GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

JANUARY 2009

APPENDIX 8

SINGAPORE QUALITY OVERALL SUMMARY New Drug Applications and Generic Drug Applications (Chemicals)

The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e., Chemistry, Manufacturing and Controls) portion of a New Drug Application (NDA) or a Generic Drug Application (GDA) for a chemical drug product. Both hard copy and electronic copy of the Singapore QOS shall be submitted for review. The applicant is responsible for completing all sections and fields as much as possible. Sections and fields that are not applicable should be indicated with NA. An explanatory note must immediately follow all NA entries. INTRODUCTION Proprietary Name of Drug Product INN Common Name of Drug Substance Product Owner Name Licence Holder Name Dosage Form Strength(s) Route of Administration Proposed Indication(s) Other introductory information:

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

JANUARY 2009

S DRUG SUBSTANCE S 1 GENERAL INFORMATION Check appropriate box. DMF (open) part is attached. DMF (open and restricted) and Letter of Access to be submitted by DDMMYYYY (within one month of PRISM submission), OR Letter of Access to the DMF filed with HSA (015:________) is provided. * CEP (Certificate of Suitability from EDQM) for Drug Substance is attached. CEP Number: CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients is attached. Drug Substance meets the current USP/PhEur/BP/JP (delete as appropriate) requirements. Drug Substance meets other pharmacopoeia standards. Drug Substance meets in-house specifications. Drug Substance meets other pharmacopoeia standards. Analytical methods and appropriate analytical method validation data are included in the dossier. Drug Substance meets in-house specifications. Analytical methods and appropriate analytical method validation data are included in the dossier. * If CEP is provided and Ph.Eur standard is claimed for drug substance, please fill in S1, S2.1, S4.4 and #S7
If CEP is provided and other standards are claimed for drug substance, please fill in S1, S2.1, S4.1 to S4.5 and # S7 (#To be provided if re-test period/shelf life is not stated on CEP)

S 1.1 Nomenclature Hard Copy Location/Pages: E-Copy Location/File Name: Chemical Name: Other names: (e.g. INN, BAN, USAN, common name) Company or laboratory code: Chemical Abstracts Service (CAS) registry number: S 1.2 Structure Hard Copy Location/Pages: E-Copy Location/File Name: Structural formula (including stereochemistry): Molecular formula:
[insert structure]

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Molecular Mass: S 1.3 General Properties Hard Copy Location/Pages: E-Copy Location/File Name: Physical description (e.g., appearance, colour, physical state): Physical form (e.g., polymorphic form, solvate, hydrate): Solubilities (e.g., in common solvents, aqueous/non-aqueous solubility profile): pH and pKa values: Other (e.g., partition coefficients, melting or boiling points, optical rotation, refractive index (for a liquid), hygroscopicity, UV absorption maxima and molar absorptivity):

S 2 MANUFACTURE S 2.1 Manufacturer(s) Name, address, and activity of each manufacturer, including contractors, and each proposed production site or facility involved in manufacture and testing: Activity Site of Manufacture Site of Release testing Site of Batch Release
* For information only.

Name and Address

*GMP Compliance (Please indicate Approving Agency)

S 2.2 Description of Manufacturing Process and Process Controls Hard Copy Location/Pages: E-Copy Location/File Name: Typical production batch size: Flow diagram of the synthetic process(es):

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S 2.3 Control of Materials Hard Copy Location/Pages: E-Copy Location/File Name: S 2.4 Controls of Critical Steps and Intermediates Hard Copy Location/Pages: E-Copy Location/File Name: S 2.5 Process Validation and/or Evaluation Hard Copy Location/Pages: E-Copy Location/File Name: S 2.6 Manufacturing Process Development Hard Copy Location/Pages: E-Copy Location/File Name:

S 3 CHARACTERISATION S 3.1 Elucidation of Structure and other Characteristics Hard Copy Location/Pages: E-Copy Location/File Name:

S 3.2 Impurities Summary of potential and actual impurities arising from the synthesis, manufacture and/or degradation: Chemical Name/Laboratory Code Origin/Type of Impurity Structure
[insert structure]

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JANUARY 2009

Process-related impurities (e.g., residual solvents): Compound Name Step in Process

S 4 CONTROL OF THE DRUG SUBSTANCE S 4.1 Specification Standard Claimed for the Drug Substance (e.g., USP, BP, etc.): Test Method (e.g., HPLC) Source (e.g., USP, inhouse) Acceptance Criteria

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S 4.2 Analytical Procedures S 4.3 Validation of Analytical Procedures

For each test, please indicate yes or no as appropriate Test Name Precision - Repeatability - Intermediate Precision - Reproducibility Limit of Quantitation Method Description System Suitability Limit of Detection (Please specify)

Robustness

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Selectivity

Or Others

Accuracy

Linearity

Range

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JANUARY 2009

S 4.4 Batch Analyses Batch Type (production/pilot) Date of Production

Batch Number

Batch Size

Site of Production

S 4.5 Justification of Specification Hard Copy Location/Pages: E-Copy Location/File Name: Test Justification of Specifications

S 5 REFERENCE STANDARDS OR MATERIALS Hard Copy Location/Pages: E-Copy Location/File Name: Batch Number Primary Reference Standard Working Standard Source (e.g., USP, in-house)

S 6 CONTAINER CLOSURE SYSTEM Description of the container closure system(s) for the storage of the drug substance:

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JANUARY 2009

S 7 STABILITY S 7.1 Stability Summary and Conclusions Stability study details: Storage Conditions (C, % RH, light) Batch Number Batch Size Site of Manufacture Completed Test Intervals (months)

Summary and discussion of all stability study results: Hard Copy Location/Pages: E-Copy Location/File Name: Proposed storage conditions and re-test period (or shelf life, as appropriate): Container Closure System Storage Conditions Re-test Period (or Shelf Life, as appropriate)

S 7.2 Post-approval Stability Protocol and Stability Commitment Stability protocol for commitment batches (if applicable): Protocol Parameter Number of batches and batch sizes Tests and acceptance criteria Container closure system(s) Testing frequency Storage conditions (and tolerances) of samples Other Description

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S 7.3 Stability Data Hard Copy Location/Pages: E-Copy Location/File Name: P DRUG PRODUCT P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT (1) Description of the dosage form:

(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis (including overages, if any): Strength (Label claim): Components Quality Standard Quantity per unit % Function

Total (3) Composition, i.e., qualitative list of all components of proprietary materials (e.g., capsule shells, colouring blends, imprinting inks, etc.): Proprietary Material Qualitative Composition Quantitative Composition

(4) Description of accompanying reconstitution diluent(s), if applicable:

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P 2 PHARMACEUTICAL DEVELOPMENT P 2.1 Components of the Drug Product Hard Copy Location/Pages: E-Copy Location/File Name: P 2.2 Drug Product

P 2.2.1 Formulation Development Hard Copy Location/Pages: E-Copy Location/File Name: P 2.2.2 Overages Hard Copy Location/Pages: E-Copy Location/File Name: P 2.2.3 Physicochemical and Biological Properties Hard Copy Location/Pages: E-Copy Location/File Name: P 2.3 Manufacturing Process Development Discussion of the development of the manufacturing process of the drug product (e.g., optimization of the process, selection of the method of sterilization, etc.): Hard Copy Location/Pages: E-Copy Location/File Name: P 2.4 Container Closure System Discussion of the suitability of the container closure system (described in P 7) used for the storage, transportation (shipping), and use of the drug product (e.g., physicochemical tests, biological reactivity tests, leaching, etc.): Hard Copy Location/Pages: E-Copy Location/File Name: P 2.5 Microbiological Attributes Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies): Hard Copy Location/Pages: E-Copy Location/File Name:

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P 2.6 Compatibility Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, etc.): Hard Copy Location/Pages: E-Copy Location/File Name:

P 3 MANUFACTURE P 3.1 Manufacturer(s) Name, address, and activity of each manufacturer, including contractors, and each proposed production site or facility involved in manufacture and testing of product intended for Singapore: Activity Site of Fabrication, Manufacturing Site of Primary Packaging Site of Secondary Packaging Site of Release Testing Site of Batch Release P 3.2 Batch Formula List of all components of the dosage form to be used in the manufacturing process, and their amounts on a per batch basis (including overages, if any): Strength (Label claim): Batch Size (Number of dosage units): Component and Quality Standard (and Grade, if applicable) Quantity per batch Name and Address

Total

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P 3.3 Description of Manufacturing Process and Process Controls Hard Copy Location/Pages: E-Copy Location/File Name: Flow diagram of the manufacturing process(es): P 3.4 Controls of Critical Steps and Intermediates Hard Copy Location/Pages: E-Copy Location/File Name: P 3.5 Process Validation and/or Evaluation Hard Copy Location/Pages: E-Copy Location/File Name: Please check appropriate boxes. Development Pharmaceutics Report Validation Scheme ____ (e.g. 2) Pilot batches were used in the validation study ____ (e.g. 3) full production batches were used in the validation study Type of Validation Retrospective Prospective Concurrent* Others; please specify: * Prior consultation with HSA is required. Manufacturing site at which the validation is carried out: Batch Number (Batches must be Batch Size consecutive) Starting page #: Ending page#: Starting page #: Ending page#: Starting page #: Ending page#: Starting page #: Ending page#:

Batch Type (production/pilot/experimental)

Post-Approval Commitment

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(1)Validation protocol for commitment batches: Protocol Parameter Number of batches per strength Batch Size Description

P 4 CONTROL OF EXCIPIENTS P 4.1 Specifications Specifications for non-compendial excipients and for compendial excipients which include supplementary tests not required by the monograph(s) may be found in: Hard Copy Location/Pages: E-Copy Location/File Name: P 4.2 Analytical Procedures Hard Copy Location/Pages: E-Copy Location/File Name: P 4.3 Validation of Analytical Procedures Hard Copy Location/Pages: E-Copy Location/File Name: P 4.4 Justification of Specifications Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria, exclusion of certain tests, differences from compendial standard, etc.): Hard Copy Location/Pages: E-Copy Location/File Name: P 4.5 Excipients of Human or Animal Origin Hard Copy Location/Pages: E-Copy Location/File Name:

P 4.6 Novel Excipients

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Hard Copy Location/Pages: E-Copy Location/File Name:

P 5 CONTROL OF DRUG PRODUCT P 5.1 Specification(s) Standard Claimed for the Drug Product (e.g., USP, Ph.Eur, BP, JP etc.): Test Method (e.g., Source (e.g., HPLC) USP, In-house) Release Specification Shelf Life Specification

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P 5.2 Analytical Procedures P 5.3 Validation of Analytical Procedures

For each test, please indicate yes or no as appropriate Test Name Precision - Repeatability - Intermediate Precision - Reproducibility Limit of Quantitation Method Description System Suitability Limit of Detection (Please specify)

Robustness

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Selectivity

Or Others

Accuracy

Linearity

Range

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

JANUARY 2009

P 5.4 Batch Analyses Batch Type (production/pilot) Date of Production Site of Production Site of Batch Release

Batch Number

Batch Size

P 5.5 Characterisation of Impurities Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary of actual and potential degradation products, basis for setting the acceptance criteria, etc): Chemical Name/Laboratory Code Origin/Type of Impurity

P 5.6 Justification of Specification(s) Hard Copy Location/Pages: E-Copy Location/File Name: Test Justification of Specifications

P 6 REFERENCE STANDARDS OR MATERIALS If the reference standard is a secondary standard (in house /working standard), evidence that the secondary standard has been standardised against an official standard should be provided Data of studies performed on working standard against primary standard should be included, together with appropriate Certificate of Analysis. Hard Copy Location/Pages: E-Copy Location/File Name:

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JANUARY 2009

Batch Number Primary Reference Standard Working Standard P 7 CONTAINER CLOSURE SYSTEM Description of the container closure systems: Description of Container Closure

Source (e.g., USP, in-house)

Quantity Per Container

Pack Size

P 8 STABILITY P 8.1 Stability Summary and Conclusions Hard Copy Location/Pages: E-Copy Location/File Name: Proposed Commercial Batch Size (kg): Batch Number Batch Size Date of Manufacture Site of Manufacture Source of Active Ingredient and Batch Number Container Closure System

Storage Conditions (C, % RH, light)

Completed Test Intervals

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JANUARY 2009

In-use stability testing (where applicable): In-use Storage Conditions (C, % RH, light) Length of Storage prior to Start of In-use Stability Testing Completed In-use Test Intervals (e.g. minutes/ hours/ days)

Proposed storage conditions and shelf life: Container Closure System Storage Conditions (and In-use Storage Conditions, if applicable) Shelf Life (and In-use Period, if applicable)

P 8.2 Post-Approval Stability Protocol and Stability Commitment (1)Stability protocol for commitment batches: Protocol Parameter Number of batches per strength and batch sizes Tests and acceptance criteria Container closure system(s) Testing frequency Storage conditions (and tolerances) of samples Other (2)Stability protocol for continuing (i.e., ongoing) batches: Protocol Parameter Number of batches per strength per year and batch sizes Tests and acceptance criteria Container closure system(s) Description Description

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JANUARY 2009

(2)Stability protocol for continuing (i.e., ongoing) batches: Protocol Parameter Testing frequency Storage conditions (and tolerances) of samples Other P 8.3 Stability Data Hard Copy Location/Pages: E-Copy Location/File Name: P 9 PRODUCT INTERCHANGEABILITY P 9.1 Bioavailability / Bioequivalence Study Details of the batches used for BA/BE study Product Name Strength of Dosage Form Site of Manufacture Site of Batch Release Batch No. Batch size Product formula Same as section P.3.2 Yes No, please provide justification N/A N/A N/A Generic Product Submitted to HSA for Registration Current Registered Singapore Reference Product Description

Study Report Number BA/BE Study Site (Name & Address) Date of Inspection of Study Name of Inspecting Agency/Authority Availability of Inspection Report (Yes/No) Generic Product Used in BA/BE Study Product Name Strength of Dosage Form Site of Manufacture Reference Product Used in BA/BE Study

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JANUARY 2009

Study Report Number BA/BE Study Site (Name & Address) Site of Batch Release Country where the supply is sourced for this study:

P 9.2 Comparative Dissolution Profile Product 1: = Product 2: = Study Report Number: Profile of Product 1 Product Name Strength of Dosage Form Site of Manufacture Site of Batch Release Dissolution Method Used Country where the supply is sourced for this study: Dissolution Test Results Medium 1 Range Mean of 12 tablets RSD F2 Calculation Medium 2 Range Mean of 12 tablets RSD F2 Calculation Medium 3 Range Mean of 12 tablets RSD F2 Calculation Profile of Product 1 Profile of Product 2 Profile of Product 2

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JANUARY 2009

Graphical Presentation Statistical Analysis Hard Copy Location/Pages: E-Copy Location/File Name: Other Relevant Information:

Presented in Pages ..

A APPENDICES A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER) Hard Copy Location/Pages: E-Copy Location/File Name:

A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM, MANUFACTURER) Hard Copy Location/Pages: E-Copy Location/File Name:

A 3 NOVEL EXCIPIENTS Hard Copy Location/Pages: E-Copy Location/File Name:

Applicants Name:

Date:

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