Validation is Always Part of the Picture

Ongoing Validation

(DOE, IQ, OQ, PQ, PV)*

Pre-IND Phase I Phase II Phase III Commercial Manufacturing

* DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation

Specification DevelopmentFinal process validation

Re-validation

• The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product

• 6 sigma target

GMPValidation of new premises

VALIDATIONVALIDATION

Clean areaPremises

ManufacturingProcesses

EquipmentManufacturing Support Syst.

UtilitySystems

AnalyticalMethods

PersonnelTraining

AsepticProcessing

In-ProcessControl

- HVAC System- LAF Units- Cold Storage- Env. Monitoring- Facility Cleaning- Transfer hatches- Verifi. of classific.

- Water systems- Plant Steam- Pure/Clean Steam- Process Gases

- Sterilizers- Depyrogenators- SIP Systems- CIP Systems- Washing - Waste Systems

- Fermentors- Scales- Incubators- Filtration Units- Filling Equipment- Computerised systems

- Fermentation- Separation- Purification- Filtration- Filling

Packaging & Labeling

- Media Fills - Packaging- Labeling

- Process Measurem.- Visual Inspection- Label Control - Sampling

- GMP- Gpwning valid..- SOPs- Equipment- Processes

- Chemical - Cleaning valid- Physical - Sterility tests- Biological - Stability

Assignment of Drug Review

1.0 Regional Administrative Information

1.1 ToC of Module 1 or overall ToC,including Module 1

2.1 ToC of the CTD (Mod 2,3,4,5)

2.2 Introduction

2.3 Quality Overall Summary

2.4 Nonclinical Overview

2.5 Clinical Overview

2.7 Clinical Summary

2.6 Nonclinical Written and Tabulated Summaries

Module 1

Module 3 Module 4 Module 5

2.1

2.2

2.3

2.4 2.5

2.6 2.7

1.0

QualityNonclinical

Study ReportsClinical

Study Reports

Module 2

Paper CRF Process

Gather Data

Record on Source

Transcribe to CRF

File Copy of CRF

Monitor CRF

Updates to DM

Copy to DM

Data Processing

Issue Queries to Sites

Compare to Source

Answer Query

To DM

Is Response OK?

YES

NO

eCRF

Gather Data

Record on Source

Transcribe to e-CRF

Monitor e-CRF with Source

Generate electronic

Query

Answer on-line Queries

Approve e-CRF

e-CRF Printed for Site

Retention

Data Manager, Project Manager and Clinical Monitor Data (offline edit checks,

manual review)

Protocol Development

Protocol Concept

Stage Review/Approval

Investigator/IND HolderCooperative Group

Protocol DevelopmentDepartment Review

Institutional Scientific Review

IND HolderInstitutional Review Board

Food and Drug AdministrationProtocol Approval

Clinical Trial Monitoring

InvestigatorInstitutional Review Board

Data Safety and Monitoring BoardIND Holder

Food and Drug Administration

1-6 Months

Time Line

2-3 Months

2-3 months

2-6 years

THE R&D PROCESSDevelopment

Discovery Development

Approximately 10–15 years from idea to marketable drug

Preclinical studies Clinical studies

CHEMISTRY/ PHARMA-COLOGY

IND* PHASE I PHASE II PHASE III NDA** PHASE IV

Search for active

substances

Toxicology, efficacy

studies on various types of animals

Regulatory review

Efficacy studies on

healthy volunteers

Clinical studies on a limited scale

Comparative studies on a large number of patients

Regulatory review

Continued comparative studies*Investigational

New DrugApplication for permission to

administer a new drug to humans

50–150persons

100–200patients

500–5,000patients

Registration, market

introduction

**New Drug Application

Application for permission to market

a new drug

KNOWLEDGE

LEVEL

KNOWLEDGE

LEVEL

2–4 yrs. 2–6 months 3–6 yrs. 1–3 yrs.

TIME SPAN

Early Clinical 19

/04

/23

20

Drug Phases

Principle

Testing

Key Activities:• Submission• Single Ascending Dose study• Multi Ascending Dose study • Proof of Principle studies• Manufacture route identification• Dev. formulation for concept testing &

onwards• Dev. Patient Risk Management Plans

Achieved Objectives:• Safety• Effectiveness• Business Plan• Dose

1-3 years

Early Clinical Drug Development PRINCIPLE TESTING

Prod.Maint.

Launch and PLC

Dev. for Launch

Concepttesting

PrincipleTesting

Preclin.Dev.

Pre-nom.

LeadOpt.

LeadId.

HitId.

TargetId.

TG

MS 1 2 3 4 5 5.5 6 8 9FTIM

1 1.5 2 2.5 3 4 5

7

22

Phase I dose escalation scheme

CTMS: FlowClinical Data Warehouse

Trial Management Process

Biostatistical Analysis

FDA SubmissionProcess

Clinical Data MiningMarketingSupport

Clinical DataStore

ElectronicData Capture

Clinical TrialManagement

External Data

Trial Metrics

Clinical Data(Detailed)

Clinical Data(Summary)

Tables,Listings and

FiguresData flows impact by

change in sourcestructures

Ad Hoc Querying

Ad Hoc Querying

Portal

ReportingReporting

Desktop

Source Systems

Web Server

Data MiningData Mining

OLAP/CubesOLAP/Cubes

SDD Platform

Metadata Management

Version Control

Analysis and Reporting

Regulatory Submission and Document Management

Biomedical Trial Data

Warehouse Web

Hos

ting

21 CFR Part 11 Compliance

Data Quality, Cleansing, Validation, Aggregation,

Enrichment

ET

LQ

(De

fine

d B

usi

ne

ss R

ule

s)

ET

LQ

(De

fine

d B

usi

ne

ss R

ule

s)

Access Engines

MetaData

Clintrial Connector

Opentext

Electronic Submissions

ClintrialeTrial

eClinical

Other

Oracle

CROs

OpenText

EDC Drug Development

Sources of Error in a Study

Study report or m anuscript

Statistical analysis

D atabase

C ase report form

Source d ocum ents

ParticipantOmission, mis-communication

Transcription

Programming, summary tables

Statistical interpretation

Clinical interpretation

Data entry errors