HELM AG Module 3 Christa Clasen Ankara, 6./7. April 2006.

HELM AG

Module 3

Christa Clasen

Ankara, 6./7. April 2006

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

• 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


• 3.2.S.1.1 Nomenclature

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

• 3.2.S.1.2 StructurePhysical form, structural formula (incl. stereochemistry)

• 3.2.S.1.3 General PropertiesPhysico-chemical characterisation (solubility, physical characteristics, polymorphism, other)

3.2.S.1 General Information


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


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


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


3.2.S.2 Manufacture

3.2.S.2.2Description 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


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


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


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


3.2.S.2 Manufacture

• 3.2.S.2.6 Manufacturing ProcessDevelopment

A description and discussion about the significant

changes/improvements to the manufacturing

process and/or manufacturing site of the drug

substance is awaited


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


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


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



• 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)



• 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


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


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


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


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


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)


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


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)


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



• 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



• 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



• 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



• 3.2.P.2.5 Microbiological AttributesMicrobiological Attributes should be discussed

• 3.2.P.2.6 Compatibility

Compatibility of with reconstitution diluent(s)


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


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


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


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


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



• 3.2.P.4.1 Specification

Specification should be provided

• 3.2.P.4.2 Analytical Procedure

Analytical Procedures should be provided


Information about Validation



• 3.2.P.4.4 Justification of SpecificationJustification for the proposed specification for the excipients

• 3.2.P.4.5 Excipients of Human or AnimalOrigin

Information regarding adventitious agens should be provided.

• 3.2.P.4.6 Novel ExcipientsFor excipients used the first time or by a new route of administration detailed information according to the Drug Substance format should be provided.


3.2.P.5 Control of Drug Product

• 3.2.P.5.1 Specification(s)


• 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)



• 3.2.P.5.1 Specification(s)

Specification(s) should be provided


Analytical Procedures should be provided




Analytical Validation should be provided

• 3.2.P.5.4 Batch Analysis

Descripition of batches and results of batch analysis should be provided



• 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


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“


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


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


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


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


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


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)

HELM AG Module 3 Christa Clasen Ankara, 6./7. April 2006.

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Transcript of HELM AG Module 3 Christa Clasen Ankara, 6./7. April 2006.