validation is always part of the picture ongoing validation (doe, iq, oq, pq, pv)* pre-indphase...
TRANSCRIPT
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