developments in glp consultation & training : 1980 -2020 · developments in glp consultation...

OECD Event, Villa Tuscolana, Frascati (Roma), Italy , April 10 OECD Event, Villa Tuscolana, Frascati (Roma), Italy , April 10 –– 11,11, 2008 2008

Developments in Developments in GLP Consultation & Training : GLP Consultation & Training :

19801980--2020 2020

David LongDavid Long

Consultant Consultant -- [email protected]@orange.fr


A A ““ GrammaticalGrammatical ”” approachapproach

Past - HistoricalPresent - Perfect

Future - Immediate


GLP Consultation & TrainingGLP Consultation & Training

Impact of the situation on Consultation & Training

SituationPAST-Historical

Consultation PAST-Historical

TrainingPAST-Historical

SituationPRESENT-Perfect

SituationFUTURE-Immediate

ConsultationPRESENT-Perfect

TrainingPRESENT-Perfect

ConsultationFUTURE-Immediate

TrainingFUTURE-Immediate


PART PART II

From the Past – Historical

to the Present - Perfect



GLP : “A necessary evil”

The PAST-Historical1980 - 1995



6

There was (still is ?) resistance to change

Three things that “scientists” said as excuses for resistance

The PAST-Historical



7

What “scientists” said about GLP

1. “GLP means I can’t innovate”

The PAST-Historical



8

What we said about GLP

• Of course you can innovate

• GLP simply asks you to show where you were innovative

• GLP says plan & record your innovations so that they can be fully recognised and repeated

• GLP highlights your innovations

The PAST-Historical



9


2. “GLP removes my responsibility”

The PAST-Historical



10

What we said about GLP

• On the contrary GLP makes sure that responsibilities are defined

• Management has to be clear about who does what

• Because the responsibilities are clear, the right people get the accolades

• GLP highlights what you do well

The PAST-Historical



11


3. “I hate writing all those SOPs”

The PAST-Historical



12

What you say about GLP

• Yes there are SOPs to write - but you can simplify them – flow charts, diagrams, photos

• A good SOP system has lots of positive points –Standardisation, Training, Study Reconstruction & Troubleshooting

• SOPs release your grey matter for more interesting / motivating issues

The PAST-Historical



“Use standards (i.e. SOP's) as the liberator that relegates the problems that have already been solved to the field of routine, and leaves the creative faculties free for the problems that are still unsolved”

Based on an idea fromW. Edwards DEMING

The PAST-Historical



14

The PAST-Historical


The situation then

• GLP new to the world• Scientists with little or no knowledge of GLP• Senior scientists deliberately resisting GLP Regulations• GLP regarded as a “necessary evil” with regulatory

consequences only• No attempt by senior scientists to embrace the “Quality

Management” aspects of GLP• Safety studies concern almost exclusively animal

toxicology in drug and agricultural areas

The PAST-Historical



The situation then

• Under-estimation of importance of the role of Management

• Study Directors not well versed in their GLP responsibilities

• Quality Assurance personnel confined strictly to Quality Control activities

• Reticence by both industry and authorities to look at other Quality management approaches to help improve things

The PAST-Historical



17

Good Science ?

Reliable processes / data ?

Results acceptable ?

Study 1� � NO

Study 2

Study 3

Study 4

The PAST-Historical



18

Good Science ?



Study 1� � NO

Study 2� � NO

Study 3

Study 4

The PAST-Historical



19

Good Science ?



Study 1� � NO

Study 2� � NO

Study 3� � NO

Study 4

The PAST-Historical



20

Good Science ?



Study 1� � NO

Study 2� � NO

Study 3� � NO

Study 4� � YES

The PAST-Historical



Impact on Consultation“How can we avoid failing the inspection?”

• GLP consultant audit to identify non-compliance issues within the laboratory – GAP analysis

• GLP consultant often asked to write procedures to fill non-compliance gaps

• Very little consultation outside of animal toxicology• Concentration on Study Activities – aided and abetted by

the FDA edict that all studies must be inspected at least once during an on-going phase

The PAST-Historical



Impact on Training“Getting GLP on our training records”

• Getting to know GLP• Basic GLP training for laboratories wishing to implement

GLP Principles often centred on fundamental points :ResourcesCharacterisationRules (Prescriptive documents)Results (Descriptive documents)

Quality Assurance

The PAST-Historical



Impact on Training

• Participants with very little knowledge of GLP • Classroom style presentations predominate• Mostly the “GLP Expert” telling the participants “what

GLP is” and “how to cope”• Little discussion and debate because only few

participants know about GLP• Little room for disciplines outside of mainstream

toxicology (animal studies predominate)

The PAST-Historical



Impact on Training

• Training aimed almost exclusively getting sufficient compliance to pass inspections

• Quality Assurance personnel trained in QC activities NOT in Quality Management

The PAST-Historical



Gradual Realisation that GLP is a “Muffin”

The PRESENT-Perfect1995 - 2007




Blueberries“Cake-mix”

Case




StudiesMatrix of

Systems &Processes

Facility



The situation now

• Mainstream, safety study, scientists well versed in GLP• Systematic refusal of GLP now very rare• More scientific disciplines covered by GLP

• Safety Pharmacology• Short-term study interests

• Realisation of the complexity of Multi-site studies• Monitoring authorities more experienced and “harder” on

the roles of Management, Study Director and QA

The PRESENT-Perfect



The situation now

• Publication of a large number of OECD consensus/guidance documents• GLP and QA• Multi-site studies• Study Director Responsibilities• GLP and Computers

• Extension into areas which were not first targets of GLP• Analytical Laboratories• Clinical Laboratories (GCLP)

The PRESENT-Perfect



The situation now

• Maturation of Quality Assurance• National QA societies given some consideration by National

Monitoring authorities• Creation of QA federations• Creation of The Quality Assurance Journal

The PRESENT-Perfect



Impact on Consultation“How can we ensure the integrity of the muffin?”

• GLP consultant audit to identify non-compliance issues particularly in the “matrix” – interfaces and support areas

• Consultant specialists in areas such as:• Computer validation • 21 CFR part 11• Analytical processes

• Awakening of interest in :• Areas outside of mainstream GLP• Small companies often in biotechnology fields

The PRESENT-Perfect



Impact on Training“Training to cover all aspects of the muffin”

• Participants come to training sessions with some knowledge of GLP, often because their organisations are nominally GLP compliant

• Hence, more debate, more discussion, more workshops, more case studies

• Understanding through confrontation of ideas and opinion

The PRESENT-Perfect



PART PART IIII

Future – Immediate

“Towards a Quality Culture”



• GLP is mostly about compliance• Quality is not just Compliance

The FUTURE-Immediate2007 – 2020



The FUTURE-Immediate


QUALITY

COST TIME

COMPLIANCE


Increasing R&D Spending : Decreasing Success Rate




Same Trend for Big Pharma ?

The PRESENT-Perfect

?

?



Same Trend for Biotech ?



?

?


The cost of Failure in R&DDrugDrugDrugDrugDiscoveryDiscoveryDiscoveryDiscovery

PreclinicalPreclinicalPreclinicalPreclinical P1P1P1P1 P2P2P2P2 P3P3P3P3 ApprovalApprovalApprovalApproval TotalTotalTotalTotal

manymanymanymanyprojectsprojectsprojectsprojects

11.811.811.811.8 4.74.74.74.7 3.33.33.33.3 1.71.71.71.7 1.11.11.11.1 1111

7.17.17.17.1 1.41.41.41.4 1.61.61.61.6 0.60.60.60.6 0.10.10.10.1 11111111

6666 12121212 12121212 100100100100 40404040 170170170170

65656565 44444444 28282828 70707070 4444 441441441441

71717171 56565656 40404040 170170170170 44444444 611611611611

230230230230****

# of NCEs# of NCEs# of NCEs# of NCEsentering stageentering stageentering stageentering stage# of NCEs# of NCEs# of NCEs# of NCEsfailingfailingfailingfailingCost per NCECost per NCECost per NCECost per NCEcompleting stagecompleting stagecompleting stagecompleting stage

Cost of all failuresCost of all failuresCost of all failuresCost of all failures

TotalTotalTotalTotal

600600600600m$m$m$m$perperperperdrugdrugdrugdrug

Source : Lehman Brothers (IRS0597) &data from Zeneca, decision Support Group

230230230230****

* * * * Discovery & Infrastructure costsDiscovery & Infrastructure costsDiscovery & Infrastructure costsDiscovery & Infrastructure costs

The FUTURE- Immediate



40

The Overall R&D Scenario

Activity

Duration

% of totalcost

Number ofNewMolecularEntities

Basic Research Discovery Preclinical

Research Phase 3 Submission

1 - 2 years 1 - 2 years 1 - 2 years 5 - 6 years 1 -2 years

2 % 3 % 10 % 30 % 5 %50 %

7 - 10.000 12 6 4 12

Market

10-15years

Cost 800m$

1 NME

Phase 1 Phase 2




• GLP is only part of the regulatory act• Quality must be viewed in an

integrated manner

The FUTURE-Immediate2007 – 2020



42 Portfolio Review by R&D Committee

Decision points

GLPGLPGLPGLP GCP & GCLPGCP & GCLPGCP & GCLPGCP & GCLP

GMPGMPGMPGMP

DiscoveryDiscoveryDiscoveryDiscovery DevelopmentDevelopmentDevelopmentDevelopment

Basic Basic Basic Basic ResearchResearchResearchResearch

AppliedAppliedAppliedAppliedResearchResearchResearchResearch

PrePrePrePre----DevelopmentDevelopmentDevelopmentDevelopment

NonNonNonNon----ClinicalClinicalClinicalClinical ClinicalClinicalClinicalClinical RegistrationRegistrationRegistrationRegistration

GGGGPvPvPvPvPPPP

GGGGDDDDPPPP

QPBRQPBRQPBRQPBR






Our present R&D model is failing us

...........What the Papers say............

...........M

eeting of AAAS............





Headline in Le Monde“Toxicology is preparing its cell revolution”

• American Association for the Advancement of Sciencemeeting in Boston February 15th

• EPA announced a big cellular toxicology research project

• Toxicology using human cell lines• Kidney cell lines• Hepatocyte lines• Pancreatic cell lines• ............





“Headline in Le MondeToxicology is preparing its cell revolution”

• New techniques would make it possible to do up to 10 000 tests/day on human cell lines.....instead of 10-100 mice studies/year

• Highly automatic systems – results measure effects on genes

• Should change the paradigm of “Time to Market”• First in man becomes much more important




The situation in the future

• GLP compliance only part of the “Quality Triangle”• Increased costs and reduced success will mean that the

industry must adopt a HOLISTIC approach to quality management

• Methods will be borrowed from other Systems of Quality Management• Risk Analysis• Process approaches• Increased emphasis on Qualification & Validation




The situation in the future

• Pressure because of reduced success rate will encourage new R&D pathways• Increased emphasis on Biotechnology• Development of methods using human cell lines = genomic

toxicology• Pressure on timelines will encourage

• Even more extensive use of computerised systems• Highly automated techniques for selecting candidate drugs• Use of business risk analysis and process improvement

techniques


Impact on Consultation

• Incorporation of approaches already implemented in non-GLP areas:• Systems and process approaches, including mapping and

process models (often borrowed from ISO standards or TQM)• Risk Assessment / Analysis (from GMP/ICH)• Quality indicators and metrics• Troubleshooting techniques• Cost-effectiveness studies




Impact on Consultation

• Highly specialised consultation• Validation of specific study types• Qualification of automated systems• In-vitro specialists




Impact on Training

• Training to accompany new approaches/emphases• Process mapping and process improvement• Risk Management in all areas of interest• Quality indicators & metrics

• New training programmes in specialised areas• Techniques of auditing for QA based on risk• Responsibilities of Management linked to business risks




Impact on Training

• More In-house training courses, because need to tailor to company business processes

• Web-based individualised basic training to reduce costs of attendance at traditional training courses

• E-learning providing certificates relating to training• Qualification of professionals through the “collection” of

course attendance / diplomas




Impact on Training

• Integrated approach to quality• Interest in Quality Practices in Upstream Research

(QPBR) - less waste on recycled, repeated or inconclusive research

• Interest from universities to build in GLP aspects into degree level courses




From a recent QA job advertisement

• Our commitment to continuous improvement is at the heart of our business.......

• You’ll approach Quality from a risk management perspective considering the wider implications of the auditing process and risk to our business




Of course I might have got the future all wrong……

… I’m no futurology expert…..and…… ..

…..even experts have been wrong in the past




"Who the hell wants tohear actors talk?”




"Who the hell wants tohear actors talk?”

H.M. Warner, Warner Brothers, 1927.




"We don't like their sound, and guitar music is on the way out."

.




"We don't like their sound, and guitar music is on the way out."

Decca Recording Co. rejecting the Beatles, 1962.




"Heavier-than-air flying machines are impossible.”




"Heavier-than-air flying machines are impossible.”

Lord Kelvin, President, Royal Society, 1895.




"640K ought to be enough for anybody."




"640K ought to be enough for anybody."

Bill Gates, 1981




Thank you for listening

Good Luck in



The FUTURE - Immediate

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