Guidance on Medicinal Product Registration in Singapore 2011

8/10/2019 Guidance on Medicinal Product Registration in Singapore 2011

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GUIDANCE ON MEDICINAL PRODUCT

REGISTRATION IN SINGAPORE

Effective 1 April 2011

Please visit HSAs website athttp://www.hsa.gov.sgfor the latest

update
http://www.hsa.gov.sg/http://www.hsa.gov.sg/http://www.hsa.gov.sg/http://www.hsa.gov.sg/


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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011

HEALTH SCIENCES AUTHORITYHEALTH PRODUCTS REGULATION GROUP Page 2 of 102

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TABLE OF CONTENTS

CHAPTER A GENERAL OVERVIEW............................................................................... 9

1

FOREWORD .................................................................................................................. 9

1.1 Scope of this guidance document ..................................................................... 91.2

Medicinal product registration ..........................................................................10

2

APPLICANT RESPONSIBILITIES .................................................................................11

3 DATA PROTECTION ....................................................................................................124

PATENT LINKAGE ........................................................................................................13

CHAPTER B

REGISTRATION PROCESS ......................................................................14

5 PRE-SUBMISSION PREPARATION .............................................................................145.1 Application types ..............................................................................................145.2

Evaluation routes .............................................................................................16

5.3 Pre-Submission consultation ............................................................................165.3.1

Pre-submission inquiry ........................................................................16

5.3.2 Pre-submission meeting ......................................................................166

APPLICATION SUBMISSION .......................................................................................17

6.1

PRISM application form ...................................................................................17

6.2 Registration dossier .........................................................................................176.2.1

Softcopy and Hardcopy requirements ..................................................18

6.2.2 Language ............................................................................................196.2.3

Certifying non-original documents ........................................................20

7 APPLICATION SCREENING.........................................................................................208 APPLICATION EVALUATION .......................................................................................219

REGULATORY DECISION ...........................................................................................23

10 POST-APPROVAL CHANGES ......................................................................................2411

FEES............. ................................................................................................................24

11.1 Screening fee ...................................................................................................24

11.2

Evaluation fee ..................................................................................................24

11.2.1

Change in evaluation fees ...................................................................25

11.2.1.1 Change of Application within the Same Application Type...... 2511.2.1.2

Change of Application between Different Application Types. 25

CHAPTER C

NEW DRUG APPLICATION SUBMISSION ...............................................26

12 APPLICATION TYPES ..................................................................................................2613 EVALUATION ROUTES ................................................................................................26

13.1

Full evaluation route .........................................................................................27

13.2 Abridged evaluation route ................................................................................2713.2.1 Priority review ......................................................................................2713.2.2 Applications for non-prescription medicines .........................................27

13.3

Verification evaluation route .............................................................................2813.3.1 NDA-3 applications ..............................................................................29

14 DOCUMENTARY REQUIREMENTS .............................................................................2914.1

Administrative documents ................................................................................29

14.2 CTD overview and summaries .........................................................................3514.3

Quality documents ...........................................................................................36

14.3.1 Body of DataDrug Substance ...........................................................3614.3.2 Body of DataDrug Product ...............................................................39

14.4

Non-clinical documents ....................................................................................41

14.5 Clinical documents ...........................................................................................4114.6

Specific documentary requirements for each evaluation route .........................42

14.6.1 Full evaluation route ............................................................................42

14.6.2

Abridged evaluation route ....................................................................42

14.6.3

Verification evaluation route .................................................................42


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CHAPTER D GENERIC DRUG APPLICATION SUBMISSION ..........................................4515

APPLICATION TYPES ..................................................................................................45

15.1 Generic product ...............................................................................................4515.2 Singapore reference product ............................................................................45

16

EVALUATION ROUTES ................................................................................................46

16.1 Abridged evaluation route ................................................................................46

16.2

Verification evaluation route .............................................................................4617 DOCUMENTARY REQUIREMENTS .............................................................................47

17.1 Administrative documents ................................................................................4717.2

CTD overview and summaries .........................................................................52

17.3 Quality documents ...........................................................................................5317.3.1

Body of DataDrug Substance ...........................................................53

17.3.2 Body of DataDrug Product ...............................................................5617.4 Non-clinical and clinical documents..................................................................5917.5 Specific documentary requirements for each evaluation route .........................59

17.5.1 Abridged evaluation route ....................................................................5917.5.2

Verification evaluation route .................................................................59

CHAPTER E

BIOSIMILAR PRODUCT APPLICATION SUBMISSION...........................62

18 APPLICATION TYPES ..................................................................................................6218.1 Biosimilar product ............................................................................................6218.2

Reference product ...........................................................................................63

19 EVALUATION ROUTES ................................................................................................6320

DOCUMENTARY REQUIREMENTS .............................................................................63

20.1 Administrative documents ................................................................................6420.2 CTD overviews and summaries .......................................................................6420.3

Quality documents ...........................................................................................64

20.4 Non-clinical and clinical documents..................................................................64

CHAPTER F POST-APPROVAL PROCESS ..................................................................65

21

VARIATION APPLICATION PROCESS ........................................................................66

21.1 Pre-Submission preparation .............................................................................6621.1.1 Pre-submission inquiry ........................................................................6721.1.2

Pre-submission meeting ......................................................................67

21.2 Application submission.....................................................................................6721.2.1

PRISM application form .......................................................................67

21.2.2 Variation application dataset ................................................................6721.2.2.1 Language ............................................................................. 6821.2.2.2

Certifying non-original documents......................................... 69

21.3 Application screening .......................................................................................6921.4

Application evaluation and Regulatory decision ...............................................69

21.5 Fees.................................................................................................................7021.5.1

Screening fee ......................................................................................70

21.5.2 Evaluation fee ......................................................................................70

CHAPTER G MAJOR VARIATION (MAV) SUBMISSION ...............................................7222 MAV-1 SUBMISSIONS ..................................................................................................72

22.1

Evaluation routes .............................................................................................72

22.1.1 Full evaluation route ............................................................................7222.1.2 Abridged evaluation route ....................................................................72

22.1.2.1

Applications for non-prescription medicines.......................... 73

22.1.3 Verification evaluation route .................................................................7322.2

Documentary requirements ..............................................................................73

22.2.1

Administrative documents ....................................................................7422.2.2 CTD overviews and summaries ...........................................................75

22.2.3 Quality documents ...............................................................................75


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22.2.4 Non-clinical and clinical documents .....................................................7522.2.5

Specific documentary requirements for each evaluation route .............75

22.2.5.1 Full evaluation route ............................................................. 7522.2.5.2 Abridged evaluation route ..................................................... 7522.2.5.3

Verification evaluation route .................................................. 75

23 MAV-2 SUBMISSIONS ..................................................................................................76

23.1

Eligibility criteria ...............................................................................................7623.1.1 Me-too reclassification .......................................................................77

23.2 Documentary requirements ..............................................................................7723.2.1

Me-too reclassification .......................................................................78

CHAPTER H

MINOR VARIATION (MIV) SUBMISSION ..................................................79

24 MIV SUBMISSIONS ......................................................................................................79

CHAPTER J SUBMISSION OF A PRISM APPLICATION FORM ...................................8025 SUBMITTING A PRODUCT APPLICATION ..................................................................80

25.1

Sections of a PRISM Application ......................................................................81

25.1.1 Section 1Company Particulars .........................................................81

25.1.2

Section 2Applicant Particulars .........................................................81

25.1.3 Section 3 Application Details.............................................................8225.1.3.1 Section 3.1Type of Application .......................................... 8325.1.3.2

Section 3.2Type of Product............................................... 8325.1.3.3 Section 3.3Reference Product.......................................... 8325.1.3.4

Section 3.4Type of Dossier............................................... 83

25.1.3.5 Section 3.5Type of Format................................................ 8425.1.4 Section 4Product Information ...........................................................84

25.1.4.1

Section 4.1Product Name ................................................. 84

25.1.4.2 Section 4.2Product Formula.............................................. 8525.1.4.3

Section 4.3Ingredients Derived From Human Blood/AnimalSources .............................................................................. 90

25.1.4.4

Section 4.4Pharmacotherapeutic Group........................... 91

25.1.4.5 Section 4.5Dosage Form .................................................. 9125.1.4.6 Section 4.6Route of Administration ................................... 9225.1.4.7

Section 4.7Packaging, Shelf Life and Storage Conditions. 92

25.1.4.8 Section 4.8Forensic Classification.................................... 9425.1.4.9

Section 4.9Registration Status in Other Countries............ 94

25.1.4.10Section 4.10Product Owner Information........................... 9625.1.5 Section 5Manufacturer Particulars ...................................................96

25.1.5.1

Active Substance Manufacturer............................................ 97

25.1.5.2 Finished Product Manufacturer............................................. 9825.1.6

Section 6Information on Company Responsible for Batch Release 100

25.1.7 Section 7Supporting Attachments .................................................. 102


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LIST OF APPENDICES

APPENDIX 1 Target Processing Timelines

APPENDIX 2A Application Checklist (ICH CTDNDA and GDA)

APPENDIX 2B Application Checklist (ICH CTDMAV)

APPENDIX 3A Application Checklist (ASEAN CTDNDA and GDA)

APPENDIX 3B Application Checklist (ASEAN CTDMAV)

APPENDIX 4 Flowchart for Translation of Non-English Documents

APPENDIX 5 Guideline on Submission for Non-Prescription Medicinal Products

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 on Acceptability of Bioequivalence Study

APPENDIX 13 Guideline on Submission for Indian Generic Products Under the CECAScheme

APPENDIX 14 MIV Filing and Submission Inquiry Form

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

Chemical Drugs

APPENDIX 16 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics

APPENDIX 17 Guidance on Registration of Similar Biological Products in Singapore


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ABBREVIATIONS AND ACRONYMS

ACPMACRA

Advisory Committee on Prescription MedicinesAccounting and Corporate Regulatory Authority

ACTD ASEAN Common Technical DocumentACTR ASEAN Common Technical Requirements

ALD Audit and Licensing DivisionASEAN Association of Southeast Asian NationsATC Anatomical Therapeutic ChemicalBA BioavailabilityBE BioequivalenceBP British PharmacopoeiaBSE Bovine Spongiform EncephalopathyBWP Blood Working PartyCECA Comprehensive Economic Cooperation AgreementCEP Certificate of Suitability (Ph Eur monograph)CHMP Committee for Medicinal Products for Human Use (formerly Committee for

Proprietary Medicinal Products) (EU)

CMC Chemistry, Manufacturing and ControlsCMS Concerned Member StateCOACOO

Certificate of AnalysisCountry of Origin (Finished product manufacturer)

CPP Certificate of Pharmaceutical ProductCPMP Committee for Proprietary Medicinal ProductsCTD Common Technical DocumentCVMP Committee for Medicinal Products for Veterinary UseDMF Drug Master FileEDQM European Directorate for the Quality of MedicinesEMA European Medicines Agency (EU)

FDA Food and Drug Administration (US)FTA Free Trade AgreementGDA Generic Drug ApplicationGSL General Sale List medicineGMP Good Manufacturing PracticeHIV Human Immunodeficiency VirusHPRG 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 Pharmacopoeia

MAV Major VariationMHRA Medicines and Healthcare Products Regulatory Agency (UK)MIV Minor VariationNDA New Drug ApplicationNfG Note for GuidanceOTC Over-The-CounterP Pharmacy only medicinePD PharmacodynamicsPDF Portable document formatPh. Eur. European PharmacopoeiaPI Package Insert (Singapore), Product InformationPIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-

operation SchemePIL Patient Information LeafletPK Pharmacokinetics


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PMF Plasma Master FilePOM Prescription Only MedicinePRISM Pharmaceutical Regulatory and Information SystemQOS Quality Overall SummaryRMS Reference Member StateSPC Summary of Product Characteristics

SOP Standard Operating ProcedureSQOS Singapore Quality Overall SummaryTGA Therapeutic Goods Administration (Australia)TSE Transmissible Spongiform EncephalopathyURL Uniform Resource LocationUSP United States PharmacopeiaWHO World Health OrganisationWTO World Trade Organisation


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CHAPTER A 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 newProduct Licence for a medicinal product (i.e. drug registration) andapplications to makevariations to an existing Product Licence.

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

Medicines Act (Chapter 176) Poisons Act (Chapter 234) Misuse of Drugs Regulationssubsidiary 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 advancein orderto avoid rejection of the application. Conversely, HSA may request for information orspecify conditions not described in this document that is deemed necessary to adequatelyassess 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
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html


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1.2 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 that functionor in any other way.

A Product Licence is required before a medicinal product can be sold or supplied inSingapore (Medicines Act, section 5), unless otherwise exempted under the law. 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 to

vary the existing Product Licence or possibly obtain a new Product Licence altogether.

Forensic classification

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).

Prescription Only Medicines (POM) control is required in the following situations:a) The product poses a direct2or indirect3 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 to

present 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.

The following also needs to be taken into consideration when deciding whether a productshould be classified as a POM:

2

Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or ofhigh frequency3Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heart

disease


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i. Whether the product contains a substance which is listed in either the Narcotic DrugConvention or the Psychotropic Substances Convention;

ii. Whether the product is likely to lead to medicinal abuse or addiction if used incorrectlyor to be used for illegal purposes;

iii. Whether the product contains a substance which, by reason of its novelty orproperties, has 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.

Pharmacy Only Medicines (P) control is required for products that possess characteristicswhich are not sufficiently critical 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.

General Sales List Medicines (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.

As healthcare products are becoming increasingly complex e.g. combinations of a

medicinal product and medical device the regulation of such products will be based onhow they are classified. Thus, if there is doubt about the products classification, it isrecommended that the applicant seek clarification via email [email protected].

2 APPLICANT RESPONSIBILITIES

Applicants should note that they are responsible for the medicinal products quality,efficacy and safety throughout its life cycle. What this means is that the applicantsresponsibilities start with the registration of the medicinal product and end when theproduct licence expires or is cancelled. Since the products quality, efficacy and safety

can change at any time during the course of its life cycle, it is the applicants responsibilityto inform HSA when these changes occur as per the current guidelines.

The applicants responsibilities include:

i. To ensure that all of the information given in the application form and supportingdocuments are true and valid, and that all current data, reports and informationrelevant to the benefit/risk assessment of the medicinal product have been suppliedat the time of the application submission;

ii. To ensure that all information and material included in the application dossier onpaper exactly matches the information and material included in the electronic

submission dossier. No information has been added, removed, or changed;
mailto:[email protected]:[email protected]


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iii. To declare at the time of submission to HSA that the application submitted to HSAhas not been rejected, withdrawn, approved via appeal process or pending deferralby any drug regulatory agency or HSA reference regulatory agencies, with reasonsin each case if applicable;

iv. To notify HSA of any change in the information submitted in the application and of

any new significant safety information during the course of evaluation andthroughout the products life cyclein the Singapore market;

v. To notify HSA if the application submitted to HSA has been rejected, withdrawn ordeferred by any drug regulatory agency or HSA reference regulatory agencies, withreasons in each case if applicable, throughout the products life cycle in theSingapore market;

vi. To respond to HSAs queries or requests for more data for review, within thetimelines stipulated by HSA;

vii. To ensure that the product will be sold, supplied and recommended for use in

accordance with the approved PI/PIL and in compliance with all licence conditions,applicable legislation and guidelines;

viii. To ensure that allpost-approval licensing conditions attached to the product licenceand post-approval commitments are fulfilled within the stipulated timelines;

ix. To notify HSA of any changes to the products quality, efficacy or safety throughoutthe products life cyclein the Singapore market;

x. To notify HSA if the products marketing authorisation is withdrawn by any drugregulatory agency or the product is no longer registered in any country, with thereasons in each case, throughout the products life cyclein the Singapore market;

and,

xi. To ensure that all information provided to HSA is true and correct to the best ofhis/her knowledge and that he/she has not wilfully suppressed any material fact.The applicant is aware that if he/she makes any false statement, representation ordeclaration in connection with an application submitted to HSA, he/she shall beguilty of an offence under the Medicines Act (Chapter 176).

3 DATA PROTECTION

Sections 19A and 19B were included in the Medicines Act in 1998 to enable Singapore to

comply with its obligations under Article 39 of the WTO TRIPS Agreement. Article 39requires countries to protect the test data of a pharmaceutical product against disclosureand unfair commercial use.

Section 19D was introduced in July 2004, in order for Singapore to fulfil its obligationsunder Article 16.8.1 of the US-Singapore Free Trade Agreement (FTA), stating that thelicensing authority may not grant marketing approval for a product on the basis of thegrant of an earlier approval for a period of 5 years from the date of the earlier approval,unless with the consent of the holder of the earlier approval.


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4 PATENT LINKAGE

Provisions for linkage between patent and marketing approval were introduced in July2004, under Section 12A of the Medicines Act, in order for Singapore to fulfil itsobligations under Article 16.8.4(c) of the US-Singapore FTA.

The Medicines Act provides for a system of patent declaration by the applicant of aproduct licence and power for the licensing authority to revoke a product licence inrelation to patent infringement and patent declaration. Relevant parts include sections12A, 16 and 20 of the Act, and paragraph 5B of the Medicines (Licensing, StandardProvisions and Fees) Regulations.

All applications for new product licences shall be accompanied by patent declarationsrequired under Section 12A of the Medicines Act. The applicant is required to furnish thepatent declaration using the form set out in Part I of the Sixth Schedule of the Medicines(Licensing, Standard Provisions and Fees) (Amendment) Regulations 2004 at the time ofapplication submission, and at any other such time as HSA may require. As a generalguidance, a confirmatory declaration will be requested when an approvable regulatory

decision is issued. The applicant is required to furnish the confirmatory declaration withinthe timeframe stipulated by HSA.

All declarations required under Section 12A of the Medicines Act should be submitted inhard copies on original letterhead, signed by the person authorised to make thedeclaration on behalf of the applicant. The authorised person is ordinarily an officer of thecompany such as a director, the company secretary as registered with ACRA, orequivalent. Evidence of such authorisation by the applicant of that person to make thedeclaration on its behalf shall be submitted together with the declaration. Examples ofevidence of authorisation include a resolution of board of directors, a resolution of ageneral meeting of the company, or an extract of the relevant portion of the companysarticles of association. Declaration forms must bear the original signatures of theauthorised person and the company stamp of the applicant.

Under Section 12A (3) of the Medicines Act, the licensing authority may, if the applicanthas declared that in his opinion and to the best of his belief the patent is invalid or will notbe infringed by the performing of the act for which the licence is sought (i.e. Category Bpatent declaration), or if the licensing authority considers it appropriate in any particularcase, require the applicant to serve a notice to the proprietor of the patent in the formprescribed in Part II of the Sixth Schedule of the Medicines (Licensing, StandardProvisions and Fees) (Amendment) Regulations 2004.

If (i) there is a patent in force in respect of the medicinal product to which the application

relates, (ii) the applicant is not the proprietor of the patent, (iii) the proprietor has notconsented to nor acquiesced in the grant of the product licence, and (iv) the applicant isrequesting for grant of product licence after the expiry of the patent (i.e. Category A3patent declaration), then such an application may not be made earlier than 18 monthsbefore the expiry of the patent.

Applicants should take note that the information contained in this section is for thepurpose of guiding applicants in their patent declarations. Applicants requiring legaladvice should seek the assistance of their own legal counsel.


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CHAPTER B REGISTRATION PROCESS

One part of a productslife cycle is the pre-marketing activities, namely registration of aproduct prior to market entry. The registration process involves a series of steps as seenin Figure 1 below:

Figure 1. Registration Process for a Medicinal Product

For information on the registration processing time, refer to Appendix 1 of this guidance

document.

5 PRE-SUBMISSION PREPARATION

The first step in the registration process is one of the most important because it involvesi. Knowing which application to apply for;ii. Knowing which evaluation route to choose; and,iii. Arranging for a pre-submission consultation with HSA for advice, if required.

5.1 Application types

In applying for a newProduct Licence for a medicinal product in Singapore, there are two

categories of applications: a new drug application (NDA) and a generic drug application(GDA):

PRE-SUBMISSIONPREPARATION

APPLICATION

SUBMISSION

APPLICATIONSCREENING

APPLICATION

EVALUATION

REGULATORY

DECISION

POST-APPROVAL

CHANGES

NON-ACCEPTANCE /

WITHDRAWAL

ACCEPTANCE

APPROVAL

NON-APPROVAL /

WITHDRAWAL


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NDA New Drug Application

NDA-1: For the firststrength of a product containing a new* chemical or biological entity.

NDA-2: i) For the firststrength of a new drug product containing a new* combination of registered chemical or biological entities; containing registered chemical or biological entity(ies) in a newdosage

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

route of administration; or, containing registered chemical or biological entity(ies) for newindication(s),

dosage recommendation(s) and/or patient population(s).

ii) For new drug products that do not fall under the requirements for NDA-1,NDA-3 or GDA.

NDA-3: For subsequentstrength(s) of a new drug product that has been registered or hasbeen submitted as an NDA-1 or NDA-2. The product name, pharmaceuticaldosage form, indication, dosing regimen and patient population shall be thesameas that for the NDA-1 or NDA-2.

* Has not been registered before in Singapore

GDA Generic Drug Application

GDA-1: For the firststrength of a generic chemical product.

GDA-2: For subsequent strength(s) of the generic chemical product that has beenregistered or has been submitted as a GDA-1. The product name andpharmaceutical dosage form shall be the sameas that for the GDA-1.

A generic product is essentially similar to a currently registered product in Singapore(known as the Singapore reference product) but excludes biologics. Essentially similar4is defined as having the same qualitative and quantitative composition in terms of activesubstances, having the same pharmaceutical form and being bioequivalent. By extension,

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

A schematic diagram to illustrate the various types of applications is seen in Figure 2below:

Figure 2. Schematic diagram of application routes for drug registration.

4Note for Guidance on the Investigation of Bioavailability and Bioequivalence . CPMP/EWP/QWP/1401/98.

IS PRODUCT

REGISTERED?

Post-ApprovalProcess, Chapter F

Firststrength ofproduct?

Essentiallysimilarto a currentlyregistered product?

NDA1Contains newchemical orbiological entity?

NO

YES YES

NO

NDA2

NDA3

GDA1

GDA2NO

NOYES

YES


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5.2 Evaluation routes

There are three types of evaluation routes for registration of a new product:

Full dossier: Applies to any product that has notbeen approved by an ydrugregulatory agency at the time of submission.

Abridged dossier: Applies to any product that has been evaluated and approved byat least onedrug regulatory agency.

Verification dossier: Applies to any product that has been evaluated and approved byHSAs reference drug regulatory agencies, which include EMA*,US FDA, Health Canada, TGA and UK MHRA#.

* For products approved via the Centralised Procedure# For products approved via the national procedure or where MHRA acted as the RMS for the MRP or

Decentralised Procedures in Europe

Applicants should be familiar with the eligibility criteria for each evaluation route for theapplication type to be submitted because the documentary requirements for the full,abridged and verification routes for an NDA and GDA are different.

Applicants should refer to Chapters C, D and E for detailed information about theselection of appropriate evaluation routes for NDA, GDA and biosimilar productapplications, respectively.

5.3 Pre-submission consultation

Applicants are encouraged to contact HSA prior to submission of an application ifquestions arise or clarification is required. There are two methods to contact HSA:

i. Pre-submission Inquiry via emailii. Pre-submission Meeting

Applicants are to note that all advice given by HSA will be based on knowledge that iscurrent at the time of the consultation. Such advice is not binding and does not have adirect bearing on the eventual outcome of the application concerned.

5.3.1 Pre-submission inquiry

The applicant may submit a pre-submission inquiry via e-mail if any clarification onmedicinal product registration is needed 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.

5.3.2 Pre-submission meeting

For complex issues relating to an impending submission, applicants are advised to

consult with HSA in a pre-submission meeting. The request for a consultation should be

NOTE: Refer to Section E for more information on the application types andevaluation routes available for biosimilar products.


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made in writing, with the purpose, agenda and proposed date & time for the meeting, viaemail to [email protected].

For a submission under the full evaluation route, the applicant is required to notify HSAvia a pre-submission meeting two months prior to the intended submission date of theapplication dossier.

6 APPLICATION SUBMISSION

Application submission comprises of two parts: the PRISM application form and theregistration dossier.

6.1 PRISM application form

All applications must be made on-line via PRISM. Refer to Chapter J for guidance notesfor submitting a PRISM application.

6.2 Registration dossier

The registration dossier contains the documents to support the evaluation of thesubmitted application.

The complete dossier should be submitted within 2 working days after the PRISMapplication submission to prevent delays in processing of the application. The date ofsubmission will be defined as the date when HSA receives the complete dataset forthe application.

Registration dossiers should be in a CTD format. The CTD provides a common format forthe preparation of a well-structured submission dossier. It uses a modular framework

described in ICH Topic M45

or the ASEAN guidelines on the Common TechnicalDocument for Registration of Pharmaceuticals for Human use: Organisation of theDossier6. This guidance document should be read in conjunction with the most recentversion of the ICH CTD and the ASEAN CTD (ACTD) guidance documents.

Thus, the dossier will be in one of the two formats, either the ICH CTD or the ACTDformat. According to the chosen format, the documents will be grouped into five Modules(ICH CTD) or four Parts (ACTD). The main differences between these two formats are thenumbering and naming of the sections, as seen in Table 1:

Table 1. Format of the ICH CTD and ACTD.

Documents Location inICH CTD ACTD

Administrative Documents and ProductInformation

Module 1 Part I

Common Technical Document Overviewand Summaries

Module 2 Incorporated in Parts II, III andIV

Quality documents

Module 3 Part II

Non-clinical documents

Module 4 Part III

Clinical documents Module 5 Part IV

5http://www.ich.org/

6http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
http://www.ich.org/http://www.ich.org/http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.ich.org/


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The CTD format cannotbe changed once the application is submitted. Any subsequentvariation applications for the product should follow the same format.

6.2.1 Softcopy and Hardcopy requirements

In moving towards a greener environment, submission of the complete registrationdossieri.e. Modules 1 to 5 of the ICH CTD or Parts I to IV of the ACTD should be inelectronic format. But there is one exception: documents which require proof ofauthenticity (e.g. CPPs, approval letters not available online, authorisation letters, GMPcertificate, patent declaration, declaration letters, etc) should be submitted in electronicandhard copy format.

Applicants should ensure that all soft copiese.g. scanned documents of the dossierare legible as illegible soft copies will cause unnecessary delays in the registrationprocess.

Table 2 and 3 outline the softcopy requirements for NDAs and GDAs submitted via thefull, abridged or verification evaluation route in either ICH or ACTD, respectively:

Table 2. Soft and Hard Copy Requirements for ICH CTD dossiers.

ICH CTD

CTD Requirement#

NDA (F) NDA (A) NDA (V) GDA (A + V)

Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy HardcopyModule 1 PRISM 1 set

+ PRISM 1 set

+ PRISM 1 set

+ PRISM 1 set

+

Module 2

PRISM/CD N/A

PRISM/CD

N/A

PRISM/CD

N/A

PRISM/CD

N/AModule 3 PRISM/CD PRISM/CD PRISM/CD

Module 4 N/A N/A N/A

Module 5 PRISM/CD PRISM/CD PRISM/CD

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

+:Only documents which require proof of authenticity are required to be submitted in hardcopy for Module 1

(e.g. CPPs, approval letters not available online, authorisation letters, GMP certificate, patent declaration,declaration letters, etc)

Table 3. Soft and Hard Copy Requirements for ACTD dossiers.

ACTD

CTD Requirement#

NDA (F) NDA (A) NDA (V) GDA (A + V)

Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy

Part I PRISM 1 set+ PRISM 1 set

+ PRISM 1 set

+ PRISM 1 set

+

Part II

PRISM/CD N/A

PRISM/CD

N/A

PRISM/CD

N/A

PRISM/CD

N/APart III

OverviewOnly:

PRISM/CD

OverviewOnly:

PRISM/CD

N/A

Part IV PRISM/CD PRISM/CD PRISM/CD

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

+: Only documents which require proof of authenticity are required to be submitted in hardcopy for Module 1

(e.g. CPPs, approval letters not available online, authorisation letters, GMP certificate, patent declaration,declaration letters, etc)

NOTE: It is important to note that the implementation and use of the CTDrepresents a work in progress. It is expected that future refinements to thisguidance document will continue to be necessary as a result of experience gained.


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While Module 1/ Part I must be submitted in softcopy, it must also be submitted inhardcopy, notably for documents that require proof of authenticity, such as Letters ofAuthorisation, GMP certificates, CPPs, patent declaration forms and so forth. Officialdocuments issued by other drug regulatory agencies, declaration letters and patentdeclaration form should also be submitted as the original copy; if these documents cannotbe submitted as originals, then refer to section 6.2.3 for more information on certifying

non-original documents. Applicants should also ensure that submitted electronic copiesare identical to the hardcopy documents.

For Modules 2 to 5/Parts II to IV, applicants can opt to attach the documents either in fullinto PRISM section 7 (Supporting Attachments) or submit the softcopies (e.g. PDFformat) in a CD/DVD. However, applicants are advised not to combine PRISMattachments with a CD/DVD submissioni.e. all supporting documents must be attachedin PRISM or all supporting documents submitted in a CD/DVD.

In order to ensure that the dossier is complete, application checklists for both ICH CTDand ACTD dossiers are provided in Appendix 2A and 3A, respectively. Each checkliststates the required documents for each dossier type and application type. Refer to the

specific Appendices for more details.

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

Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicantmust provide the password(s) to access the CD/DVD contents.

Upon acceptance of the application for evaluation, applicants will be notified if additionalcopies of clinical documents (in CD/DVD) will be required.

6.2.2 Language

Information and documents supporting an application, such as certificates, approvalletters and approved product labels, must be in English and authenticated. If documentsare not originally in English, applicants should refer to Appendix 4 for the flow chart forthe translation of non-English documents.

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 ofdocument, 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;


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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 origin of a document is attested. Authentication of documents in support ofapplications 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 was issued.

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.

Certificates and documents issued in Englishby drug regulatory agencies do not requireauthentication.

Apostille

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 apostille 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 that are submitted to HSA as part of the application dossier.

6.2.3 Certifying non-original documents

A certified true copy certifies that the photocopy presented is a true and accurate copy ofthe original document. Acceptable certification of documents to support productapplications 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 requires certification by the drug regulatoryagency that issued the approval letter, a notary public or the SingaporeEmbassy/Consulate in the country where the approval letter was issued. Certification ofapproval letters is not required in the event the approval letter is available on the drugregulatory agencys website. In this instance, applicants can provide the internet address(URL) for validation by HSA.

7 APPLICATION SCREENING

After PRISM and dossier submission, the application will be screened to ensure that thecorrect application type has been chosen and that there are no deficiencies that woulddelay the registration process.

If the application type needs to be re-categorized, for example from NDA-2 to NDA-3 orGDA-1 to NDA-2, the applicant will be notified and subsequently, the PRISM application

will be amended as described in section 11.2.1.


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If any deficiencies are identified, a screening query letter via Input Request will be issuedto the applicant. The stop-clock starts whenever HSA requests for clarification oradditional information. The stop-clock ends when HSA receives a complete andsatisfactory response to the query.

The applicant will be required to submit all of the requested information and documents

within 30 calendar days from the date of the screening query letter. Any deficienciesnoted must be addressed before the dossier can be accepted for evaluation.

When the response to the screening query letter has been received, the requestedinformation and documents will be screened for completeness. The dossier will beaccepted when all requested information, and hence, the registration dossier, is found tobe adequate.

An acceptance notice will be issued to the applicant via email upon acceptance of anapplication. The date of acceptance of the application will be considered as the start ofthe evaluation timeline.

If the applicant fails to provide the requested information, or the submitted information isincomplete or contains unsolicited information, the application will not be accepted forevaluation. A non-acceptance letter will be issued by HSA and the documents will bereturned. If the applicant wishes to resubmit the dossier at a future time, it will beprocessed as a new application.

Applicants are advised to ensure that the dossier is compiled according to the requiredformat. Failure to arrange the submission dossier accordingly will lead to non-acceptanceof the dossier without screening.

8 APPLICATION EVALUATION

Upon acceptance of an application, evaluation by HSA is based on the data set submittedby the applicant. A query letter will be issued to the applicant if clarification or additionalinformation is required.

The stop-clock starts whenever HSA issues a query letter and ends when HSA receives acomplete and satisfactory response from the applicant.

If the applicant anticipates difficulty in responding in full or within the specified timeframe,then HSA should be contacted to discuss the request for information as soon as possibleafter receipt of HSAs query letter. An application will be considered withdrawn if the stop-clock time exceeds the deadline agreed upon by HSA and the applicant.

Additional supporting data submitted after acceptance of the application will not beconsidered, unless requested by HSA or mutually agreed upon by HSA and the applicantprior to acceptance.

NOTE: The screening process only determines the completeness of the registration

dossier for evaluation. Acceptance of the dossier for evaluation does not constituteacceptability of the data provided. Acceptability of the data can only be determinedduring evaluation of the application.


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For applications submitted in PRISM on or after 15 April 2009, applicants can check onthe progress of the evaluation for certain application types and evaluation routes. Table 4describes the applicable product applications and the stages to the evaluation process:

Table 4. Product Applications Applicable for Notification of Stages During Evaluation

Stages of Notification to

Applicant 1

st

Stage 2

nd

Stage 3

rd

Stage 4

th

Stage

ApplicationType

Dossiertype

Evaluation Status

Accepted forEvaluation

ActiveEvaluation

Midway inEvaluation

EvaluationCompleted

NDA-1

NDA-2

NDA-3

Full or

Abridged Application isaccepted forevaluation

This marks thestart of theevaluationtimeline

When activeevaluation is in

progress forthe application

Application isapproximately

midway throughthe evaluation

(provided thatthere were no

prior stop-clockswhich may affect

the evaluationprogress)

Applicants couldexpect to receive

the first set ofqueries from HSAduring this stage

Evaluation iscompleted for the

application

Application is nowundergoing the

regulatory decisionphase, after which

a regulatorydecision letter*

would be issued.

Applicants couldstill expect furtherqueries from HSAduring this stage

GDA-1

GDA-2

Abridged orVerification

* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a productapplication.

Applicants may view the evaluation stage via track@PRISM. Screenshots on viewing thechange in stages of a pending application are as follows:

Enter PRISM application toview stage of evaluation

Choose these options fromthe drop-down lists


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Applicants would also be notified via system-generated emails whenever an evaluationstage change occurs.

During the evaluation process, HSA may determine that the application is more suitablyevaluated via an alternate route. Any re-routing of the application will be discussed with

the applicant.

HSA may engage external evaluators, experts and advisory committees in the evaluationprocess, when necessary. These experts include scientists and clinicians from both localand overseas institutions. All external evaluators and experts are bound by agreement toprotect the information made available to them. The identity of the external evaluators iskept confidential.

9 REGULATORY DECISION

A regulatory decision is made based on the outcome of HSAs evaluation of the submitteddata package. Applicants will be notified by letter of one of the following outcomes:

Approval the application has satisfied the registration requirements for quality,safety and efficacy;

Approvablewhen the application has minor deficiencies; Non-approvablewhen the application has major deficiencies; or Rejectionwhen the response provided by the applicant fails to address the major

deficiencies highlighted in HSAs non-approvable decision.

Approval and rejection are final decisions issued by HSA.

If an approvableregulatory decision has been reached, the conditions for approval willbe stated in writing and the applicant will be required to fulfill these conditions within thestipulated timeframe.

If a non-approvableregulatory decision has been reached, the applicant will be informedof the non-approvable issues in writing. If the applicant wishes to address the non-approvable concerns raised by HSA, a reply should be made within the specifiedtimeframe. The reply should be based on the original data set as submitted to HSA;additional data which require evaluation will not be accepted. No extension of timeline willbe considered, unless mutually agreed between HSA and the applicant.

Applicants should note that issuance of a regulatory decision letter signals the end of theevaluation timeline. Appendix 1 contains information on the application timelines.

An application will be considered withdrawn if the applicant fails to reply within thestipulated timeframe subsequent to an approvable or a non-approvable decision. Once an

Active Evaluation

The evaluation stageis seen here.


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application is withdrawn, the applicant may submit a new application according toprevailing submission requirements.

Upon an approval regulatory decision, a Product Licence will be issued.

HSA may issue a product licence on the condition that certain documents/information

shall be submitted after the licence has been issued. Under such circumstances, anofficial letter of commitment is required before the licence can be issued. The letter ofcommitment should be specific, i.e. it addresses the particular issues of concern andshould provide details on how and when the post-approval licensing commitments will befulfilled. Failure to comply with these commitments may result in the suspension orrevocation of the Product Licence.

Applicants are expected to view the licensing conditions on-line in order to be reminded ofall post-approval commitments associated with the Product Licence.

10 POST-APPROVAL CHANGES

Upon issuance of a product licence, applicants will be responsible to maintain theproducts quality, efficacy and safety to the end of its life cycle. Any aspect of the productmay change throughout its life cycle for example, there can be a change inmanufacturer or manufacturing process, change in indication or dosage regimen orchange in safety profile.

HSA must be notified of any changes to the products quality, efficacy and safetyas perChapter F in this Guidance.

11 FEES

The fee structure and quanta are subject to on-going review. For updated information onfees, please visit the HSA website7.

11.1 Screening fee

The screening fee per application is payable at the time of PRISM submission. Thescreening fees are non-refundableonce the application has been successfully submittedvia PRISM.

Applicants are advised to ensure that the dossier is compiled according to the requiredformat. Failure to arrange the submission dossier accordingly will lead to non-acceptanceof the dossier without screening. In these instances, the screening fees will be forfeited.

11.2 Evaluation fee

Evaluation fees are payable upon acceptance of the dossier for evaluation. Theevaluation fees are non-refundable once the application is accepted, regardless of thefinal decision by HSA.

With effect from 15 April 2009, the progressive payment scheme was implemented toallow payment of evaluation fees by instalments. This is an optional opt-in paymentscheme catered for companies who are under the GIRO payment scheme and onlyapplicable to applications types as listed in Table 5 on the next page:

7http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/

fees.html
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/%20fees.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/%20fees.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/%20fees.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/%20fees.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/%20fees.html


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Table 5. Product Applications Applicable for Progressive Payment Scheme

Percentage of Evaluation Fee Payable at Each Stage

ApplicationType

EvaluationRoute

Evaluation Status

Accepted for

Evaluation

Active

Evaluation

Midway in

Evaluation

Evaluation

CompletedNDA-1

NDA-2

NDA-3

Full or

Abridged30% 40% 20% 10%

GDA-1

GDA-2

Abridged orVerification*

* Progressive payment scheme for the verification evaluation route for GDAs will be in effect from 1 Jan 2011

For applicants that had chosen the progressive payment scheme, in the event of anapplication withdrawal at any point in time during the evaluation stage, any fees that hadbeen charged, but not yet collected, would still have to be paid; all evaluation fees thathad been paid are non-refundable.

11.2.1 Change in evaluation fees

Changes in the evaluation fees may occur if there are changes to the application type.

11.2.1.1 Change of Application within the Same Application Type

Re-categorisation of the application within the same application type (e.g. from NDA-2 toNDA-3, or GDA-1 to GDA-2) would be carried out by the HSA officer during screeningprior to acceptance of the application. As there are differences in evaluation fees fordifferent application types, the change in application type would be communicated to theapplicant during the screening process. Applicants may opt to withdraw the application ifthey do not agree to the change in application type; applicants are to note that in theseinstances, the screening fee is non-refundable.

If there are no objections communicated to HSA, the application would be accepted with

the new application type and the new evaluation fee would be charged accordingly.

11.2.1.2 Change of Application between Different Application Types

Re-categorisation of GDA to NDA or vice versa requires withdrawal of the originalapplication before acceptance and resubmission of the application according to thecorrect application type.

The screening fees for the original application are non-refundable. As such, applicantsare advised to consult HSA on the correct application category when in doubt.

NOTE: To apply for the progressive payment for applications under the fullevaluation route, the applicant must contact HSA [email protected] to request for a hardcopy progressive

payment application form prior to the submission in PRISM.

NOTE:Non-GIRO paying applicants may need to make an additional payment totop-up any differences in fees. Similarly, any excess in evaluation fees collectedwould be refunded to the applicant upon acceptance.
mailto:[email protected]:[email protected]


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13.1 Full evaluation route

Full evaluation will apply to a product that has notbeen approved by an ydrug regulatoryagency at the time of submission.

13.2 Abridged evaluation route

Abridged evaluation will apply to a product that has been approved by at least onedrugregulatory agency at the time of submission.

13.2.1 Priority review

For NDAs submitted via the abridged evaluation route, the applicant may request forpriority review for a life-saving drug if there are unmet medical needs. The followingstates the criteria that will be considered for priority review:

a) 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.

b) Disease conditions that are of local public health concerns will be given primaryconsideration for priority review. Currently these include: cancer; and, infectious diseases: dengue, tuberculosis, hepatitis and malaria.

The request for priority review should be made at the point of application submissionandaccompanied by justification which warrants a priority review and how the product isexpected to benefit 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/or volume of requests through the exemption route ona named-patient basis;

The unmet needs, current available treatment options and standard therapies, andthe 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; Clinical evidence supporting the claims of significant improvement compared to

available treatments.

HSA reserves the right to deny a request for priority review if it is deemed appropriate.The decision for the granting of priority review would be conveyed to the applicant at thepoint of acceptanceof the application for evaluation.

13.2.2 Applications for non-prescription medicines

If the NDA is for a non-prescription medicine and is submitted via the abridged evaluationroute, the applicant may submit a writtenrequest for a waiver of clinical data submission.

Eligibility for waiver is subject to the criteria defined in Appendix 5 Guideline onSubmission Requirements for Non-Prescription Medicines. However, HSA reserves theright to request for the complete clinical data set if it is deemed appropriate.


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13.3 Verification evaluation route

Medicinal products with similar indication(s), dosing regimen(s), patient group(s), and/ordirection(s) for use that have been approved by at least two of the following HSAsreference drug regulatory agencies may be submitted via the verification evaluation route.HSAs reference drug regulatory agencies are:

Australia Therapeutic Goods Administration (TGA); Health Canada (HC); US Food and Drug Administration (FDA); the European Medicines Agency (EMA) via the Central ised Proc edure; UK Medicines and Healthcare Products Regulatory Agency (UK MHRA) via

the national procedure, or, as the Reference Member State (RMS) via the Mutual Recognition Procedure or

Decentralised Procedure.

However, approval by these reference regulatory agencies does not obligate HSA toapprove the application. HSA may also re-categorise applications to other evaluation

routes if deemed appropriate.

One of the reference drug regulatory agencies must be declared as the primaryreferenceagency. The chosen primary reference agency is defined as the reference agency forwhich the qualifying supporting documents (as outlined in this guidance) will besubmitted.

Additional eligibility criteria for the verification route include: The application must be submitted within three yearsfrom the approval date by the

chosen primary reference agency; All aspects of the drug products quality, including but not limited tothe formulation,

manufacturing site(s), release and shelf life specifications and primary packaging,

must be identical as that currently approved by the chosen primary referenceagency;

The product does not need a more stringent assessment as a result of differencesin local disease patterns and/or medical practices (e.g. some anti-infectives).

The product and its intended usei.e. indication(s), dosing regimen(s) and patientgroup(s) has not been rejected, withdrawn, approved via appeal process orpending deferral by a drug regulatory agency for safety and/or efficacy reasons;and,

The product is not a biological product.

The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for useshould be the most stringent amongst those approved by the reference regulatoryagencies. In the event that the chosen primary reference agency does not bear the moststringent indication(s), dosing regimen(s), patient group(s) and/or direction(s) of use, theclinical assessment report from the other reference agency that met such requirementsshould be submitted. The clinical assessment report from the other reference agency tobe submitted may be obtained from the public domain. The proposed PI/PIL should beidentical to that approved by this reference agency (with the exception of country-specificinformation).

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 onereference agency via an accelerated/fast-track approval, approval under exceptional

circumstances or equivalent approval process, the applicant should consult HSA on theeligibility of such a product through the verification route prior to submission.


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Comprehensive Table of Contents (section 1.1)

The comprehensive table of contents is a complete list of alldocuments provided in theapplication dossier by Module/Part. The location of each document should be identifiedby the Module/Part number. If a hardcopy registration dossier is submitted, then thelocation of each document should be identified by the volume number and tab identifier

(name of the document or section heading according to the ACTD or ICH CTD format).

Introduction (section 1.2)

Applicants should give a concise summary of the application and justify the need for theapplication for example, whether the product presents an advantage to patient groupsin terms of improved quality, safety and efficacy compared to available alternatives.

Applicants should also justify the lack of certain documents within the dossier and anydeviation from the guidelines.

Application Form(section 1.3)

A printout of the PRISM application form is to be included in the dossier.

Labelling, Package Insert and Patient Information Leaflet (section 1.4)

Applicants are required to provide the artwork/drafts of the proposed Singapore productlabels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependentupon the forensic classification of the product to be registered, as described in the tablebelow:

Forensic Classification in Singapore

POM P GSL

Package Insert (PI), also known as prescribinginformation, SPC, or product monograph

Required Optional Optional

Patient Information Leaflet (PIL), also known asconsumer medicine information (CMI)

Optional, unlesswarranted

Required Required

All artwork and drafts should be legible. Any handwritten information is not acceptable.Separate labels 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.

Appendix 6 contains specific details on product labelling requirements for Singapore.

Approved SPC/PI/PIL (section 1.5)

In this section, the applicant shall submit the following:i. the approved SPC, PI and/or PIL from the drug regulatory agency that issued the

proof of approval; and,ii. the approved SPC, PI and/or PIL from all of HSAs reference drug regulatory

agencies, where applicable.

Assessment Report from Reference Agencies (section 1.6)

This section refers only to applications submitted under the verification evaluation route.Assessment reports and supporting documents issued by the primary reference agency


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and inserted into this section must be unredacted and unedited. Applicants should refer tosection 14.6.3 for specific details on the required documents.

Description of Batch Numbering System (section 1.7)

Detailed information on the system of assigning unique codes to different production

batches of the product should be provided to allow for batch identification. Whereapplicable, examples of the batch numbering system should be included to illustrate howthe batch number enables identification.

Proof of Approval (section 1.8, 1.9)

Proof of approval is not required for NDAs undergoing a full evaluation.

For an abridged evaluation of an NDA product, proof of approval by any drug regulatoryagency is required. Proof of approval must come in the form of:

an official approval letter, or equivalent document (e.g. Certificate of PharmaceuticalProduct), which certifies the registration status of the drug product; and

the SPC, PI and/or PIL approved by the drug regulatory agency that issued theapproval letter.

If the SPC is in a non-English language, applicants should refer section 6.2.2 for moreinformation.

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.

Approval letters should be either an original copy or a certified true copy and in English.Applicants should refer to section 6.2.2 and 6.2.3 for more details.

HSA reserves the right to request for a Certificate of Pharmaceutical Product (CPP), ifdeemed appropriate.

If the brand name (trade name) of the product as registered in the country which issuedthe proof of approval is different from that proposed in Singapore, the applicant isrequired to submit a declaration letter from the product owner to declare that bothproducts marketed under the different brand names are identicalin all aspects of quality,safety and efficacy except for the brand name.

Authorisation Letters (section 1.10)

All submitted authorisation letters shall be hardcopy originals on the authorisingcompanys (i.e. Product Owners) letterhead, dated and signed by the designatedauthorised person in the company.

If the Product Owner is not the local Applicant Firm, Manufacturer and/or Batch Releaser,then the following authorisation letter(s) must be submitted:

i. from Product Owner to the Applicant Firm(1.10.1) this letter authorises the localapplicant firm to apply for and be the Product Licence Holder for a specificmedicinal product.

ii. from Product Owner to Manufacturer(1.10.2) this letter authorises the specified

manufacturer to produce, pack and/or label the drug product intended forSingapore. If there are multiple drug product manufacturers, then the applicant mayopt to submit one authorisation letter which clearly states all of the manufacturers


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(names and addresses) and their responsibilities related to the drug product. Forbiologic drug products, an additionalauthorisation letter from the Product Owner tothe Drug Substance Manufacturer is required.

iii. from Product Owner to Batch Releaser(1.10.3)this letter authorises the specifiedcompany to batch release the drug product. If there are multiple sites responsiblefor batch release of the product, then the applicant may opt to submit one

authorisation letter which clearly states all of the batch releasers (names andaddresses) and their responsibilities.

Applicants are to ensure that all names and addresses in the authorisation letters must beconsistent with the information provided in PRISM and the dossier. For Manufacturersand Batch Releasers, the actual site address of the named company should be stated inthe letter(s) i.e. do notstate the office address. Any discrepancy found will delay theregistration process.

All authorisation letters should also state specific product details, including the productname, dosage form and strength.

Applicants also have the option to combine authorisation letters as stated above into onedocument, provided that all names, addresses and responsibilities are clearly stated.

GMP Certification/Proof of GMP Compliance (section 1.11)

Documentary evidence must be provided to certify that the manufacturer(s) complies withcurrent applicable GMP standards. Applicants must submit a GMP certificate issued by adrug regulatory agency for al ldrug product manufacturing sites including, but not limitedto, bulk product manufacturers, primary packagers and secondary packagers. A CPPmay be submitted in lieuof a GMP certificate provided that the manufacturers name(s)and address(es) is(are) stated on the CPP. Applicants should note that the names andaddresses of all manufacturers should be consistent throughout the application i.e.GMP certificate, Letter of Authorisation, CTD section S2.1 and P3.1 and PRISM.

Proof of GMP compliance must not expire within six (6) months from the time ofsubmission to HSA and must be in hardcopy, in English and either an original or certified

true copy. Applicants should refer to section 6.2.2 and 6.2.3 for more details.It should be noted that diluents used for reconstituting the drug product and are packagedtogether with the drug product will be considered as part of the final drug product. Thus,manufacturer(s) of the supplied diluent(s) will follow the same requirements applicable tothe drug producte.g. proof of GMP compliance.

For biologic NDA applications, proof of GMP compliance for the drug substance must besubmitted in addition to the aforementioned GMP requirements.

For products manufactured in the USA, if the ap

Guidance on Medicinal Product Registration in Singapore 2011

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