Dr. D. MarcozziDr. D. MarcozziHead of Clinical and CSV QA dept. of SIGMA-TAUHead of Clinical and CSV QA dept. of SIGMA-TAU

Milano, 31 marzo, 2005

Qual è il Processo della Qual è il Processo della Computer System Validation?Computer System Validation?

Riunione Gruppo Riunione Gruppo GCPGCP

Parleremo di:Parleremo di:

FORNITORI

CONVALIDA

Nuova visione delle CONVALIDE

Analisi e Gestione del RISCHIO

Cos’è la CONVALIDA?Cos’è la CONVALIDA?

Si si …un bel Si si …un bel vestito….vestito….

Cos’è la CONVALIDA?Cos’è la CONVALIDA?

Cos’è la CONVALIDA?Cos’è la CONVALIDA?

Mi dicono Mi dicono che avrei che avrei fatto una fatto una

CONVALIDACONVALIDA????

Cos’è la CONVALIDA?Cos’è la CONVALIDA?

O meglio………….

Che cos’è la Computerized Che cos’è la Computerized System Validation (CSV)System Validation (CSV)

Primo: cos’è un Computerized Primo: cos’è un Computerized System?System?

Personnel

Software

Documentation

InstrumentHardware

Documentation

Control System

Operating Environment

Procedures

Infrastructure

Validation is….Validation is….

“Establishing documented evidence which provides a

high degree of assurance that a specific process

will consistently produce a product

meeting its pre-determined specifications

and quality attributes”

CurrentCurrent

Validation is the entire procedure of gathering

documented evidence that a computer-related process or

a system performs

according to its intended function

reliably and consistently throughout its life.

DocumentedDocumented

Process/systemProcess/system

Pre-DeterminedPre-Determined

Quality AttributesQuality Attributes

Entire ProcedureEntire Procedure

Reliably and Reliably and consistentlyconsistently

LifeLife

Le parole “CHIAVE”Le parole “CHIAVE”

The life cycle concept of The life cycle concept of Computer ValidationComputer Validation

Validation is a PROCESS, not an event

Validation activities span the entire System Life Cycle:

Planning Requirements Analysis Design Implementation Testing Acceptance On going Retirement

Requirements

System

Selection

Specify

&

Design

BuildSupplier

Testing

User

Qualification

Operation

Maintenance

Do

cu

me

nta

tio

n

Planning and ImplementationPlanning and ImplementationA Life cycle approachA Life cycle approach

URS

FS OQ

DS

PQ

IQ

System

Build

Planning and ImplementationPlanning and ImplementationA Life cycle approachA Life cycle approach

Planning

Specifications

Test Planning (IQ,OQ,PQ)

Review

Validation Plan

URS, FS, DS (required)

Doc. come testare il sistema

Validation Report

Testing Test e risultati

Planning and ImplementationPlanning and ImplementationA Life cycle approachA Life cycle approach

Validation activity and “life cycle”

PROJECT ACTIVITY

USER REQUIREMENTSFUNCTIONAL SPEC.

HW E SW DES. SPEC.SW MODULE DES. SPEC.

MECH. & ELECTRIC SPEC.

HW MANUF. & ASSEMBLYCODE SW MODULES

EQUIP. MANUF. & ASSEMBLY

HW TESTINGSW MOD.& INTEGR. TESTING

EQUIP TESTING

HW, SW, EQUIP. INSTALL.HW ACCEPTANCE TESTING

SYSTEM ACCEPTANCE TEST.

MAINTENANCECHANGE CONTROL

LIFE CYCLE PHASE

PLANNING & SPECIFICATION

DESIGN

CONSTRUCTION

TESTING

INSTALLATION

ACCEPTANCE TESTING

OPERATION

VALIDATION ACTIVITY

VALIDATION PLANSUPPLIER AUDITS

SPEC. REVIEW

DESIGN REVIEW

COSTRUCTION & CODE REVIEW

MONITOR SUPPLIER

IQ

OQPQ

VALIDATION REPORT

ONGOING OPERATION

Validation Scope and EffortValidation Scope and Effort

Validation Scope and Effort

should be commensurate with impact and value

of data, process, results. . .

size and complexity of the system and

how critical it is in

your routine and non-routine operations

Tanto più un sistema è critico e complesso tanto maggiore

sarà lo “sforzo” di convalida…quindi…

Sistemi Standard

Sistemi Customizzati

Sistemi Be-spoke

Basic Approach to ValidationBasic Approach to Validation

Validation is a process, not an event

Planning activity should be performed as a Team

Keep the validation process under control

Le finalità….da GCPLe finalità….da GCP

Qualora si avvalga di sistemi elettronici di

elaborazione dei dati e/o sistemi di inserimento a

distanza per la gestione dei dati relativi alla

sperimentazione, lo Sponsor….

Garantire e documentare che il sistema elettronico

per l’elaborazione dei dati sia conforme ai requisiti

di completezza, precisione, affidabilità stabiliti dallo

Sponsor e che questi siano conformi alle

caratteristiche prefissate (cioè Validazione)

Le finalitàLe finalità

Validating Data

Validating the

System handling

the Data

Nel 1999… l’FDANel 1999… l’FDA

Pubblica una nuova Guidance for Industry

“Computerized System Used in Clinical Trials”

Per essere accettabili, i dati debbono soddisfare certi elementi fondamentali di qualità se raccolti e

registrati elettronicamente o su carta

I dati debbono essere: ttribuibili (Source & Recorder are Known)

eggibili (Human readable) ontemporanei (Recorded when observed)

riginali (Honest data/not fraud)ccurati (Correct, repeatable results)

AL

CO

A

ALCOA

Ed ora… gli attori…Ed ora… gli attori…

CLIENTECLIENTE

FORNITOREFORNITORE

CLIENTECLIENTE

FORNITOREFORNITORE

USERUSER ITIT

QAQA

CLIENTECLIENTE

COMMERCIALECOMMERCIALE

e……e……

FORNITOREFORNITORE

QAQA

According to specific rules or guidelines defined for each environment

Il peso del QA….Il peso del QA….

ITQA

Il peso del QA….Il peso del QA….

Qualità della documentazione

Requisiti Regolatori

Requisiti di Processo

Requisiti Tecnici

Pianificazione e Testing

Qualifica dei fornitori

QA

IT

Il QA… ovunque nella Il QA… ovunque nella CSVCSV

Valutazione Fornitori

Risk Assessment

Definizione Requisiti Utente

Definizione delle politiche di convalida

Piani e test di convalida

Revisione ed Approvazione dei documenti di convalida

Il QA… ovunque nella Il QA… ovunque nella CSVCSV

Approvazione dei cambiamenti

Revisione ed Approvazione delle SOPs di convalida e CSV generali

Audit periodici

Punto di riferimento normative CSV

E le SOPs?E le SOPs? Training Vendor Evaluation Gestione Documentazione di Convalida Change Control Configuration Management Problem Reporting Security Back-up Restore Archiving Clinical Data Maintenance Disaster Recovery/Business Continuity Periodic Review

QAQA

COMMERCIALECOMMERCIALE

e……e……

FORNITOREFORNITORE

PQURS

FS OQ

DS IQ

System Build

Planning and ImplementationPlanning and ImplementationA Life cycle approachA Life cycle approach

Evaluation should preferably be derived from a

reliable audit of the software developer (supplier),

performed by the end user’s organization or a

trusted and competent third part.

Da GMP….. Da GMP…..

...Validation should be considered as part of the complete

life cycle of a computer system. This cycle includes the

stages

of planning, specification, programming, testing,

commissioning, documentation, operation, monitoring and

modifying… (by supplier!).

The software is a critical component of a computerized

system. The user of such software should take all reasonable

steps to ensure that it has been produced in accordance with

a System of Quality Assurance.

CS Validation CS Validation Documents Documents

Client responsibility Supplier responsibility

Planning

GAMP

Specifications

Testing

Validation Summary

On-Going

Test Plan

Design Spec.

Functional Spec.

Quality and Project Plan

Factory/Site Acceptance Test

Master Index

Validation Report.

Report IQR, OQR, PQR

Audit Report

Validation Plans

Validation Master Plan

User Requirement Specifications

SOPs

ProtocolliDQ, IQ, OQ, PQ

SOPs User Manuals

Why do we have to audit the Why do we have to audit the Suppliers?Suppliers?

The primary purpose of an audit is to The primary purpose of an audit is to assessassess the the

controlscontrols, , proceduresprocedures, and , and practicespractices which are in which are in

place for the place for the developmentdevelopment and and maintenancemaintenance of a of a

productproduct

Is a form of review that provides Is a form of review that provides confidenceconfidence

concerning the concerning the validityvalidity and and accuracyaccuracy of a of a productproduct or or

processprocess nownow and in the and in the futurefuture

Audits should be viewed as a Audits should be viewed as a learninglearning experienceexperience and and

should be conducted should be conducted asas a a cooperativecooperative efforteffort

SW Supplier EvaluationSW Supplier Evaluation

“To ensure that the supplier produces a quality

product, and to obtain information to plan

computer validation activities”

“Tools”

Collection of available information Request for Information (questionnaire) Audit Follow up

Intent

COSTS

RISKSEVALUATION

THROUGH REFERENCES

EVALUATION THROUGH

EXPERIENCES

REQUEST FOR INFORMATION

3RD PARTY AUDIT

SPECIFIC FIRM AUDIT

Supplier Evaluation ToolsSupplier Evaluation Tools

Supplier Qualification modelSupplier Qualification model

Information from other companies or from market

Request for Information (RFI)

Telephone Audit

Site Audit

SY

ST

EM

RIS

K C

AT

EG

OR

Y

EV

AL

UA

TIO

N C

OS

T

Check…Independence of SW Check…Independence of SW Validation Validation

Validation activities should be Validation activities should be conducted using the basic quality conducted using the basic quality

assurance precept of assurance precept of ““independenceindependence of of reviewreview”.”.

Self-validation is extremely difficult; Self-validation is extremely difficult; an an independentindependent reviewreview is always is always

better.better.

Computer system validation should be performed by persons other than those responsible for

building the system.

Check…Independence of SW Check…Independence of SW ValidationValidation

Validation: Client Validation: Client Responsibility ! Responsibility !

Manufacturer has flexibility in choosing how to apply the validation principles, but retains ultimate responsibility for demonstrating that the software has been validated.

NormativeGuidelines

PLANNING

Client Responsibility !Client Responsibility !

Client with regulatory responsibility

needs to assess the adequacy of the

software developer’s activities and

determine what additional efforts are

needed to establish that the software

is validated.

...but

Validation Responsibility is always on the Client’s side

Supplier selection (and supplier)is important

Validated Packages don’t Validated Packages don’t exist!!exist!!

SupplierSupplier maymay provideprovide a a

““ValidationValidation PackagePackage”, showing ”, showing

that the that the standardstandard versionversion of of

the product has been the product has been

validatedvalidated “in “in FactoryFactory””

ClientClient has to perform an “ has to perform an “on-on-SiteSite” Validation ” Validation

Quindi….Quindi….

La validazione è una nostra responsabilità

Si deve Validare nel nostro “ambiente” Non è una responsabilità del Fornitore

del sistema

I sistemi forniti (anche quelli più standard) sono validabili, da validare e non già

validati

Quanto più il fornitore è affidabile…di QUALITA’

Tanto meno sforzo di convalida dovremo

pianificare

Dopo e sempre Validare!!!

Prima Verificare!!!

Ora parliamo di Ora parliamo di

RISK MANAGEMENT….RISK MANAGEMENT….

RISK ANALYSIS…..RISK ANALYSIS…..

Solo un accenno…. Solo un accenno…. prendiamo spunto dalla prendiamo spunto dalla

realtà!realtà!

Da FDA….Da FDA….

Pharmaceutical Pharmaceutical CGMPs CGMPs for the 21for the 21st st centurycentury

A A RRisk-isk-BBased ased AApproach pproach FFinal inal RReport eport september 2004september 2004

In August 2002, FDA announced a significant new initiative, In August 2002, FDA announced a significant new initiative, Pharmaceutical Current Manufacturing Practices (CGMPs)Pharmaceutical Current Manufacturing Practices (CGMPs) for for the the 2121stst Century Century, to enhance and modernize the regulation of , to enhance and modernize the regulation of pharmaceutical manufacturing and product quality for pharmaceutical manufacturing and product quality for veterinary and human drugs…. veterinary and human drugs….

Objective:Objective:

Encourage implementation of risk-based approaches that Encourage implementation of risk-based approaches that focus both industry and Agency attention on critical areasfocus both industry and Agency attention on critical areas

Da FDA….Da FDA….

21 CFR Part 11 Guidance…21 CFR Part 11 Guidance…

Whit the issuance in 2003 of the guidance for Whit the issuance in 2003 of the guidance for industry industry part11, Electronic Records,part11, Electronic Records, ElectronicElectronic Signature-Signature- Scope and Application,Scope and Application, many barriers to many barriers to scientific and technological advances were removed, scientific and technological advances were removed, and the use of and the use of risk-based approachesrisk-based approaches to managing to managing computer systems is encouraged.computer systems is encouraged.

Risk AnalysisRisk Analysis//

Computer Validation Computer Validation

Protect against the risks to patient safety

Maximize the business benefits

Help to determine the extent of validation

Give a rationale to justify Validation approach in case of Inspection

Concentrate the validation effort

A Good StartA Good Start Perform AssessmentPerform Assessment

Dove siamo?

Dove vogliamo andare?

Da cosa cominciamo?

Risk Analysis: the ValueRisk Analysis: the Value

The more you know about your computer system

TestThe more you focus the validation

Better you will use your resources…. and Better you will use your resources…. and money!money!

Nuovo approccio alle Nuovo approccio alle Convalide….Convalide….

Nel 1990 GAMP…

Good Automated Manufacturing Practice

Scopo della linea-guida è quello di assistere le aziende farmaceutiche, biotecnologiche, medical devices nell’implementazione di sistemi

automatizati validati e compliant con i requisiti normativi

Nasce nell’ambient

e GMP

…nuove GAMP… 2001

Le nuove GAMP coprono tutti i requirements GMP, GCP, GLP e GDP

Si potrebbero chiamare GA “M-C-L-D” P

Più attenzione al Processo!

Nuovo approccio alle Nuovo approccio alle Convalide….Convalide….

Da…Da… PerformancePerformance

ProcessProcessA…..A…..

QUALIFICATION !QUALIFICATION !

FINE…..FINE…..

Grazie per la Grazie per la

PAZIENZA!!PAZIENZA!!