalityriskmanagementapproachcanfurtherensurethequalityofthedrug(medicinal)producttothepatientby
providingaproactivemeanstoidentifyandcontrolpotentialqualityissuesduringdevelopment,manufacturing,and
distribution(ICHQ9(R1)).
❑Aproactiveapproachtoqualityriskmanagementisbeneficial,asitfacilitatesrobustproductdesignandcontinual
improvement,anditisofstrategicimportanceinachievinganeffectivepharmaceuticalqualitysystem(ICHQ9(R1)).
❑Useofqualityriskmanagementcanimprovethedecision-makingifaqualityproblemarises(ICHQ9(R1)).
❑Inthedevelopmentphaseandaspartofvalidation,qualityriskmanagementispartofbuildingknowledgeand
understandingriskscenarios,sothatappropriateriskcontrolcanbedecideduponforuseduringthecommercial
manufacturingphase(ICHQ9(R1)).
❑Theapplicationofdigitalizationandemergingtechnologiesinthemanufactureandcontrolofdrug(medicinal)productscan
leadtoriskreduction,whensuchtechnologiesarefitfortheirintendeduse.However,theycanalsointroduceotherrisksthat
mayneedtobecontrolled.Theapplicationofqualityriskmanagementtothedesign,validationandtechnologytransferof
advancedproductionprocessesandanalyticalmethods,advanceddataanalysismethodsandcomputerizedsystems
isimportant(ICHQ9(R1)).
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

15. ❑Anunderstandingofformalityinqualityriskmanagementmayleadtoresourcesbeingusedmoreefficiently,wherelowerrisk
issuesaredealtwithvialessformalmeans,freeingupresourcesformanaginghigherriskissuesandmorecomplexproblems
thatmayrequireincreasedlevelsofrigorandeffort.Anunderstandingofformalitycanalsosupportrisk-baseddecision-
making,wherethelevelofformalitythatisappliedmayreflectthedegreeofimportanceofthedecision,aswellasthe
levelofuncertaintyandcomplexitywhichmaybepresent(ICHQ9(R1)).
❑Appropriateuseofqualityriskmanagementcanfacilitatebutdoesnotobviateindustry’sobligationtocomplywith
regulatoryrequirementsanddoesnotreplaceappropriatecommunicationsbetweenindustryandregulators.Quality
riskmanagementshouldnotbeusedinamannerwheredecisionsaremadethatjustifyapracticethatwouldotherwise,in
accordancewithregulationsand/orguidance,bedeemedunacceptable(ICHQ9(R1)).
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

16. Principles of Quality Risk Management(ICH Q9(R1)).
Twoprimaryprinciplesofqualityriskmanagementare:
1
The evaluation of the risk to quality should be based on scientific knowledgeand ultimately
link to the protection of the patient. (Note: Risk to quality includes situations where product
availability may be impacted, leading to potential patient harm.)
2
Thelevel of effort, formality and documentation of the quality risk management process
should be commensurate with the level of risk.
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

17. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

18. Hazardous Situation
An exposure to a
Hazard(the bomb)
Risk
Isthe combination of probability
ofoccurrence ofharm through exposure to
the hazard (the bomb) and theseverity of that
harm (being injured by the explosion).
Hazard
Potential source of
harm (the bomb)
Harm
Damage to health caused
by exposure to hazard
(the bomb)
The Hazard leads to the Hazardous Situation The Hazardous Situation may lead to Harm
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

19. Hazard:
Biological contamination
of the drug product is the
potential source of
harm(hazard) that can
impactpatienthealth
Hazardous Situation:
Injection of medicine with
biological contamination into the
patient
Risk:
The combination of probability
ofoccurrence of patient harmby
injection of medicine with
biological contamination into the
patient (hazardous situation)
and theseverity of thatharm
Harm
Illness (potentially severe) or
even death​ of the patient
Damage to healthcaused by
patient exposure to medicine
with biological contamination
QRM TIP:
It is important to identify hazards to product
quality that mayultimately lead to patient harm
The Hazardous Situation may
lead to Harm
The Hazard leads to the Hazardous
Situation
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

20. ❑Understand and influence the factors (hazards) which impact regulators and industry business
❑Create awareness and a culture
❑Supports an effective pro-active behaviour
✓Open factual dialogue
✓Make decisions traceable and consistent
❑Provide assurance
✓Risks are adequately managed
✓Compliance to external and internal requirements
❑Recognize risks at a desired level Zero risk not possible
✓Zero risk note possible
Benefits of risk management
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

21. How can Q9 be implemented?
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

22. “The investigation of risks is at
once a scientific activity and an
expression of culture”
Kasperson, Renn, Slovicet al. (1988)
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

23. Overview of a typical quality risk
management process
Key Elements and Steps
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024

24. old new
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

25. Highlights the need to
identify hazards and
not risksduring the first
step of the risk
assessmentprocess, to
remove any distractions
about risksthat may
interfere with the hazard
identification activity.
Example: When a Risk
Assessment team is focused only on
identifying hazards, they do not have
to think about any related
probabilities of occurrence -they
only have to consider what the
potential hazards may be in relation
to the risk question under
consideration.
This is also the case in relation to
severity of harm –during hazard
identification, there is no need to
spend time working to estimate the
severity of the harm that may be
presented by a hazard; that comes
later, after the hazards have been
identified.
The change from“Risk Identification” to“Hazard Identification” can bring several benefits
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

26. Qualityriskmanagementshouldincludesystematicprocessesdesignedtocoordinate,facilitateandimprovescience-based
decision-makingwithrespecttorisk.Possiblestepsusedtoinitiateandplanaqualityriskmanagementprocessmight
includethefollowing:
✓Definetheproblemand/orriskquestion,includingpertinentassumptionsidentifyingthepotentialforrisk;
✓Assemblebackgroundinformationand/ordataonthepotentialhazard,harmorhumanhealthimpactrelevanttothe
riskassessment;
✓Identifyaleaderandnecessaryresources;
✓Specifyatimeline,deliverablesandappropriatelevelofdecision-makingfortheriskmanagementprocess.
Initiating a Quality Risk Management Process
1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

27. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Responsibilities
❑Qualityriskmanagementactivitiesareusually,butnotalways,undertakenbyinterdisciplinaryteams.Whenteamsare
formed,theyshouldincludeexpertsfromtheappropriateareas(e.g.,qualityunit,productdevelopment,business
development,engineering,regulatoryaffairs,productionoperations,salesandmarketing,supplychain,legal,statistics
andclinical)inadditiontoindividualswhoareknowledgeableaboutthequalityriskmanagementprocess.
❑Decision makers should
✓take responsibility for coordinating quality risk management across various functions and departments of their
organization;
✓assure that a quality risk management process is defined, deployed and reviewed and that adequate resources and
knowledge are available; and
✓assure that subjectivity in quality risk management activities is managed and minimized, to facilitate scientifically
robust risk-based decision-making.
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

28. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Riskassessmentconsistsoftheidentificationofhazardsandtheanalysisandevaluationofrisksassociatedwithexposure
tothosehazards.Qualityriskassessmentsbeginwithawell-definedproblemdescriptionorriskquestion.Whentheriskin
questioniswelldefined,anappropriateriskmanagementtoolandthetypesofinformationneededtoaddresstherisk
questionwillbemorereadilyidentifiable.
Asanaidtoclearlydefiningtherisk(s)forriskassessmentpurposes,threefundamentalquestionsareoftenhelpful:
1.Whatmightgowrong?
2.Whatisthelikelihood(probability)itwillgowrong?
3.Whataretheconsequences(severity)?
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

29. 1
Initiate
2
Risk Assessment
3
Risk Control
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Risk Communication
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Risk Review
oHazardidentificationisasystematicuseofinformationtoidentifyhazardsreferringtotheriskquestionorproblem
description.
oInformationcanincludehistoricaldata,theoreticalanalysis,informedopinions,andtheconcernsofstakeholders.
oHazardidentificationaddressesthe“Whatmightgowrong?”question,includingidentifyingthepossibleconsequences.
oThisprovidesthebasisforfurtherstepsinthequalityriskmanagementprocess.
I.Hazard identification
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

30. 1
Initiate
2
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3
Risk Control
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Risk Communication
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Risk Review
oInfirststep,thedatarequiredforhazardidentificationneedstobe
collectedrelatedtoproductandprocesses.Thisdatacomesfrom
literaturesourceorfromtheproductspecificknowledge.
oTheriskcanariseduringfollowingstages:
a)Risksrelatedtoproductcharacteristic
b)Risksrelatedtoproductsuppliers
c)Risksrelatedtofacility
d)RisksrelatedtoManufacturingprocesses
e)RisksrelatedtoDistribution,Packagingandlabelling
oThedatafromallthepossiblesourcesneedstobegathered
whichwillbeorganizedusingvarioustoolsinthenextstep.
I.Hazard identification
➢Gather the data
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

31. 1
Initiate
2
Risk Assessment
3
Risk Control
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Risk Communication
5
Risk Review
oThedataneedstobeorganizedintoapresentableformusingvarioustoolsfore.g..
a)Flowchart
b)Processmap
c)Checklist
d)Paretocharts
e)Ishikawadiagram(fishbone)
I.Hazard identification
➢Organize the data
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

32. 1
Initiate
2
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3
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Risk Review
Methods Machines Materials
Measurement
Systems
Environmen
t
People
Impact to
product
quality
that can
lead to
patient
harm
Hazards Hazards
Hazards
Hazards Hazards Hazards
Environment People
TheFishboneDiagramisasimpletechnique
thatiscommonlyusedtostructurequalityrisk
managementactivities,byorganizingdataand
facilitatingdecisionmaking.
Forexample,inaproductionprocess,a
fishbonecanusedtolookatthe6main
productionareas:methods,machines,materials,
measurementsystems,environment,and
people.Hazardsidentifiedinanyoftheseareas
canleadtohazardoussituationsandpatient
harmandneedtobefurtherevaluated.
QRM Tools for Hazard ID
Cause and Effect Diagram (aka. Fishbone or Ishikawa Diagram)
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

33. 1
Initiate
2
Risk Assessment
3
Risk Control
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Risk Communication
5
Risk Review
Fishbone Analysis Example
New isolator fill line(3)-Hazard ID
Risk Evaluation
Risk Analysis
Hazard Identification
CCIT = Container closure integrity test
CpK= Process capability
RH = Relative humidity
An Ishikawa diagram is used as a
structured tool to identify the areas
where hazards may appear
What hazards are possible in case of media fills?
What hazards are possible
because of failure during vial
sterilization?
What hazards
arepossible due to
failures in product
exposure time?
What hazards are
possible when product
not stored appropriately?
What hazards can
occur in case of
temperature
modification?
Note: This slide is based on materials and figures submitted to the ICH Q9(R1) EWG by the Parenteral Drug Association (PDA).
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

34. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
QRM Tools for Hazard ID
Process Mapping
Risk Evaluation
Risk Analysis
Hazard Identification
Data&ProcessMappingisanotherstructuredtoolto
visualizeeachstep&connectthehardware,software,
personnel,anddocumentationineachprocess,facilitating
comprehensivedataintegrityhazardidentification.
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

35. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
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Risk Review
CASE STUDY
Hazard ID in New Product Development
Risk Evaluation
Risk Analysis
Hazard Identification
Thiscasestudy,whichconcernsatabletmanufacturingprocess,describesa2-stepQRMapproach,whereaninitial
hazardidentificationthatconsiderstheCriticalQualityAttributes(CQA)oftheproductislinkedwithasubsequentrisk
assessmentofthevariousmanufacturingunitoperations.Theultimategoalwastodefineanappropriatecontrolstrategy
toassureproductqualityandpatientsafety.
Note: This slide is based on materials and figures submitted to the ICH Q9(R1) EWG by the International Society for Pharmaceutical Engineering (ISPE).
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

36. 1
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oistheestimationoftheriskassociatedwiththeidentifiedhazards.Itisthequalitativeorquantitativeprocessoflinking
thelikelihoodofoccurrenceandseverityofharms.Insomeriskmanagementtools,theabilitytodetecttheharm
(detectability)alsofactorsintheestimationofrisk.
oTypesofriskanalysis
a)Qualitativeriskanalysis
b)Quantitativeriskanalysis
II. Risk Analysis
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

37. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
II. Risk Analysis
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

38. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Preliminary Hazard Analysis (PHA)
Risk Evaluation
Risk Analysis
Hazard Identification
•Perform one hazard analysis per product
•Consider intended use and user populations
•Identify hazards to product quality that mayultimately lead to patient harmand that are related to manufacturing,
testing, shipment, use, etc.
•Consider normal and fault conditions; consider normal use and foreseeable misuse
Document
Purpose
•Identify potential hazards, hazardous situations, and harmtopatient(Note: a hazardmaybeassociatedwith
multiple harms)
•Evaluate residual risk after mitigation
Quality Attribute /
Product
Requirement
Hazard Sequence of Events Hazardous
Situation
Harm
Sterility
Biological contamination of
the drug product
Drug product is contaminated during manufacture
and patientinjects into blood stream
Injection of
bacteria or fungi
Potential for
severe illness
or death
Purity
Cross-contamination of
oneproduct with another
product
Drugproductis cross-
contaminatedduringmanufacturing with another
product and patienttakes the medicine
Unintended
medicine
administered to
patient
Potential for
severe illness
or death
Identify the
hazard Identify the
hazardous situation
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

39. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Failure Mode EffectsAnalysis(FMEA)
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

40. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

41. Assigning Stratified Scores
for factors having low impact or risk
for factors having moderate impact or risk
for factors having high impact or risk
if Total Score > 200 : Require Immediate Action Plan
Stage 1-Process Design
A.Team Formation
B.Define QTPP
C.Identifying The CQAs
D.Define the Process Steps
E.Risk Analysis (Create RAMM and Score it)
F.Risk Mitigation
G.Define CPPs and CMAs
H.Define Design Spaceand Control Strategy
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments
1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review

42. Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments
1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review

43. Risk Mitigation
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments
1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review

44. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
ocomparestheidentifiedandanalyzedriskagainstgivenriskcriteria.Riskevaluationsconsiderthestrengthofevidence
forallthreeofthefundamentalquestions.
oIndoinganeffectiveriskassessment,therobustnessofthedatasetisimportantbecauseitdeterminesthequalityofthe
output.Revealingassumptionsandreasonablesourcesofuncertaintywillenhanceconfidenceinthisoutputand/orhelp
identifyitslimitations.
oUncertaintyisduetoacombinationofincompleteknowledgeaboutaprocessanditsexpectedorunexpectedvariability.
Typicalsourcesofuncertaintyincludegapsinknowledge,gapsinpharmaceuticalscienceandprocessunderstanding,
sourcesofharm(e.g.,failuremodesofaprocess,sourcesofvariability),andprobabilityofdetectionofproblems.
III. Risk Evaluation
Risk Evaluation
Risk Analysis
Hazard Identification
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

45. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
oIncludesdecision-makingtoreduceand/oracceptrisks.Thepurposeofriskcontrolistoreducetherisktoanacceptable
level.Theamountofeffortusedforriskcontrolshouldbeproportionaltothesignificanceoftherisk.Decisionmakers
mightusedifferentprocesses,includingbenefit-costanalysis,forunderstandingtheoptimallevelofriskcontrol.
oRiskcontrolmightfocusonthefollowingquestions:
1.Istheriskaboveanacceptablelevel?
2.Whatcanbedonetoreduceoreliminaterisks?
3.Whatistheappropriatebalanceamongbenefits,risksandresources?
4.Arenewrisksintroducedasaresultoftheidentifiedrisksbeingcontrolled?
Risk Control
Risk acceptance
Risk reduction
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

46. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Risk Control
Risk acceptance
Risk reduction
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

47. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
oFocusesonprocessesformitigationoravoidanceofqualityriskwhenitexceedsaspecified(acceptable)level.Risk
reductionmightincludeactionstakentomitigatetheseverityandprobabilityofharm.Processesthatimprovethe
detectabilityofhazardsandqualityrisksmightalsobeusedaspartofariskcontrolstrategy.
oTheimplementationofriskreductionmeasurescanintroducenewrisksintothesystemorincreasethesignificanceof
otherexistingrisks.Hence,itmightbeappropriatetorevisittheriskassessmenttoidentifyandevaluateanypossible
changeinriskafterimplementingariskreductionprocess.
I. Risk Reduction
Risk acceptance
Risk reduction
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

48. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
oisadecisiontoacceptrisk.Forsometypesofharms,eventhebestqualityriskmanagementpracticesmightnotentirely
eliminaterisk.Inthesecircumstances,itmightbeagreedthatanappropriatequalityriskmanagementstrategyhasbeen
appliedandthatqualityriskisreducedtoaspecified(acceptable)level.This(specified)acceptablelevelwilldependon
manyparametersandshouldbedecidedonacase-by-casebasis.
I. Risk Acceptance
Risk acceptance
Risk reduction
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

49. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
othedecisionmakersandothers.Partiescancommunicateatanystageoftheriskmanagementprocess.Theoutput/result
ofthequalityriskmanagementprocessshouldbeappropriatelycommunicatedanddocumented(seeFig.1:solid
arrows).Communicationsmightincludethoseamonginterestedparties;e.g.,regulatorsandindustry,industryandthe
patient,withinacompany,industryorregulatoryauthority,etc.Theincludedinformationmightrelatetotheexistence,
nature,form,probability,severity,acceptability,control,treatment,detectabilityorotheraspectsofriskstoquality.
Communicationneednotbecarriedoutforeachandeveryriskacceptance.Betweentheindustryandregulatory
authorities,communicationconcerningqualityriskmanagementdecisionsmightbeconductedthroughexistingchannels
asspecifiedinregulationsandguidances.
Risk Communication
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

50. 1
Initiate
2
Risk Assessment
3
Risk Control
4
Risk Communication
5
Risk Review
oRiskmanagementshouldbeanongoingpartofthequalitymanagementprocess.Amechanismtoreviewormonitor
eventsshouldbeimplemented.Theoutput/resultsoftheriskmanagementprocessshouldbereviewedtotakeinto
accountnewknowledgeandexperience.Onceaqualityriskmanagementprocesshasbeeninitiated,thatprocessshould
continuetobeutilizedforeventsthatmightimpacttheoriginalqualityriskmanagementdecision,whethertheseevents
areplanned(e.g.,resultsofproductreview,inspections,audits,changecontrol)orunplanned(e.g.,rootcausefrom
failureinvestigations,recall).Thefrequencyofanyreviewshouldbebaseduponthelevelofrisk.Riskreviewmight
includereconsiderationofriskacceptancedecisions
Risk Review
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024
Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Overview of a typical quality
risk management process
Conclusion
Summary,
Questions and Comments

51. Definition and Concepts
History, Objectives, Applications
and Regulations
Key Elements and Steps
Key Elements and Steps
for Execution of QbD
Conclusion
Summary,
Questions and Comments
Quality Risk Management (QRM)-Introduction of Risk Analysis and Mitigation Matrix (RAMM) Tools, Mohammad M. Sepahi, PhD –January, 2024

52. Thank You
Questions and comments?
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هک تسا نیا نآ زا رتمهم یلو:
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