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Challenges of implementation of ICH Q 9of ICH Q 9
a regulatory perspective
Jacques MorénasJacques MorénasDeputy DirectorInspectorate and Companies DepartmentThe French Health Products Safety Agency (AFSSAPS)telephone : 33 1 55 87 39 17fax : 33 1 55 87 39 12e-mail : jacques morenas@afssaps sante fr
International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use
e-mail : jacques.morenas@afssaps.sante.fr
Disclaimer:
The information within this presentation is basedThe information within this presentation is basedon the presenter's expertise and experience,and represents the views of the presenter for thepurposes of a training workshop.
Kuala Lumpur, July 2010
Quality Risk Management is not a single processQuality Risk ManagementStart
Process-step
is not a single process
Risk identification
step
Decision
Risk
Feedback procedure
analysis
StartStart
Sub-process
Sub-Sub-process
Etc.
Start
Kuala Lumpur, July 2010 EndEndEnd
AgendaAgenda
Principles and environmentWhat is an acceptable “risk to quality”?p q yRisk management approaches for companiescompaniesRisk management approaches for regulatorsregulatorsChanging periods
Kuala Lumpur, July 2010
AgendaPrinciples and environmentWhat is an acceptable “risk to quality”?p q yRisk management approaches for companiescompaniesRisk management approaches for regulatorsCh i i dChanging periods
Kuala Lumpur, July 2010
The hurdles
I i t l
?Increasing external requirementsfor best practice, transparency and
Growingcomplexity and scope of risks?transparency and
compliance• Public / Community• Governments
• Globalisation“Multinational”
• Multi-factor approachesR l t t ti• Regulators
• Patients• Investors / Creditors
• Regulatory expectations• Acceptance of
risk and uncertaintyIncreasing efforts and costs
• DocumentationP j tefforts and costs
for sustainability• Projects• Systems• Interfaces
Kuala Lumpur, July 2010
Empowerment & flexibility
An appropriate integrated approach h l t t i t ffi i tlhelp to meet requirements more efficiently
Quality Risk
Proactive disclosure,
Improve communication
through sharingManagementbuild trust and
understanding
through sharingbest practice and integrating tools
Master complexity and aggregation
Kuala Lumpur, July 2010
and aggregationby providing tools and methodology
Vision of the futureVision of the future
“science-based”&&
“risk-based”behaviorbehavior
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Incremental steps
Pharmaceutical Development (Q8)Pharmaceutical Development (Q8)
Incremental steps
Changed Pharmaceutical Development (Q8)Pharmaceutical Development (Q8)Past: Data transfer / Variable output
Future: Knowledge transfer / Consistent output
ChangedParadigm
Quality Risk Management (Q9)Quality Risk Management (Q9)Q11
Past: Informal approach
Future: Opportunity to use a structureand process thinking
Q11
Pharmaceutical Quality Systems (Q10)Pharmaceutical Quality Systems (Q10)Past: Large variability on Q-systems9
Kuala Lumpur, July 2010Future: Consistency on Q-systemsQ
9
PAT ICH Q8ICH Q10
Design space
ICH Q9
ICH Q11ICH Q11
How industry will apply the (new) concepts?What will change?
Kuala Lumpur, July 2010
g
DefinitionsDefinitionsQuality Degree to which a set
of inherent properties f d t t
Risk
of a product, system or process fulfills requirementscombination of theRisk combination of the probability of occurrence of harm and the severity of that harm
Systematic process for the assessment, control, communication and review
f i k t th lit f th
& Management
QRM of risks to the quality of the drug (medicinal) product across the product lifecycle
QRM
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p y
Product lifecycle for medicinal yproducts
Research
Preclinical PhasePhase
Clinical Phases
Launch
Safety ManufacturingGLP
Q lit
EfficacyGCPGMP
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QualityICH Q9
GMP
Principles of Quality Risk ManagementPrinciples of Quality Risk Management
Two primary principles:Two primary principles:
Th l ti fThe evaluation of the risk to quality should be based on
The level of effort, formality and documentation of the quality risk
scientific knowledgeand ultimately link to the protection
of the quality risk management process should be commensurate with the level of riskto the protection
of the patientwith the level of risk
Kuala Lumpur, July 2010
Initiate
A General Risk Assessment
Risk Identification
InitiateQuality Risk Management Process
Quality Risk
Risk Evaluation
Risk Analysis
ManagementProcess m
unic
a tio
n
Risk Evaluationunacceptable
Risk Control
Risk Reduction
RiskM
anage
Risk
Com
m Risk Reduction
Risk Acceptance
emen ttools
Team approach
Risk Review
Output / Result of theQuality Risk Management Process
Kuala Lumpur, July 2010
Review Events
What makes Q9 different?What makes Q9 different?
It provides principles and a framework p p pfor decision making
Q9 is a quality improvement methodologyIt is a “guidance” not an “SOP”It is a guidance not an SOP
SimpleFlexibleN t d tNot mandatory
It supports science-based decision makingFacilitates communication and transparencySupports build up trust
Q9 is for both industry and competent authorities (CA)
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Role of Quality Risk ManagementRole of Quality Risk Management
CommercialConclusionsProcessProduct Commercial Manufacturing
Conclusions & Tech. Transfer
Process Development
Product Development
ManufacturingProcess / prior
Product / prior
ProcessHistory for life
Product and Process
RiskAssessment
ocess / p oKnowledge
pKnowledge
RiskAssessment
RiskControl
ycycle mgmt
RiskReview
Development Knowledge
Assessment
Manuf. Process Design Space
Excipient & Drug Subst.
Assessment
Product quality &control strategy
Control
Continual Improvement
Review
g pDrug Subst. Design Space
Opportunities to apply Quality Risk Management
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Process understanding
AgendaAgenda
P i i l d i tPrinciples and environmentWhat is an acceptable “risk to quality”?Risk management approaches for companiespRisk management approaches for regulatorsChanging periodsChanging periods
Kuala Lumpur, July 2010
What is an acceptable “risk” to quality?What is an acceptable risk to quality?
D i i ki ti it b th t k h ldDecision making activity by the stakeholders.To be considered:Is the risk on an acceptable level?Is the risk on an acceptable level?What can be done to reduce or eliminate risks?Wh t i th i t b lWhat is the appropriate balance between benefits, risks and resources?Do measurements introduce new risks?Do measurements introduce new risks?
Kuala Lumpur, July 2010
What is an acceptable “risk” to quality ?What is an acceptable risk to quality ?Who has to accept risk?D i i k ( )Decision maker(s)
Person (s) with the competence and authority to make appropriate and timely pp p yquality risk management decisionsDecision makers might also be stakeholders
StakeholderAny individual, group or organization that can be affected by a riskby a riskThe primary stakeholders are the patient, healthcare professional, regulatory authority, and industry
Kuala Lumpur, July 2010
What is an acceptable “risk” to quality?What is an acceptable risk to quality?
This has to be decided in the context of each specific risk pmanagement problemPut in precise and definite data receive a clear answerE bl d i i k t k d d t tEnable decision makers to make good and transparent decisionsAccept risk, if the effort to reduce a risk will solve theAccept risk, if the effort to reduce a risk will solve the specific problem. Keep in view: The protection of the patientIt’s up to the organization whether they accept risks that meet the principles of QRM
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What is an acceptable “risk” to quality?p q y
A tAn event
Considerations:“Industrial risk” could be different from “political risk”Notion of "risk" could be not the same for industry andNotion of "risk" could be not the same for industry and competed health authority (CA) CA are often face to face with public opinion and politiciansp p pCompromise according to ICH Q9: “link back to the protection of the patient”
Kuala Lumpur, July 2010
What is a residual risk?
Residual risk address hazards that have been assessed and risks that have been acceptedthat have not yet been identifiedwhich have been identified but the risks have not been correctly assessedwhich are not yet linkedwhich are not yet linked
Is the risk transferred to an acceptable level?Consider current scientific knowledge & techniquesConsider current scientific knowledge & techniquesFulfil all legal and internal obligations
As hazards remainKuala Lumpur, July 2010
As hazards remain zero risk is never possible
Risk acceptance as part of risk controlp p
Discuss the appropriate balance among benefits risks andDiscuss the appropriate balance among benefits, risks, and resourcesBe careful to emphasize the principles: the patients’ interests and good science/dataRisk acceptance is not:
I i t l i t ti d t d i f tiInappropriately interpreting data and informationHiding risks from the regulatorsDodging legal requirementsDodging legal requirements
See a possible decision tree in
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the back-up slides
AgendaAgenda
Principles and environmentWhat is an acceptable “risk to quality”?p q yRisk management approaches for companiescompaniesRisk management approaches for regulatorsCh i i dChanging periods
Kuala Lumpur, July 2010
Managing risks in a companyManaging risks in a company
Company
Strategy risks Operational risks Financial risks Compliance risks
Environmental
Regulatory
Quality / GMPEnterprise risk management
Kuala Lumpur, July 2010
g
Existing organisationg g
O tiOperations
Support
Quality UnitManufacturing Procurement etc
Quality Assurance
Quality Management
y
Quality Control
Validation
Kuala Lumpur, July 2010 Risk Management
How can Q9 be implemented?The ICH Q9 document:
Main body explains the “What?”Annex I give ideas on the “How?”Annex II give ideas on the “Where?”
It can be implemented by industryPharmaceutical Development (ICH Q8) and p ( )Quality Systems (ICH Q10) will indicate the “When?”
“It helps pre ent o erl restricti e and nnecessar“It helps prevent overly restrictive and unnecessary requirements being imposed by either industry or regulators” (ICH Q9)
Kuala Lumpur, July 2010
How can Q9 be implemented?
Existing
ICH Q9
Existinginternaldocumentationsystem
Whereto be insystem future?
(Mission, Policy)
What to do?( Di ti )(e.g. Directives)
How to do?(e g Guidelines)(e.g. Guidelines)
Detailed instructions(e.g. Standard Operating Procedures) Records
Kuala Lumpur, July 2010Rules & Procedures
(internal regulations)Records &
Reports
When to use Quality Risk Management?y g
Should risksbe assessed?
Are there clear rulesfor decision making?
1. What might go wrong?2. What is the likelihood (probability)
it will go wrong?3. What are the consequences (severity)?No
Agree on a team
No“formal RM“
Can you answerthe risk assessment
questions?
YYes“no RM“
Risk assessment not required(No flexibility)
Agree on a team(small project)
Select a Risk Management tool(e.g. see ICH Q9 Annex I)
Yes“informal RM“
Initiate Risk assessment(risk identification, analysis & evaluation)
Follow procedures(e.g. Standard Operating Procedures)
Document results
Carry out on theRisk Management tool
Run risk control(select appropriate measures)
Kuala Lumpur, July 2010
Document results,decisions and actions Document the steps
Contributing items to manage quality risksContributing items to manage quality risksSystem Risk (facility & people):
i t f t i k i t te.g. interfaces, operators risk, environment, components like: equipment, IT, design elements
System Risk (organisation):y ( g )e.g. quality systems, controls, measurements, documentation, regulatory compliance
Process Risk:e.g. process operations and quality parameters
Product Risk (safety & efficacy):Product Risk (safety & efficacy):e.g. quality attributes: measured data according to specifications
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p
Agendag
P i i l d i tPrinciples and environmentWhat is an acceptable “risk to quality”?Risk management approaches for companiespRisk management approaches for regulatorsChanging periodsChanging periods
Kuala Lumpur, July 2010
Implementation in assessmentImplementation in assessment
E l ti fEvaluation of :Impact of proposed changesI f d i iImpact of deviationsImpact of “out of specification” results
EMA Process Analytical Technology (PAT) team Ginvolving assessors and GMP inspectors
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Implementation in assessmentImplementation in assessment
Revised documents such as note for guidance for Real Time Release Testing (previously Parametric Release)
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Implementation in inspectionImplementation in inspection
Three possible areas have been alreadyThree possible areas have been already identified:Planning of inspection• Planning of inspection
• Conducting an inspection• Management of suspected quality defects
Kuala Lumpur, July 2010
Planning of inspectionPlanning of inspection
Inspection frequency and depth should be adapted subject to (and for example) :* Examination of a site master file (if available)* Review of the products manufactured by the company* Review of the reports from previous inspections* Review of the follow-up actions (if any) arising from previous inspections* Review of product recalls initiated since the previous inspection an* Review of product recalls initiated since the previous inspection an examination of relevant product defects notified since the previous inspection* Review of the analysis of any samples analyzed by the Competent Authority since the previous inspectionsince the previous inspectionEtc …
Kuala Lumpur, July 2010
Planning of inspection
Categories Description Inspection intervals
Planning of inspection
Categories Description Inspection intervals
Poor compliance level
The last inspection revealed major or critical deficiencies ≥ 6 X - 1
Acceptable compliance level
The two last inspections have revealed no critical deficiency and less than 6 major deficiencies 2
X(= regulatory interval)
Good compliance level
The two last inspections have revealed no critical and no major deficiency
X + 1X + 1
Kuala Lumpur, July 2010
Planning of inspectionPlanning of inspection
The objectives of Competent Authorities is to optimize the inspection resources
Using both QRM and PQS (Pharmaceutical Quality System g Q Q ( Q y ywhich could be ICH Q10), confidence between industry and GMP inspectors should be increased with an impact on inspection frequency and depthinspection frequency and depth
Kuala Lumpur, July 2010
Conducting an inspectionHow can QRM activity be inspected ?
Conducting an inspection
If the company explains that ICH Q9 has been used as reference for establishing the QRM, it will be used by inspectors.
If not, inspectors might review :p gWhether the quality risk management performed is integrated
in the Quality System of the organizationTraceability, transparencyHow was the decision made ?Was a (risk) problem / question defined ?Did the process performed answer this question ?W th i t f ti ll t d t ll t ?Were the appropriate functions allocated to all teams ?Were the right documents recognized ?Was the decision based on scientific knowledge ?
Kuala Lumpur, July 2010
Management of suspected quality defectsManagement of suspected quality defects
Defining an SOP based on QRM principles for dealing with suspected quality defectssuspected quality defects
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Agendag
P i i l d i tPrinciples and environmentWhat is an acceptable “risk to quality”?Risk management approaches for companiespRisk management approaches for regulatorsChanging periodsChanging periods
Kuala Lumpur, July 2010
QRMCommunication
facilitates trust d d t diand understanding
Regulatorsoperation
Industryoperationoperation
- Reviews- Inspections
operation- Submissions
- Manufacturing
Kuala Lumpur, July 2010
Integration of QRMIntegration of QRM
A common understanding and application of quality risk management principles could facilitate mutual confidence and promote more consistent decisions among regulatorsand promote more consistent decisions among regulators on the basis of the same information.
This collaboration could be important in the development of policies and guidelines that integrate and support quality risk management practices.q y g p
Kuala Lumpur, July 2010
Lessons learnedIt is easy to use Quality Risk Management in supporting decision makingg
How to prioritise work?What next?
Quality Risk Management requires teamworkIt seems to be time consumingN “It t f ti ”No one says: “It was a waste of time”
Aid for rationalisation of the decisionFor a better transparencyFor a better transparency
Increasing transparency is often requestedIs this relay the desired state?
Kuala Lumpur, July 2010
y
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