QRM in GLPFrom Compliance to Business Improvement

Janssen Pharmaceutica N.V.

Sandra Wens

Global Research & Development Quality Assurance / GLPQA

June 8th, 2011

QRM in GLP - From Compliance to Business Improvement

Introduction

• What is QRM

• GLP environment

• The changing role of QA

QRM in GLP

• How it started in GLPQA at Janssen

• QRM examples - GLP departments at Janssen

• Future of QRM

2

What is QRM - What is a risk?

A risk is a future event

which may or may not occur

with (usually) an adverse effect

3

Risks are pervasive

4

What is QRM - What is a risk?

How do we manage risks?

5

What does risk management not imply?

• Taking more risks, less quality

• Cut down on quality

• Exclude all risks

• A new practice

• Complicated

• Additional bureaucracy

6

What does risk management imply?

• Systematic process designed to improve (science-based) decision-making by gaining insight to risks (probability, impact)

• ICH Q9 – June 2006 ‘Quality risk management’

– Q9 is a quality improvement methodology

– Guidance document

– Supports science-based decision making

7

What does risk management imply?

• A systematic process for the assessment, control, communication and review of risks

8

RiskAssessment

RiskReview

RiskControl

QR

M T

ools

Ris

k C

om

mu

nic

ati

on

Continuous Feedback for New or

Existing Risks

Tool example

9

Voorbeeld van proces!

What does risk management imply?

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• Know your processes

– Base oneself on facts

• Identify what’s important (through Risk Analysis)

– Patient at the centre

– Stay compliant

• Focus on what is important

• Communicate and document your decisions

• Check if it works

Principles of QRM

11

Probably mitigate the

risk

Accept the risk

Mitigate the risk

Probably accept the

risk

PROBABILITY

IMPA

CT

Balance Risks

12

ChanceSeriousness

Reward

Given all the risk factors, is the reward worth taking the risks?

Risk management: benefits

• Improved, streamlined processes

– Processes often historically developed and benefits of certain steps not questioned anymore

• Better-founded decision-making

– Helps thoroughly analyzing and considering different alternatives

– Helps to define audit strategy (which, frequency, focus,…)

• Better focus on resources and priorities

13

The GLP regulations are the most stringent of all GXPs in

defining the requirements for a QA audit program

Introduction - GLP regulations

•Protocol, Critical phases and report audits•Required for each GLP study

Study specific audits

•Inspection of GLP labs focusing on general items like equipment, labelling, SOP management

Facility audits

•Not required by regulations•Concept of system audits is introduced since about 10 years•Looks at systems that are used across studies

Process-based or System

audits

GLP Required

The GLP regulations are the most stringent of all GXPs in

defining the requirements for a QA audit program

Introduction - GLP regulations

•Protocol, Critical phases and report audits•Required for each GLP study

Study specific audits

•Inspection of GLP labs focusing on general items like equipment, labelling, SOP management

Facility audits

•Not required by regulations•Concept of system audits is introduced since about 10 years•Looks at systems that are used across studies

Process-based or System

audits

GLP Required

Ris

k B

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ed

Ap

pro

ac

h

16

Times are changing

Times are changing

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Past:• Easy world• Exponential growth Pharma

Industry

Now:• More complex world• Do more with less• New technologies (e-data)• New scientific development

• Quality Risk Management

• The job of a QA professional is evolving from a standard, audit-driven, reactive process towards a proactive, customer-focused approach.

• Accelerating business growth through innovative quality solutions

The Changing Role of QA

QRM in GLP - From Compliance to Business Improvement

QRM in GLP

• How it started

• QRM examples - GLP departments at Janssen

– QRM Case 1

– QRM Case 2

• Future of QRM

19

How it started

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• 2007 • 2008• ICH Q9 Quality

Risk Management

• A few “believers” in GLPQA practiced QRM • GLPQA QRM template

was developed

• 1-day QRM workshop for global GLPQA ;

• Template + Mindset

• 2006 • 2009

• GLPQA team to identify and prioritize QRM opportunities to feed 2009 G&Os

• QRM roll outin GLP business

• 2010 - 2011

• QRM projectsin partnerschip with

• Business Partners:• Bioanalysis

department• Histology

department• PK sample

shipment• ...

4 QRM projects ongoing

QRM 1 Bioequivalence studies

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Read study info

protocol

IdentifyValidatedMethod

CAL

Thaw,pipette,extractsamples QC and

Cals

Analyzesamples, QC and

Calsby

LC-MS/MS

internalreport

Plasma Samples

QC4-6-15

CAL15% RE

CalculateAnd

validate

QC

Weigh outDry stock

QAQAQA

Introduction – Bioanalysis workflow

Bioanalysis protocol • Duplication of existing information

• From clinical protocol• From Bioanalysis SOPs• From Bioanalysis Method validation

• Risk to mistakes and QA observations

• Not a regulatory requirement• Heritage from the past when this was done in the form of a GLP

study

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – situation

Alternative process No protocol, no BA number

Risk IdentificationWhat can go wrong?

QA is not aware of study

Risk assessment Probability: HImpact: M

Pro’s and con’s of each alternative

Time efficient

Risk reducing controls QA receives weekly automated report from planning database

Residual risk Probability: LImpact: M

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – FMEA Summary

• Workload BA and QA

• Traceability BE studies

• Communication on new BE study to QA via automated Cognos report

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – Result

• QA review of Bioequivalence studies

= Very detailed review, due to FDA focus

• Lots of QA comments with low added value• In combination with workload and strict timelines gives rise to

frustrations and tension between QA and Bioanalysis

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – Situation

type of audit

# audits observations

no obs minor obs

total total nature

protocol 3 2 5 2 (1) receipt of samples before finalization of BA protocol (2x)

protocol am.

0 1 1 1 (1) receipt of samples before finalization of BA protocol am.

exp. phase 3 2 5 3 (1) receipt of samples before finalization of BA protocol

(1) late distribution of BA protocol

(2) confirmation of sample reception not distributed to TK scientist and GLPQA

report 0 2 2 7 (3) switch to CSTIM system was not documented clearly

(2) report/raw data inconsistency (2x)

(2) report/raw data inconsistency with BA protocol (2x)

(2) indexlist checked by 1 person in stead of 2

(2) raw data inconsistency

Analysis of observations from the Bioanalysis part of Bioequivalence (BE) studies for Beerse (january 2007 to october 2008)

(1) A bioanalytical protocol is not strictly necessary for BE studies. If no protocol is written, these observations do not have to be made.(2) These observations would also have been picked up if the BE audit would have been conducted in the same way as for a “normal” Bioanalysis study.(3) This is an exceptional situation

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – Data collection

GLPQA review of BE studies - Risk managementA comparison was made between the items that are reviewed by the BA QC group and GLPQA for BE studies. (BA QC follows the same review process for all BA studies, GLPQA puts more effort in Bioanalysis from BE studies than in other Bioanalysis).Currently for BE studies, the following items are not reviewed by QC, only by GLPQA:

Items currently reviewed by GLPQA, not by BA QC (specifically for BE studies)

covered during other regular in life audits?

System audits?

Risk (IxP) Effort FDA focus?

Conclusion: Check during BE study?

Comments

Impact Probability Yes No

Raw data on preparation of QC samples and calibrators (freshly prepared calibration stds are reviewed by QC)

spot checks spot checks H M H Yes X Area of focus!

Personel files and training of personel involved in the study

only new employees spot checks M M (Many new temp. employees at BA)

M No (X) only for personnel that is new, that has just left,…

Validation status of computerized systems No spot checks H L L No (X) Only new systems and upgrades

LCMS logbook and PPG calibrations spot checks spot checks M L M (Yes) (X) Only in case issues are noted on STF1

Freezer logs No spot checks L (alarms generated before impact on samples

L M Yes X System audits show that a robust system is in place

Labelling and condition of samples study specific (sporadically)

spot checks M (follow up by BA support) L M No X

Calibration/control of pipettes, balances, pH meters

spot checks spot checks L L H No X

Preparation of buffers and reagents spot checks spot checks M L H No X

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – Risk ranking

• Workload QA (about 40% (from 8 to 5 working days))

• Compliance level remains high

Simplify Bioanalysis

proces

Apply risk based

approach to QA audit

QRM case 1 – Result

QRM 2 Bioanalysis in preclinical studies

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• Study specific audits– For each Bioanalysis study (part)

• Protocol audit• At least 1 experimental phase audit• Report audit

– Overlap between experimental phase and report audits

– Audit approach and focus differs between auditors

• 1 Bioanalysis system audit every 2 years– Extensive scope (covers all processes from sample

reception till reporting of results)

• QA and QC alignment can be improved

Optimize QA auditprogram

Align QA and QC efforts

QRM case 2 – Situation

•Type of audits

•Timing•Frequency•Scope•Focus

Optimize QA auditprogram

•Ensure that critical process steps are covered with correct focus ad minimal overlap

Align QA and QC efforts

QRM case 2 – Scope

• Multidisciplinary team

– QA

– Bioanalysis• Lab technician• QC person• Support group representative

Optimize QA auditprogram

Align QA and QC efforts

QRM case 2 – Approach: Who?

Process excellence and QRM tools

– Define• Project charter + business case

• Stakeholder analysis + communication plan

• Voice of the Customer (QA + Bioanalysis)

– Measure• Process mapping

• Define Customer needs (CTQs)

• Priority matrix

• Data collection plan

– Analyse• Analyse data -Brainstorm and rank solutions (QRM)

– Innovate and Improve• Implementation plan

• Develop metrics

– Control• Monitor metrics

Optimize QA auditprogram

Align QA and QC efforts

QRM case 2 – Approach: How?

• BA and QA outcome in good agreement

– System audit• High added value• Multidisciplinary team• Focus on processes

– Experimental phase audits• Low added value • QA audit takes place before QC review• Overlap with report audit

– Not sure if all critical steps are covered adequately by QC/QA.

Optimize QA

auditprogram

Align QA and QC efforts

QRM case 2 – VOC results

–Focus on critical aspects–Minimal overlap with QC review –Minimal overlap with different types of QA audit

–Maintain High compliance level –More focus on processes

Optimize QA

auditprogram

Align QA and QC efforts

QRM case 2 – Define customerneeds

Priority matrix

Study-specific audits Output variables    Focus on critical

aspectsMinimal overlap with QC review

Minimal overlap with different types of QA audit

High compliance level

More focus on processes

Total

Weight (1-10) 10 5 5 3 8  Input and process variables  Checklists 9 9 9 1 5 232Training 9 5 5 5 9 227Timing 5 5 0 1 0 78Inspection reports 0 0 0 5 0 15Raw data and report 0 0 0 9 0 27Bioanalysis processes (SOPs) 5 0 0 9 1 85QA program 1 0 5 9 9 134Bioanalysis planning 0 0 0 0 0 0Bioanalysis equipment 0 0 0 5 0 15Protocol 0 0 0 0 0 0Regulations 5 0 0 9 0 77Corrective actions 0 0 0 5 0 15QAAD 0 0 0 0 0 0QC process 0 0 0 5 0 15Bioanalysis email (start analysis) 1 0 0 0 0 10Auditor 9 5 5 5 9 227Analyst 0 0 0 9 0 27# samples 0 0 0 0 0 0# batches 0 0 0 0 0 0Method validation (raw data) 0 0 0 9 0 27Method 1 0 0 9 0 37Bioanalysis Systems (Watson and Analyst) 0 0 0 5 0 15

Legend: relationship between output and input/process variables0 = no relationship1 = weak relationship5 = moderate relationship9 = strong relationship

Checklists and training for auditors!

Optimize QA

auditprogram

Align QA and QC efforts

QRM case 2 – Priority matrix

Analysis of Bioanalysis Audit findings from last 2.5 years

Optimize QA auditprogram

Align QA and QC efforts

QRM case 2 – Data analysis

parameter Experimental phase audits

System audits

Number of audits

125 1

Number of observations

17 15

Total working days

60 10

• 1 system audit to be subdivided in different smaller system audits with frequency depending on risk factors such as criticality of process and previous audit findings

• Decreased number of experimental phase audits

• Enhanced checklists for study specific reviews by QA and QC

– Minimal overlap between different QA/QC checks

– Cover critical aspects with correct focus

Optimize QA

auditprogram

Align QA and QC effortsQRM case 2 – Result

• Better focused audit program to areas of greatest risk

• Efficient use of resources

• Better collaboration/appreciation by business partners

• Maintain and enhance high compliance level

Optimize QA

auditprogram

Align QA and QC effortsQRM case 1 + 2 Results

We believe that a customized implementation of risk management and process excellence tools, embraced by both QA and business partners, will accelerate business growth through innovative quality solutions.

Conclusion

Examples of projects

• Are all critical activities of study performance

– Documented, Adequately documented or Documented exaggerated

• Harmonization documentation practices: different practices within one test facility

– Rodents versus Non-rodents

• Review of documents/processes

– Quality Assurance versus Quality Control

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Future of QRM?

• QRM already established in a lot of other branches of industry

• QRM in GxPs:

– FDA cGMP’s

– ICH Q9

– FDA GLP (21 CFR part 58) modernization 

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It is not necessarily the strongest that survives, nor the most intelligent, but the one most responsive to change.

(Darwin, 1809-1882)

Mitigating risk requires a different mindset than ensuring quality

Future of QRM?

Thank You