Challenges of implementation of ICH Q 9of ICH Q 9 a ...

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 : [email protected]

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

In front of that …..In front of that …..

You could feel lonely


AgendaAgenda

Principles and environmentWhat is an acceptable “risk to quality”?p q yRisk management approaches for companiescompaniesRisk management approaches for regulatorsregulatorsChanging periods


AgendaPrinciples and environmentWhat is an acceptable “risk to quality”?p q yRisk management approaches for companiescompaniesRisk management approaches for regulatorsCh i i dChanging periods


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


Today…


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


and aggregationby providing tools and methodology

Vision of the futureVision of the future

“science-based”&&

“risk-based”behaviorbehavior


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?


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


p y

Product lifecycle for medicinal yproducts

Research

Preclinical PhasePhase

Clinical Phases

Launch

Safety ManufacturingGLP

Q lit

EfficacyGCPGMP


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


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


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)


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


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


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?


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


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


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”


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


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


Managing risks in a companyManaging risks in a company

Company

Strategy risks Operational risks Financial risks Compliance risks

Environmental

Regulatory

Quality / GMPEnterprise risk management


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)


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)


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


p

Agendag



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


Implementation in assessmentImplementation in assessment

Revised documents such as note for guidance for Real Time Release Testing (previously Parametric Release)


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


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 …


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


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


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 ?


Management of suspected quality defectsManagement of suspected quality defects

Defining an SOP based on QRM principles for dealing with suspected quality defectssuspected quality defects


Agendag



The ultimate goal of QRMg Q

Sharing information and ideas


QRMCommunication

facilitates trust d d t diand understanding

Regulatorsoperation

Industryoperationoperation

- Reviews- Inspections

operation- Submissions

- Manufacturing


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


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?


y

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