Appendix 8_Singapore Quality Overall Summary for Chemical Drugs

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009 SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

APPENDIX 8 SINGAPORE QUALITY OVERALL SUMMARYNew 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 SingaporeQOS shall be submitted for review.

The applicant is responsible for completing all sections and fields as much as possible. Sections andfields that are not applicable should be indicated with NA. An explanatory note must immediatelyfollow all NA entries.

INTRODUCTION

Proprietary Name of Drug Product

INN Common Name of DrugSubstance

Product Owner Name

Licence Holder Name

Dosage Form

Strength(s)

Route of Administration

Proposed Indication(s)

Other introductory information:

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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 (withinone 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 andappropriate analytical method validation data are included in the dossier.

Drug Substance meets in-house specifications. Analytical methods and appropriateanalytical 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 #S7If 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


Structural formula (including stereochemistry): [insert structure]

Molecular formula:



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Molecular Mass:

S 1.3 General Properties


Physical description (e.g., appearance, colour, physical state):

Physical form (e.g., polymorphic form, solvate, hydrate):

Solubilities (e.g., in common solvents, aqueous/non-aqueoussolubility 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 proposedproduction site or facility involved in manufacture and testing:

Activity Name and Address *GMP Compliance (Pleaseindicate Approving Agency)

Site of Manufacture

Site of Release testing

Site of Batch Release

* For information only.

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


S 2.4 Controls of Critical Steps and Intermediates



S 2.5 Process Validation and/or Evaluation


S 2.6 Manufacturing Process Development



S 3 CHARACTERISATION

S 3.1 Elucidation of Structure and other Characteristics



S 3.2 Impurities

Summary of potential and actual impurities arising from the synthesis, manufacture and/or degradation:

ChemicalName/Laboratory Code

Origin/Type of Impurity Structure

[insert structure]



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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, in-house)

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 Metho

dDescription

S

electivity

Linearity

Range

Accuracy

Precis

ion

-

Rep

eatability

-

Intermediate

Precis

ion

-

Rep

roducibility

LimitofDetection

LimitofQuantitation

Robustness

SystemSuitability

O

rOthers

(Ple

asespecify)

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S 4.4 Batch Analyses

Batch Number Batch SizeBatch Type

(production/pilot)Date of

ProductionSite of Production

S 4.5 Justification of Specification



Test Justification of Specifications

S 5 REFERENCE STANDARDS OR MATERIALS



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

Primary Reference Standard

Working Standard

S 6 CONTAINER CLOSURE SYSTEM

Description of the container closure system(s) for the storage of the drug substance:



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S 7 STABILITY

S 7.1 Stability Summary and Conclusions

Stability study details:

StorageConditions

(C, % RH, light)

BatchNumber

Batch Size Site of Manufacture

Completed Test Intervals(months)

Summary and discussion of all stability study results:


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 Description

Number of batches and batch sizes

Tests and acceptance criteria

Container closure system(s)

Testing frequency

Storage conditions (and tolerances) of samples

Other



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S 7.3 Stability Data


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


P 2.2 Drug Product

P 2.2.1 Formulation Development



P 2.2.2 Overages



P 2.2.3 Physicochemical and Biological Properties


P 2.3 Manufacturing Process Development

Discussion of the development of the manufacturing process of the drug product (e.g., optimizationof the process, selection of the method of sterilization, etc.):



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 reactivitytests, leaching, etc.):


P 2.5 Microbiological Attributes

Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies):





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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.):


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 Name and Address

Site of Fabrication, Manufacturing

Site of Primary Packaging

Site of Secondary Packaging

Site of Release Testing


P 3.2 Batch Formula

List of all components of the dosage form to be used in the manufacturing process, and their amountson 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

Total



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P 3.3 Description of Manufacturing Process and Process Controls



Flow diagram of the manufacturing process(es):

P 3.4 Controls of Critical Steps and Intermediates


P 3.5 Process Validation and/or Evaluation



Please check appropriate boxes.

Development Pharmaceutics Report Starting page #:Ending page#:

Validation Scheme Starting page #:Ending page#:

____ (e.g. 2) Pilot batches were used in the

validation study

Starting page #:

Ending page#:

____ (e.g. 3) full production batches were used inthe validation study

Starting page #:Ending page#:

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 beconsecutive)

Batch SizeBatch Type

(production/pilot/experimental)

Post-Approval Commitment



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(1)Validation protocol for commitment batches:


Number of batches per strength

Batch Size

P 4 CONTROL OF EXCIPIENTS

P 4.1 Specifications

Specifications for non-compendial excipients and for compendial excipients which includesupplementary tests not required by the monograph(s) may be found in:


P 4.2 Analytical Procedures



P 4.3 Validation of Analytical Procedures



P 4.4 Justification of Specifications

Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptancecriteria, exclusion of certain tests, differences from compendial standard, etc.):



P 4.5 Excipients of Human or Animal Origin


P 4.6 Novel Excipients



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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.,HPLC)

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

ReleaseSpecification

Shelf LifeSpecification



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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 Metho

dDescription

S

electivity

Linearity

Range

Accuracy

Precis

ion

-

Rep

eatability

-

Intermediate

Precis

ion

-

Rep

roducibility

LimitofDetection

LimitofQuantitation

Robustness

SystemSuitability

O

rOthers

(Ple

asespecify)

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P 5.4 Batch Analyses

Batch Number Batch SizeBatch Type

(production/pilot)Date of

ProductionSite of

ProductionSite of Batch

Release

P 5.5 Characterisation of Impurities

Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary ofactual and potential degradation products, basis for setting the acceptance criteria, etc):

Chemical Name/LaboratoryCode

Origin/Type of Impurity

P 5.6 Justification of Specification(s)


Test Justification of Specifications

P 6 REFERENCE STANDARDS OR MATERIALS

If the reference standard is a secondary standard (in house /working standard), evidence that thesecondary standard has been standardised against an official standard should be provided Data ofstudies performed on working standard against primary standard should be included, together withappropriate Certificate of Analysis.




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

Primary Reference StandardWorking Standard

P 7 CONTAINER CLOSURE SYSTEM

Description of the container closure systems:

Description of Container Closure Quantity Per Container Pack Size

P 8 STABILITY

P 8.1 Stability Summary and Conclusions



Proposed Commercial Batch Size (kg):

BatchNumber

Batch Size Date of Manufacture

Site ofManufacture

Source of ActiveIngredient andBatch Number

ContainerClosureSystem

Storage Conditions (C, % RH,light)

Completed Test Intervals



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In-use stability testing (where applicable):

In-use Storage Conditions(C, % RH, light)

Length of Storage prior to Startof In-use Stability Testing

Completed In-use Test Intervals(e.g. minutes/ hours/ days)

Proposed storage conditions and shelf life:

Container ClosureSystem

Storage Conditions (and In-useStorage Conditions, if

applicable)

Shelf Life (and In-use Period, ifapplicable)

P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1)Stability protocol for commitment batches:


Number of batches per strength and batchsizes



Testing frequency


Other

(2)Stability protocol for continuing (i.e., ongoing) batches:


Number of batches per strength per year andbatch sizes





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(2)Stability protocol for continuing (i.e., ongoing) batches:


Testing frequency


Other

P 8.3 Stability Data



P 9 PRODUCT INTERCHANGEABILITY

P 9.1 Bioavailability / Bioequivalence Study

Details of the batches usedfor BA/BE study

Generic Product Submitted toHSA for Registration

Current RegisteredSingapore Reference

Product

Product Name

Strength of Dosage Form

Site of ManufactureSite of Batch Release N/A

Batch No.

Batch size N/A

Product formula Same as section P.3.2

Yes

No, please providejustification

N/A

Study Report NumberBA/BE Study Site (Name & Address)

Date of Inspection of Study

Name of Inspecting Agency/Authority

Availability of Inspection Report (Yes/No)

Generic Product Usedin BA/BE Study

Reference Product Usedin BA/BE Study

Product Name

Strength of Dosage FormSite of Manufacture



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Study Report Number

BA/BE Study Site (Name & Address)


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 Profile of Product 2

Product Name

Strength of Dosage Form

Site of Manufacture


Dissolution Method Used

Country where the supply issourced for this study:

Dissolution Test Results Profile of Product 1 Profile of Product 2

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



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Graphical Presentation Presented in Pages ..

Statistical Analysis



Other Relevant Information:

A APPENDICES

A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)



A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM, MANUFACTURER)


A 3 NOVEL EXCIPIENTS



Applicants Name: Date:

Documents

Appendix 8_Singapore Quality Overall Summary for Chemical Drugs