Guidance on Medicinal Product Registration in Singapore 2009_Main Doc Only

7/29/2019 Guidance on Medicinal Product Registration in Singapore 2009_Main Doc Only

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GUIDANCE ON MEDICINAL PRODUCTREGISTRATION IN SINGAPORE

Effective 1 January 2009

Please visit HSAs website at http://www.hsa.gov.sg for the latestupdate


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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Page 2 of 64

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TABLE OF CONTENTS

GENERAL OVERVIEW1 Foreword...........................................................................................................................7 MEDICINAL PRODUCT REGISTRATION

2 Application Types..............................................................................................................83 Dossier Types ................................................................................................................... 94 Dossier Format................................................................................................................11REGISTRATION PROCESS5 Pre-Submission Preparations .........................................................................................126 Application submission.................................................................................................... 13

6.1 PRISM Application..............................................................................................136.2 Dossier Requirements ........................................................................................31

6.2.1 NDA submissions..................................................................................316.2.2 GDA Submissions................................................................................. 34

6.3 Submission Requirements..................................................................................366.3.1 Hardcopy And Softcopy Requirements................................................. 37

6.4 Documentary Requirements...............................................................................386.4.1 Language..............................................................................................386.4.2 Administrative Documents ....................................................................406.4.3 CTD Overview and Summaries ............................................................446.4.4 Quality Documents................................................................................456.4.5 Non-clinical Documents ........................................................................486.4.6 Clinical Documents ............................................................................... 49

7 Application Screening ..................................................................................................... 498 Application Evaluation.....................................................................................................509 Regulatory Decision........................................................................................................50POST-APPROVAL PROCESS10 Post-Approval Changes..................................................................................................52

10.1 Dossier Format ...................................................................................................5310.2 Variation Application Process.............................................................................5310.3 Major Variation Applications ............................................................................... 54

10.3.1 MAV-1 Applications...............................................................................5510.3.2 MAV-2 Applications...............................................................................59

10.4 Minor Variation Applications ............................................................................... 60OTHER INFORMATION11 Data Protection and Data Exclusivity..............................................................................6212 Patent Linkage................................................................................................................ 6213 Responsibilities of the Applicant .....................................................................................6314 Fees ................................................................................................................................64


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LIST OF APPENDICES

APPENDIX 1 Target Processing Timelines

APPENDIX 2 Application Checklist (ICH CTD)

APPENDIX 3 Application Checklist (ACTD)

APPENDIX 4 Guideline on Submission for Non-Prescription Medicinal Products

APPENDIX 5 Flowchart for Translation of Non-English Documents

APPENDIX 6 Points to Consider for Singapore Labelling

APPENDIX 7 Patent Declaration Form

APPENDIX 8 Singapore Quality Overall Summary for Chemical Drugs

APPENDIX 9 Singapore Quality Overall Summary for Biologics

APPENDIX 10 Guideline on the Registration of Human Plasma-derived MedicinalProducts

APPENDIX 11 Guideline on the Registration of Human Medicinal Products ContainingMaterials of Animal Origin

APPENDIX 12 Product Interchangeability and Biowaiver Request for ChemicalGeneric Drug Applications

APPENDIX 12A Quick Reference for Acceptability of Bioequivalence Study

APPENDIX 13 MIV Filing and Submission Inquiry Form

APPENDIX 14 Guideline on Minor Variation Applications (MIV-1 & MIV-2) forChemical Drugs

APPENDIX 14A Checklist for Minor Variation Applications (MIV-1) for Chemical Drugs

APPENDIX 14B Checklist for Minor Variation Applications (MIV-2) for Chemical Drugs

APPENDIX 15 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics

APPENDIX 15A Checklist for Minor Variation Applications (MIV-1) for Biologics

APPENDIX 15B Checklist for Minor Variation Applications (MIV-2) for Biologics


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ABBREVIATIONS AND ACRONYMS

ACRA Accounting and Corporate Regulatory AuthorityACTD ASEAN Common Technical DocumentACTR ASEAN Common Technical RequirementsADEC Australian Drug Evaluation Committee

ASEAN Association of Southeast Asian NationsATC Anatomical Therapeutic ChemicalBA BioavailabilityBAN British Approved NameBE BioequivalenceBP British PharmacopoeiaBSE Bovine Spongiform EncephalopathyBWP Blood Working PartyCAS Chemical Abstracts ServiceCEP Certificate of Suitability (Ph Eur monograph)CHMP Committee for Medicinal Products for Human Use (formerly Committee

for Proprietary Medicinal Products) (EU)

CJD Creutzfeldt-Jakob DiseaseCMC Chemistry, Manufacturing and ControlsCMI Consumer Medicine InformationCMS Concerned Member StateCOO Country of Origin (Finished product manufacturer)CPP Certificate of Pharmaceutical ProductCPMP Committee for Proprietary Medicinal ProductsCTD Common Technical DocumentCVMP Committee for Medicinal Products for Veterinary UseCWD Chronic Wasting DiseaseDMF Drug Master File

EDQM European Directorate for the Quality of MedicinesEMEA European Medicines Agency (formally the European Agency for theEvaluation of Medicinal Products) (EU)

F2 Similarity factorFDA Food and Drug Administration (US)FTA Free Trade AgreementGDA Generic Drug ApplicationGSL General Sale List medicineGMP Good Manufacturing PracticeHBV Hepatitis B VirusHCV Hepatitis C VirusHIV Human Immunodeficiency Virus

HPLC High Performance Liquid ChromatographyHPRG Health Products Regulation GroupHSA Health Sciences Authority (Singapore)ICH International Conference on Harmonisation (of Technical

Requirements for Registration of Pharmaceuticals for Human use)INN International Non-proprietary NamesJP Japanese PharmacopoeiaMAV Major VariationMHRA Medicines and Healthcare Products Regulatory Agency (UK)MIV Minor VariationMQA Manufacturing and Quality AuditNAT Nucleic Acid Test

NDA New Drug ApplicationNfG Note for GuidanceOIE Office International des Episooties


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OTC Over-The-CounterP Pharmacy only medicinePD PharmacodynamicsPDF Portable document formatPh Eur European PharmacopoeiaPI Package Insert (Singapore), Product Information

PIC/S Pharmaceutical Inspection Convention and Pharmaceutical InspectionCo-operation Scheme

PIL Patient Information LeafletPK PharmacokineticsPMF Plasma Master FilePOM Prescription Only MedicinePRISM Pharmaceutical Regulatory and Information SystemQOS Quality Overall SummaryRH Relative HumidityRMS Reference Member StateRNA Ribonucleic AcidRSD Relative Standard Deviation

SMF Site Master FileSmPC Summary of Product CharacteristicsSOP Standard Operating ProcedureSQOS Singapore Quality Overall SummaryTGA Therapeutic Goods Administration (Australia)TRIPS Trade-Related Aspects of Intellectual Property RightsTSE Transmissible Spongiform EncephalopathyUK United KingdomURL Uniform Resource LocationUS United StatesUSA United States of AmericaUSAN United States Adopted Name

USP United States PharmacopeiavCJD Variant Creutzfeldt-Jakob DiseaseWHO World Health OrganisationWTO World Trade Organisation


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GENERAL OVERVIEW

1 FOREWORD

This guidance document is intended to provide assistance in the submission ofapplications relating to medicinal products in Singapore, including applications for a new

Product Licence for a medicinal product (i.e. drug registration) and applications to makevariations to an existing Product Licence.

This document should be read in conjunction with the current laws governingpharmaceutical products in Singapore, which includes the following:

Medicines Act (Chapter 176) Poisons Act (Chapter 234) Misuse of Drugs Regulations subsidiary legislation under the Misuse of Drugs

Act (Chapter 185) Sale of Drugs Act (Chapter 282) Medicines (Advertisement and Sale) Act (Chapter 177)

If there is any contradiction between this document and any written law, the latter shalltake precedence.

As the licensing authority under the Medicines Act, the Chief Executive of the HealthSciences Authority (HSA) and the officers in HSAs Health Products Regulation Group(HPRG) have the authority to grant, renew, vary, suspend and revoke licences andcertificates under the Medicines Act. Applicants are strongly encouraged to familiarisethemselves with the contents of this guidance document before submitting theirapplications.

1.1 Scope of this guidance document

This guidance document describes the procedures and requirements for submitting anapplication to obtain a new Product Licence or to make variations to an existingregistered medicinal product.

Applicants are expected to comply with the procedures and requirements laid out in thisguidance. However, alternative approaches to the specified procedures and requirementsmay be accepted, provided there is adequate scientific evidence and justification. Anyalternative approach should be discussed with HSA and agreed upon in advance in orderto avoid rejection of the application. Conversely, HSA may request for information orspecify conditions not described in this document but is deemed necessary to adequately

assess the safety, efficacy and quality of the product under evaluation.

Take note that, within this document, the term quality may be used to describe chemical,pharmaceutical and biological data while the term non-clinical may be used to describepreclinical, pharmacological and toxicological data.

Applicants are advised to check HSAs website1 for the latest version of this guidancedocument and other related medicinal product registration guidelines.

1http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html


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MEDICINAL PRODUCT REGISTRATION

Under the Medicines Act, a medicinal product refers to any substance or article (notbeing an instrument, apparatus or appliance) which is manufactured, sold, supplied,imported or exported for use wholly or mainly in the following ways:

use by being administered to one or more human beings for a medicinal purpose;

and/or, use as an ingredient in the preparation of a substance or article which is to be

administered to one or more human beings for a medicinal purpose.

A medicinal purpose means any one or more of the following purposes: treating or preventing disease; diagnosing disease or ascertaining the existence, degree or extent of a

physiological condition; contraception; inducing anaesthesia; and/or, otherwise preventing or interfering with the normal operation of a physiological

function, whether permanently or temporarily, and whether by way of terminating,

reducing or postponing, or increasing or accelerating, the operation of thatfunction or in any other way.

Unless otherwise exempted under the law, a Product Licence is required before amedicinal product can be sold or supplied in Singapore (Medicines Act, section 5). EachProduct Licence is specific to a product:

of a particular name; with a particular formulation; in a particular dosage form (i.e. physical presentation) and strength; and with a particular set of approved indications and directions for use.

Any changes to the above parameters may result in the need to submit an application tovary the existing Product Licence or possibly obtain a new Product Licence altogether.

2 APPLICATION TYPES

In applying for a new Product Licence for a medicinal product in Singapore, there are twotypes of applications: a new drug application (NDA) and a generic drug application(GDA):

NDA New Drug Application for an innovator productNDA-1 : For the first strength of an innovator product containing a new

chemicalentity or a biological entity.

NDA-2 : For the first strength of an innovator product containing a new* combination of registered chemical/biological

entities; containing registered chemical/biological entity(ies) in a new dosage

form; containing registered chemical/biological entity(ies) for use by a

different route of administration and marketed under a different productname; or,

containing registered chemical/biological entity(ies) for newindication(s), dosage recommendation(s) and/or patient population(s)and marketed under a different product name.

has not been registered for medicinal use in Singapore


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NDA-3 : For subsequent strength(s) of an innovator product that has beenregistered or has been submitted as an NDA-1 or NDA-2. The productname and pharmaceutical dosage form shall be the same as that for theNDA-1 or NDA-2.

GDA Generic Drug Application for a product that is essentially similar to a currently

registered product in Singapore (not applicable to biologics).GDA-1 : For the first strength of a generic product.GDA-2 : For subsequent strength(s) of the generic product that has been

registered or has been submitted as a GDA-1. The product name andpharmaceutical dosage form shall be the same as that for the GDA-1.

A schematic diagram to illustrate the various types of applications is seen in Figure 1below:

Figure 1. Schematic diagram of application routes for drug registration.

3 DOSSIER TYPES

There are three types of evaluation dossiers for a new drug application. Figure 2 below isa schematic diagram to illustrate the various types of evaluation dossiers:

Figure 2. Schematic diagram of evaluation dossiers for drug registration.

IS PRODUCTREGISTERED?

Post-ApprovalProcess section

First strength ofproduct?

Essentially similarto a currentlyregistered product?

NDA 1Contains new chemical/biological entity?

NO

YESYES

NO

NDA 2NDA 3

GDA 1

GDA 2

NO

NOYES

YES

Approved by atleast two of HSAsreferenceagencies?

NDA 1 Is productregistered withany competentagency?

NO

NDA 2NDA 3

FULL DOSSIER

ABRIDGEDDOSSIER

YES

NO

YES

VERIFICATIONDOSSIER


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3.1 Full Dossier

The full dossier evaluation route applies to a drug product that has not been approved byany competent drug regulatory agency at the time of submission for registration to HSA.This route applies to an innovator product containing a new chemical/biological entity,new combination of chemical/biological entities or an innovative use of a registered

product.

3.2 Abridged Dossier

The abridged evaluation route applies to a drug product that has been evaluated andapproved by at least one competent drug regulatory agency.

3.3 Verification Dossier

The verification evaluation route applies to a medicinal product that has been evaluatedand approved by at least two of the following HSAs reference drug regulatory agencies:

Australia Therapeutic Goods Administration (TGA); Health Canada (HC); US Food and Drug Administration (FDA); the European Medicines Agency (EMEA)*; or UK Medicines and Healthcare Products Regulatory Agency (MHRA)#.

* For products approved via the Centralised Procedure.# For products approved by UK MHRA through the national procedure or where the UK MHRA acted as the

Reference Member State (RMS) for the Decentralised and Mutual Recognition Procedures in Europe.

However, approval by these reference regulatory agencies does not obligate HSA toapprove the application.

A verification dossier must be submitted within 3 years from the date of approval by thechosen primary reference agency. The primary reference agency is defined as thereference agency for which the qualifying supporting documents, as outlined in thisguidance, will be submitted by the applicant.

The approved indication(s), dosing regimen(s), patient group(s), and/or direction(s) foruse must be similar across the reference regulatory agencies. If there are apparentdifferences, the application will be re-routed to the abridged route. HSA reserves the rightto accept only the most stringent indication(s), dosing regimen(s), patient group(s) and/ordirection(s) of use amongst those approved by the reference regulatory agencies.

Furthermore, all aspects of the drug products quality must be identical as that currentlyapproved by the chosen primary reference regulatory agency that has evaluated andapproved the product. This includes, but is not limited to, the formulation, site(s) ofmanufacture, release and shelf life specifications, primary packaging and the PI/PIL.

HSA will not accept a verification dossier if the application falls within one of thecategories listed below:

The product is a biologics; The product and its intended use including indication(s), dosing regimen(s) and

patient group(s) have been rejected, the application withdrawn from, approved viaappeal process or pending deferral by a competent drug regulatory agency forsafety and/or efficacy reasons;


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The product needs a more stringent assessment as a result of differences in localdisease patterns and/or medical practices (e.g. blood products, vaccines andsome anti-infectives).

For a product with a proposed indication that has been designated as an orphan drug byat least one reference agency, or a product that has been approved by at least one

reference agency via accelerated/fast-track approval, approval under exceptionalcircumstances, or equivalent approval process, the applicant should consult HSA on theeligibility of such a product through the verification route prior to submission.

4 DOSSIER FORMAT

Applications shall be submitted to HSA using the Common Technical Document (CTD)format. The CTD provides a common format for the preparation of a well-structuredsubmission dossier. It uses a modular framework described in ICH Topic M42 or theASEAN guidances on the Common Technical Document for Registration ofPharmaceuticals for Human use: Organisation of the Dossier3. This guidance documentshould be read in conjunction with the most recent version of the ICH CTD and the

ASEAN CTD (ACTD) guidance documents.

Thus, submission will be in one of the two formats, either the ICH CTD or the ACTDformat. According to the chosen format, in each application, the documents will begrouped into five Modules (ICH CTD) or four Parts (ACTD); the main differences betweenthese two formats are the numbering and naming of the sections, as seen in Table 1below:

Documents Location in

ICH CTD ACTD

Administrative Documents and

Product Information

Module 1 Part 1

Common Technical DocumentOverview and Summaries

Module 2 Incorporated in Parts 2, 3 and 4

Quality documents

Module 3 Part 2

Non-clinical documents

Module 4 Part 3

Clinical documents Module 5 Part 4

Table 1. Format of the ICH CTD and ACTD.

The CTD format cannot be changed once the application is approved. Any subsequentvariation applications for the product would need to follow the same format.

2http://www.ich.org/

3http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html

NOTE: It is important to note that the implementation and use of the CTD

represents a work in progress. It is expected that future refinements to thisguidance document will continue to be necessary as a result of experiencegained.


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REGISTRATION PROCESS

One part of a Product Life Cycle is the pre-marketing activities, namely registration of aproduct prior to market entry. The registration process involves a series of steps as canbe seen in Figure 3 below:

Figure 3. Registration Process for a Medicinal Product

5 PRE-SUBMISSION PREPARATIONS

This first step in the registration process is one of the most important because it involvescompiling all of the necessary documents into a CTD format for submission to HSA.However, if questions arise or clarification is needed during the preparations, theapplicant is encouraged to contact HSA via one of two methods:

1. Pre-Submission Inquiry via e-mail2. Pre-Submission Consultation

PRE-SUBMISSIONPREPARATIONS

APPLICATIONSUBMISSION

APPLICATIONSCREENING

APPLICATIONEVALUATION

REGULATORYDECISION

POST-APPROVALCHANGES

NON-ACCEPTANCE /WITHDRAWAL

ACCEPTANCE


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5.1 Pre-Submission Inquiry

The applicant may submit a Pre-Submission Inquiry via e-mail if any clarification isneeded prior to submission. The e-mail address is:[email protected]. The subject of the e-mail should state, Pre-submission inquiry, in order for the e-mail to be sent to the relevant officer.

Once the inquiry has been received, an officer will look into the matter and a response willbe sent back to the applicant.

5.2 Pre-Submission Consultation

For larger or complex issues relating to an impending submission, applicants are advisedto consult with HSA in a pre-submission consultation. The request for a consultationshould be made in writing, with the purpose and agenda for the consult stated, via emailto [email protected].

For a full dossier submission, the applicant is required to notify HSA two months prior to

the intended submission date of the application dossier.

Advice given by HSA will be based on knowledge that is current at the time of theconsultation. However, such advice is not binding and does not have direct bearing onthe eventual outcome of the application concerned.

6 APPLICATION SUBMISSION

There are two parts in submitting an application for product registration: through on-linePRISM and CTD dossier submission.

6.1 PRISM Application

HSA only accepts applications on-line via PRISM (Pharmaceutical Regulatory andInformation System). Applicants are advised to visit the prism@hsa4 webpage for furtherdetails on PRISM.

A separate product licence, and therefore a separate application form, would be requiredfor each pharmaceutical dosage form and strength of the medicinal product. Separateapplication forms are also required for the following:

Powder for injections containing different amounts of drug substance percontainer;

Concentrates for reconstitution labelled with the actual amount of drug substance

before reconstitution; and, Pre-filled syringes.

Examples are listed in the table on the next page:

4http://www.hsa.gov.sg/publish/hsaportal/en/services/prism.html


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Examples Labelled strengthbefore reconstitution

Appl ication type

25mg/vial1 Powder forInjection 50mg/vial

Submit as 2 separate applications:One as NDA-1/GDA-1 and the other as NDA-3/GDA-2

2mg/ml in a vial2 Solution for

Injection 2mg/ml pre-filled syringe

Submit as 2 separate applications:

One as NDA-1/GDA-1 and the other as NDA-2/GDA-110mg/5ml3 Concentrate

20mg/10ml


4 Concentrate 2mg/ml: presented in5ml vial and 10ml vial

Submit as a single application with two pack sizes(i.e., 5ml and 10ml)

100 iu/ml5 Pre-filledsyringe 400 iu/4 ml


6.1.1 PRISM section 1 Company Particu lars

Each application for a Product Licence is company-specific. The company named in this

section must be based and registered in Singapore. The company must be authorised bya responsible person in the company or organisation that owns the medicinal productbefore it can apply for a Product Licence for a specific medicinal product in Singapore.

In this section, input the company telephone and fax numbers; the name, address andBusiness Registration number will be automatically entered. If there is a direct telephoneand/or fax number, input it into this section to ensure no communication delays betweenHSA and the applicant.

The company bears full responsibility for ensuring that all available and relevantinformation is submitted in support of an application. For every successful application forregistration of a medicinal product granted approval, a Product Licence will be issued in

the name of the company, which will be the product licence holder.

6.1.2 PRISM section 2 Applicant Particulars

The person named in this section should be a permanent staff of the company andresiding in Singapore. If the applicant is an external party engaged by the applicantcompany to submit the application on their behalf (i.e. consultant), an original letter ofauthorisation from the applicant company must be submitted (see section 6.5.2Administrative Documents Authorisation Letters).

In this section, input the particulars of the named person name, NRIC/FIN and

designation. For PRISM sections 2.4 and 2.5, the company address and contact details(as in PRISM section 1) may be entered as an alternative, as seen in the example on thenext page:


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Care should be taken to ensure that the contact details are entered correctly to ensure nocommunication delays between HSA and the applicant. Applicants are advised toimmediately notify HSA if there is any change to this PRISM section, especially to thecontact details.

From this point on, any mention of the word applicant in this guidance document willrefer to the person named within this PRISM section.

6.1.3 PRISM section 3 Application Details

In this PRISM section, enter specific details of the application, such as the applicationtype, dossier type, format type and any reference product(s), if applicable. Below is anexample of PRISM section 3:

Company address

may be entered

Direct telephone andfax numbers incompany may beentered


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Type of Application (section 3.1)

Input the type of application to be submitted to HSA.

If the type of application is entered incorrectly, and it needs to be changed within the same application type (e.g. from NDA-2 to NDA-3), HSA will send an

Input Request to allow the amendment; or, to a different application type (e.g. NDA-1 to GDA-1), then the original PRISM

application must be withdrawn first before re-submission under the correctapplication type.

HSA reserves the right to re-categorise the application type when appropriate.

Type of Product (section 3.2)

Input either Chemical Drug for chemical drug products or Biological Drug for biologicdrug products. Please note that once the product type is set, it cannot be changed.

A biological medicinal product (a biologic) refers to products derived from biologicalsystems, which include:

Whole cells or organisms, e.g. whole virus/bacterium used as a vaccine; Part of organisms, e.g. sub-unit vaccines, blood/serum-derived products; Macromolecules extracted from or produced by organisms, e.g. proteins, nucleic

acids, proteoglycans, cytokines and growth factors; and, Biotechnology products, e.g. recombinant hormones, enzymes, antibodies, DNA

vaccines;but does not include:

Metabolites from micro-organisms, e.g. antibiotics; and, Macromolecules produced by chemical synthesis, e.g. peptides/oligo-nucleotides

produced by chemical synthesisers.

Applicants are advised to contact HSA, via Pre-Submission Inquiry or consultation, asstated in section 5.1 of this document, when in doubt on whether the drug product isconsidered a chemical or biologic drug.

Reference Product (section 3.3)

This section refers only to GDA-1, GDA-2 or NDA-3 applications.

For all GDA applications, applicants need to specify the Singapore Reference ProductsSIN number, which can be obtained by searching HSAs online database5. If a GDA-2

application is not submitted at the same time as a GDA-1 application, applicants arerequired to specify both the Singapore Reference Products and the GDA-1 products SINnumbers. If an NDA-3 application is not submitted at the same time as an NDA-1 or NDA-2 application, then, the Singapore-registered NDA-1 or NDA-2 products SIN numbershould be inputted.

Type of Dossier (section 3.5)

Only one option can be selected from the drop-down menu full, abridged or verification.

HSA reserves the right to re-categorise the dossier type when appropriate. The applicantwill be informed if re-categorisation is necessary.

5http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load


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Type of Format (section 3.6)

Indicate whether the dossier format is ICH CTD or ACTD. Once the format type has beenset in PRISM, it cannot be changed.

Applicants are expected to organise the documents into the respective CTD sections

before submitting the dossier to HSA. Explanatory notes on the documents required canbe found in section 6.5 Documentary Requirements of this guidance.

6.1.4 PRISM section 4 Product Information

Product Name (section 4.1)

The Product Name is the products trade name that is shown on the product labelling i.e. inner label, outer carton, package insert (PI) and/or patient information leaflet (PIL).

Applicants should ensure that the medicinal product name: does not suggest greater safety or efficacy than that supported by clinical data; does not imply superiority over another similar product in Singapore; does not imply the presence of substance(s) not present in the product; and shall not be confused with another product.

If the proposed product name is not acceptable, the applicant will be informed of thereasons at the screening stage, and will be asked to amend it.

For this PRISM section, the Product Name should be entered in the following format:

Product NamePharmaceuticalDosage Form

Product Strength Product Standard(optional)

Applicants are advised to use the same format for the product labelling and PI/PIL.However, in the PI, the International Non-proprietary Name (INN) or common name of theactive substance(s) may be used when referring to the active ingredient(s)s properties.

The product strength represents the amount of the active substance in thepharmaceutical dosage form, which is stated as per unit dose or concentration.Concentration can be stated as a unit of mass (e.g. mg/g), a unit of volume (e.g. mg/mL)or as a percentage (e.g. %w/v or %w/w).

For specific pharmaceutical dosage forms, there are additional points to take note of asseen in the table on the next page:

ABC Injection 5mg/ml USP

Medicinal Product Name


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Product Format Example

Fixed-combination Strength of each activeingredient separated by a /

Multi-Tab Tablet100mg/25mg

Single-dose preparation,total use

State the amount of activeingredient per unit dose

Ingredient 300mg per vial

Multi-dose preparation State the concentration per mL, per puff, per drop,per kg, per m2, etc.

Powder for reconstitution,oral

State the concentration afterreconstitution

Antibiotic 200mg/5mL

Powder for reconstitution,injection or infusion

State the amount of activeingredient before reconstitutionor dilution

Ingredient 300mg per vial

Transdermal patches State the amount of activeingredient released in 24 hours

Trans-Patch 24mg/24 hrs

Product Formula (section 4.2)

The Product Formula is a list of all of the active substance(s) and excipients (includingwater) that are present in the final pharmaceutical dosage form.

The name for each ingredient should be listed by its INN. Proper or commercial namesfor ingredients such as printing inks or colourants are permissible but internal

abbreviations, acronyms or codes for any ingredient are not acceptable. Ingredientsrelated to the pharmaceutical dosage form, such as tablet film coating or capsule shell,should be indicated within parentheses before the ingredient name see the next pagefor an example:


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The grade for each ingredient should be specified e.g. BP, USP, Ph. Eur., JP or in-house.

Quantities of each active substance and excipient must be expressed in internationalunits of measure, wherever appropriate. If an active substance is present in the form of a

salt, the quantity should be clearly stated in the following format:

XX phosphate (active substance salt) 32mg eqv XX.

Information on residual amounts of certain materials, such as antibiotics, thiomersal andmaterials of biological origin (e.g. human serum albumin), added or present in the drugproduct must be declared. Information to declare includes the following:

the materials name enter (Residual), followed by the materials name in the

Name of Substance field; the materials grade, if applicable; the materials limit in the product enter , followed by the limit in the Strength

field.

An example is shown in the screenshot on the next page:

Film coating ingredient

Printing ink

Enter the strength ofthe active substancebase here.


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Ingredients Derived From Human Blood/Animal Sources (section 4.3)

A screenshot of PRISM section 4.3 is seen below:

Ingredients Derived From Human Blood (4.3(a))

Human plasma-derived products used as an active substance, as an excipient or withinthe manufacturing process, must be declared in this PRISM section.

If the answer is Yes, the following information must be inserted as per the format below: the source product the ingredient is derived from i.e. the species and nature of

the product; its role in the drug product i.e. as an active substance, excipient or within the

manufacturing process; and, the country of the source product.

A screenshot of PRISM section 4.3(a) is given on the next page:

This strength willactually be entered here


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If constrained by PRISMs text limit, reference to a document uploaded into PRISMsection 7 is permissible e.g. Yes see file xyz.doc attached in PRISM.

Ingredients Derived From Animals (4.3(b))

Animal-derived materials used either as an excipient or within the manufacturing processmust be declared in this PRSIM section.

If the answer is Yes, the following information must be inserted as per the format below: the source product and species the ingredient is derived from; its role in the drug product (i.e. excipient or within the manufacturing process);

and, the country of the source product.

If constrained by PRISMs text limit, reference to a document uploaded into PRISMsection 7 is permissible e.g. Yes see file xyz.doc attached in PRISM.

Pharmacotherapeutic Group (section 4.4)

Indicate the WHO Anatomical Therapeutic Chemical (ATC) code for each distincttherapeutic indication proposed for a product, if available. Applicants may refer to theWHO Collaborating Centre for Drug Statistics Methodology6 for the ATC Code and moreinformation.

6http://www.whocc.no/

NOTE: additional information is required when human plasma-derived products are used.Refer to Appendix 10 for details on the data requirements for submission.

NOTE: refer to Appendix 11 for details on the data requirements for submission.


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Dosage Form (section 4.5)


The dosage form is the pharmaceutical dosage form of the drug product, e.g. tablet,

injection and cream. The dosage form should be as specific as possible because eachform is considered distinct e.g. effervescent powder, powder for reconstitution,modified-release tablet and gastro-resistant capsule. In certain cases, the dosage formmay also include information about the container closure system e.g. pre-filled syringe,spray pump and pressurised container.

Route of Administration (section 4.6)

A screenshot of PRISM section 4.6 is given below:

Include all routes of administration proposed for the product.

Choose from the droplistand Save before addinganother option


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Packaging, Shelf Life and Storage Conditions (section 4.7)


Container Closure System (CCS) (section 4.7.1) refers to the container immediatelyenclosing the dosage form. Information should be specific, including the type ofmaterial(s) used, colour, size, etc. For example, 1mL Type I amber glass vial andPVC/PVdC blister with Alu foil.

Quantity per CCS (section 4.7.2) refers to the quantity/amount of the dosage form percontainer closure system. For example, 10 tablets/blister, 5ml/vial and 15g/tube maybe entered.

CCS per Pack Size (section 4.7.5) refers to the number of container closure systems ineach commercial pack of the product. For example, for a commercial box of 50 tablets

packed as 5 blister strips of 10 tablets in each strip, the pack size should be 5.

Shelf Life (section 4.7.3) refers to the proposed shelf life of the drug product, whichshould be supported by stability data. If there is more than one component in a drugproduct (e.g. powder for injection and diluent as a composite pack) and each componenthas a different shelf life, the shorter shelf life is to be used as the shelf life of thecomposite pack. HSA reserves the right to amend the proposed shelf life after review ofthe stability data submitted in the dossier.

Storage Condition (section 4.7.4) refers to the proposed storage condition of the drugproduct for example, store below 25C, do not freeze, keep away from light, etc whichshould be supported by stability data. HSA reserves the right to amend the proposed

storage condition after review of the stability data submitted in the dossier.

An example is shown on the next page:


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Furthermore, information on shelf life after the first opening of the product (e.g. eye drops)and shelf life after reconstitution (e.g. lyophilised powder for reconstitution) should beprovided and supported by stability data. The information should be inserted in PRISM

sections 4.7.6 and 4.7.7, respectively:

Forensic Classification (section 4.8)

State the forensic classification proposed for the drug product in Singapore.

Medicinal products approved for registration in Singapore are classified under threeforensic classes:

Prescription Only Medicine (POM); Pharmacy only medicine (P); or General Sale List medicine (GSL).

POM control is required in the following situations:a) The product poses a direct7 or indirect8 danger to human health, even when used

correctly, if used without medical supervision;b) The product is frequently and widely used incorrectly, and as a result is likely topresent a direct or indirect danger to human health;

c) The product requires further investigation into its activity and/or side effects; or,d) The product is normally prescribed by a doctor or dentist to be administered

parenterally.

7

Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or ofhigh frequency8

Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heartdisease


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The following also needs to be taken into consideration when deciding whether a productshould be classified as a POM:i. Whether the product contains a substance which is listed in either the Narcotic Drug

Convention or the Psychotropic Substances Convention;ii. Whether the product is likely, if incorrectly used to present medicinal abuse, lead to

addiction or used for illegal purposes;

iii. Whether the product contains a substance which by reason of its novelty or propertieshas the potential to fall within point (ii) above;

iv. Whether the product, by reason of its pharmaceutical characteristics, is reserved fortreatments which can only be instituted in a hospital;

v. Whether the product is used in the treatment of conditions which must be diagnosedin a hospital or in an institution with special diagnostic facilities; or,

vi. Whether the product is intended for outpatients but may produce serious side effects,which would require medical supervision throughout the treatment.

P control is required for products that possess characteristics which are not sufficientlycritical to warrant POM control but for which the following apply:a) Consultation with a pharmacist is necessary to confirm the appropriate choice of

therapy;b) The contraindications, drug interactions, precautions or warnings need reinforcement

by a pharmacist or are not easily recognised by the purchaser; or,c) Special precaution is needed in the storage and handling of the product.

GSL control is sufficient in the following situations:a) The product is reasonably safe and can be sold or supplied without the need for

supervision by a registered doctor, dentist or pharmacist;b) The contraindications, drug interactions, precautions and warnings are easily

recognised by the consumer; and,c) The hazard to health, the risk of misuse, the risk of misdiagnosis, or the need to take

special precaution in the storage and handling the product is small.

HSA reserves the right to approve the product under a different forensic classification, asdeemed appropriate.

Registration Status in Other Countries (section 4.9)

Applicants are required to provide information on the registration status of the applicationin other countries at the time of submission. A screenshot of PRISM section 4.9 is givenon the next page:


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For each country, the applicant must state the application status and status date. For thecountry of origin and all reference agencies, the applicant must state the applicationstatus, status date, application details and forensic classification. This is described inTable 2 below.

Country Application Status Status Date Application Details

APPROVAL State the approvaldate

REJECTION orWITHDRAWAL

State the date ofrejection/withdrawal

State the reason(s)

For all countries

DEFERRAL

e.g. non-approvable,

approvable, conditionalapproval, conditionalmarketingauthorization, etc.

State the date ofdeferment

State the reason(s)

APPROVAL State the approvaldate

State the approvedindication(s) and dosingregimen(s)

PENDINGEVALUATION

State thesubmission date

State the expected regulatorydecision date, if applicable

For all referenceagencies andcountry of origin(if applicable)

PENDINGSUBMISSION

- State the expected submissiondate

Table 2. Registration Status of Drug Product in Other Countries.

For products approved via an appeal process, following either a negativeopinion/rejection/non-approvable decision or an approvable/conditional approvabledecision, the applicant must provide reasons for the initial regulatory decision along withthe subsequent approval.

The screenshot on the next page is an example of an entry into PRISM section 4.9:


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For applications submitted to the European Union agencies, applicants should identify thetype of application i.e. centralised, decentralised, mutual recognition or national. Fordecentralised and mutual recognition applications, the reference member state should beindicated.

For products approved by the UK MHRA, applicants are required to indicate whetherapproval was granted through the national procedure or whether the MHRA acted asReference Member State (RMS) or as Concerned Member State (CMS) for theDecentralised and Mutual Recognition Procedures in Europe.

The applicant is required to update HSA on the registration status of any pendingapplications in other countries while pending evaluation by HSA. The applicant shallinform HSA of any rejection, withdrawal or deferral of any application and provide detailsof the reason(s) once it becomes known.

In the event that the PRISM text space does not allow input of full details of theindication(s), dosing regimen(s), and/or reason(s), a brief description may be entered.The full details should be attached in softcopy (PDF) in PRISM section 7 (SupportingAttachments) and in hardcopy in section 1.16 of the CTD Module 1/Part 1. The documentshould be in the format as seen in Table 3 on the next page:


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Country Applicationstatus

Status Date Approved applicationindication/dosing regimen details*

Approvedforensic

classification

Country 1 Approved 12 Jan 2005 Adjuvant treatment of colorectal cancerstage III (Dukes C) following completeresection of primary tumour.

POM

Country 2 Approved 2 Feb 2006 Adjuvant treatment of colorectal cancerfollowing surgery POM

Country 3 Withdrawnby applicant

14 April 2002 Indication submitted Adjuvanttreatment of colorectal cancer.Withdrawn due to insufficient long-termefficacy data (only phase II datasubmitted).

Re-submitted on 16 June 2005 withcompleted phase III data for Adjuvanttreatment of colorectal cancer followingsurgery.

POM

Country 4 Approved 21 Nov 2004 Adjuvant treatment of colorectal cancerstage III (Dukes C) following complete

removal of primary tumour.

Notice of Compliance with Conditionsissued on 16 April 2003 based onpromising efficacy results withcondition to furnish confirmatoryefficacy data.

POM

Country 5 Pending Submitted:

15 Jun 2005

Adjuvant treatment of colorectal cancerstage III (Dukes C) following surgery.

POM

* Applicable to information on reference agencies, Country of Origin, and all rejections/withdrawals/deferrals Applicable to information on reference agencies and Country of Origin.

Table 3. Format for Submission of the Registration Status in Other Countries.

Product Owner Information (section 4.10)

Input the full name and address of the legally registered owner of the product formulation,i.e. the drug product. An example is given below:


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6.1.5 PRISM section 5 Manufacturer Particulars

Enter information on the various manufacturers involved in all aspects of producing thefinal drug product. Information to be entered include:

Manufacturer type involved either in Active Substance or Finished Productmanufacture;

Manufacturers name;

Manufacturing operation involved in bulk production, packing, labelling or anycombination of the three; and,

Manufacturers address input both the manufacturing site and office (i.e.headquarters) address.

For example,

Multiple entries of manufacturers are possible as manufacturers of active substance(s),drug product and diluent used to reconstitute the product (if packed and sold togetherwith the drug product) must be declared. Primary/secondary packaging sites must also bedeclared but for secondary packagers, enter (Secondary packager) after the name of themanufacturer.

Note that all manufacturers names and addresses should be consistent throughout all ofthe documents submitted in the application, such as GMP certificates, CPPs, Letters of

Authorisation, Module 3/Part II of the CTD and so forth.

6.1.6 PRISM section 6 Batch Release details

Enter the name, site/plant address and office address of the company responsible forbatch release of the drug product in the exporting country:

The screenshot on the next page is an example of an entry into PRISM section 6:


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If there are multiple companies responsible for batch release, the applicant must declare

all of the sites.

6.1.7 PRISM section 7 Suppor ting Attachments

Before completion of the on-line application, applicants must attach all documents relatingto Module 1/Part I of the CTD into this PRISM section. For the remaining Modules/Parts,applicants can opt to either attach the documents in full into this PRISM section orsubmitsoft copies of the documents in a CD.

A screenshot example is given on the next page:


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Here are some additional points to note: Use Portable Document Format (PDF) whenever possible; Do not combine documents if the content is unrelated for example, do not

submit a GMP certificate with Letters of Authorisation as a single PDF; Ensure that the documents are appropriately named for easier recognition to

facilitate screening more detail in the file name will enhance recognition of itscontents;

During scanning of documents, applicants are advised not to break seals ofauthenticated documents as this will render them invalid.

6.2 DOSSIER REQUIREMENTS

The submission of the complete dossier should take place within 2 working days afterthePRISM application submission to prevent delays in processing of the application. Thedate of submission will be defined as the date when HSA receives the completedataset for the application.

The dossier requirements for each application will differ, depending on the type ofapplication and type of dossier. It is advisable that the applicant familiarise him/her-selfwith the requirements prior to submitting an application. The Application Checklist inAppendix 2 or 3 of this guidance will serve as a guide to the necessary documents

required for submission.

6.2.1 NDA submissions

For an NDA, there are different dossier requirements for each of the three evaluationroutes. The dossier type and data requirements are as follows:

6.2.1.1 Full dossier

Full information on chemical/biological development, pharmaceutical/geneticdevelopment, toxicological, pharmacological and clinical data needs to be submitted insupport of the application.

The technical documents required include:


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complete Chemistry, Manufacturing and Controls (CMC) or quality documents forboth drug substance and drug product;

complete pharmaco-toxicological or non-clinical documents; and, complete clinical documents; i.e. all study reports from phase I to phase III,

including tables and appendices.

6.2.1.2 Abridged dossier

For the abridged route, all aspects of the products quality and direction(s) for use(including dosing regimen(s), indication(s) and patient group(s)) should be the same asthat approved by the competent drug regulatory agency that issued the proof of approval.

The technical documents required include: complete quality documents for both drug substance and drug product; a non-clinical overview; and, a clinical overview, summaries of clinical efficacy and clinical safety, synopses of

relevant studies, a tabular listing of the clinical development programme and studyreports of the pivotal studies (the tables and appendices to the pivotal study

reports may be submitted upon request by HSA).

If the abridged NDA is for a non-prescription medicine, the applicant may submit a writtenrequest for a waiver of clinical data submission. Eligibility for waiver is subject to thecriteria defined in Appendix 4 Guideline on Submission Requirements for Non-Prescription Medicines. However, HSA still reserves the right to request for the completeclinical data set if it is deemed appropriate.

For NDAs submitted via the abridged route, the applicant may request for priority reviewfor life-saving drug if there are unmet medical needs. The following states the criteriabased on which a drug application for a new product will be considered for priority review:

The drug is intended for treatment of a serious life-threatening condition anddemonstrates the potential to address local unmet medical needs, as defined by: the absence of a treatment option; or the lack of safe and effective alternative treatment, and the drug would be a

significant improvement compared to available marketed products, asdemonstrated byi. evidence of increased effectiveness in treatment, prevention, or diagnosis;

orii. elimination or substantial reduction of a treatment-limiting drug reaction.

Disease conditions that are of local public health concerns will be given primary

consideration for priority review. Currently these include: cancer infectious diseases: dengue, tuberculosis, hepatitis and malaria.

The request for priority review should be accompanied by justification on why theapplication concerned warrants a priority review and how the product is expected tobenefit patients, as substantiated by the following evidence:

The seriousness of the disease condition, local and worldwide mortality rates,anticipated morbidity and debilitation as a consequence of the disease;

Local epidemiology data and volume of requests through the exemption route ona named-patient basis;

The unmet needs, current available treatment options and standard therapies, and

the inadequacy of current therapies; The extent to which the product is expected to have a major impact on medical

practice, its major benefit, and how it addresses the unmet needs;


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Clinical evidence supporting the claims of significant improvement compared toavailable treatments.

HSA reserves the right to deny a request for priority review if it is deemed appropriate.

6.2.1.3 Verification dossier

For the verification route, one of the two reference drug regulatory agencies must bedeclared as the primary reference agency. All aspects of the products quality anddirection(s) for use (including dosing regimen(s), indication(s) and patient group(s))should be the same as that approved by the chosen primary reference agency.

The technical documents required include: complete quality documents for both drug substance and drug product, which

includes:i. the initial dossier submitted to the primary reference agency;ii. all Questions and Answers between the primary reference agency and

sponsor the Answers should include supporting documents used in

response to the Questions; and,iii. all post-approval variations approved by the primary reference agency up to

the time of submission to HSA; a non-clinical overview; and, a clinical overview, summaries of clinical efficacy and clinical safety, synopses of

relevant studies, a tabular listing of the clinical development programme and studyreports of the pivotal studies (the tables and appendices to the pivotal studyreports may be submitted upon request by HSA).

The complete assessment report and other relevant supporting documents from theprimary reference agency must be submitted along with the relevant application dossiersections, as tabulated below:

Primary referenceagency

Documentary requirements

Australia TGA Clinical and quality assessment reports, including allannexes, question and answer documents between thesponsor and the Agency

Delegates overview

Pre-ADEC response

ADEC minutes

Assessment reports and/or documents pertaining to post-approval variations, if applicable

Health Canada Clinical and quality assessment reports, including allannexes, question and answer documents between thesponsor and the Agency


EMEA Summary of CHMP Opinion

European Assessment Reports (i.e., Rapporteur, Co-Rapporteur as well as the Joint Clinical and Joint qualityassessment reports), including all annexes, question andanswer documents between the sponsor and the Agency

Assessment reports and/or documents pertaining to post-

approval variations, if applicable


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Primary referenceagency

Documentary requirements

UK MHRA Clinical and quality assessment reports, including allannexes, question and answer documents between thesponsor and the Agency

Assessment reports and/or documents pertaining to post-

approval variations, if applicableUS FDA Clinical and quality assessment reports (unredacted),

including all annexes, question and answer documentsbetween the sponsor and the Agency


The assessment reports must be unredacted or unedited. Reports obtained from thepublic domain are deemed unacceptable.

The following additional documents are required at the time of submission to HSA:

Official approval letter or an equivalent document, from the relevant referenceregulatory agencies that certify the registration status of the drug product;

GMP certificate of the drug product manufacturer(s) from the primary referenceagency;

SmPC/Package Insert (PI)/Patient Information Leaflet (PIL) currently approved bythe reference regulatory agencies that issued the approval letters;

Official letter declaring that the application as submitted to HSA or similardirection(s) of use, indication(s), dosing regimen(s) and/or patient group(s) havenot been rejected, withdrawn, approved via appeal process9, or pending deferral10by any competent regulatory agency, with reasons in each case if applicable; and

Official letter declaring that all aspects of the products quality intended for sale inSingapore are identical as currently approved by the primary reference regulatory

agency. This includes, but is not limited to, the formulation, site(s) of manufacture,release and shelf life specifications, primary packaging and the PI/PIL. Forexample, if a product was approved by FDA and EMEA and the assessmentreport was from EMEA, the Singapore proposed product and PI/PIL should beidentical to the currently approved EMEA product.

Data submitted to HSA must be the same as the data package submitted to the referenceregulatory agencies. Differences between the dossier submitted to HSA and datareviewed by the reference regulatory agencies will not only delay the processing of theapplication, but may also lead to re-routing of the dossier to the abridged evaluation routeif significant undisclosed differences have been discovered.

6.2.2 GDA Submissions

Generic drug applications require approval from at least one competent drug regulatoryagency.

A generic product is essentially similar to a currently registered product in Singapore(known as the Singapore reference product) but excludes biologics. Essentially similar11is defined as having the same qualitative and quantitative composition in terms of activesubstances, having the same pharmaceutical form and being bioequivalent. By extension,

9Approval via appeal process includes, but is not limited to, the following: approval following negative

opinion, approval following rejection, approval following non-approvable etc.10Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,conditional marketing authorisation, notice of compliance with conditions etc.11

Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.


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the concept of essentially similar also applies to different conventional immediaterelease oral dosage forms (i.e. tablets and capsules) which contain the same activeingredient(s).

For generic products containing a different salt or ester form of the active substancecompared to the Singapore reference product, applicants are required to submit data to

demonstrate that the different salt/ester form does not affect the pharmacokinetic,pharmacodynamic, efficacy or toxicity profile of the active substance in the referenceproduct.

GDAs generally are not required to include non-clinical (animal) and clinical (human) datato establish a drug products safety and efficacy. Instead, the generic product must fulfilthe following criteria:

a) the generic drug product is the same pharmaceutical dosage form as theSingapore reference product;

b) the route of administration of the generic drug product is the same as theSingapore reference product;

c) the conditions of use for the generic drug product fall within the directions for use

[including indication(s), dosing regimen(s) and patient group(s)] for the Singaporereference product; and,

d) the generic drug product is bioequivalent with the Singapore reference product.

With effect from 1st April 2004, in vivo bioequivalence (BE) data is required forPrescription Only Medicines (POM) in oral solid dosage forms. Also, GDA-2 applicationswill require bioequivalence data if the application is for a Prescription Only Medicine(POM) in an oral solid dosage form, even if the first strength (GDA-1) application wassubmitted to HSA before 1 April 2004. Applicants are advised to consult HSA forguidance to determine whether the GDA-2 application requires in vivo bioequivalencedata.

Take note that the in vivo BE requirement may be extended to other medicinal productcategories in the future.

Singapore Reference Product

The Singapore reference product must be a currently registered product. It must also bethe same pharmaceutical dosage form and strength as the proposed generic drug (withthe exception of conventional, immediate release oral solid dosage form). Applicants areadvised to search HSAs online database12 to identify the Singapore reference product.Applicants submitting GDAs should also refer to Appendix 12 for further details onproduct interchangeability and biowaiver request.

The applicant is encouraged to contact HSA to discuss the acceptability of a GDA if thegeneric product does not have a registered Singapore reference product of the samestrength. In these instances, applicants shall provide a scientific justification for HSAsconsideration. However, a generic drug application for a higher strength than theSingapore reference product will not be accepted.

Applicants are also advised to refer to section 11.1 and 11.2 for information on DataProtection and Data Exclusivity and Patent Linkage, respectively, for additionalinformation.

12http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load


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6.3 SUBMISSION REQUIREMENTS

Table 4 outlines the CTD Modules/Parts required for NDAs and GDAs submitted as a full,abridged or verification dossier:

Documents Location in Module/Part required for

ICH CTD ACTD FullNDA

Abridged NDA Verificat ion NDA GDA

AdministrativeDocuments andProduct Information

Module 1 Part 1 Yes Yes Yes Yes

Common TechnicalDocument Overviewand Summaries

Module 2 Incorporatedin Parts 2, 3

and 4

Yes Yes Yes Yes

Quality documents

Module 3 Part 2 Yes Yes Yes Yes

Non-clinicaldocuments

Module 4 Part 3 Yes ICH: NoACTD: Overview

only

ICH: NoACTD: Overview

only

No

Clinical documents Module 5 Part 4 Yes Study report(s) of

pivotal studiesand synopses ofall studies (phaseI-IV) relevant to

requestedindication, dosing

and/or patientgroup

Study report (s)

of pivotal studiesand synopses ofall studies (phaseI-IV) relevant to

requestedindication, dosing

and/or patientgroup

No

Non-clinical overview included in Module 2 of the ICH CTD.

Table 4. Dossier Submission Requirements for NDA and GDA.


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6.3.1 HARDCOPY and SOFTCOPY REQUIREMENTS

Table 5 outlines the softcopy and hardcopy required for NDAs and GDAs submitted as afull, abridged or verification dossier:

CTD Requirement#

NDA(F) NDA(A) NDA(V) GDAICH CTD

Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy

Module 1 PRISM 1 set PRISM 1 set PRISM 1 set PRISM 1 set

Module 2 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional

Module 3 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional

Module 4 PRISM/CD Optional N/A N/A N/A N/A N/A N/A

Module 5 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional N/A N/A

CTD Requirement#

NDA(F)

NDA(A)

NDA(V)

GDAACTD

Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy

Part 1 PRISM 1 set PRISM 1 set PRISM 1 set PRISM 1 setPart 2 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional

Part 3 PRISM/CD OptionalOverview

Only:PRISM/CD

OverviewOnly:

Optional

OverviewOnly:

PRISM/CD

OverviewOnly:

OptionalN/A N/A

Part 4 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional N/A N/A#

F: full route;A: abridged route; V: verification route; N/A: not applicable

Table 5. Requirements for ICH CTD and ACTD dossiers.

In order to ensure that the dossier is complete, application checklists for both ICH CTDand ACTD dossiers are provided in Appendix 2 and 3, respectively. Each checklist states

the required documents for each dossier type and application type tick boxes markedwith * indicate a mandatory document for the application. Refer to the specific Appendixfor more details.

An electronic copy of the complete CTD dossier is to be submitted with the application i.e. Modules 1 to 5 of the ICH CTD or Parts 1 to 4 of the ACTD. Applicants areresponsible to ensure that the e-copies e.g. scanned documents of the dossier arelegible.

As mentioned earlier in section 6.1.7 of this document, all administrative documents[Module 1 (ICH CTD) or Part 1 (ACTD)] are to be attached as soft copies into PRISMsection 7 (Supporting Attachments).

For the remaining Modules/Parts, applicants can opt to either attach the documents in fullinto PRISM section 7 (Supporting Attachments) orsubmit soft copies (e.g. PDF format) ofthe documents in a CD. However, applicants are advised not to combine PRISMattachments with a CD submission i.e. all supporting documents must be attached inPRISM orall supporting documents submitted in a CD.

When submitting a CD, applicants are encouraged to organise the dossier via the CTDformat, using folders and subfolders, and to include bookmarks to facilitatescreening/reading of the reports.

Applicants shall ensure that access to the CD is not restricted. If so, the applicant must

provide the password(s) to access the CD contents.


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When applicable, upon acceptance, applicants will be notified to submit additionalcopy(ies) of clinical documents (in CD).

Applicants should also note that hardcopy submission of all administrative documents inCTD Module 1/Part 1, as indicated in Table 5, are also required for the application.Applicants should ensure that the electronic copies are identical to the hardcopy

documents.

If an electronic copy of the complete CTD dossier is not possible, HSA will accept thecomplete dossier in hardcopy.

For hardcopy submissions, each Module/Part should be bound into separate volumesand numbered sequentially, starting from 1 for example Module 5, Vol. 1 of 3. Eachvolume should also be labelled according to the section(s) it contains.

For example,

A document is a set of pages that is numbered sequentially and divided from otherdocuments by a tab. Page numbering should be at the document level and not at the

volume or module level; i.e. the entire submission should never be numberedconsecutively by page. In general, all documents should have page numbers. Since thepage numbering is at the document level, there should only be one set of page numbersfor each document.

Cross-referencing to documents is acceptable by referring to the CTD module, volume,tab identifier and page number (for example, refer to Module 3, Vol. 6, P.4.3 MethodValidation, p 23).

Volumes packed in sturdy cardboard boxes should be clearly labelled with the contents(e.g. Module 2, Volume 1 to 5), and the boxes should not weigh more than 20 kilograms.

6.4 DOCUMENTARY REQUIREMENTS

6.4.1 Language

Information and documents supporting an application, such as certificates and approvalletters, must be in English and authenticated. If documents are not originally in English,applicants should refer to Appendix 5 for the flow chart for the translation of non-Englishdocuments.

Authentication of foreign documents for use in Singapore is required when theauthenticity of the documents cannot be determined.

If the foreign document is an original and bears the seal and signature of a recognisedgovernment agency, the document does not require notarisation. Any other type of

ABCTablet 250mg

Module 3Vol. 3 of 4

3.2.P.7 to3.2.P.8

Product Name, generic name ofthe drug and the ApplicantCompany

This volume contains informationon drug product container

closure system and stability


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document, such as declarations, translations, photocopies, documents lacking an originalsignature, etc., must be notarised by a notary public in the country where the documentwas issued before the document can be authenticated. The notary public will sign thedocument and affix their seal. Notarisation is generally not required for documentsexecuted in Singapore for use in Singapore.

As an example, for notarisation the information included on the document could be: The name of the notary; A statement that the notary is duly admitted to practice in the place of issue of the

certificate; The names of the signatories and the capacity in which they have executed the

document, whether on their own behalf or in an official or representative capacity; A statement authenticating the signatures of the parties and, where appropriate,

indicating that evidence has been produced to the notary proving the capacity inwhich they have executed the document;

The place and date of issue of the notarial certificate; and The signature and seal of the notary.

Authentication (also known as legalisation or consularisation) refers to the processwhereby the origins of a document are attested. Authentication of documents in supportof applications made to HSA can be done by:

The Ministry of Foreign Affairs of the country in which the document was issued;or

The Singapore Embassy/Consulate in the country where the document wasissued.

Applicants are advised to consult the Singapore Embassy/Consulate in the country wherethe document originated on local requirements for document legalisation, as these maydeviate from the process as outlined in the preceding paragraph.

By international agreement, an apostille can be issued for documents that are to be usedin another country that is party to the Hague convention. When an apostil stamp isattached to a document, it is exempted from all forms of confirmation; i.e. no furtherlegalisation from a foreign embassy is normally required. Although Singapore at presentis not a party of the Hague Convention, an apostille is acceptable for the authentication ofdocuments to be submitted to HSA as part of the application dossier.

Certificates and documents issued in English by the national drug regulatory agency donot require legalisation.

A certified true copy certifies that the photocopy presented is a true and accurate copy ofthe

originaldocument. Acceptable certification of documents to support drug product

applications to HSA can be done by the Company Director or Company Secretary asregistered with ACRA or above, or by an independent authority such as a lawyer, notarypublic, Commissioner for Oaths/Declarations/Affidavits, Justice of Peace, the originalissuer of the document or Embassy/Consulate. A notarised copy is the same as acertified true copy.

A certified true copy of approval letters (see section 6.5.2 Proof of Approval) requirescertification by the drug regulatory agency that issued the approval letter, notary public orSingapore Embassy/Consulate in the country where the approval letter was issued.Certification of approval letters is not required in the event the approval letter is availableon the drug regulatory agencys website. In this instance, applicants shall provide the

internet address (URL) for validation by HSA.


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6.4.2 Administrative Documents

The administrative documents relate to Module 1 of the ICH CTD or Part 1 of the ACTD.The following sections are to be submitted:

Comprehensive Table of Contents (1.1)

The comprehensive table of contents is a complete list of all documents provided in theapplication dossier by Module/Part. The location of each document should be identifiedby the Module/Part number. For hardcopy submissions, the location of each documentshould be identified by the volume number and tab identifier (name of the document orsection heading according to the ACTD or ICH CTD format).

Introduct ion (1.2)

Applicants should give a concise and precise summary of the application and justify theneed for the application for example, whether the product presents an advantage topatient groups in terms of improved quality, safety and efficacy compared to available

alternatives. Applicants should also justify the lack of certain documents within thedossier and any deviation from the guidelines.

Appl ication Form (1.3)

A printout of the PRISM application form is to be included in the dossier. Take note that aseparate application form is required for each pharmaceutical dosage form.

Labelling, Package Insert and Patient Information Leaflet (1.4)

Applicants are required to provide the artwork/drafts of the proposed Singapore productlabels, PI and/or PIL, as described in the table below:

Forensic Classification in Singapore

POM P GSL

Package Insert (PI), also known asprescribing information, SmPC, or productmonograph

Required Optional Optional

Patient Information Leaflet (PIL), also knownas consumer medicine information (CMI)

Optional,unless

warranted

Required Required

The artwork/drafts should be legible. Any handwritten information is not acceptable.

Separate drafts must be submitted for each different pack size of the drug product.

The product labels, PI and/or PIL must be in English. If non-English text is included in thelabelling, applicants must provide an official statement to declare that the non-English textis complete, accurate and unbiased information and is consistent with the English text.Applicants should also highlight any non-English country-specific labelling requirementson the artwork/drafts if the labelling is shared with other countries.

Appendix 6 of this guidance contains specific details on product labelling requirements forSingapore.


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Approved SmPC/PI/PIL (1.5)

In this section, the applicant shall submit the following:a) the approved SmPC, PI and/or PIL from the products Country of Origin;b) the approved SmPC, PI and/or PIL from the drug regulatory agency that issued

the proof of approval, if different from the Country of Origin; and,

c) the approved SmPC, PI and/or PIL from each of HSAs reference drug regulatoryagencies, where applicable.

Assessment Report from Reference Agencies (1.6)

This section refers only to verification dossier submissions. Assessment reports andsupporting documents issued by the primary reference agency and inserted into thissection must be unredacted and unedited. Applicants should refer to section 6.2.1.3 forspecific details on the required documents.

Descrip tion of Batch Numbering System (1.7)

Detailed information on the system of assigning unique codes to different productionbatches of the product should be provided to allow for batch identification.

Proof of Approval (1.8, 1.9)

Proof of approval is not required for full dossier submissions.

For abridged NDA and GDA submissions of an imported product, proof of approval byany competent drug regulatory agency is required. Proof of approval must come in theform of:

an official approval letter, or equivalent document (e.g. Certificate ofPharmaceutical Product), which certifies the registration status of the drug

product; and the GMP certificate(s) of the drug product manufacturer(s) from the relevant

authority; and the SmPC, PI and/or PIL approved by the drug regulatory agency that issued the

approval letter.

If the SmPC is in a non-English language, applicants should refer section 6.4.1 of thisguidance document. In addition, a declaration is required stating that the translationsubmitted conforms to the SmPC/PI/PIL currently approved by the drug regulatoryagency concerned.

Note that all aspects of the products quality and intended direction(s) for use inSingapore should be the same as approved by the drug regulatory agency that issued theapproval letter. For verification dossiers, the products quality and intended direction(s) foruse in Singapore should be the same as approved by the primary reference regulatoryagency.

For verification dossier, the following documents are required at the time of submission toHSA: official approval letters, or equivalent document, from the relevant HSAs reference

regulatory agencies that certify the registration status of the drug product; a GMP certificate of