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Module 3. Christa Clasen Ankara, 6./7. April 2006. Module 3. 3.1 Table of Content 3.2 Body of Data 3.2.S Drug Substance 3.2.P Drug Product 3.2.A Appendices 3.2.R Regional Information 3.3 Literature References. 3.2.S Drug Substance. 3.2.S.1 General Information

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module 3

Module 3

Christa Clasen

Ankara, 6./7. April 2006

module 31
Module 3
  • 3.1 Table of Content
  • 3.2 Body of Data
  • 3.2.S Drug Substance
  • 3.2.P Drug Product
  • 3.2.A Appendices
  • 3.2.R Regional Information
  • 3.3 Literature References

Christa Clasen Ankara, 6./7. April 2006

3 2 s drug substance
3.2.S Drug Substance
  • 3.2.S.1 General Information
  • 3.2.S.2 Manufacture
  • 3.2.S.3 Characterisation
  • 3.2.S.4 Control of drug substance
  • 3.2.S.5 Reference Standards or Materials
  • 3.2.S.6 Container Closure System
  • 3.2.S.7 Stability

Christa Clasen Ankara, 6./7. April 2006

3 2 s 1 general information
3.2.S.1 General Information
  • 3.2.S.1.1 Nomenclature

INN, Compendial name, chemical name, other name, laboratory codes, CAS – number

  • 3.2.S.1.2 Structure

Physical form, structural formula (incl. stereochemistry)

  • 3.2.S.1.3 General Properties

Physico-chemical characterisation (solubility, physical characteristics, polymorphism, other)

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture
3.2.S.2 Manufacture
  • 3.2.S.2.1 Manufacturer
  • 3.2.S.2.2 Description of Manufacturing Process and Process Controls
  • 3.2.S.2.3 Controls of Materials
  • 3.2.S.2.4 Control of Critical Steps and

Intermediates

  • 3.2.S.2.5 Process Validation and/or Evaluation
  • 3.2.S.2.6 Manufacturing Process

Development

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture1
3.2.S.2 Manufacture
  • 3.2.S.2.1 Manufacturer
    • Address office
    • Address plant

Company profile is not obligatory

    • If starting materials/ or used intermediates already contains a key-structure of the final drug substance, information of those manufacturer(s) are required

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture2
3.2.S.2 Manufacture
  • 3.2.S.2.2 Description of Manufacturing Process and Process Controls

Applicant‘s Part:

    • Synthetic route: overview
    • Flow chart
    • Brief narrative description of the process

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture3
3.2.S.2 Manufacture

3.2.S.2.2 Description of Manufacturing Process and Process Controls

Restricted Part:

  • Synthetic route: Overview
  • Flow chart including molecular formula, weights, yields, chemical structures of starting materials, intermediates, reagents and drug substance reflecting stereochemistry, operating conditions and used solvents
  • Narrative description of the process covering in more detail the information given in the flow-chart

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture4
3.2.S.2 Manufacture
  • 3.2.S.2.3 Control of Materials
    • List of used raw materials identifying where each material is used in the process.
    • Control of starting materials (Specifications, Description of Test methods)
    • Control of solvents and other reagents (Specifications, Description of Test methods)
    • If starting materials already contains the key-structure of the final API, a synthesis-outline (including solvents, reagents, catalysts, potential Impurities) for these starting materials are required

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture5
3.2.S.2. Manufacture
  • 3.2.S.2.4 Control of Critical Steps and

Intermediates

    • Control of Intermediates (Specifications, Description of test methods)
    • Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture6
3.2.S.2 Manufacture
  • 3.2.S.2.5 Process Validation and/or Evaluation

Process Validation studies should be included (only for aseptic processes or sterilisation)

In any case:

Validation studies have to be perfomed

and needs to be available at request

Christa Clasen Ankara, 6./7. April 2006

3 2 s 2 manufacture7
3.2.S.2 Manufacture
  • 3.2.S.2.6 Manufacturing Process Development

A description and discussion about the significant

changes/improvements to the manufacturing

process and/or manufacturing site of the drug

substance is awaited

Christa Clasen Ankara, 6./7. April 2006

3 2 s 3 characterisation
3.2.S.3 Characterisation
  • 3.2.S.3.1. Eludication of Structure and other

Characteristics

    • Evidence of the chemical structure (elemental analysis, mass spectrum, 1H-NMR, 13C-NMR, IR, UV, other)
    • Potential isomerism
    • Stereochemistry
    • Polymorphism

Christa Clasen Ankara, 6./7. April 2006

3 2 s 3 characterisation1
3.2.S.3 Characterisation
  • 3.2.S.3.2. Impurities
    • List of potential impurities originating from the route of synthesis
    • List of potential impurities arising during the production and purification
    • List of actual existing impurities (synthesis by-products, degradation products)
    • List of potential residual solvents
    • List of actual residual solvents in API
    • Evidence of the chemical structure (elemental analysis, mass spectrum, 1H-NMR, 13C-NMR, IR, UV, other) for each Impurity

Christa Clasen Ankara, 6./7. April 2006

3 2 s 4 control of drug substance
3.2.S.4 Control of Drug Substance
  • 3.2.S.4.1 Specification
    • According to which pharmacopoeia, in-house
    • Characteristics
    • Identification tests
    • Purity tests (including limits for known, total, unidentified single and unidentified total)
    • Other tests
    • Assay

Christa Clasen Ankara, 6./7. April 2006

3 2 s 4 control of drug substance1
3.2.S.4 Control of Drug Substance
  • 3.2.S.4.2 Analytical Procedures

Reference to pharmacopoeia, or

detailed description of all tests

  • 3.2.S.4.3 Validation of Analytical

Procedures

Validation of all used methods according to ICH

Guidelines Q2A and Q2B (if they are not

pharmacopoeial)

Christa Clasen Ankara, 6./7. April 2006

3 2 s 4 control of drug substance2
3.2.S.4 Control of Drug Substance
  • 3.2.S.4.4 Batch analysis
    • Batches tested (date of manufacture, place of manufacture, batch size)
    • Results of tests (3 - 5 consecutive certificates of analysis)
  • 3.2.S.4.5 Justification of the drug substance

specification

    • Comments on the Choice of Routine Tests
    • Justification of Specification Limits

Christa Clasen Ankara, 6./7. April 2006

3 2 s 5 reference standards or materials
3.2.S.5. Reference Standards or Materials
  • List of used Reference Standards or Materials
  • Preparation of Reference Standards, if appropriate
  • Elucidation of Structure for synthesized Materials
  • Specification for Reference materials
  • Description of Test Methods
  • Validation of Analytical Methods if not covered by 3.2.S.4.3

Christa Clasen Ankara, 6./7. April 2006

3 2 s 6 container closure system
3.2.S.6 Container Closure System
  • Description of Container Closure System including Identity of Materials and their specification
  • Discussion of suitability of Packaging material

Christa Clasen Ankara, 6./7. April 2006

3 2 s 7 stability
3.2.S.7 Stability
  • 3.2.S.7.1. Stability Summaries and

Conclusions

    • Program of stability studies (including forced degradation studies if appropriate, e.g. testing parameters, packaging material, storage conditions, batch number, manufacturing date, batch size
    • Conclusion

Christa Clasen Ankara, 6./7. April 2006

3 2 s 7 stability1
3.2.S.7 Stability
  • 3.2.S.7.2 Post-approval Stability Protocol

and Stability Commitment

Program of stability study including testing parameters, packaging material, storage conditions, batch number, manufacturing date, batch size, which will be performed post-approval

Christa Clasen Ankara, 6./7. April 2006

3 2 s 7 stability2
3.2.S.7 Stability
  • 3.2.S.7.3 Stability data

Results of:

    • Long-term study (initial, 3, 6, 9, 12, 18, 24, 36 months) for at least 3 batches
    • Accelerated study (initial, 1, 2, 3, 6 months) for the same batches as long-term study
    • Intermediate study (initial, 3, 6, 9, 12, 18, 24, 36 months) for at least 3 batches, if appropriate
    • Forced degradation study (alkaline conditions, acidic conditions, higher temperature, oxidative condition, light)

Christa Clasen Ankara, 6./7. April 2006

3 2 p drug product
3.2.P Drug Product
  • 3.2.P.1 Description and Compostion of the Drug Product
  • 3.2.P.2 Pharmaceutical Development
  • 3.2.P.3 Manufacture
  • 3.2.P.4 Control of Excipients
  • 3.2.P.5 Control of Drug Product
  • 3.2.P.6 Reference Standards or Materials
  • 3.2.P.7 Container Closure System
  • 3.2.P.8 Stability

Christa Clasen Ankara, 6./7. April 2006

3 2 p 1 description and composition of the drug product
3.2.P.1 Description and Composition of the Drug Product
  • Description of dosage form
  • List of components and their amount
  • Function of components
  • Reconstitution diluent(s)

Christa Clasen Ankara, 6./7. April 2006

3 2 p 2 pharmaceutical development
3.2.P.2 Pharmaceutical Development
  • 3.2.P.2.1 Components of Drug Product
  • 3.2.P.2.2 Drug Product
  • 3.2.P.2.3 Manufacturing Process Development
  • 3.2.P.2.4 Container Closure System
  • 3.2.P.2.5 Microbiological Attributes
  • 3.2.P.2.6 Compatibility

Christa Clasen Ankara, 6./7. April 2006

3 2 p 2 pharmaceutical development1
3.2.P.2 Pharmaceutical Development
  • 3.2.P.2.1 Components of the Drug Product
    • 3.2.P.2.1.1 Drug Substance
      • Compatibility with Excipients
      • Key physicochemical Characteristics
    • 3.2.P.2.1.2 Excipients
      • Justification of Choice

Christa Clasen Ankara, 6./7. April 2006

3 2 p 2 pharmaceutical development2
3.2.P.2 Pharmaceutical Development
  • 3.2.P.2.2 Drug Product
    • 3.2.P.2.2.1 Formulation Development

Brief summary, which is describing the development

    • 3.2.P.2.2.2 Overages

Justification of Overages

    • 3.2.P.2.2.3 Physicochemical and Biological Properties

Christa Clasen Ankara, 6./7. April 2006

3 2 p 2 pharmaceutical development3
3.2.P.2 Pharmaceutical Development
  • 3.2.P.2.3 Manufacturing Process Development

Selection and optimisation of the manufacturing process with its particular critical steps

  • 3.2.P.2.4 Container Closure System

Suitability of the Container Closure System used for storage, transportation and drug product

Christa Clasen Ankara, 6./7. April 2006

3 2 p 2 pharmaceutical development4
3.2.P.2 Pharmaceutical Development
  • 3.2.P.2.5 Microbiological AttributesMicrobiological Attributes should be discussed
  • 3.2.P.2.6 Compatibility

Compatibility of with reconstitution diluent(s)

Christa Clasen Ankara, 6./7. April 2006

3 2 p 3 manufacture
3.2.P.3 Manufacture
  • 3.2.P.3.1 Manufacturer(s)
  • 3.2.P.3.2 Batch Formula
  • 3.2.P.3.3 Description of Manufacturing Process and Process Controls
  • 3.2.P.3.4 Controls of Critical Steps
  • 3.2.P.3.5 Process Validation and/or Evaluation

Christa Clasen Ankara, 6./7. April 2006

3 2 p 3 manufacture1
3.2.P.3 Manufacture
  • 3.2.P.3.1 Manufacturer(s)

Name, address and responsibility of each manufacturer

  • 3.2.P.3.2 Batch Formula

Batch formula incl. all components with amounts and references

Christa Clasen Ankara, 6./7. April 2006

3 2 p 3 manufacture2
3.2.P.3 Manufacture
  • 3.2.P.3.3 Description of Manufacturing Process and Process Controls
    • Flow diagram
    • Narrative description of the manufacturing process
    • Process parameters
    • Proposals for justification of reprocessing of materials

Christa Clasen Ankara, 6./7. April 2006

3 2 p 3 manufacture3
3.2.P.3 Manufacture
  • 3.2.P.3.4 Controls of Critical Steps and Intermediates
    • Critical Steps:

Test and acceptance criteria

    • Intermediates:

Information of quality and control

  • 3.2.P.3.5 Process validation and/or evaluation

Description, documentation, results of validation and/or evaluation studies

Christa Clasen Ankara, 6./7. April 2006

3 2 p 4 control of excipients
3.2.P.4 Control of Excipients
  • 3.2.P.4.1 Specifications
  • 3.2.P.4.2 Analytical Procedures
  • 3.2.P.4.3 Validation of Analytical Procedures
  • 3.2.P.4.4 Justification of Specification
  • 3.2.P.4.5 Excipients of Human or Animal Origin
  • 3.2.P.4.6 Novel Excipients

Christa Clasen Ankara, 6./7. April 2006

3 2 p 4 control of excipients1
3.2.P.4 Control of Excipients
  • 3.2.P.4.1 Specification

Specification should be provided

  • 3.2.P.4.2 Analytical Procedure

Analytical Procedures should be provided

  • 3.2.P.4.3 Validation of Analytical Procedures

Information about Validation

Christa Clasen Ankara, 6./7. April 2006

3 2 p 4 control of excipients2
3.2.P.4 Control of Excipients
  • 3.2.P.4.4 Justification of Specification

Justification for the proposed specification for the excipients

  • 3.2.P.4.5 Excipients of Human or Animal

Origin

Information regarding adventitious agens should be provided.

  • 3.2.P.4.6 Novel Excipients

For excipients used the first time or by a new route of administration detailed information according to the Drug Substance format should be provided.

Christa Clasen Ankara, 6./7. April 2006

3 2 p 5 control of drug product
3.2.P.5 Control of Drug Product
  • 3.2.P.5.1 Specification(s)
  • 3.2.P.5.2 Analytical Procedures
  • 3.2.P.5.3 Validation of Analytical Procedures
  • 3.2.P.5.4 Batch Analysis
  • 3.2.P.5.5 Characterisation of Impurities
  • 3.2.P.5.6 Justification of Specification(s)

Christa Clasen Ankara, 6./7. April 2006

3 2 p 5 control of drug product1
3.2.P.5 Control of Drug Product
  • 3.2.P.5.1 Specification(s)

Specification(s) should be provided

  • 3.2.P.5.2 Analytical Procedures

Analytical Procedures should be provided

Christa Clasen Ankara, 6./7. April 2006

3 2 p 5 control of drug product2
3.2.P.5 Control of Drug Product
  • 3.2.P.5.3 Validation of Analytical Procedures

Analytical Validation should be provided

  • 3.2.P.5.4 Batch Analysis

Descripition of batches and results of batch analysis should be provided

Christa Clasen Ankara, 6./7. April 2006

3 2 p 5 control of drug product3
3.2.P.5 Control of Drug Product
  • 3.2.P.5.5 Characterisation of Impurities

Characterisation of Impurities

 if not provided in 3.2.S.3.2 (Impurities)

  • 3.2.P.5.6 Justification of Specification(s)

Justification of proposed specification(s) should be provided

Christa Clasen Ankara, 6./7. April 2006

3 2 p 6 reference standards or materials
3.2.P.6 Reference Standards or Materials

Information about reference standards or materials should be provided

 if not provided in 3.2.S.5 „Reference standards or materials“

Christa Clasen Ankara, 6./7. April 2006

3 2 p 7 container closure system
3.2.P.7 Container Closure System
  • Identity and specification of each primary packaging components
  • Brief description of non-functional secondary packaging component
  • Information about functional secondary packaging component

Christa Clasen Ankara, 6./7. April 2006

3 2 p 8 stability
3.2.P.8 Stability
  • 3.2.P.8.1 Stability Summary and Conclusion
  • 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
  • 3.2.P.8.3 Stability Data

Christa Clasen Ankara, 6./7. April 2006

3 2 p 8 stability1
3.2.P.8 Stability
  • 3.2.P.8.1 Stability Summary and Conclusion

The Stability Summary should include:

    • Types of Studies
    • Results of Studies
    • Conclusion with respect to storage conditions and shelf-life

Christa Clasen Ankara, 6./7. April 2006

3 2 p 8 stability2
3.2.P.8 Stability
  • 3.2.P.8.2 Post-approval Stability Protocol

Post-approval stability protocoll and the stability commitment should be provided

  • 3.2.P.8.3 Stability Data
    • Presentation of the results in an

appropriate format

    • Information of analytical procedures incl.

validation

Christa Clasen Ankara, 6./7. April 2006

3 2 a appendices
3.2.A Appendices
  • 3.2.A.1 Facilities and Equipment
  • 3.2.A.2 Adventitious Agents Safety

Evaluation

  • 3.2.A.3 Novel Excipients

Christa Clasen Ankara, 6./7. April 2006

3 2 r regional information eu
3.2.R Regional Information (EU)
  • Process Validation Scheme for Drug Product
  • Medical Devices
  • Certificate(s) of Suitability
  • TSE templates (place in 3.2.A.2)

Christa Clasen Ankara, 6./7. April 2006