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Validation of new premises

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					 Validation is Always Part of the Picture

                                                                    Commercial
             Pre-IND        Phase I      Phase II      Phase III
                                                                   Manufacturing




                                           Final process validation
          Specification Development
                                                                   Re-validation
        Ongoing Validation
        (DOE, IQ, OQ, PQ, PV)*                      * DOE = Design of Experiment
                                                      IQ = Installation Qualification
• The extent of IQ, OQ, PQ, validation, etc.          OQ = Operational Qualification
  depends on complexity of product                    PQ = Performance Qualification
• 6 sigma target                                      PV = Process Validation
             GMPValidation of new premises

                                               VALIDATION


  Clean area                 Utility           Manufacturing                               Manufacturing
                                                                      Equipment
  Premises                  Systems            Support Syst.                                Processes
- HVAC System             - Water systems      - Sterilizers         - Fermentors          - Fermentation
- LAF Units               - Plant Steam        - Depyrogenators      - Scales              - Separation
- Cold Storage            - Pure/Clean Steam   - SIP Systems         - Incubators          - Purification
- Env. Monitoring         - Process Gases      - CIP Systems         - Filtration Units    - Filtration
- Facility Cleaning                            - Washing             - Filling Equipment   - Filling
- Transfer hatches                             - Waste Systems       - Computerised
- Verifi. of classific.                                                 systems



   Aseptic                Packaging &           In-Process            Personnel              Analytical
 Processing                 Labeling              Control              Training              Methods
- Media Fills             - Packaging          - Process Measurem.   - GMP                 - Chemical - Cleaning valid
                          - Labeling           - Visual Inspection   - Gpwning valid..     - Physical - Sterility tests
                                               - Label Control       - SOPs                - Biological - Stability
                                               - Sampling            - Equipment
                                                                     - Processes
Assignment of Drug Review
                              1.0 Regional Administrative Information
                              1.1 ToC of Module 1 or overall ToC,
                                  including Module 1
                   Module 1

                      1.0                      2.1 ToC of the CTD (Mod 2,3,4,5)

                      2.1                      2.2 Introduction
Module 2                                       2.3 Quality Overall Summary
                      2.2
                                               2.4 Nonclinical Overview
                      2.4       2.5
                                               2.5 Clinical Overview
           2.3
                      2.6         2.7          2.6 Nonclinical Written and
                                                   Tabulated Summaries
      Module 3      Module 4      Module 5     2.7 Clinical Summary
                  Nonclinical     Clinical
    Quality      Study Reports Study Reports
                  Paper CRF Process
Gather      Record on   Transcribe    File Copy      Monitor      Updates
 Data        Source       to CRF       of CRF         CRF          to DM


                         Copy to                      Data
                          DM                       Processing




          To            Is Response     NO        Issue Queries
          DM                OK?                      to Sites



         Answer         Compare to
         Query            Source
                              eCRF

   Gather       Record on            Transcribe               Monitor e-CRF
    Data         Source               to e-CRF                 with Source




e-CRF Printed                          Answer                   Generate
                 Approve
   for Site                            on-line                  electronic
                  e-CRF
  Retention                            Queries                    Query




                              Data Manager, Project Manager and
                            Clinical Monitor Data (offline edit checks,
                                         manual review)
      Protocol Development
Time                 Stage            Review/Approval
Line
 1-6 Months      Protocol Concept       Investigator/IND Holder
                                           Cooperative Group

                                            Department Review
  2-3 Months   Protocol Development
                                      Institutional Scientific Review

                                                IND Holder
 2-3 months     Protocol Approval      Institutional Review Board
                                      Food and Drug Administration

                                              Monitoring
  2-6 years       Clinical Trial                  Investigator
                                         Institutional Review Board
                                      Data Safety and Monitoring Board
                                                  IND Holder
                                       Food and Drug Administration
               THE R&D PROCESS                                                  Development


 Preclinical studies                                        Clinical studies




                                                                                                             27/02/2012
      Discovery                     Early Clinical                      Development
CHEMISTRY/        IND*            PHASE I      PHASE II        PHASE III        NDA**             PHASE IV
 PHARMA-
 COLOGY
 Search for     Regulatory         Efficacy       Clinical     Comparative   Regulatory  Continued
   active         review          studies on   studies on a    studies on a    review   comparative
 substances   *Investigational     healthy     limited scale      large                    studies
                 New Drug         volunteers                    number of
 Toxicology,                                                                KNOWLEDGE
                Application for
                                   50–150                        patients
   efficacy                                      100–200
                permission to                                                 LEVEL     Registration,
 studies on   administer a new     persons       patients
                                                                                           market
various types  drug to humans                                   500–5,000
                                                                                        introduction
 of animals KNOWLEDGE                                            patients
                                                                              **New Drug
                  LEVEL                                                        Application
                                                                              Application for
                                                                           permission to market
                                                                                a new drug

TIME SPAN

  2–4 yrs.     2–6 months                        3–6 yrs.                       1–3 yrs.

    Approximately 10–15 years from idea to marketable drug
                                                                                                         72
Drug Phases
             Early Clinical Drug Development
                  PRINCIPLE TESTING
Key Activities:                                                         Achieved Objectives:
• Submission                                                            • Safety
• Single Ascending Dose study                                           • Effectiveness
• Multi Ascending Dose study                                            • Business Plan
• Proof of Principle studies                                            • Dose
• Manufacture route identification                  Principl
• Dev. formulation for concept testing &
  onwards                                                  e
• Dev. Patient Risk Management Plans                 Testing


                                                   1-3 years

MS     1        2        3         4          5         FTIM    5.5       6       7       8           9


 Target       Hit     Lead     Lead         Pre-    Preclin. Principle Concept Dev. for Launch     Prod.
    Id.       Id.       Id.     Opt.       nom.        Dev.   Testing   testing Launch and PLC    Maint.


TG                       1        1.5         2                   2.5         3       4       5
                                                                                                           74
Phase I dose escalation scheme
                           CTMS: Flow
                            Clinical Data Warehouse


 Electronic
Data Capture


                       Clinical Data
Clinical Trial             Store
Management


                           Trial Metrics                   Trial Management Process

External Data


                           Clinical Data
                                                            Biostatistical Analysis
                            (Detailed)




                                           Clinical Data                Tables,
                                            (Summary)                                 FDA Submission
                                                                     Listings and
                                                                                         Process
                                                                       Figures
Data flows impact by
 change in source
     structures




                                                                                        Marketing
                                                           Clinical Data Mining
                                                                                         Support
 Source
Systems                EDC Drug Development                                                                             Portal


                                                            21 CFR Part 11 Compliance

Clintrial     Clintrial Connector                                                                 Data Mining
 eTrial                                                      SDD Platform
                                                                       Analysis
OpenText           Opentext                                            and
                                                          Version      Reporting
                                                          Control                                  Reporting

eClinical




                                                                                    Web Hosting
                             (Defined Business Rules)




                                                              Biomedical                                        Web Server
 Oracle                                                       Trial Data                           Ad Hoc
                                                              Warehouse                            Querying
                      ETLQ




 CROs                                                   Regulatory Submission and
                                                         Document Management

                                                                                                  OLAP/Cubes      Desktop

                      Meta
 Other                Data
                                                         Metadata Management
                                                                                                                    Electronic
            Access Engines                                                                                         Submissions
          Data Quality, Cleansing,
          Validation, Aggregation,
                Enrichment
Sources of Error in a Study

             Participant
                                   Omission, mis-communication
         Source documents
                                   Transcription
          Case report form
                                   Data entry errors
              Database             Programming, summary tables

         Statistical analysis      Statistical interpretation

     Study report or manuscript Clinical interpretation

				
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